Title 21-Food and Drugs--Volume 9

§ 600.2 Mailing addresses.

(a) Licensed biological products regulated by the Center for Biologics Evaluation and Research (CBER). Unless otherwise stated in paragraph (c) of this section, or as otherwise prescribed by FDA regulation, all submissions to CBER referenced in parts 600 through 680 of this chapter, as applicable, must be sent to: Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. Examples of such submissions include: Biologics license applications (BLAs) and their amendments and supplements, biological product deviation reports, fatality reports, and other correspondence. Biological products samples must not be sent to this address but must be sent to the address in paragraph (c) of this section.

(b) Licensed biological products regulated by the Center for Drug Evaluation and Research (CDER). Unless otherwise stated in paragraphs (b)(1), (b)(2), or (c) of this section, or as otherwise prescribed by FDA regulation, all submissions to CDER referenced in parts 600, 601, and 610 of this chapter, as applicable, must be sent to: CDER Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901B Ammendale Rd., Beltsville, MD 20705. Examples of such submissions include: BLAs and their amendments and supplements, and other correspondence.

(1) Biological Product Deviation Reporting (CDER). All biological product deviation reports required under § 600.14 must be sent to: Division of Compliance Risk Management and Surveillance, Office of Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

(2) Advertising and Promotional Labeling (CDER). All advertising and promotional labeling supplements required under § 601.12(f) of this chapter must be sent to: Division of Drug Marketing, Advertising and Communication, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

(c) Samples and Protocols for licensed biological products regulated by CBER or CDER. (1) Biological product samples and/or protocols, other than radioactive biological product samples and protocols, required under §§ 600.13, 600.22, 601.15, 610.2, 660.6, 660.36, or 660.46 of this chapter must be sent by courier service to: Food and Drug Administration, Center for Biologics Evaluation and Research, ATTN: Sample Custodian, 10903 New Hampshire Ave., Bldg. 75, Rm. G707, Silver Spring, MD 20993-0002. The protocol(s) may be placed in the box used to ship the samples to CBER. A cover letter should not be included when submitting the protocol with the sample unless it contains pertinent information affecting the release of the lot.

(2) Radioactive biological products required under § 610.2 of this chapter must be sent by courier service to: Food and Drug Administration, Center for Biologics Evaluation and Research, ATTN: Sample Custodian, c/o White Oak Radiation Safety Program, 10903 New Hampshire Ave., Bldg. 52-72, Rm. G406A, Silver Spring, MD 20993-0002.

(d) Address information for submissions to CBER and CDER other than those listed in parts 600 through 680 of this chapter are included directly in the applicable regulations.

(e) Obtain updated mailing address information for biological products regulated by CBER at http://www.fda.gov/BiologicsBloodVaccines/default.htm, or for biological products regulated by CDER at http://www.fda.gov/Drugs/default.htm.

[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13114, Mar. 26, 2009; 78 FR 19585, Apr. 2, 2013; 80 FR 18091, Apr. 3, 2015; 79 FR 33090, June 10, 2014]

§ 600.3 Definitions.

As used in this subchapter:

(a) Act means the Public Health Service Act (58 Stat. 682), approved July 1, 1944.

(b) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the authority involved has been delegated.

(c) Commissioner of Food and Drugs means the Commissioner of the Food and Drug Administration.

(d) Center for Biologics Evaluation and Research means Center for Biologics Evaluation and Research of the Food and Drug Administration.

(e) State means a State or the District of Columbia, Puerto Rico, or the Virgin Islands.

(f) Possession includes among other possessions, Puerto Rico and the Virgin Islands.

(g) Products includes biological products and trivalent organic arsenicals.

(h) Biological product means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

(1) A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes but is not limited to filterable viruses, bacteria, rickettsia, fungi, and protozoa.

(2) A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.

(3) A toxin is a product containing a soluble substance poisonous to laboratory animals or to man in doses of 1 milliliter or less (or equivalent in weight) of the product, and having the property, following the injection of non-fatal doses into an animal, of causing to be produced therein another soluble substance which specifically neutralizes the poisonous substance and which is demonstrable in the serum of the animal thus immunized.

(4) An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal which specifically neutralizes the toxin against which the animal is immune.

(5) A product is analogous:

(i) To a virus if prepared from or with a virus or agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the specific strain used.

(ii) To a therapeutic serum, if composed of whole blood or plasma or containing some organic constituent or product other than a hormone or an amino acid, derived from whole blood, plasma, or serum.

(iii) To a toxin or antitoxin, if intended, irrespective of its source of origin, to be applicable to the prevention, treatment, or cure of disease or injuries of man through a specific immune process.

(6) A protein is any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size. When two or more amino acid chains in an amino acid polymer are associated with each other in a manner that occurs in nature, the size of the amino acid polymer for purposes of this paragraph (h)(6) will be based on the total number of amino acids in those chains, and will not be limited to the number of amino acids in a contiguous sequence.

(i) Trivalent organic arsenicals means arsphenamine and its derivatives (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of man.

(j) A product is deemed applicable to the prevention, treatment, or cure of diseases or injuries of man irrespective of the mode of administration or application recommended, including use when intended through administration or application to a person as an aid in diagnosis, or in evaluating the degree of susceptibility or immunity possessed by a person, and including also any other use for purposes of diagnosis if the diagnostic substance so used is prepared from or with the aid of a biological product.

(k) Proper name, as applied to a product, means the name designated in the license for use upon each package of the product.

(l) Dating period means the period beyond which the product cannot be expected beyond reasonable doubt to yield its specific results.

(m) Expiration date means the calendar month and year, and where applicable, the day and hour, that the dating period ends.

(n) The word standards means specifications and procedures applicable to an establishment or to the manufacture or release of products, which are prescribed in this subchapter or established in the biologics license application designed to insure the continued safety, purity, and potency of such products.

(o) The word continued as applied to the safety, purity and potency of products is interpreted to apply to the dating period.

(p) The word safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.

(q) The word sterility is interpreted to mean freedom from viable contaminating microorganisms, as determined by the tests conducted under § 610.12 of this chapter.

(r) Purity means relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances.

(s) The word potency is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.

(t) Manufacturer means any legal person or entity engaged in the manufacture of a product subject to license under the act; “Manufacturer” also includes any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards.

(u) Manufacture means all steps in propagation or manufacture and preparation of products and includes but is not limited to filling, testing, labeling, packaging, and storage by the manufacturer.

(v) Location includes all buildings, appurtenances, equipment and animals used, and personnel engaged by a manufacturer within a particular area designated by an address adequate for identification.

(w) Establishment has the same meaning as “facility” in section 351 of the Public Health Service Act and includes all locations.

(x) Lot means that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel.

(y) A filling refers to a group of final containers identical in all respects, which have been filled with the same product from the same bulk lot without any change that will affect the integrity of the filling assembly.

(z) Process refers to a manufacturing step that is performed on the product itself which may affect its safety, purity or potency, in contrast to such manufacturing steps which do not affect intrinsically the safety, purity or potency of the product.

(aa) Selling agent or distributor means any person engaged in the unrestricted distribution, other than by sale at retail, of products subject to license.

(bb) Container (referred to also as “final container”) is the immediate unit, bottle, vial, ampule, tube, or other receptacle containing the product as distributed for sale, barter, or exchange.

(cc) Package means the immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the preceding sentence, is used, the container shall be deemed to be the package.

(dd) Label means any written, printed, or graphic matter on the container or package or any such matter clearly visible through the immediate carton, receptacle, or wrapper.

(ee) Radioactive biological product means a biological product which is labeled with a radionuclide or intended solely to be labeled with a radionuclide.

(ff) Amendment is the submission of information to a pending license application or supplement, to revise or modify the application as originally submitted.

(gg) Supplement is a request to approve a change in an approved license application.

(hh) Distributed means the biological product has left the control of the licensed manufacturer.

(ii) Control means having responsibility for maintaining the continued safety, purity, and potency of the product and for compliance with applicable product and establishment standards, and for compliance with current good manufacturing practices.

(jj) Assess the effects of the change, as used in § 601.12 of this chapter, means to evaluate the effects of a manufacturing change on the identity, strength, quality, purity, and potency of a product as these factors may relate to the safety or effectiveness of the product.

(kk) Specification, as used in § 601.12 of this chapter, means the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a product. For the purpose of this definition, acceptance criteria means numerical limits, ranges, or other criteria for the tests described.

(ll) Complete response letter means a written communication to an applicant from FDA usually describing all of the deficiencies that the agency has identified in a biologics license application or supplement that must be satisfactorily addressed before it can be approved.

(mm) Resubmission means a submission by the biologics license applicant or supplement applicant of all materials needed to fully address all deficiencies identified in the complete response letter. A biologics license application or supplement for which FDA issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.

[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975; 55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July 24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR 66634, Nov. 7, 2000; 69 FR 18766, Apr. 8, 2004; 70 FR 14982, Mar. 24, 2005; 73 FR 39610, July 10, 2008; 77 FR 26174, May 3, 2012; 85 FR 10063, Feb. 21, 2020]

§ 600.10 Personnel.

(a) [Reserved]

(b) Personnel. Personnel shall have capabilities commensurate with their assigned functions, a thorough understanding of the manufacturing operations which they perform, the necessary training and experience relating to individual products, and adequate information concerning the application of the pertinent provisions of this subchapter to their respective functions. Personnel shall include such professionally trained persons as are necessary to insure the competent performance of all manufacturing processes.

(c) Restrictions on personnel—(1) Specific duties. Persons whose presence can affect adversely the safety and purity of a product shall be excluded from the room where the manufacture of a product is in progress.

(2) Sterile operations. Personnel performing sterile operations shall wear clean or sterilized protective clothing and devices to the extent necessary to protect the product from contamination.

(3) Pathogenic viruses and spore-forming organisms. Persons working with viruses pathogenic for man or with spore-forming microorganisms, and persons engaged in the care of animals or animal quarters, shall be excluded from areas where other products are manufactured, or such persons shall change outer clothing, including shoes, or wear protective covering prior to entering such areas.

(4) Live vaccine work areas. Persons may not enter a live vaccine processing area after having worked with other infectious agents in any other laboratory during the same working day. Only persons actually concerned with propagation of the culture, production of the vaccine, and unit maintenance, shall be allowed in live vaccine processing areas when active work is in progress. Casual visitors shall be excluded from such units at all times and all others having business in such areas shall be admitted only under supervision. Street clothing, including shoes, shall be replaced or covered by suitable laboratory clothing before entering a live vaccine processing unit. Persons caring for animals used in the manufacture of live vaccines shall be excluded from other animal quarters and from contact with other animals during the same working day.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119, Dec. 30, 2003]

§ 600.11 Physical establishment, equipment, animals, and care.

(a) Work areas. All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. Precautions shall be taken to exclude extraneous infectious agents from manufacturing areas. Work rooms shall be well lighted and ventilated. The ventilation system shall be arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product. Filling rooms, and other rooms where open, sterile operations are conducted, shall be adequate to meet manufacturing needs and such rooms shall be constructed and equipped to permit thorough cleaning and to keep air-borne contaminants at a minimum. If such rooms are used for other purposes, they shall be cleaned and prepared prior to use for sterile operations. Refrigerators, incubators and warm rooms shall be maintained at temperatures within applicable ranges and shall be free of extraneous material which might affect the safety of the product.

(b) Equipment. Apparatus for sterilizing equipment and the method of operation shall be such as to insure the destruction of contaminating microorganisms. The effectiveness of the sterilization procedure shall be no less than that achieved by an attained temperature of 121.5 °C maintained for 20 minutes by saturated steam or by an attained temperature of 170 °C maintained for 2 hours with dry heat. Processing and storage containers, filters, filling apparatus, and other pieces of apparatus and accessory equipment, including pipes and tubing, shall be designed and constructed to permit thorough cleaning and, where possible, inspection for cleanliness. All surfaces that come in contact with products shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use. For products for which sterility is a factor, equipment shall be sterile, unless sterility of the product is assured by subsequent procedures.

(c) Laboratory and bleeding rooms. Rooms used for the processing of products, including bleeding rooms, shall be effectively fly-proofed and kept free of flies and vermin. Such rooms shall be so constructed as to insure freedom from dust, smoke and other deleterious substances and to permit thorough cleaning and disinfection. Rooms for animal injection and bleeding, and rooms for smallpox vaccine animals, shall be disinfected and be provided with the necessary water, electrical and other services.

(d) Animal quarters and stables. Animal quarters, stables and food storage areas shall be of appropriate construction, fly-proofed, adequately lighted and ventilated, and maintained in a clean, vermin-free and sanitary condition. No manure or refuse shall be stored as to permit the breeding of flies on the premises, nor shall the establishment be located in close proximity to off-property manure or refuse storage capable of engendering fly breeding.

(e) Restrictions on building and equipment use—(1) Work of a diagnostic nature. Laboratory procedures of a clinical diagnostic nature involving materials that may be contaminated, shall not be performed in space used for the manufacture of products except that manufacturing space which is used only occasionally may be used for diagnostic work provided spore-forming pathogenic microorganisms are not involved and provided the space is thoroughly cleaned and disinfected before the manufacture of products is resumed.

(2) Spore-forming organisms for supplemental sterilization procedure control test. Spore-forming organisms used as an additional control in sterilization procedures may be introduced into areas used for the manufacture of products, only for the purposes of the test and only immediately before use for such purposes: Provided, That (i) the organism is not pathogenic for man or animals and does not produce pyrogens or toxins, (ii) the culture is demonstrated to be pure, (iii) transfer of test cultures to culture media shall be limited to the sterility test area or areas designated for work with spore-forming organisms, (iv) each culture be labeled with the name of the microorganism and the statement “Caution: microbial spores. See directions for storage, use and disposition.”, and (v) the container of each culture is designed to withstand handling without breaking.

(3) Work with spore-forming microorganisms. (i) Manufacturing processes using spore-forming microorganisms conducted in a multiproduct manufacturing site must be performed under appropriate controls to prevent contamination of other products and areas within the site. Prevention of spore contamination can be achieved by using a separate dedicated building or by using process containment if manufacturing is conducted in a multiproduct manufacturing building. All product and personnel movement between the area where the spore-forming microorganisms are manufactured and other manufacturing areas must be conducted under conditions that will prevent the introduction of spores into other areas of the facility.

(ii) If process containment is employed in a multiproduct manufacturing area, procedures must be in place to demonstrate adequate removal of the spore-forming microorganism(s) from the manufacturing area for subsequent manufacture of other products. These procedures must provide for adequate removal or decontamination of the spore-forming microorganisms on and within manufacturing equipment, facilities, and ancillary room items as well as the removal of disposable or product dedicated items from the manufacturing area. Environmental monitoring specific for the spore-forming microorganism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination.

(4) Live vaccine processing. Live vaccine processing must be performed under appropriate controls to prevent cross contamination of other products and other manufacturing areas within the building. Appropriate controls must include, at a minimum:

(i)(A) Using a dedicated manufacturing area that is either in a separate building, in a separate wing of a building, or in quarters at the blind end of a corridor and includes adequate space and equipment for all processing steps up to, but not including, filling into final containers; and

(B) Not conducting test procedures that potentially involve the presence of microorganisms other than the vaccine strains or the use of tissue culture cell lines other than primary cultures in space used for processing live vaccine; or

(ii) If manufacturing is conducted in a multiproduct manufacturing building or area, using procedural controls, and where necessary, process containment. Process containment is deemed to be necessary unless procedural controls are sufficient to prevent cross contamination of other products and other manufacturing areas within the building. Process containment is a system designed to mechanically isolate equipment or an area that involves manufacturing using live vaccine organisms. All product, equipment, and personnel movement between distinct live vaccine processing areas and between live vaccine processing areas and other manufacturing areas, up to, but not including, filling in final containers, must be conducted under conditions that will prevent cross contamination of other products and manufacturing areas within the building, including the introduction of live vaccine organisms into other areas. In addition, written procedures and effective processes must be in place to adequately remove or decontaminate live vaccine organisms from the manufacturing area and equipment for subsequent manufacture of other products. Written procedures must be in place for verification that processes to remove or decontaminate live vaccine organisms have been followed.

(5) Equipment and supplies—contamination. Equipment and supplies used in work on or otherwise exposed to any pathogenic or potentially pathogenic agent shall be kept separated from equipment and supplies used in the manufacture of products to the extent necessary to prevent cross-contamination.

(f) Animals used in manufacture—(1) Care of animals used in manufacturing. Caretakers and attendants for animals used for the manufacture of products shall be sufficient in number and have adequate experience to insure adequate care. Animal quarters and cages shall be kept in sanitary condition. Animals on production shall be inspected daily to observe response to production procedures. Animals that become ill for reasons not related to production shall be isolated from other animals and shall not be used for production until recovery is complete. Competent veterinary care shall be provided as needed.

(2) Quarantine of animals—(i) General. No animal shall be used in processing unless kept under competent daily inspection and preliminary quarantine for a period of at least 7 days before use, or as otherwise provided in this subchapter. Only healthy animals free from detectable communicable diseases shall be used. Animals must remain in overt good health throughout the quarantine periods and particular care shall be taken during the quarantine periods to reject animals of the equine genus which may be infected with glanders and animals which may be infected with tuberculosis.

(ii) Quarantine of monkeys. In addition to observing the pertinent general quarantine requirements, monkeys used as a source of tissue in the manufacture of vaccine shall be maintained in quarantine for at least 6 weeks prior to use, except when otherwise provided in this part. Only monkeys that have reacted negatively to tuberculin at the start of the quarantine period and again within 2 weeks prior to use shall be used in the manufacture of vaccine. Due precaution shall be taken to prevent cross-infection from any infected or potentially infected monkeys on the premises. Monkeys to be used in the manufacture of a live vaccine shall be maintained throughout the quarantine period in cages closed on all sides with solid materials except the front which shall be screened, with no more than two monkeys housed in one cage. Cage mates shall not be interchanged.

(3) Immunization against tetanus. Horses and other animals susceptible to tetanus, that are used in the processing steps of the manufacture of biological products, shall be treated adequately to maintain immunity to tetanus.

(4) Immunization and bleeding of animals used as a source of products. Toxins or other nonviable antigens administered in the immunization of animals used in the manufacture of products shall be sterile. Viable antigens, when so used, shall be free of contaminants, as determined by appropriate tests prior to use. Injections shall not be made into horses within 6 inches of bleeding site. Horses shall not be bled for manufacturing purposes while showing persistent general reaction or local reaction near the site of bleeding. Blood shall not be used if it was drawn within 5 days of injecting the animals with viable microorganisms. Animals shall not be bled for manufacturing purposes when they have an intercurrent disease. Blood intended for use as a source of a biological product shall be collected in clean, sterile vessels. When the product is intended for use by injection, such vessels shall also be pyrogen-free.

(5) [Reserved]

(6) Reporting of certain diseases. In cases of actual or suspected infection with foot and mouth disease, glanders, tetanus, anthrax, gas gangrene, equine infectious anemia; equine encephalomyelitis, or any of the pock diseases among animals intended for use or used in the manufacture of products, the manufacturer shall immediately notify the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b)).

(7) Monkeys used previously for experimental or test purposes. Monkeys that have been used previously for experimental or test purposes with live microbiological agents shall not be used as a source of kidney tissue for the manufacture of vaccine. Except as provided otherwise in this subchapter, monkeys that have been used previously for other experimental or test purposes may be used as a source of kidney tissue upon their return to a normal condition, provided all quarantine requirements have been met.

(8) Necropsy examination of monkeys. Each monkey used in the manufacture of vaccine shall be examined at necropsy under the direction of a qualified pathologist, physician, or veterinarian having experience with diseases of monkeys, for evidence of ill health, particularly for (i) evidence of tuberculosis, (ii) presence of herpes-like lesions, including eruptions or plaques on or around the lips, in the buccal cavity or on the gums, and (iii) signs of conjunctivitis. If there are any such signs or other significant gross pathological lesions, the tissue shall not be used in the manufacture of vaccine.

(g) Filling procedures. Filling procedures shall be such as will not affect adversely the safety, purity or potency of the product.

(h) Containers and closures. All final containers and closures shall be made of material that will not hasten the deterioration of the product or otherwise render it less suitable for the intended use. All final containers and closures shall be clean and free of surface solids, leachable contaminants and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use. After filling, sealing shall be performed in a manner that will maintain the integrity of the product during the dating period. In addition, final containers and closures for products intended for use by injection shall be sterile and free from pyrogens. Except as otherwise provided in the regulations of this subchapter, final containers for products intended for use by injection shall be colorless and sufficiently transparent to permit visual examination of the contents under normal light. As soon as possible after filling final containers shall be labeled as prescribed in § 610.60 et seq. of this chapter, except that final containers may be stored without such prescribed labeling provided they are stored in a sealed receptacle labeled both inside and outside with at least the name of the product, the lot number, and the filling identification.

[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119, Dec. 30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR 59003, Oct. 18, 2007; 80 FR 18092, Apr. 3, 2015]

§ 600.12 Records.

(a) Maintenance of records. Records shall be made, concurrently with the performance, of each step in the manufacture and distribution of products, in such a manner that at any time successive steps in the manufacture and distribution of any lot may be traced by an inspector. Such records shall be legible and indelible, shall identify the person immediately responsible, shall include dates of the various steps, and be as detailed as necessary for clear understanding of each step by one experienced in the manufacture of products.

(b) Records retention—(1) General. Records shall be retained for such interval beyond the expiration date as is necessary for the individual product, to permit the return of any clinical report of unfavorable reactions. The retention period shall be no less than five years after the records of manufacture have been completed or six months after the latest expiration date for the individual product, whichever represents a later date.

(2) Records of recall. Complete records shall be maintained pertaining to the recall from distribution of any product upon notification by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, to recall for failure to conform with the standards prescribed in the regulations of this subchapter, because of deterioration of the product or for any other factor by reason of which the distribution of the product would constitute a danger to health.

(3) Suspension of requirement for retention. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, may authorize the suspension of the requirement to retain records of a specific manufacturing step upon a showing that such records no longer have significance for the purposes for which they were made: Provided, That a summary of such records shall be retained.

(c) Records of sterilization of equipment and supplies. Records relating to the mode of sterilization, date, duration, temperature and other conditions relating to each sterilization of equipment and supplies used in the processing of products shall be made by means of automatic recording devices or by means of a system of recording which gives equivalent assurance of the accuracy and reliability of the record. Such records shall be maintained in a manner that permits an identification of the product with the particular manufacturing process to which the sterilization relates.

(d) Animal necropsy records. A necropsy record shall be kept on each animal from which a biological product has been obtained and which dies or is sacrificed while being so used.

(e) Records in case of divided manufacturing responsibility. If two or more establishments participate in the manufacture of a product, the records of each such establishment must show plainly the degree of its responsibility. In addition, each participating manufacturer shall furnish to the manufacturer who prepares the product in final form for sale, barter or exchange, a copy of all records relating to the manufacturing operations performed by such participating manufacturer insofar as they concern the safety, purity and potency of the lots of the product involved, and the manufacturer who prepares the product in final form shall retain a complete record of all the manufacturing operations relating to the product.

[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]

§ 600.13 Retention samples.

Manufacturers shall retain for a period of at least 6 months after the expiration date, unless a different time period is specified in additional standards, a quantity of representative material of each lot of each product, sufficient for examination and testing for safety and potency, except Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood Cells, Plasma, and Source Plasma and Allergenic Products prepared to a physician's prescription. Samples so retained shall be selected at random from either final container material, or from bulk and final containers, provided they include at least one final container as a final package, or package-equivalent of such filling of each lot of the product as intended for distribution. Such sample material shall be stored at temperatures and under conditions which will maintain the identity and integrity of the product. Samples retained as required in this section shall be in addition to samples of specific products required to be submitted to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research (see mailing addresses in § 600.2). Exceptions may be authorized by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, when the lot yields relatively few final containers and when such lots are prepared by the same method in large number and in close succession.

[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]

§ 600.14 Reporting of biological product deviations by licensed manufacturers.

(a) Who must report under this section? (1) You, the manufacturer who holds the biological product license and who had control over the product when the deviation occurred, must report under this section. If you arrange for another person to perform a manufacturing, holding, or distribution step, while the product is in your control, that step is performed under your control. You must establish, maintain, and follow a procedure for receiving information from that person on all deviations, complaints, and adverse events concerning the affected product.

(2) Exceptions:

(i) Persons who manufacture only in vitro diagnostic products that are not subject to licensing under section 351 of the Public Health Service Act do not report biological product deviations for those products under this section but must report in accordance with part 803 of this chapter;

(ii) Persons who manufacture blood and blood components, including licensed manufacturers, unlicensed registered blood establishments, and transfusion services, do not report biological product deviations for those products under this section but must report under § 606.171 of this chapter;

(iii) Persons who manufacture Source Plasma or any other blood component and use that Source Plasma or any other blood component in the further manufacture of another licensed biological product must report:

(A) Under § 606.171 of this chapter, if a biological product deviation occurs during the manufacture of that Source Plasma or any other blood component; or

(B) Under this section, if a biological product deviation occurs after the manufacture of that Source Plasma or any other blood component, and during manufacture of the licensed biological product.

(b) What do I report under this section? You must report any event, and information relevant to the event, associated with the manufacturing, to include testing, processing, packing, labeling, or storage, or with the holding or distribution, of a licensed biological product, if that event meets all the following criteria:

(1) Either:

(i) Represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product; or

(ii) Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and

(2) Occurs in your facility or another facility under contract with you; and

(3) Involves a distributed biological product.

(c) When do I report under this section? You should report a biological product deviation as soon as possible but you must report at a date not to exceed 45-calendar days from the date you, your agent, or another person who performs a manufacturing, holding, or distribution step under your control, acquire information reasonably suggesting that a reportable event has occurred.

(d) How do I report under this section You must report on Form FDA-3486.

(e) Where do I report under this section? (1) For biological products regulated by the Center for Biologics Evaluation and Research (CBER), send the completed Form FDA 3486 to the CBER Document Control Center (see mailing address in § 600.2(a)), or submit electronically using CBER's electronic Web-based application.

(2) For biological products regulated by the Center for Drug Evaluation and Research (CDER), send the completed Form FDA-3486 to the Division of Compliance Risk Management and Surveillance (HFD-330) (see mailing addresses in § 600.2). CDER does not currently accept electronic filings.

(3) If you make a paper filing, you should identify on the envelope that a biological product deviation report (BPDR) is enclosed.

(f) How does this regulation affect other FDA regulations? This part supplements and does not supersede other provisions of the regulations in this chapter. All biological product deviations, whether or not they are required to be reported under this section, should be investigated in accordance with the applicable provisions of parts 211 and 820 of this chapter.

[65 FR 66634, Nov. 7, 2000, as amended at 70 FR 14982, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

§ 600.15 Temperatures during shipment.

The following products shall be maintained during shipment at the specified temperatures:

(a) Products.

Product | Temperature

Cryoprecipitated AHF | −18 °C or colder.

Measles and Rubella Virus Vaccine Live | 10 °C or colder.

Measles Live and Smallpox Vaccine | Do.

Measles, Mumps, and Rubella Virus Vaccine Live | Do.

Measles and Mumps Virus Vaccine Live | Do.

Measles Virus Vaccine Live | Do.

Mumps Virus Vaccine Live | Do.

Fresh Frozen Plasma | −18 °C or colder.

Liquid Plasma | 1 to 10 °C.

Plasma | −18 °C or colder.

Platelet Rich Plasma | Between 1 and 10 °C if the label indicates storage between 1 and 6 °C, or all reasonable methods to maintain the temperature as close as possible to a range between 20 and 24 °C, if the label indicates storage between 20 and 24 °C.

Platelets | Between 1 and 10 °C if the label indicates storage between 1 and 6 °C, or all reasonable methods to maintain the temperature as close as possible to a range between 20 to 24 °C, if the label indicates storage between 20 and 24 °C.

Poliovirus Vaccine Live Oral Trivalent | 0 °C or colder.

Poliovirus Vaccine Live Oral Type I | Do.

Poliovirus Vaccine Live Oral Type II | Do.

Poliovirus Vaccine Live Oral Type III | Do.

Red Blood Cells (liquid product) | Between 1 and 10 °C.

Red Blood Cells Frozen | −65 °C or colder.

Rubella and Mumps Virus Vaccine Live | 10 °C or colder.

Rubella Virus Vaccine Live | Do.

Smallpox Vaccine (Liquid Product) | 0 °C or colder.

Source Plasma | −5 °C or colder.

Source Plasma Liquid | 10 °C or colder.

Whole Blood | Blood that is transported from the collecting facility to the processing facility shall be transported in an environment capable of continuously cooling the blood toward a temperature range of 1 to 10 °C, or at a temperature as close as possible to 20 to 24 °C for a period not to exceed 6 hours. Blood transported from the storage facility shall be placed in an appropriate environment to maintain a temperature range between 1 to 10 °C during shipment.

Yellow Fever Vaccine | 0 °C or colder.

(b) Exemptions. Exemptions or modifications shall be made only upon written approval, in the form of a supplement to the biologics license application, approved by the Director, Center for Biologics Evaluation and Research.

[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 56449, Oct. 20, 1999]

§ 600.20 Inspectors.

Inspections shall be made by an officer of the Food and Drug Administration having special knowledge of the methods used in the manufacture and control of products and designated for such purposes by the Commissioner of Food and Drugs, or by any officer, agent, or employee of the Department of Health and Human Services specifically designated for such purpose by the Secretary.

[38 FR 32048, Nov. 20, 1973]

§ 600.21 Time of inspection.

The inspection of an establishment for which a biologics license application is pending need not be made until the establishment is in operation and is manufacturing the complete product for which a biologics license is desired.

[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983; 64 FR 56449, Oct. 20, 1999; 84 FR 12508, Apr. 2, 2019]

§ 600.22 [Reserved]

§ 600.80 Postmarketing reporting of adverse experiences.

(a) Definitions. The following definitions of terms apply to this section:

Adverse experience. Any adverse event associated with the use of a biological product in humans, whether or not considered product related, including the following: An adverse event occurring in the course of the use of a biological product in professional practice; an adverse event occurring from overdose of the product whether accidental or intentional; an adverse event occurring from abuse of the product; an adverse event occurring from withdrawal of the product; and any failure of expected pharmacological action.

Blood Component. As defined in § 606.3(c) of this chapter.

Disability. A substantial disruption of a person's ability to conduct normal life functions.

Individual case safety report (ICSR). A description of an adverse experience related to an individual patient or subject.

ICSR attachments. Documents related to the adverse experience described in an ICSR, such as medical records, hospital discharge summaries, or other documentation.

Life-threatening adverse experience. Any adverse experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse experience as it occurred, i.e., it does not include an adverse experience that, had it occurred in a more severe form, might have caused death.

Serious adverse experience. Any adverse experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Unexpected adverse experience: Any adverse experience that is not listed in the current labeling for the biological product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

(b) Review of adverse experiences. Any person having a biologics license under § 601.20 of this chapter must promptly review all adverse experience information pertaining to its product obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers. Applicants are not required to resubmit to FDA adverse product experience reports forwarded to the applicant by FDA; applicants, however, must submit all followup information on such reports to FDA. Any person subject to the reporting requirements under paragraph (c) of this section must also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse experiences to FDA.

(c) Reporting requirements. The applicant must submit to FDA postmarketing 15-day Alert reports and periodic safety reports pertaining to its biological product as described in this section. These reports must be submitted to the Agency in electronic format as described in paragraph (h)(1) of this section, except as provided in paragraph (h)(2) of this section.

(1)(i) Postmarketing 15-day “Alert reports”. The applicant must report each adverse experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant.

(ii) Postmarketing 15-day “Alert reports”—followup. The applicant must promptly investigate all adverse experiences that are the subject of these postmarketing 15-day Alert reports and must submit followup reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.

(iii) Submission of reports. The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, also apply to any person whose name appears on the label of a licensed biological product as a manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any other participant involved in divided manufacturing. To avoid unnecessary duplication in the submission to FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of persons other than the applicant of the final biological product may be met by submission of all reports of serious adverse experiences to the applicant of the final product. If a person elects to submit adverse experience reports to the applicant rather than to FDA, the person must submit, by any appropriate means, each report to the applicant within 5 calendar days of initial receipt of the information by the person, and the applicant must then comply with the requirements of this section. Under this circumstance, a person who elects to submit reports to the applicant of the final product shall maintain a record of this action which must include:

(A) A copy of all adverse biological product experience reports submitted to the applicant of the final product;

(B) The date the report was received by the person;

(C) The date the report was submitted to the applicant of the final product; and—

(D) The name and address of the applicant of the final product.

(2) Periodic adverse experience reports. (i) The applicant must report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years from the date of issuance of the biologics license, and then at annual intervals. The applicant must submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of issuance of the biologics license) and each annual report within 60 days of the anniversary date of the issuance of the biologics license. Upon written notice, FDA may extend or reestablish the requirement that an applicant submit quarterly reports, or require that the applicant submit reports under this section at different times than those stated. Followup information to adverse experiences submitted in a periodic report may be submitted in the next periodic report.

(ii) Each periodic report is required to contain:

(A) Descriptive information. (1) A narrative summary and analysis of the information in the report;

(2) An analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the applicant's patient identification code for nonvaccine biological product reports or by the unique case identification number for vaccine reports, adverse reaction term(s), and date of submission to FDA);

(3) A history of actions taken since the last report because of adverse experiences (for example, labeling changes or studies initiated);

(4) An index consisting of a line listing of the applicant's patient identification code for nonvaccine biological product reports or by the unique case identification number for vaccine reports and adverse reaction term(s) for ICSRs submitted under paragraph (c)(2)(ii)(B) of this section; and

(B) ICSRs for serious, expected and, nonserious adverse experiences. An ICSR for each adverse experience not reported under paragraph (c)(1)(i) of this section (all serious, expected and nonserious adverse experiences). All such ICSRs must be submitted to FDA (either individually or in one or more batches) within the timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must only be submitted to FDA once.

(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.

(d) Scientific literature. A 15-day Alert report based on information in the scientific literature must be accompanied by a copy of the published article. The 15-day Alert reporting requirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse experiences) apply only to reports found in scientific and medical journals either as case reports or as the result of a formal clinical trial.

(e) Postmarketing studies. Applicants are not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse experience obtained from a postmarketing clinical study (whether or not conducted under a biological investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the product caused the adverse experience.

(f) Information reported on ICSRs for nonvaccine biological products. ICSRs for nonvaccine biological products include the following information:

(1) Patient information.

(i) Patient identification code;

(ii) Patient age at the time of adverse experience, or date of birth;

(iii) Patient gender; and

(iv) Patient weight.

(2) Adverse experience.

(i) Outcome attributed to adverse experience;

(ii) Date of adverse experience;

(iii) Date of report;

(iv) Description of adverse experience (including a concise medical narrative);

(v) Adverse experience term(s);

(vi) Description of relevant tests, including dates and laboratory data; and

(vii) Other relevant patient history, including preexisting medical conditions.

(3) Suspect medical product(s).

(i) Name;

(ii) Dose, frequency, and route of administration used;

(iii) Therapy dates;

(iv) Diagnosis for use (indication);

(v) Whether the product is a combination product as defined in § 3.2(e) of this chapter;

(vi) Whether the product is a prescription or nonprescription product;

(vii) Whether adverse experience abated after product use stopped or dose reduced;

(viii) Whether adverse experience reappeared after reintroduction of the product;

(ix) Lot number;

(x) Expiration date;

(xi) National Drug Code (NDC) number, or other unique identifier; and

(xii) Concomitant medical products and therapy dates.

(4) Initial reporter information.

(i) Name, address, and telephone number;

(ii) Whether the initial reporter is a health care professional; and

(iii) Occupation, if a health care professional.

(5) Applicant information.

(i) Applicant name and contact office address;

(ii) Telephone number;

(iii) Report source, such as spontaneous, literature, or study;

(iv) Date the report was received by applicant;

(v) Application number and type;

(vi) Whether the ICSR is a 15-day “Alert report”;

(vii) Whether the ICSR is an initial report or followup report; and

(viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).

(g) Information reported on ICSRs for vaccine products. ICSRs for vaccine products include the following information:

(1) Patient information.

(i) Patient name, address, telephone number;

(ii) Patient age at the time of vaccination, or date of birth;

(iii) Patient gender; and

(iv) Patient birth weight for children under age 5.

(2) Adverse experience.

(i) Outcome attributed to adverse experience;

(ii) Date and time of adverse experience;

(iii) Date of report;

(iv) Description of adverse experience (including a concise medical narrative);

(v) Adverse experience term(s);

(vi) Illness at the time of vaccination;

(vii) Description of relevant tests, including dates and laboratory data; and

(viii) Other relevant patient history, including preexisting medical conditions.

(3) Suspect medical product(s), including vaccines administered on the same date.

(i) Name;

(ii) Dose, frequency, and route or site of administration used;

(iii) Number of previous vaccine doses;

(iv) Vaccination date(s) and time(s);

(v) Diagnosis for use (indication);

(vi) Whether the product is a combination product (as defined in § 3.2(e) of this chapter);

(vii) Whether the adverse experience abated after product use stopped or dose reduced;

(viii) Whether the adverse experience reappeared after reintroduction of the product;

(ix) Lot number;

(x) Expiration date;

(xi) National Drug Code (NDC) number, or other unique identifier; and

(xii) Concomitant medical products and therapy dates.

(4) Vaccine(s) administered in the 4 weeks prior to the vaccination date.

(i) Name of vaccine;

(ii) Manufacturer;

(iii) Lot number;

(iv) Route or site of administration;

(v) Date given; and

(vi) Number of previous doses.

(5) Initial reporter information.

(i) Name, address, and telephone number;

(ii) Whether the initial reporter is a health care professional; and

(iii) Occupation, if a health care professional.

(6) Facility and personnel where vaccine was administered.

(i) Name of person who administered vaccine;

(ii) Name of responsible physician at facility where vaccine was administered; and

(iii) Name, address (including city, county, and state), and telephone number of facility where vaccine was administered.

(7) Applicant information.

(i) Applicant name and contact office address;

(ii) Telephone number;

(iii) Report source, such as spontaneous, literature, or study;

(iv) Date received by applicant;

(v) Application number and type;

(vi) Whether the ICSR is a 15-day “Alert report”;

(vii) Whether the ICSR is an initial report or followup report; and

(viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).

(h) Electronic format for submissions. (1) Safety report submissions, including ICSRs, ICSR attachments, and the descriptive information in periodic reports, must be in an electronic format that FDA can process, review, and archive. FDA will issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(2) Persons subject to the requirements of paragraph (c) of this section may request, in writing, a temporary waiver of the requirements in paragraph (h)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (h)(1) of this section. Requests for waivers must be submitted in accordance with § 600.90.

(i) Multiple reports. An applicant should not include in reports under this section any adverse experience that occurred in clinical trials if they were previously submitted as part of the biologics license application. If a report refers to more than one biological product marketed by an applicant, the applicant should submit the report to the biologics license application for the product listed first in the report.

(j) Patient privacy. For nonvaccine biological products, an applicant should not include in reports under this section the names and addresses of individual patients; instead, the applicant should assign a unique code for identification of the patient. The applicant should include the name of the reporter from whom the information was received as part of the initial reporter information, even when the reporter is the patient. The names of patients, health care professionals, hospitals, and geographical identifiers in adverse experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter. For vaccine adverse experience reports, these data will become part of the CDC Privacy Act System 09-20-0136, “Epidemiologic Studies and Surveillance of Disease Problems.” Information identifying the person who received the vaccine or that person's legal representative will not be made available to the public, but may be available to the vaccinee or legal representative.

(k) Recordkeeping. The applicant must maintain for a period of 10 years records of all adverse experiences known to the applicant, including raw data and any correspondence relating to the adverse experiences.

(l) Revocation of biologics license. If an applicant fails to establish and maintain records and make reports required under this section with respect to a licensed biological product, FDA may revoke the biologics license for such a product in accordance with the procedures of § 601.5 of this chapter.

(m) Exemptions. Manufacturers of the following listed products are not required to submit adverse experience reports under this section:

(1) Whole blood or components of whole blood.

(2) In vitro diagnostic products, including assay systems for the detection of antibodies or antigens to retroviruses. These products are subject to the reporting requirements for devices.

(n) Disclaimer. A report or information submitted by an applicant under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the biological product caused or contributed to an adverse effect. An applicant need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the biological product caused or contributed to an adverse effect. For purposes of this provision, this paragraph also includes any person reporting under paragraph (c)(1)(iii) of this section.

[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct. 20, 1999; 70 FR 14982, Mar. 24, 2005; 79 FR 33090, June 10, 2014]

§ 600.81 Distribution reports.

(a) Reporting requirements. The applicant must submit to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research, information about the quantity of the product distributed under the biologics license, including the quantity distributed to distributors. The interval between distribution reports must be 6 months. Upon written notice, FDA may require that the applicant submit distribution reports under this section at times other than every 6 months. The distribution report must consist of the bulk lot number (from which the final container was filled), the fill lot numbers for the total number of dosage units of each strength or potency distributed (e.g., fifty thousand per 10-milliliter vials), the label lot number (if different from fill lot number), labeled date of expiration, number of doses in fill lot/label lot, date of release of fill lot/label lot for distribution at that time. If any significant amount of a fill lot/label lot is returned, include this information. Disclosure of financial or pricing data is not required. As needed, FDA may require submission of more detailed product distribution information. Upon written notice, FDA may require that the applicant submit reports under this section at times other than those stated. Requests by an applicant to submit reports at times other than those stated should be made as a request for a waiver under § 600.90.

(b)(1) Electronic format. Except as provided for in paragraph (b)(2) of this section, the distribution reports required under paragraph (a) of this section must be submitted to the Agency in an electronic format that FDA can process, review, and archive. FDA will issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(2) Waivers. An applicant may request, in writing, a temporary waiver of the requirements in paragraph (b)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (b)(1) of this section. Requests for waivers must be submitted in accordance with § 600.90.

[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449, Oct. 20, 1999; 70 FR 14983, Mar. 24, 2005; 79 FR 33091, June 10, 2014]

§ 600.82 Notification of a permanent discontinuance or an interruption in manufacturing.

(a) Notification of a permanent discontinuance or an interruption in manufacturing. (1) An applicant of a biological product, other than blood or blood components for transfusion, which is licensed under section 351 of the Public Health Service Act, and which may be dispensed only under prescription under section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing of a permanent discontinuance of manufacture of the biological product or an interruption in manufacturing of the biological product that is likely to lead to a meaningful disruption in supply of that biological product in the United States if:

(i) The biological product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such biological product used in emergency medical care or during surgery; and

(ii) The biological product is not a radiopharmaceutical biological product.

(2) An applicant of blood or blood components for transfusion, which is licensed under section 351 of the Public Health Service Act, and which may be dispensed only under prescription under section 503(b) of the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing of a permanent discontinuance of manufacture of any product listed in its license or an interruption in manufacturing of any such product that is likely to lead to a significant disruption in supply of that product in the United States if:

(i) The product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such product used in emergency medical care or during surgery; and

(ii) The applicant is a manufacturer of a significant percentage of the U.S. blood supply.

(b) Submission and timing of notification. Notifications required by paragraph (a) of this section must be submitted to FDA electronically in a format that FDA can process, review, and archive:

(1) At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or

(2) If 6 months' advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after such a permanent discontinuance or interruption in manufacturing occurs.

(c) Information included in notification. Notifications required by paragraph (a) of this section must include the following information:

(1) The name of the biological product subject to the notification, including the National Drug Code for such biological product, or an alternative standard for identification and labeling that has been recognized as acceptable by the Center Director;

(2) The name of the applicant of the biological product;

(3) Whether the notification relates to a permanent discontinuance of the biological product or an interruption in manufacturing of the biological product;

(4) A description of the reason for the permanent discontinuance or interruption in manufacturing; and

(5) The estimated duration of the interruption in manufacturing.

(d)(1) Public list of biological product shortages. FDA will maintain a publicly available list of biological products that are determined by FDA to be in shortage. This biological product shortages list will include the following information:

(i) The names and National Drug Codes for such biological products, or the alternative standards for identification and labeling that have been recognized as acceptable by the Center Director;

(ii) The name of each applicant for such biological products;

(iii) The reason for the shortage, as determined by FDA, selecting from the following categories: Requirements related to complying with good manufacturing practices; regulatory delay; shortage of an active ingredient; shortage of an inactive ingredient component; discontinuation of the manufacture of the biological product; delay in shipping of the biological product; demand increase for the biological product; or other reason; and

(iv) The estimated duration of the shortage.

(2) Confidentiality. FDA may choose not to make information collected to implement this paragraph available on the biological product shortages list or available under section 506C(c) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356c(c)) if FDA determines that disclosure of such information would adversely affect the public health (such as by increasing the possibility of hoarding or other disruption of the availability of the biological product to patients). FDA will also not provide information on the public shortages list or under section 506C(c) of the Federal Food, Drug, and Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade secrets and commercial or financial information that is considered confidential or privileged under § 20.61 of this chapter.

(e) Noncompliance letters. If an applicant fails to submit a notification as required under paragraph (a) of this section and in accordance with paragraph (b) of this section, FDA will issue a letter to the applicant informing it of such failure.

(1) Not later than 30 calendar days after the issuance of such a letter, the applicant must submit to FDA a written response setting forth the basis for noncompliance and providing the required notification under paragraph (a) of this section and including the information required under paragraph (c) of this section; and

(2) Not later than 45 calendar days after the issuance of a letter under this paragraph, FDA will make the letter and the applicant's response to the letter public, unless, after review of the applicant's response, FDA determines that the applicant had a reasonable basis for not notifying FDA as required under paragraph (a) of this section.

(f) Definitions. The following definitions of terms apply to this section:

Biological product shortage or shortage means a period of time when the demand or projected demand for the biological product within the United States exceeds the supply of the biological product.

Intended for use in the prevention or treatment of a debilitating disease or condition means a biological product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning.

Life supporting or life sustaining means a biological product that is essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.

Meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a biological product by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time.

Significant disruption means a change in production that is reasonably likely to lead to a reduction in the supply of blood or blood components by a manufacturer that substantially affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time.

[80 FR 38939, July 8, 2015]

§ 600.90 Waivers.

(a) An applicant may ask the Food and Drug Administration to waive under this section any requirement that applies to the applicant under §§ 600.80 and 600.81. A waiver request under this section is required to be submitted with supporting documentation. The waiver request is required to contain one of the following:

(1) An explanation why the applicant's compliance with the requirement is unnecessary or cannot be achieved,

(2) A description of an alternative submission that satisfies the purpose of the requirement, or

(3) Other information justifying a waiver.

(b) FDA may grant a waiver if it finds one of the following:

(1) The applicant's compliance with the requirement is unnecessary or cannot be achieved,

(2) The applicant's alternative submission satisfies the requirement, or

(3) The applicant's submission otherwise justifies a waiver.

[59 FR 54042, Oct. 27, 1994, as amended at 79 FR 33092, June 10, 2014]

§ 601.2 Applications for biologics licenses; procedures for filing.

(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter), on forms prescribed for such purposes, and shall submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance; statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter; or was not subject to such requirements in accordance with § 56.104 or § 56.105, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter. A full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product for introduction or delivery for introduction into interstate commerce; summaries of results of tests performed on the lot(s) represented by the submitted sample(s); specimens of the labels, enclosures, and containers, and if applicable, any Medication Guide required under part 208 of this chapter proposed to be used for the product; and the address of each location involved in the manufacture of the biological product shall be listed in the biologics license application. The applicant shall also include a financial certification or disclosure statement(s) or both for clinical investigators as required by part 54 of this chapter. An application for a biologics license shall not be considered as filed until all pertinent information and data have been received by the Food and Drug Administration. The applicant shall also include either a claim for categorical exclusion under § 25.30 or § 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter. The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. An application for any of the following specified categories of biological products subject to licensure shall be handled as set forth in paragraph (c) of this section:

(1) Therapeutic DNA plasmid products;

(2) Therapeutic synthetic peptide products of 40 or fewer amino acids;

(3) Monoclonal antibody products for in vivo use; and

(4) Therapeutic recombinant DNA-derived products.

(b) [Reserved]

(c)(1) To obtain marketing approval for a biological product subject to licensure which is a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product, an applicant shall submit a biologics license application in accordance with paragraph (a) of this section except that the following sections in parts 600 through 680 of this chapter shall not be applicable to such products: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, 610.53, and 610.62 of this chapter.

(2) To the extent that the requirements in this paragraph (c) conflict with other requirements in this subchapter, this paragraph (c) shall supersede other requirements.

(d) Approval of a biologics license application or issuance of a biologics license shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure the continued safety, purity, and potency of such products. Applicable requirements for the maintenance of establishments for the manufacture of a product subject to this section shall include but not be limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter.

(e) Any establishment and product license for a biological product issued under section 351 of the Public Health Service Act (42 U.S.C. 201 et seq.) that has not been revoked or suspended as of December 20, 1999, shall constitute an approved biologics license application in effect under the same terms and conditions set forth in such product license and such portions of the establishment license relating to such product.

(f) Withdrawal from sale of approved biological products. A holder of a biologics license application (BLA) must report to FDA, in accordance with the requirements of §§ 207.61 and 207.65, the withdrawal from sale of an approved biological product. The information must be submitted to FDA within 30 working days of the biological product's withdrawal from sale. The following information must be submitted: The holder's name; product name; BLA number; the National Drug Code; and the date on which the product is expected to be no longer in commercial distribution. The reason for the withdrawal of the biological product is requested but not required to be submitted.

(g) Master files—(1) Biologics license applications under section 351 of the Public Health Service Act not permitted to incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file. Except as provided in paragraphs (g)(2) and (3) of this section, a biologics license application under section 351 of the Public Health Service Act may not incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file, including a drug master file submitted under § 314.420 of this chapter, for the product, including for a biological product constituent part of a combination product.

(2) Former approved applications deemed to be licenses for biological products pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009. An application for a biological product that:

(i) Is a former approved application under section 505 of the Federal Food, Drug, and Cosmetic Act that, pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009, has been deemed to be a license for the biological product under section 351 of the Public Health Service Act; and

(ii) At the time it was so deemed, incorporated by reference drug substance, drug substance intermediate, and/or drug product information contained in a drug master file submitted under § 314.420 of this chapter, may continue to incorporate by reference the information contained in that drug master file. Amendments and supplements to such applications may also continue to incorporate by reference the information contained in that drug master file.

(3) Non-biological product constituent parts of combination products regulated under biologics license applications under section 351 of the Public Health Service Act. A biologics license application under section 351 of the Public Health Service Act may incorporate by reference drug substance, drug substance intermediate, and/or drug product information contained in a master file, including a drug master file submitted under § 314.420 of this chapter, for any non-biological product constituent part of a combination product.

(4) Biologics license applications under section 351 of the Public Health Service Act permitted to incorporate by reference information contained in a master file that is not drug substance, drug substance intermediate, or drug product information. Nothing in paragraph (g)(1) of this section limits or restricts a biologics license application under section 351 of the Public Health Service Act from incorporating by reference information contained in any master file, including a drug master file submitted under § 314.420 of this chapter, that is not drug substance, drug substance intermediate, or drug product information.

(5) Investigational new drug applications. Nothing in paragraph (g)(1) of this section limits or restricts an investigational new drug application for a product that would be subject to licensure under section 351 of the Public Health Service Act from incorporating by reference any information, including drug substance, drug substance intermediate, and drug product information, contained in a master file, including a drug master file submitted under § 314.420 of this chapter.

[64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015; 80 FR 37974, July 2, 2015; 81 FR 60221, Aug. 31, 2016; 89 FR 9756, Feb. 12, 2024]

§ 601.3 Complete response letter to the applicant.

(a) Complete response letter. The Food and Drug Administration will send the biologics license applicant or supplement applicant a complete response letter if the agency determines that it will not approve the biologics license application or supplement in its present form.

(1) Description of specific deficiencies. A complete response letter will describe all of the deficiencies that the agency has identified in a biologics license application or supplement, except as stated in paragraph (a)(2) of this section.

(2) Inadequate data. If FDA determines, after a biologics license application or supplement is filed, that the data submitted are inadequate to support approval, the agency might issue a complete response letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed product labeling.

(3) Recommendation of actions for approval. When possible, a complete response letter will recommend actions that the applicant might take to place its biologics license application or supplement in condition for approval.

(b) Applicant actions. After receiving a complete response letter, the biologics license applicant or supplement applicant must take either of the following actions:

(1) Resubmission. Resubmit the application or supplement, addressing all deficiencies identified in the complete response letter.

(2) Withdrawal. Withdraw the application or supplement. A decision to withdraw the application or supplement is without prejudice to a subsequent submission.

(c) Failure to take action. (1) FDA may consider a biologics license applicant or supplement applicant's failure to either resubmit or withdraw the application or supplement within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application or supplement, unless the applicant has requested an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for such an extension. FDA may consider an applicant's failure to resubmit the application or supplement within the extended time period or request an additional extension to be a request by the applicant to withdraw the application.

(2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application or supplement should not be withdrawn and to request an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn.

[73 FR 39611, July 10, 2008]

§ 601.4 Issuance and denial of license.

(a) A biologics license shall be issued upon a determination by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research that the establishment(s) and the product meet the applicable requirements established in this chapter. A biologics license shall be valid until suspended or revoked.

(b) If the Commissioner determines that the establishment or product does not meet the requirements established in this chapter, the biologics license application shall be denied and the applicant shall be informed of the grounds for, and of an opportunity for a hearing on, the decision. If the applicant so requests, the Commissioner shall issue a notice of opportunity for hearing on the matter pursuant to § 12.21(b) of this chapter.

[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar. 24, 2005]

§ 601.5 Revocation of license.

(a) A biologics license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products manufactured under such license or to discontinue the manufacture of a particular product for which a license is held and waiving an opportunity for a hearing on the matter.

(b)(1) The Commissioner shall notify the licensed manufacturer of the intention to revoke the biologics license, setting forth the grounds for, and offering an opportunity for a hearing on the proposed revocation if the Commissioner finds any of the following:

(i) Authorized Food and Drug Administration employees after reasonable efforts have been unable to gain access to an establishment or a location for the purpose of carrying out the inspection required under § 600.21 of this chapter,

(ii) Manufacturing of products or of a product has been discontinued to an extent that a meaningful inspection or evaluation cannot be made,

(iii) The manufacturer has failed to report a change as required by § 601.12 of this chapter,

(iv) The establishment or any location thereof, or the product for which the license has been issued, fails to conform to the applicable standards established in the license and in this chapter designed to ensure the continued safety, purity, and potency of the manufactured product,

(v) The establishment or the manufacturing methods have been so changed as to require a new showing that the establishment or product meets the requirements established in this chapter in order to protect the public health, or

(vi) The licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use.

(2) Except as provided in § 601.6 of this chapter, or in cases involving willfulness, the notification required in this paragraph shall provide a reasonable period for the licensed manufacturer to demonstrate or achieve compliance with the requirements of this chapter, before proceedings will be instituted for the revocation of the license. If compliance is not demonstrated or achieved and the licensed manufacturer does not waive the opportunity for a hearing, the Commissioner shall issue a notice of opportunity for hearing on the matter under § 12.21(b) of this chapter.

[64 FR 56451, Oct. 20, 1999]

§ 601.6 Suspension of license.

(a) Whenever the Commissioner has reasonable grounds to believe that any of the grounds for revocation of a license exist and that by reason thereof there is a danger to health, the Commissioner may notify the licensed manufacturer that the biologics license is suspended and require that the licensed manufacturer do the following:

(1) Notify the selling agents and distributors to whom such product or products have been delivered of such suspension, and

(2) Furnish to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research, complete records of such deliveries and notice of suspension.

(b) Upon suspension of a license, the Commissioner shall either:

(1) Proceed under the provisions of § 601.5(b) of this chapter to revoke the license, or

(2) If the licensed manufacturer agrees, hold revocation in abeyance pending resolution of the matters involved.

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

§ 601.7 Procedure for hearings.

(a) A notice of opportunity for hearing, notice of appearance and request for hearing, and grant or denial of hearing for a biological drug pursuant to this part, for which the exemption from the Federal Food, Drug, and Cosmetic Act in § 310.4 of this chapter has been revoked, shall be subject to the provisions of § 314.200 of this chapter except to the extent that the notice of opportunity for hearing on the matter issued pursuant to § 12.21(b) of this chapter specifically provides otherwise.

(b) Hearings pursuant to §§ 601.4 through 601.6 shall be governed by part 12 of this chapter.

(c) When a license has been suspended pursuant to § 601.6 and a hearing request has been granted, the hearing shall proceed on an expedited basis.

[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12, 1977]

§ 601.8 Publication of revocation.

The Commissioner, following revocation of a biologics license under 21 CFR 601.5(b), will publish a notice in the Federal Register with a statement of the specific grounds for the revocation.

[74 FR 20585, May 5, 2009]

§ 601.9 Licenses; reissuance.

(a) Compliance with requirements. A biologics license, previously suspended or revoked, may be reissued or reinstated upon a showing of compliance with requirements and upon such inspection and examination as may be considered necessary by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.

(b) Exclusion of noncomplying location. A biologics license, excluding a location or locations that fail to comply with the requirements in this chapter, may be issued without further application and concurrently with the suspension or revocation of the license for noncompliance at the excluded location or locations.

(c) Exclusion of noncomplying product(s). In the case of multiple products included under a single biologics license application, a biologics license may be issued, excluding the noncompliant product(s), without further application and concurrently with the suspension or revocation of the biologics license for a noncompliant product(s).

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

§ 601.12 Changes to an approved application.

(a) General. (1) As provided by this section, an applicant must inform the Food and Drug Administration (FDA) (see mailing addresses in § 600.2 of this chapter) about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).

(2) Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or nonclinical laboratory studies the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

(3) Notwithstanding the requirements of paragraphs (b), (c), and (f) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the product or in an annual report).

(4) The applicant must promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented in accordance with paragraphs (f)(1) and (f)(2) of this section.

(5) A supplement or annual report must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the cover letter.

(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes). (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

(2) These changes include, but are not limited to:

(i) Except as provided in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation, including inactive ingredients, or in the specifications provided in the approved application;

(ii) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;

(iii) Changes in the virus or adventitious agent removal or inactivation method(s);

(iv) Changes in the source material or cell line;

(v) Establishment of a new master cell bank or seed; and

(vi) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s), or an addition, deletion, or substitution of steps in an aseptic processing operation.

(3) The applicant must obtain approval of the supplement from FDA prior to distribution of the product made using the change. Except for submissions under paragraph (e) of this section, the following shall be contained in the supplement:

(i) A detailed description of the proposed change;

(ii) The product(s) involved;

(iii) The manufacturing site(s) or area(s) affected;

(iv) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;

(v) The data derived from such studies;

(vi) Relevant validation protocols and data; and

(vii) A reference list of relevant standard operating procedures (SOP's).

(4) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked: “Prior Approval Supplement-Expedited Review Requested.

(c) Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change. (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. The supplement shall be labeled “Supplement—Changes Being Effected in 30 Days” or, if applicable under paragraph (c)(5) of this section, “Supplement—Changes Being Effected.”

(2) These changes include, but are not limited to:

(i) [Reserved]

(ii) An increase or decrease in production scale during finishing steps that involves different equipment; and

(iii) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters.

(iv) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.

(3) Pending approval of the supplement by FDA, and except as provided in paragraph (c)(5) of this section, distribution of the product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of this section shall be contained in the supplement.

(4) If within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:

(i) The change requires approval prior to distribution of the product in accordance with paragraph (b) of this section; or

(ii) Any of the information required under paragraph (c)(3) of this section is missing; the applicant shall not distribute the product made using the change until FDA determines that compliance with this section is achieved.

(5) In certain circumstances, FDA may determine that, based on experience with a particular type of change, the supplement for such change is usually complete and provides the proper information, and on particular assurances that the proposed change has been appropriately submitted, the product made using the change may be distributed immediately upon receipt of the supplement by FDA. These circumstances may include substantial similarity with a type of change regularly involving a “Supplement—Changes Being Effected” supplement or a situation in which the applicant presents evidence that the proposed change has been validated in accordance with an approved protocol for such change under paragraph (e) of this section.

(6) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the products made with the manufacturing change.

(d) Changes to be described in an annual report (minor changes). (1) Changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product shall be documented by the applicant in an annual report submitted each year within 60 days of the anniversary date of approval of the application. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, may approve a written request for an alternative date to combine annual reports for multiple approved applications into a single annual report submission.

(2) These changes include, but are not limited to:

(i) Any change made to comply with a change to an official compendium, except a change described in paragraph (c)(2)(iv) of this section, that is consistent with FDA statutory and regulatory requirements.

(ii) The deletion or reduction of an ingredient intended only to affect the color of the product, except that a change intended only to affect Blood Grouping Reagents requires supplement submission and approval prior to distribution of the product made using the change in accordance with the requirements set forth in paragraph (b) of this section;

(iii) An extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the application;

(iv) A change within the container closure system for a nonsterile product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;

(v) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form product, without a change from one container closure system to another;

(vi) The addition by embossing, debossing, or engraving of a code imprint to a solid dosage form biological product other than a modified release dosage form, or a minor change in an existing code imprint; and

(vii) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application, or deletion of an alternative analytical procedure.

(3) The following information for each change shall be contained in the annual report:

(i) A list of all products involved; and

(ii) A full description of the manufacturing and controls changes including: the manufacturing site(s) or area(s) involved; the date the change was made; a cross-reference to relevant validation protocols and/or SOP's; and relevant data from studies and tests performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

(iii) A statement by the holder of the approved application or license that the effects of the change have been assessed.

(4) The applicant shall submit the report to the FDA office responsible for reviewing the application. The report shall include all the information required under this paragraph for each change made during the annual reporting interval which ends on the anniversary date in the order in which they were implemented.

(e) An applicant may submit one or more protocols describing the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect.

(f) Labeling changes. (1) Labeling changes requiring supplement submission—FDA approval must be obtained before distribution of the product with the labeling change. Except as described in paragraphs (f)(2) and (f)(3) of this section, an applicant shall submit a supplement describing a proposed change in the package insert, package label, container label, or, if applicable, a Medication Guide required under part 208 of this chapter, and include the information necessary to support the proposed change. An applicant cannot use paragraph (f)(2) of this section to make any change to the information required in § 201.57(a) of this chapter. An applicant may report the minor changes to the information specified in paragraph (f)(3)(i)(D) of this section in an annual report. The supplement shall clearly highlight the proposed change in the labeling. The applicant shall obtain approval from FDA prior to distribution of the product with the labeling change.

(2) Labeling changes requiring supplement submission—product with a labeling change that may be distributed before FDA approval. (i) An applicant shall submit, at the time such change is made, a supplement for any change in the package insert, package label, or container label to reflect newly acquired information, except for changes to the package insert required in § 201.57(a) of this chapter (which must be made under paragraph (f)(1) of this section), to accomplish any of the following:

(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter;

(B) To add or strengthen a statement about abuse, dependence, psychological effect, or overdosage;

(C) To add or strengthen an instruction about dosage and administration that is intended to increase the safety of the use of the product; and

(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness.

(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the product that FDA specifically requests be submitted under this provision.

(ii) Pending approval of the supplement by FDA, the applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the supplement is submitted. The supplement shall clearly identify the change being made and include necessary supporting data. The supplement and its mailing cover shall be plainly marked: “Special Labeling Supplement—Changes Being Effected.”

(3) Labeling changes requiring submission in an annual report. (i) An applicant shall submit any final printed package insert, package label, container label, or Medication Guide required under part 208 of this chapter incorporating the following changes in an annual report submitted to FDA each year as provided in paragraph (d)(1) of this section:

(A) Editorial or similar minor changes;

(B) A change in the information on how the product is supplied that does not involve a change in the dosage strength or dosage form;

(C) A change in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter for a Medication Guide; and

(D) A change to the information required in § 201.57(a) of this chapter as follows:

(1) Removal of a listed section(s) specified in § 201.57(a)(5) of this chapter; and

(2) Changes to the most recent revision date of the labeling as specified in § 201.57(a)(15) of this chapter.

(E) A change made pursuant to an exception or alternative granted under § 201.26 or § 610.68 of this chapter.

(ii) The applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the change is made.

(4) Advertisements and promotional labeling. Advertisements and promotional labeling shall be submitted to the Center for Biologics Evaluation and Research or Center for Drug Evaluation and Research in accordance with the requirements set forth in § 314.81(b)(3)(i) of this chapter.

(5) The submission and grant of a written request for an exception or alternative under § 201.26 or § 610.68 of this chapter satisfies the requirements in paragraphs (f)(1) through (f)(2) of this section.

(6) For purposes of paragraph (f)(2) of this section, information will be considered newly acquired if it consists of data, analyses, or other information not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.

(g) Failure to comply. In addition to other remedies available in law and regulations, in the event of repeated failure of the applicant to comply with this section, FDA may require that the applicant submit a supplement for any proposed change and obtain approval of the supplement by FDA prior to distribution of the product made using the change.

(h) Administrative review. Under § 10.75 of this chapter, an applicant may request internal FDA review of FDA employee decisions under this section.

[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998. Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766, Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov. 18, 2008; 80 FR 18092, Apr. 3, 2015]

§ 601.14 Regulatory submissions in electronic format.

(a) General. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files.)

(b) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format as described in paragraph (a) of this section. This requirement is in addition to the provisions of §§ 601.2(a) and 601.12(f) that require applicants to submit specimens of the labels, enclosures, and containers, or to submit other final printed labeling. Submissions under this paragraph must be made in accordance with part 11 of this chapter except for the requirements of § 11.10(a), (c) through (h), and (k), and the corresponding requirements of § 11.30.

[68 FR 69020, Dec. 11, 2003]

§ 601.15 Foreign establishments and products: samples for each importation.

Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter) must be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment must accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c)). For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Center for Biologics Evaluation and Research or Center for Drug Evaluation and Research accompanies each shipment.

[70 FR 14983, Mar. 24, 2005, as amended at 80 FR 18092, Apr. 3, 2015]

§ 601.20 Biologics licenses; issuance and conditions.

(a) Examination—compliance with requirements. A biologics license application shall be approved only upon examination of the product and upon a determination that the product complies with the standards established in the biologics license application and the requirements prescribed in the regulations in this chapter including but not limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter.

(b) Availability of product. No biologics license shall be issued unless:

(1) The product intended for introduction into interstate commerce is available for examination, and

(2) Such product is available for inspection during all phases of manufacture.

(c) Manufacturing process—impairment of assurances. No product shall be licensed if any part of the process of or relating to the manufacture of such product, in the judgment of the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, would impair the assurances of continued safety, purity, and potency as provided by the regulations contained in this chapter.

(d) Inspection—compliance with requirements. A biologics license shall be issued or a biologics license application approved only after inspection of the establishment(s) listed in the biologics license application and upon a determination that the establishment(s) complies with the standards established in the biologics license application and the requirements prescribed in applicable regulations.

(e) One biologics license to cover all locations. One biologics license shall be issued to cover all locations meeting the establishment standards identified in the approved biologics license application and each location shall be subject to inspection by FDA officials.

[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

§ 601.21 Products under development.

A biological product undergoing development, but not yet ready for a biologics license, may be shipped or otherwise delivered from one State or possession into another State or possession provided such shipment or delivery is not for introduction or delivery for introduction into interstate commerce, except as provided in sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, as amended, and the regulations thereunder (21 CFR parts 312 and 812).

[64 FR 56451, Oct. 20, 1999]

§ 601.22 Products in short supply; initial manufacturing at other than licensed location.

A biologics license issued to a manufacturer and covering all locations of manufacture shall authorize persons other than such manufacturer to conduct at places other than such locations the initial, and partial manufacturing of a product for shipment solely to such manufacturer only to the extent that the names of such persons and places are registered with the Commissioner of Food and Drugs and it is found upon application of such manufacturer, that the product is in short supply due either to the peculiar growth requirements of the organism involved or to the scarcity of the animal required for manufacturing purposes, and such manufacturer has established with respect to such persons and places such procedures, inspections, tests or other arrangements as will ensure full compliance with the applicable regulations of this subchapter related to continued safety, purity, and potency. Such persons and places shall be subject to all regulations of this subchapter except §§ 601.2 to 601.6, 601.9, 601.10, 601.20, 601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and places authorized under this section to conduct the initial and partial manufacturing of a product for shipment solely to a manufacturer of a product subject to licensure under § 601.2(c), the following additional regulations shall not be applicable: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, and 610.53 of this chapter. Failure of such manufacturer to maintain such procedures, inspections, tests, or other arrangements, or failure of any person conducting such partial manufacturing to comply with applicable regulations shall constitute a ground for suspension or revocation of the authority conferred pursuant to this section on the same basis as provided in §§ 601.6 to 601.8 with respect to the suspension and the revocation of licenses.

[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64 FR 56452, Oct. 20, 1999; 80 FR 37974, July 2, 2015]

§ 601.27 Pediatric studies.

(a) Required assessment. Except as provided in paragraphs (b), (c), and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. Where the course of the disease and the effects of the product are similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled effectiveness studies in adults, usually supplemented with other information in pediatric patients, such as pharmacokinetic studies. In addition, studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another. Assessments required under this section for a product that represents a meaningful therapeutic benefit over existing treatments must be carried out using appropriate formulations for the age group(s) for which the assessment is required.

(b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section until after licensing of the product for use in adults. Deferral may be granted if, among other reasons, the product is ready for approval in adults before studies in pediatric patients are complete, pediatric studies should be delayed until additional safety or effectiveness data have been collected. If an applicant requests deferred submission, the request must provide an adequate justification for delaying pediatric studies, a description of the planned or ongoing studies, and evidence that the studies are being or will be conducted with due diligence and at the earliest possible time.

(2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the product may be licensed for use in adults subject to the requirement that the applicant submit the required assessments within a specified time.

(c) Waivers—(1) General. FDA may grant a full or partial waiver of the requirements of paragraph (a) of this section on its own initiative or at the request of an applicant. A request for a waiver must provide an adequate justification.

(2) Full waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section if the applicant certifies that:

(i) The product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of pediatric patients;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or

(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.

(3) Partial waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:

(i) The product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed;

(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in that age group; or

(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

(4) FDA action on waiver. FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.

(5) Definition of “meaningful therapeutic benefit”. For purposes of this section, a product will be considered to offer a meaningful therapeutic benefit over existing therapies if FDA estimates that:

(i) If approved, the product would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population. Examples of how improvement might be demonstrated include, e.g., evidence of increased effectiveness in treatment, prevention, or diagnosis of disease; elimination or substantial reduction of a treatment-limiting drug reaction; documented enhancement of compliance; or evidence of safety and effectiveness in a new subpopulation; or

(ii) The product is in a class of products or for an indication for which there is a need for additional therapeutic options.

(d) Exemption for orphan drugs. This section does not apply to any product for an indication or indications for which orphan designation has been granted under part 316, subpart C, of this chapter.

[63 FR 66671, Dec. 2, 1998]

§ 601.28 Annual reports of postmarketing pediatric studies.

Sponsors of licensed biological products shall submit the following information each year within 60 days of the anniversary date of approval of each product under the license to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter):

(a) Summary. A brief summary stating whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population to support appropriate labeling for the pediatric population have been initiated. Where possible, an estimate of patient exposure to the drug product, with special reference to the pediatric population (neonates, infants, children, and adolescents) shall be provided, including dosage form.

(b) Clinical data. Analysis of available safety and efficacy data in the pediatric population and changes proposed in the labeling based on this information. An assessment of data needed to ensure appropriate labeling for the pediatric population shall be included.

(c) Status reports. A statement on the current status of any postmarketing studies in the pediatric population performed by, or on behalf of, the applicant. The statement shall include whether postmarketing clinical studies in pediatric populations were required or agreed to, and, if so, the status of these studies shall be reported to FDA in annual progress reports of postmarketing studies under § 601.70 rather than under this section.

[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

§ 601.29 Guidance documents.

(a) FDA has made available guidance documents under § 10.115 of this chapter to help you comply with certain requirements of this part.

(b) The Center for Biologics Evaluation and Research (CBER) maintains a list of guidance documents that apply to the center's regulations. The lists are maintained on the Internet and are published annually in the Federal Register. You may request a copy of the CBER list from the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.

[65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

§ 601.30 Scope.

This subpart applies to radiopharmaceuticals intended for in vivo administration for diagnostic and monitoring use. It does not apply to radiopharmaceuticals intended for therapeutic purposes. In situations where a particular radiopharmaceutical is proposed for both diagnostic and therapeutic uses, the radiopharmaceutical must be evaluated taking into account each intended use.

§ 601.31 Definition.

Link to an amendment published at 91 FR 60004, Sept. 22, 2026.

For purposes of this part,diagnostic radiopharmaceutical means:

(a) An article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons; or

(b) Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such article as defined in paragraph (a) of this section.

§ 601.32 General factors relevant to safety and effectiveness.

FDA's determination of the safety and effectiveness of a diagnostic radiopharmaceutical includes consideration of the following:

(a) The proposed use of the diagnostic radiopharmaceutical in the practice of medicine;

(b) The pharmacological and toxicological activity of the diagnostic radiopharmaceutical (including any carrier or ligand component of the diagnostic radiopharmaceutical); and

(c) The estimated absorbed radiation dose of the diagnostic radiopharmaceutical.

§ 601.33 Indications.

(a) For diagnostic radiopharmaceuticals, the categories of proposed indications for use include, but are not limited to, the following:

(1) Structure delineation;

(2) Functional, physiological, or biochemical assessment;

(3) Disease or pathology detection or assessment; and

(4) Diagnostic or therapeutic patient management.

(b) Where a diagnostic radiopharmaceutical is not intended to provide disease-specific information, the proposed indications for use may refer to a biochemical, physiological, anatomical, or pathological process or to more than one disease or condition.

§ 601.34 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria:

(1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy.

(2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es).

(3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology.

(4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management.

(5) For a claim that does not fall within the indication categories identified in § 601.33, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim.

(b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient followup.

§ 601.35 Evaluation of safety.

Link to an amendment published at 91 FR 60004, Sept. 22, 2026.

(a) Factors considered in the safety assessment of a diagnostic radiopharmaceutical include, among others, the following:

(1) The radiation dose;

(2) The pharmacology and toxicology of the radiopharmaceutical, including any radionuclide, carrier, or ligand;

(3) The risks of an incorrect diagnostic determination;

(4) The adverse reaction profile of the drug;

(5) Results of human experience with the radiopharmaceutical for other uses; and

(6) Results of any previous human experience with the carrier or ligand of the radiopharmaceutical when the same chemical entity as the carrier or ligand has been used in a previously studied product.

(b) The assessment of the adverse reaction profile includes, but is not limited to, an evaluation of the potential of the diagnostic radiopharmaceutical, including the carrier or ligand, to elicit the following:

(1) Allergic or hypersensitivity responses,

(2) Immunologic responses,

(3) Changes in the physiologic or biochemical function of the target and nontarget tissues, and

(4) Clinically detectable signs or symptoms.

(c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA may require, among other information, the following types of data:

(A) Pharmacology data,

(B) Toxicology data,

(C) Clinical adverse event data, and

(D) Radiation safety assessment.

(2) The amount of new safety data required will depend on the characteristics of the product and available information regarding the safety of the diagnostic radiopharmaceutical, and its carrier or ligand, obtained from other studies and uses. Such information may include, but is not limited to, the dose, route of administration, frequency of use, half-life of the ligand or carrier, half-life of the radionuclide, and results of clinical and preclinical studies. FDA will establish categories of diagnostic radiopharmaceuticals based on defined characteristics relevant to risk and will specify the amount and type of safety data that are appropriate for each category (e.g., required safety data may be limited for diagnostic radiopharmaceuticals with a well established, low-risk profile). Upon reviewing the relevant product characteristics and safety information, FDA will place each diagnostic radiopharmaceutical into the appropriate safety risk category.

(d) Radiation safety assessment. The radiation safety assessment must establish the radiation dose of a diagnostic radiopharmaceutical by radiation dosimetry evaluations in humans and appropriate animal models. The maximum tolerated dose need not be established.

§ 601.40 Scope.

This subpart applies to certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).

§ 601.41 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.

FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.

§ 601.42 Approval with restrictions to assure safe use.

(a) If FDA concludes that a biological product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the biological product, such as:

(1) Distribution restricted to certain facilities or physicians with special training or experience; or

(2) Distribution conditioned on the performance of specified medical procedures.

(b) The limitations imposed will be commensurate with the specific safety concerns presented by the biological product.

§ 601.43 Withdrawal procedures.

(a) For biological products approved under § 601.41 or § 601.42, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:

(1) A postmarketing clinical study fails to verify clinical benefit;

(2) The applicant fails to perform the required postmarketing study with due diligence;

(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;

(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;

(5) The promotional materials are false or misleading; or

(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.

(b) Notice of opportunity for a hearing. The Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research will give the applicant notice of an opportunity for a hearing on the Center's proposal to withdraw the approval of an application approved under § 601.41 or § 601.42. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.

(c) Submission of data and information. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.

(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register in accordance with §§ 12.32(e) and 15.20 of this chapter.

(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.

(d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.

(e) Procedures for hearings. Hearings held under this section will be conducted in accordance with the provisions of part 15 of this chapter, with the following modifications:

(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.

(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.

(f) Judicial review. The Commissioner's decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under § 10.35 of this chapter.

[57 FR 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003; 70 FR 14984, Mar. 24, 2005]

§ 601.44 Postmarketing safety reporting.

Biological products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.

§ 601.45 Promotional materials.

For biological products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.

§ 601.46 Termination of requirements.

If FDA determines after approval that the requirements established in § 601.42, § 601.43, or § 601.45 are no longer necessary for the safe and effective use of a biological product, it will so notify the applicant. Ordinarily, for biological products approved under § 601.41, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the biological product's clinical benefit and the biological product would be appropriate for approval under traditional procedures. For biological products approved under § 601.42, the restrictions would no longer apply when FDA determines that safe use of the biological product can be assured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30.

§ 601.50 Confidentiality of data and information in an investigational new drug notice for a biological product.

(a) The existence of an IND notice for a biological product will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged.

(b) The availability for public disclosure of all data and information in an IND file for a biological product shall be handled in accordance with the provisions established in § 601.51.

(c) Notwithstanding the provisions of § 601.51, the Food and Drug Administration shall disclose upon request to an individual on whom an investigational biological product has been used a copy of any adverse reaction report relating to such use.

[39 FR 44656, Dec. 24, 1974]

§ 601.51 Confidentiality of data and information in applications for biologics licenses.

(a) For purposes of this section the biological product file includes all data and information submitted with or incorporated by reference in any application for a biologics license, IND's incorporated into any such application, master files, and other related submissions. The availability for public disclosure of any record in the biological product file shall be handled in accordance with the provisions of this section.

(b) The existence of a biological product file will not be disclosed by the Food and Drug Administration before a biologics license application has been approved unless it has previously been publicly disclosed or acknowledged. The Food and Drug Administration will maintain a list available for public disclosure of biological products for which a license application has been approved.

(c) If the existence of a biological product file has not been publicly disclosed or acknowledged, no data or information in the biological product file is available for public disclosure.

(d)(1) If the existence of a biological product file has been publicly disclosed or acknowledged before a license has been issued, no data or information contained in the file is available for public disclosure before such license is issued, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IND that was required to be filed in Docket Number 95S-0158 in the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

(e) After a license has been issued, the following data and information in the biological product file are immediately available for public disclosure unless extraordinary circumstances are shown:

(1) All safety and effectiveness data and information.

(2) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial or financial information in § 20.61 of this chapter.

(3) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of:

(i) Names and any information that would identify the person using the product.

(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.

(4) A list of all active ingredients and any inactive ingredients previously disclosed to the public, as defined in § 20.81 of this chapter.

(5) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and it is shown to fall within the exemption established in § 20.61 of this chapter.

(6) All correspondence and written summaries of oral discussions relating to the biological product file, in accordance with the provisions of part 20 of this chapter.

(7) All records showing the manufacturer's testing of a particular lot, after deletion of data or information that would show the volume of the drug produced, manufacturing procedures and controls, yield from raw materials, costs, or other material falling within § 20.61 of this chapter.

(8) All records showing the testing of and action on a particular lot by the Food and Drug Administration.

(f) The following data and information in a biological product file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61 of this chapter:

(1) Manufacturing methods or processes, including quality control procedures.

(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.

(3) Quantitative or semiquantitative formulas.

(g) For purposes of this regulation, safety and effectiveness data include all studies and tests of a biological product on animals and humans and all studies and tests on the drug for identity, stability, purity, potency, and bioavailability.

[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR 13717, Mar. 24, 2004; 70 FR 14984, Mar. 24, 2005; 88 FR 45066, July 14, 2023]

§ 601.70 Annual progress reports of postmarketing studies.

Link to an amendment published at 91 FR 60004, Sept. 22, 2026.

(a) General requirements. This section applies to all required postmarketing studies (e.g., accelerated approval clinical benefit studies, pediatric studies) and postmarketing studies that an applicant has committed, in writing, to conduct either at the time of approval of an application or a supplement to an application, or after approval of an application or a supplement. Postmarketing studies within the meaning of this section are those that concern:

(1) Clinical safety;

(2) Clinical efficacy;

(3) Clinical pharmacology; and

(4) Nonclinical toxicology.

(b) What to report. Each applicant of a licensed biological product shall submit a report to FDA on the status of postmarketing studies for each approved product application. The status of these postmarketing studies shall be reported annually until FDA notifies the applicant, in writing, that the agency concurs with the applicant's determination that the study commitment has been fulfilled, or that the study is either no longer feasible or would no longer provide useful information. Each annual progress report shall be accompanied by a completed transmittal Form FDA-2252, and shall include all the information required under this section that the applicant received or otherwise obtained during the annual reporting interval which ends on the U.S. anniversary date. The report must provide the following information for each postmarketing study:

(1) Applicant's name.

(2) Product name. Include the approved product's proper name and the proprietary name, if any.

(3) Biologics license application (BLA) and supplement number.

(4) Date of U.S. approval of BLA.

(5) Date of postmarketing study commitment.

(6) Description of postmarketing study commitment. The description must include sufficient information to uniquely describe the study. This information may include the purpose of the study, the type of study, the patient population addressed by the study and the indication(s) and dosage(s) that are to be studied.

(7) Schedule for completion and reporting of the postmarketing study commitment. The schedule should include the actual or projected dates for submission of the study protocol to FDA, completion of patient accrual or initiation of an animal study, completion of the study, submission of the final study report to FDA, and any additional milestones or submissions for which projected dates were specified as part of the commitment. In addition, it should include a revised schedule, as appropriate. If the schedule has been previously revised, provide both the original schedule and the most recent, previously submitted revision.

(8) Current status of the postmarketing study commitment. The status of each postmarketing study should be categorized using one of the following terms that describes the study's status on the anniversary date of U.S. approval of the application or other agreed upon date:

(i) Pending. The study has not been initiated, but does not meet the criterion for delayed.

(ii) Ongoing. The study is proceeding according to or ahead of the original schedule described under paragraph (b)(7) of this section.

(iii) Delayed. The study is behind the original schedule described under paragraph (b)(7) of this section.

(iv) Terminated. The study was ended before completion but a final study report has not been submitted to FDA.

(v) Submitted. The study has been completed or terminated and a final study report has been submitted to FDA.

(9) Explanation of the study's status. Provide a brief description of the status of the study, including the patient accrual rate (expressed by providing the number of patients or subjects enrolled to date, and the total planned enrollment), and an explanation of the study's status identified under paragraph (b)(8) of this section. If the study has been completed, include the date the study was completed and the date the final study report was submitted to FDA, as applicable. Provide a revised schedule, as well as the reason(s) for the revision, if the schedule under paragraph (b)(7) of this section has changed since the previous report.

(c) When to report. Annual progress reports for postmarketing study commitments entered into by applicants shall be reported to FDA within 60 days of the anniversary date of the U.S. approval of the application for the product.

(d) Where to report. Submit two copies of the annual progress report of postmarketing studies to the Center for Biologics Evaluation and Research or Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter).

(e) Public disclosure of information. Except for the information described in this paragraph, FDA may publicly disclose any information concerning a postmarketing study, within the meaning of this section, if the agency determines that the information is necessary to identify an applicant or to establish the status of the study including the reasons, if any, for failure to conduct, complete, and report the study. Under this section, FDA will not publicly disclose trade secrets, as defined in § 20.61 of this chapter, or information, described in § 20.63 of this chapter, the disclosure of which would constitute an unwarranted invasion of personal privacy.

[65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

§ 601.90 Scope.

This subpart applies to certain biological products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. This subpart applies only to those biological products for which: Definitive human efficacy studies cannot be conducted because it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance; and field trials to study the product's efficacy after an accidental or hostile exposure have not been feasible. This subpart does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation for the products to which it does apply.

§ 601.91 Approval based on evidence of effectiveness from studies in animals.

(a) FDA may grant marketing approval for a biological product for which safety has been established and for which the requirements of § 601.90 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the biological product is reasonably likely to produce clinical benefit in humans. In assessing the sufficiency of animal data, the agency may take into account other data, including human data, available to the agency. FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when:

(1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;

(2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;

(3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and

(4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.

(b) Approval under this subpart will be subject to three requirements:

(1) Postmarketing studies. The applicant must conduct postmarketing studies, such as field studies, to verify and describe the biological product's clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical. Such postmarketing studies would not be feasible until an exigency arises. When such studies are feasible, the applicant must conduct such studies with due diligence. Applicants must include as part of their application a plan or approach to postmarketing study commitments in the event such studies become ethical and feasible.

(2) Approval with restrictions to ensure safe use. If FDA concludes that a biological product shown to be effective under this subpart can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to ensure safe use of the biological product, commensurate with the specific safety concerns presented by the biological product, such as:

(i) Distribution restricted to certain facilities or health care practitioners with special training or experience;

(ii) Distribution conditioned on the performance of specified medical procedures, including medical followup; and

(iii) Distribution conditioned on specified recordkeeping requirements.

(3) Information to be provided to patient recipients. For biological products or specific indications approved under this subpart, applicants must prepare, as part of their proposed labeling, labeling to be provided to patient recipients. The patient labeling must explain that, for ethical or feasibility reasons, the biological product's approval was based on efficacy studies conducted in animals alone and must give the biological product's indication(s), directions for use (dosage and administration), contraindications, a description of any reasonably foreseeable risks, adverse reactions, anticipated benefits, drug interactions, and any other relevant information required by FDA at the time of approval. The patient labeling must be available with the product to be provided to patients prior to administration or dispensing of the biological product for the use approved under this subpart, if possible.

§ 601.92 Withdrawal procedures.

(a) Reasons to withdraw approval. For biological products approved under this subpart, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:

(1) A postmarketing clinical study fails to verify clinical benefit;

(2) The applicant fails to perform the postmarketing study with due diligence;

(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;

(4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this subpart;

(5) The promotional materials are false or misleading; or

(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.

(b) Notice of opportunity for a hearing. The Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research will give the applicant notice of an opportunity for a hearing on the proposal to withdraw the approval of an application approved under this subpart. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.

(c) Submission of data and information. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.

(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register in accordance with §§ 12.32(e) and 15.20 of this chapter.

(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.

(d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.

(e) Procedures for hearings. Hearings held under this section will be conducted in accordance with the provisions of part 15 of this chapter, with the following modifications:

(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.

(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of CBER may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.

(f) Judicial review. The Commissioner of Food and Drugs' decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under § 10.35 of this chapter.

[67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005]

§ 601.93 Postmarketing safety reporting.

Biological products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.

§ 601.94 Promotional materials.

For biological products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.

§ 601.95 Termination of requirements.

If FDA determines after approval under this subpart that the requirements established in §§ 601.91(b)(2), 601.92, and 601.93 are no longer necessary for the safe and effective use of a biological product, FDA will so notify the applicant. Ordinarily, for biological products approved under § 601.91, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the biological product's clinical benefit. For biological products approved under § 601.91, the restrictions would no longer apply when FDA determines that safe use of the biological product can be ensured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30 of this chapter.

§ 606.3 Definitions.

As used in this part:

(a) Blood means a product that is a fluid containing dissolved and suspended elements which was collected from the vascular system of a human.

(b) Unit means the volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood from one donor.

(c) Blood component means a product containing a part of human blood separated by physical or mechanical means.

(d) Plasma for further manufacturing means that liquid portion of blood separated and used as material to prepare another product.

(e) Plasmapheresis means the procedure in which blood is removed from the donor, the plasma is separated from the formed elements and at least the red blood cells are returned to the donor.

(f) Plateletpheresis means the procedure in which blood is removed from a donor, a platelet concentrate is separated, and the remaining formed elements are returned to the donor along with a portion of the residual plasma.

(g) Leukapheresis means the procedure in which blood is removed from the donor, a leukocyte concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor.

(h) Facilities means any area used for the collection, processing, compatibility testing, storage or distribution of blood and blood components.

(i) Processing means any procedure employed after collection, and before or after compatibility testing of blood, and includes the identification of a unit of donor blood, the preparation of components from such unit of donor blood, serological testing, labeling and associated recordkeeping.

(j) Compatibility testing means the procedures performed to establish the matching of a donor's blood or blood components with that of a potential recipient.

(k) Distributed means:

(1) The blood or blood components have left the control of the licensed manufacturer, unlicensed registered blood establishment, or transfusion service; or

(2) The licensed manufacturer has provided Source Plasma or any other blood component for use in the manufacture of a licensed biological product.

(l) Control means having responsibility for maintaining the continued safety, purity, and potency of the product and for compliance with applicable product and establishment standards, and for compliance with current good manufacturing practices.

[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45370, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45886, Aug. 16, 2007; 80 FR 29894, May 22, 2015]

§ 606.20 Personnel.

(a) [Reserved]

(b) The personnel responsible for the collection, processing, compatibility testing, storage or distribution of blood or blood components shall be adequate in number, educational background, training and experience, including professional training as necessary, or combination thereof, to assure competent performance of their assigned functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. All personnel shall have capabilities commensurate with their assigned functions, a thorough understanding of the procedures or control operations they perform, the necessary training or experience, and adequate information concerning the application of pertinent provisions of this part to their respective functions.

(c) Persons whose presence can adversely affect the safety and purity of the products shall be excluded from areas where the collection, processing, compatibility testing, storage or distribution of blood or blood components is conducted.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]

§ 606.40 Facilities.

Facilities shall be maintained in a clean and orderly manner, and shall be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operations. The facilities shall:

(a) Provide adequate space for the following when applicable:

(1) Private and accurate examinations of individuals to determine their eligibility as blood donors.

(2) The withdrawal of blood from donors with minimal risk of contamination, or exposure to activities and equipment unrelated to blood collection.

(3) The storage of blood or blood components pending completion of tests.

(4) The quarantine storage of blood or blood components in a designated location pending repetition of those tests that initially gave questionable serological results.

(5) The storage of finished products prior to distribution.

(6) The quarantine storage, handling and disposition of products and reagents not suitable for use.

(7) The orderly collection, processing, compatibility testing, storage and distribution of blood and blood components to prevent contamination.

(8) The adequate and proper performance of all steps in plasmapheresis, plateletpheresis and leukapheresis procedures.

(9) The orderly conduction of all packaging, labeling and other finishing operations.

(b) Provide adequate lighting, ventilation and screening of open windows and doors.

(c) Provide adequate, clean, and convenient handwashing facilities for personnel, and adequate, clean, and convenient toilet facilities for donors and personnel. Drains shall be of adequate size and, where connected directly to a sewer, shall be equipped with traps to prevent back-siphonage.

(d) Provide for safe and sanitary disposal for the following:

(1) Trash and items used during the collection, processing and compatibility testing of blood and blood components.

(2) Blood and blood components not suitable for use or distribution.

[40 FR 53532, Nov. 18, 1975, as amended at 80 FR 29895, May 22, 2015]

§ 606.60 Equipment.

(a) Equipment used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be maintained in a clean and orderly manner and located so as to facilitate cleaning and maintenance. The equipment shall be observed, standardized and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual and shall perform in the manner for which it was designed so as to assure compliance with the official requirements prescribed in this chapter for blood and blood products.

(b) Equipment that shall be observed, standardized and calibrated with at least the following frequency, include but are not limited to:

Equipment | Performance check | Frequency | Frequency of calibration

Temperature recorder | Compare against thermometer | Daily | As necessary.

Refrigerated centrifuge | Observe speed and temperature | Each day of use | Do.

Hematocrit centrifuge | Standardize before initial use, after repairs or adjustments, and annually. Timer every 3 mo.

General lab centrifuge | Tachometer every 6 mo.

Automated blood-typing machine | Observe controls for correct results | Each day of use

Hemoglobinometer | Standardize against cyanmethemoglobin standard | ......do

Refractometer | Standardize against distilled water | ......do

Blood container scale | Standardize against container of known weight | ......do | As necessary.

Water bath | Observe temperature | ......do | Do.

Rh view box | ......do | ......do | Do.

Autoclave | ......do | Each time of use | Do.

Serologic rotators | Observe controls for correct results | Each day of use | Speed as necessary.

Laboratory thermometers | Before initial use.

Electronic thermometers | Monthly.

Vacuum blood agitator | Observe weight of the first container of blood filled for correct results | Each day of use | Standardize with container of known mass or volume before initial use, and after repairs or adjustments.

(c) Equipment employed in the sterilization of materials used in blood collection or for disposition of contaminated products shall be designed, maintained and utilized to ensure the destruction of contaminating microorganisms. The effectiveness of the sterilization procedure shall be no less than that achieved by an attained temperature of 121.5 °C (251 °F) maintained for 20 minutes by saturated steam or by an attained temperature of 170 °C (338 °F) maintained for 2 hours with dry heat.

[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45 FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13, 1992]

§ 606.65 Supplies and reagents.

All supplies and reagents used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be stored in a safe, sanitary and orderly manner.

(a) All surfaces coming in contact with blood and blood components intended for transfusion shall be sterile, pyrogen-free, and shall not interact with the product in such a manner as to have an adverse effect upon the safety, purity, potency or effectiveness of the product. All final containers and closures for blood and blood components not intended for transfusion shall be clean and free of surface solids and other contaminants.

(b) Each blood collecting container and its satellite container(s), if any, shall be examined visually for damage or evidence of contamination prior to its use and immediately after filling. Such examination shall include inspection for breakage of seals, when indicated, and abnormal discoloration. Where any defect is observed, the container shall not be used, or, if detected after filling, shall be properly discarded.

(c) Representative samples of each lot of the following reagents or solutions shall be tested on a regularly scheduled basis by methods described in the Standard Operating Procedures Manual to determine their capacity to perform as required:

Reagent or solution | Frequency of testing

Anti-human globulin | Each day of use.

Blood grouping reagents | Do.

Lectins | Do.

Antibody screening and reverse grouping cells | Do.

Hepatitis test reagents | Each run.

Syphilis serology reagents | Do.

Enzymes | Each day of use.

(d) Supplies and reagents that do not bear an expiration date shall be stored in such a manner that the oldest is used first.

(e) Supplies and reagents shall be used in a manner consistent with instructions provided by the manufacturer.

(f) Items that are required to be sterile and come into contact with blood should be disposable whenever possible.

[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]

§ 606.100 Standard operating procedures.

(a) In all instances, except clinical investigations, standard operating procedures shall comply with published additional standards in part 640 of this chapter for the products being processed; except that, references in part 640 relating to licenses, licensed establishments and submission of material or data to or approval by the Director, Center for Biologics Evaluation and Research, are not applicable to establishments not subject to licensure under section 351 of the Public Health Service Act.

(b) Establishments must establish, maintain, and follow written standard operating procedures for all steps in the collection, processing, compatibility testing, storage, and distribution of blood and blood components for allogeneic transfusion, autologous transfusion, and further manufacturing purposes; for all steps in the investigation of product deviations related to § 606.171; and for all steps in recordkeeping related to current good manufacturing practice and other applicable requirements and standards. Such procedures must be available to the personnel for use in the areas where the procedures are performed. The written standard operating procedures must include, but are not limited to, descriptions of the following, when applicable:

(1) Criteria used to determine donor eligibility, including acceptable medical history criteria.

(2) Methods of performing donor qualifying tests and measurements, including minimum and maximum values for a test or procedure when a factor in determining acceptability.

(3) Solutions and methods used to prepare the site of phlebotomy to give maximum assurance of a sterile container of blood.

(4) Method of accurately relating the product(s) to the donor.

(5) Blood collection procedure, including in-process precautions taken to measure accurately the quantity of blood removed from the donor.

(6) Methods of component preparation, including any time restrictions for specific steps in processing.

(7) All tests and repeat tests performed on blood and blood components during manufacturing.

(8) Pretransfusion testing, where applicable, including precautions to be taken to identify accurately the recipient blood samples and crossmatched donor units.

(9) Procedures for investigating adverse donor and recipient reactions.

(10) Storage temperatures and methods of controlling storage temperatures for all blood products and reagents as prescribed in §§ 600.15 and 610.53 of this chapter.

(11) Length of expiration dates, if any, assigned for all final products as prescribed in § 610.53 of this chapter.

(12) Criteria for determining whether returned blood is suitable for reissue.

(13) Procedures used for relating a unit of blood or blood component from the donor to its final disposition.

(14) Quality control procedures for supplies and reagents employed in blood collection, processing and pretransfusion testing.

(15) Schedules and procedures for equipment maintenance and calibration.

(16) Labeling procedures, including safeguards to avoid labeling mixups.

(17) Procedures of plasmapheresis, plateletpheresis, and leukapheresis, if performed, including precautions to be taken to ensure reinfusion of a donor's own cells.

(18) Procedures for preparing recovered plasma, if performed, including details of separation, pooling, labeling, storage, and distribution.

(19) Procedures under §§ 610.46 and 610.47 of this chapter:

(i) To identify previously donated blood and blood components from a donor who later tests reactive for evidence of human immunodeficiency virus (HIV) infection or hepatitis C virus (HCV) infection when tested under § 610.40 of this chapter, or when a blood establishment is made aware of other reliable test results or information indicating evidence of HIV or HCV infection;

(ii) To quarantine in-date blood and blood components previously donated by such a donor that are intended for use in another person or further manufacture into injectable products, except pooled components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;

(iii) To notify consignees to quarantine in-date blood and blood components previously donated by such a donor intended for use in another person or for further manufacture into injectable products, except pooled components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;

(iv) To determine the suitability for release, destruction, or relabeling of quarantined in-date blood and blood components;

(v) To notify consignees of the results of the HIV or HCV testing performed on the donors of such blood and blood components;

(vi) To notify the transfusion recipient, the recipient's physician of record, or the recipient's legal representative that the recipient received blood or blood components at increased risk of transmitting HIV or HCV, respectively.

(20) Procedures for donor deferral as prescribed in § 610.41 of this chapter.

(21) Procedures for donor notification and notification of the referring physician of an autologous donor, including procedures for the appropriate followup if the initial attempt at notification fails, as prescribed in § 630.40 of this chapter.

(22) Procedures to control the risks of bacterial contamination of platelets, including all steps required under § 606.145.

(c) All records pertinent to the lot or unit maintained pursuant to these regulations shall be reviewed before the release or distribution of a lot or unit of final product. The review or portions of the review may be performed at appropriate periods during or after blood collecting, processing, compatibility testing and storing. A thorough investigation, including the conclusions and followup, of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications shall be made and recorded.

(d) In addition to the requirements of this subpart and in conformity with this section, any facility may utilize current standard operating procedures such as the manuals of the organizations, as long as such specific procedures are consistent with, and at least as stringent as, the requirements contained in this part.

(1) American Association of Blood Banks.

(2) American National Red Cross.

(3) Other organizations or individual blood banks, subject to approval by the Director, Center for Biologics Evaluation and Research.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, Aug. 19, 1999; 66 FR 31176, June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015]

§ 606.110 Plateletpheresis, leukapheresis, and plasmapheresis.

(a) The use of plateletpheresis and leukapheresis procedures to obtain a product for a specific recipient may be at variance with the additional standards for specific products prescribed in this part provided that: (1) A physician has determined that the recipient must be transfused with the leukocytes or platelets from a specific donor, and (2) the procedure is performed under the supervision of a responsible physician who is aware of the health status of the donor, and the physician has determined and documented that the donor's health permits plateletpheresis or leukapheresis.

(b) Plasmapheresis of donors who do not meet the donor requirements of §§ 630.10, 630.15, 640.64 and 640.65 of this chapter for the collection of plasma containing rare antibodies shall be permitted only with the prior approval of the Director, Center for Biologics Evaluation and Research.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 80 FR 29895, May 22, 2015]

§ 606.120 Labeling, general requirements.

(a) Labeling operations shall be separated physically or spatially from other operations in a manner adequate to prevent mixups.

(b) The labeling operation shall include the following labeling controls:

(1) Labels shall be held upon receipt, pending review and proofing against an approved final copy, to ensure accuracy regarding identity, content, and conformity with the approved copy.

(2) Each type of label representing different products shall be stored and maintained in a manner to prevent mixups, and stocks of obsolete labels shall be destroyed.

(3) All necessary checks in labeling procedures shall be utilized to prevent errors in translating test results to container labels.

(c) All labeling shall be clear and legible.

[50 FR 35469, Aug. 30, 1985]

§ 606.121 Container label.

(a) The container label requirements are designed to facilitate the use of a uniform container label for blood and blood components intended for use in transfusion or further manufacture by all blood establishments.

(b) The label provided by the collecting facility and the initial processing facility must not be removed, altered, or obscured, except that the label may be altered to indicate the proper name of the product, with any appropriate modifiers and attributes, and other information required to identify accurately the contents of a container after blood components considered finished products have been prepared.

(c) The container label must include the following information, as well as other specialized information as required in this section for specific products:

(1) The proper name of the product in a prominent position, with any appropriate modifiers and attributes.

(2) The name, address, unique facility identifier, and, if a licensed product, the license number of each manufacturer; except the container label for blood and blood components for further manufacture is not required to include a unique facility identifier.

(3) The donor or lot number relating the unit to the donor. If pooled, all donor numbers, all donation numbers, or a pool number that is traceable to each individual unit comprising the pool.

(4)(i) The expiration date, including the day, month, and year, and, if the dating period for the product is 72 hours or less, including any product prepared in a system that might compromise sterility, the hour of expiration.

(ii) If Source Plasma intended for manufacturing into noninjectable products is pooled, the expiration date for the pool is determined from the collection date of the oldest unit in the pool, and the pooling records must show the collection date for each unit in the pool.

(5) For Whole Blood, Plasma, Platelets, and partial units of Red Blood Cells, the volume of the product, accurate to within ±10 percent; or optionally for Platelets, the volume or volume range within reasonable limits.

(6) Where applicable, the name and volume of source material.

(7) The recommended storage temperature (in degrees Celsius).

(8) If the product is intended for transfusion, the statements:

(i) “Rx only.”

(ii) “See circular of information for indications, contraindications, cautions, and methods of infusion.”

(iii) “Properly identify intended recipient.”

(iv) “This product may transmit infectious agents.”

(v) The appropriate donor classification statement, i.e., “paid donor” or “volunteer donor,” in no less prominence than the proper name of the product.

(A) A paid donor is a person who receives monetary payment for a blood donation.

(B) A volunteer donor is a person who does not receive monetary payment for a blood donation.

(C) Benefits, such as time off from work, membership in blood assurance programs, and cancellation of nonreplacement fees that are not readily convertible to cash, do not constitute monetary payment within the meaning of this paragraph.

(9) If the product is intended for transfusion or as is otherwise appropriate, the ABO group and Rh type of the donor must be designated conspicuously. For Cryoprecipitated Antihemophiliac Factor (AHF), the Rh type may be omitted. The Rh type must be designated as follows:

(i) If the test using Anti-D Blood Grouping Reagent is positive, the product must be labeled: “Rh positive.”

(ii) If the test using Anti-D Blood Grouping Reagent is negative, but the test for weak D (formerly Du) is positive, the product must be labeled: “Rh positive.”

(iii) If the test using Anti-D Blood Grouping Reagent is negative and the test for weak D (formerly Du) is negative, the product must be labeled: “Rh negative.”

(10) If the product is not intended for transfusion, a statement as applicable: “Caution: For Manufacturing Use Only,” or “Caution: For Use in Manufacturing Noninjectable Products Only,” or other cautionary statement as approved by the Director, Center for Biologics Evaluation and Research (CBER).

(11) If the product is intended for further manufacturing use, a statement listing the results of all the tests for relevant transfusion-transmitted infections required under § 610.40 of this chapter for which the donation has been tested and found negative; except that the container label for Source Plasma is not required to list the negative results of serological syphilis testing under § 640.65(b) of this chapter.

(12) The blood and blood components must be labeled in accordance with § 610.40 of this chapter, when the donation is tested and demonstrates evidence of infection due to a relevant transfusion-transmitted infection(s).

(13) The container label of blood or blood components intended for transfusion must bear encoded information in a format that is machine-readable and approved for use by the Director, CBER.

(i) Who is subject to this machine-readable requirement? All blood establishments that manufacture, process, repack, or relabel blood or blood components intended for transfusion and regulated under the Federal Food, Drug, and Cosmetic Act or the Public Health Service Act.

(ii) What blood products are subject to this machine-readable requirement? All blood and blood components intended for transfusion are subject to the machine-readable information label requirement in this section.

(iii) What information must be machine-readable? Each label must have machine-readable information that contains, at a minimum:

(A) A unique facility identifier;

(B) Lot number relating to the donor;

(C) Product code; and

(D) ABO and Rh of the donor, except as described in paragraphs (c)(9) and (i)(5) of this section.

(iv) How must the machine-readable information appear? The machine-readable information must:

(A) Be unique to the blood or blood component;

(B) Be surrounded by sufficient blank space so that the machine-readable information can be scanned correctly; and

(C) Remain intact under normal conditions of use.

(v) Where does the machine-readable information go? The machine-readable information must appear on the label of any blood or blood component which is or can be transfused to a patient or from which the blood or blood component can be taken and transfused to a patient.

(d) Unless otherwise approved by the Director, CBER, the container label for blood and blood components intended for transfusion must be white and print must be solid black, with the following additional exceptions:

(1) The ABO and Rh blood groups must be printed as follows:

(i) Rh positive: Use black print on white background and use solid black or other solid color for ABO.

(ii) Rh negative: Use white print on black background for Rh and use black outline on a white background for ABO.

(2) The proper name of the product, with any appropriate modifiers and attributes, the donor classification statement, and the statement “properly identify intended recipient” may be printed in solid red or in solid black.

(3) The following color scheme may be used for differentiating ABO Blood groups:

Blood group | Color of label

O | Blue

A | Yellow

B | Pink

AB | White

(4) Special labels, such as those described in paragraphs (h) and (i) of this section, may be color-coded.

(e) Container label requirements for particular products or groups of products.

(1) Whole Blood labels must include:

(i) The name of the applicable anticoagulant approved for use by the Director, CBER.

(ii) The volume of anticoagulant.

(iii) If tests for unexpected antibodies are positive, blood intended for transfusion must be labeled: “Contains (name of antibody).”

(2) Except for frozen, deglycerolized, or washed Red Blood Cell products, Red Blood Cell labels must include:

(i) The type of anticoagulant, and if applicable, the volume of Whole Blood and type of additive solution, with which the product was prepared.

(ii) If tests for unexpected antibodies are positive and the product is intended for transfusion, the statement: “Contains (name of antibody).”

(3) If tests for unexpected antibodies are positive, Plasma intended for transfusion must be labeled: “Contains (name of antibody).”

(4) Recovered plasma labels must include:

(i) In lieu of an expiration date, the date of collection of the oldest material in the container.

(ii) For recovered plasma not meeting the requirements for manufacture into licensable products, the statement: “Not for Use in Products Subject to License Under Section 351 of the Public Health Service Act.”

(iii) The type of anticoagulant with which the product was prepared.

(5) Source Plasma labels must include the following information:

(i) The cautionary statement, as specified in paragraph (c)(10) of this section, must follow the proper name with any appropriate modifiers and attributes and be of similar prominence as the proper name.

(ii) The statement “Store at −20 °C or colder,” provided, that where plasma is intended for manufacturing into noninjectable products, this statement may be replaced by a statement of the temperature appropriate for manufacture of the final product to be prepared from the plasma.

(iii) The total volume or weight of plasma and total quantity and type of anticoagulant used.

(iv) When plasma collected from a donor is reactive for a serologic test for syphilis, a statement that the plasma is reactive and must be used only for the manufacturing of positive control reagents for the serologic test for syphilis.

(v) Source Plasma diverted for Source Plasma Salvaged must be relabeled “Source Plasma Salvaged” as prescribed in § 640.76 of this chapter. Immediately following the proper name of the product, with any appropriate modifiers and attributes, the labeling must prominently state as applicable, “STORAGE TEMPERATURE EXCEEDED −20 °C” or “SHIPPING TEMPERATURE EXCEEDED −5 °C.”

(vi) A statement as to whether the plasma was collected from normal donors, or from donors in specific collection programs approved by the Director, CBER. In the case of specific collection programs, the label must state the defining characteristics of the plasma. In the case of immunized donors, the label must state the immunizing antigen.

(f) Blood and blood components determined to be unsuitable for transfusion must be prominently labeled “NOT FOR TRANSFUSION,” and the label must state the reason the unit is considered unsuitable. The provision does not apply to blood and blood components intended solely for further manufacture.

(g) [Reserved]

(h) The following additional information must appear on the label for blood and blood components shipped in an emergency prior to completion of required tests, in accordance with § 610.40(g) of this chapter:

(1) The statement: “FOR EMERGENCY USE ONLY BY __ .”

(2) Results of any tests prescribed under §§ 610.40 and 640.5(b) or (c) of this chapter completed before shipment.

(3) Indication of any tests prescribed under §§ 610.40 and 640.5(b) or (c) of this chapter not completed before shipment.

(i) The following additional information must appear on the label for blood and blood components intended for autologous transfusion:

(1) Information adequately identifying the patient, e.g., name, date of birth, hospital, and identification number.

(2) Date of donation.

(3) The statement: “AUTOLOGOUS DONOR.”

(4) The ABO and Rh blood group and type, except as provided in paragraph (c)(9) of this section.

(5) Each container of blood and blood component intended for autologous use and obtained from a donor who fails to meet any of the donor eligibility requirements under § 630.10 of this chapter or who is reactive to or positive for one or more tests for evidence of infection due to relevant transfusion-transmitted infections under § 610.40 of this chapter must be prominently and permanently labeled “FOR AUTOLOGOUS USE ONLY” and as otherwise required under § 610.40 of this chapter. Such units also may have the ABO and Rh blood group and type on the label.

(6) Units of blood and blood components originally intended for autologous use, except those labeled as prescribed under paragraph (i)(5) of this section, may be issued for allogeneic transfusion provided the container label complies with all applicable provisions of paragraphs (b) through (e) of this section. In such case, the special label required under paragraphs (i)(1), (i)(2), and (i)(3) of this section must be removed or otherwise obscured.

(j) A tie-tag attached to the container may be used for providing the information required by paragraphs (e)(1)(iii), (e)(2)(ii), and (e)(3), (h), or (i)(1), (i)(2), and (i)(3) of this section.

[77 FR 16, Jan. 3, 2012, as amended at 80 FR 29895, May 22, 2015]

§ 606.122 Circular of information.

A circular of information must be available for distribution if the product is intended for transfusion. The circular of information must provide adequate directions for use, including the following information:

(a) Instructions to mix the product before use.

(b) Instructions to use a filter in the administration equipment.

(c) The statement “Do Not Add Medications” or an explanation concerning allowable additives.

(d) A description of the product, its source, and preparation, including the name and proportion of the anticoagulant used in collecting the Whole Blood from each product is prepared.

(e) A statement that the product was prepared from blood that was found negative when tested for relevant transfusion-transmitted infections, as required under § 610.40 of this chapter (include each test that was performed).

(f) The statement: “Warning: The risk of transmitting infectious agents is present. Careful donor selection and available laboratory tests do not eliminate the hazard.”

(g) The names of cryoprotective agents and other additives that may still be present in the product.

(h) The names and results of all tests performed when necessary for safe and effective use.

(i) The use of the product, indications, contradications, side effects and hazards, dosage and administration recommendations.

(j) [Reserved]

(k) For Red Blood Cells, the circular of information must contain:

(1) Instructions to administer a suitable plasma volume expander if Red Blood Cells are substituted when Whole Blood is the indicated product.

(2) A warning not to add Lactated Ringer's Injection U.S.P. solution to Red Blood Cell products.

(l) For Platelets, the circular of information must contain:

(1) The approximate volume of plasma from which a sample unit of Platelets is prepared.

(2) Instructions to begin administration as soon as possible, but not more than 4 hours after entering the container.

(m) For Plasma, the circular of information must contain:

(1) A warning against further processing of the frozen product if there is evidence of breakage or thawing.

(2) Instructions to thaw the frozen product at a temperature appropriate for the product.

(3) When applicable, instructions to begin administration of the product within a specified time after thawing.

(4) Instructions to administer to ABO-group-compatible recipients.

(5) A statement that this product has the same risk of transmitting infectious agents as Whole Blood; other plasma volume expanders without this risk are available for treating hypovolemia.

(n) For Cryoprecipitated AHF, the circular of information must contain:

(1) A statement that the average potency is 80 or more International Units of antihemophilic factor.

(2) The statement: “Usually contains at least 150 milligrams of fibrinogen”; or, alternatively, the average fibrinogen level determined by assay of representative units.

(3) A warning against further processing of the product if there is evidence of breakage or thawing.

(4) Instructions to thaw the product for no more than 15 minutes at a temperature of between 30 and 37 °C.

(5) Instructions to store at room temperature after thawing and to begin administration as soon as possible but no more than 4 hours after entering the container or after pooling and within 6 hours after thawing.

(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is the preferred diluent.

(7) Adequate instructions for pooling to ensure complete removal of all concentrated material from each container.

(8) The statement: “Good patient management requires monitoring treatment responses to Cryoprecipitated AHF transfusions with periodic plasma factor VIII or fibrinogen assays in hemophilia A and hypofibrinogenemic recipients, respectively.”

[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 64 FR 45371, Aug. 19, 1999; 77 FR 18, Jan. 3, 2012; 80 FR 29895, May 22, 2015]

§ 606.140 Laboratory controls.

Laboratory control procedures shall include:

(a) The establishment of scientifically sound and appropriate specifications, standards and test procedures to assure that blood and blood components are safe, pure, potent and effective.

(b) Adequate provisions for monitoring the reliability, accuracy, precision and performance of laboratory test procedures and instruments.

(c) Adequate identification and handling of all test samples so that they are accurately related to the specific unit of product being tested, or to its donor, or to the specific recipient, where applicable.

§ 606.145 Control of bacterial contamination of platelets.

(a) Blood collection establishments and transfusion services must assure that the risk of bacterial contamination of platelets is adequately controlled using FDA approved or cleared devices or other adequate and appropriate methods found acceptable for this purpose by FDA.

(b) In the event that a blood collection establishment identifies platelets as bacterially contaminated, that establishment must not release for transfusion the product or any other component prepared from the same collection, and must take appropriate steps to identify the organism.

(c) In the event that a transfusion service identifies platelets as bacterially contaminated, the transfusion service must not release the product and must notify the blood collection establishment that provided the platelets. The transfusion service must take appropriate steps to identify the organism; these steps may include contracting with the collection establishment or a laboratory to identify the organism. The transfusion service must further notify the blood collection establishment either by providing information about the species of the contaminating organism when the transfusion service has been able to identify it, or by advising the blood collection establishment when the transfusion service has determined that the species cannot be identified.

(d) In the event that a contaminating organism is identified under paragraph (b) or (c) of this section, the collection establishment's responsible physician, as defined in § 630.3(i) of this chapter, must determine whether the contaminating organism is likely to be associated with a bacterial infection that is endogenous to the bloodstream of the donor, in accordance with a standard operating procedure developed under § 606.100(b)(22). This determination may not be further delegated.

[80 FR 29895, May 22, 2015]

§ 606.151 Compatibility testing.

Standard operating procedures for compatibility testing shall include the following:

(a) A method of collecting and identifying the blood samples of recipients to ensure positive identification.

(b) The use of fresh recipient serum or plasma samples less than 3 days old for all pretransfusion testing if the recipient has been pregnant or transfused within the previous 3 months.

(c) Procedures to demonstrate incompatibility between the donor's cell type and the recipient's serum or plasma type.

(d) A provision that, if the unit of donor's blood has not been screened by a method that will demonstrate agglutinating, coating and hemolytic antibodies, the recipient's cells shall be tested with the donor's serum (minor crossmatch) by a method that will so demonstrate.

(e) Procedures to expedite transfusion in life-threatening emergencies. Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by a physician.

[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45371, Aug. 19, 1999; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001]

§ 606.160 Records.

(a)(1) Records shall be maintained concurrently with the performance of each significant step in the collection, processing, compatibility testing, storage and distribution of each unit of blood and blood components so that all steps can be clearly traced. All records shall be legible and indelible, and shall identify the person performing the work, include dates of the various entries, show test results as well as the interpretation of the results, show the expiration date assigned to specific products, and be as detailed as necessary to provide a complete history of the work performed.

(2) Appropriate records shall be available from which to determine lot numbers of supplies and reagents used for specific lots or units of the final product.

(b) Records shall be maintained that include, but are not limited to, the following when applicable:

(1) Donor records:

(i) Donor selection, including medical interview and examination and where applicable, informed consent.

(ii) Permanent and temporary deferrals for health reasons including reason(s) for deferral.

(iii) Donor adverse reaction complaints and reports, including results of all investigations and followup.

(iv) Therapeutic bleedings, including signed requests from attending physicians, the donor's disease and disposition of units.

(v) Immunization, including informed consent, identification of the antigen, dosage and route of administration.

(vi) Blood collection, including identification of the phlebotomist.

(vii) Records to relate the donor with the unit number of each previous donation from that donor.

(viii) Records concerning the following activities performed under §§ 610.46 and 610.47 of this chapter: Quarantine; consignee notification; testing; notification of a transfusion recipient, the recipient's physician of record, or the recipient's legal representative; and disposition.

(ix) The donor's postal address provided at the time of donation where the donor may be contacted within 8 weeks after donation.

(x) Records of notification of donors deferred or determined not to be eligible for donation, including appropriate followup if the initial attempt at notification fails, performed under § 630.40 of this chapter.

(xi) Records of notification of the referring physician of a deferred autologous donor, including appropriate followup if the initial attempt at notification fails, performed under § 630.40 of this chapter.

(2) Processing records:

(i) Blood processing, including results and interpretation of all tests and retests.

(ii) Component preparation, including all relevant dates and times.

(iii) Separation and pooling of recovered plasma.

(iv) Centrifugation and pooling of source plasma.

(v) Labeling, including initials of the person(s) performing the procedure.

(3) Storage and distribution records:

(i) Distribution and disposition, as appropriate, of blood and blood products.

(ii) Visual inspection of whole blood and red blood cells during storage and immediately before distribution.

(iii) Storage temperature, including initialed temperature recorder charts.

(iv) Reissue, including records of proper temperature maintenance.

(v) Emergency release of blood, including signature of requesting physician obtained before or after release.

(4) Compatibility test records:

(i) Results of all compatibility tests, including crossmatching, testing of patient samples, antibody screening and identification.

(ii) Results of confirmatory testing.

(5) Quality control records:

(i) Calibration and standardization of equipment.

(ii) Performance checks of equipment and reagents.

(iii) Periodic check on sterile technique.

(iv) Periodic tests of capacity of shipping containers to maintain proper temperature in transit.

(v) Proficiency test results.

(6) Transfusion reaction reports and complaints, including records of investigations and followup.

(7) General records:

(i) Sterilization of supplies and reagents prepared within the facility, including date, time interval, temperature and mode.

(ii) Responsible personnel.

(iii) Biological product deviations.

(iv) Maintenance records for equipment and general physical plant.

(v) Supplies and reagents, including name of manufacturer or supplier, lot numbers, expiration date and date of receipt.

(vi) Disposition of rejected supplies and reagents used in the collection, processing and compatibility testing of blood and blood components.

(c) A donor number shall be assigned to each accepted donor, which relates the unit of blood collected to that donor, to his medical record, to any component or blood product from that donor's unit of blood, and to all records describing the history and ultimate disposition of these products.

(d) Records shall be retained for such interval beyond the expiration date for the blood or blood component as necessary to facilitate the reporting of any unfavorable clinical reactions. You must retain individual product records no less than 10 years after the records of processing are completed or 6 months after the latest expiration date for the individual product, whichever is the later date. When there is no expiration date, records shall be retained indefinitely.

(e) Records of deferred donors. (1) Establishments must maintain at each location a record of all donors found to be ineligible or deferred at that location so that blood and blood components from an ineligible donor are not collected and/or released while the donor is ineligible or deferred; and

(2) Establishments must maintain at all locations operating under the same license or under common management a cumulative record of donors deferred from donation under § 610.41 of this chapter because their donation tested reactive under § 610.40(a)(1) of this chapter for evidence of infection due to HIV, HBV, or HCV. In addition, establishments other than Source Plasma establishments must include in this cumulative record donors deferred from donation under § 610.41 of this chapter because their donation tested reactive under § 610.40(a)(2) of this chapter for evidence of infection due to HTLV or Chagas disease.

(3) The cumulative record described in paragraph (e)(2) of this section must be updated at least monthly to add donors newly deferred under § 610.41 of this chapter due to reactive tests for evidence of infection due to HIV, HBV, or HCV, and, if applicable, HTLV or Chagas disease.

(4) Establishments must revise the cumulative record described in paragraph (e)(2) of this section to remove donors who have been requalified under § 610.41(b) of this chapter.

[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996; 64 FR 45371, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015]

§ 606.165 Distribution and receipt; procedures and records.

(a) Distribution and receipt procedures shall include a system by which the distribution or receipt of each unit can be readily determined to facilitate its recall, if necessary.

(b) Distribution records shall contain information to readily facilitate the identification of the name and address of the consignee, the date and quantity delivered, the lot number of the unit(s), the date of expiration or the date of collection, whichever is applicable, or for crossmatched blood and blood components, the name of the recipient.

(c) Receipt records shall contain the name and address of the collecting facility, date received, donor or lot number assigned by the collecting facility and the date of expiration or the date of collection, whichever is applicable.

§ 606.170 Adverse reaction file.

(a) Records shall be maintained of any reports of complaints of adverse reactions regarding each unit of blood or blood product arising as a result of blood collection or transfusion. A thorough investigation of each reported adverse reaction shall be made. A written report of the investigation of adverse reactions, including conclusions and followup, shall be prepared and maintained as part of the record for that lot or unit of final product by the collecting or transfusing facility. When it is determined that the product was at fault in causing a transfusion reaction, copies of all such written reports shall be forwarded to and maintained by the manufacturer or collecting facility.

(b) When a complication of blood collection or transfusion is confirmed to be fatal, the Director, Office of Compliance and Biologics Quality, CBER, must be notified by telephone, facsimile, express mail, or electronically transmitted mail as soon as possible. A written report of the investigation must be submitted to the Director, Office of Compliance and Biologics Quality, CBER, by mail, facsimile, or electronically transmitted mail (for mailing address, see § 600.2(a) of this chapter), within 7 days after the fatality by the collecting facility in the event of a donor reaction, or by the facility that performed the compatibility tests in the event of a transfusion reaction.

[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50 FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, Aug. 19, 1999; 67 FR 9586, Mar. 4, 2002; 77 FR 18, Jan. 3, 2012; 80 FR 18092, Apr. 3, 2015]

§ 606.171 Reporting of product deviations by licensed manufacturers, unlicensed registered blood establishments, and transfusion services.

(a) Who must report under this section? You, a licensed manufacturer of blood and blood components, including Source Plasma; an unlicensed registered blood establishment; or a transfusion service who had control over the product when the deviation occurred, must report under this section. If you arrange for another person to perform a manufacturing, holding, or distribution step, while the product is in your control, that step is performed under your control. You must establish, maintain, and follow a procedure for receiving information from that person on all deviations, complaints, and adverse events concerning the affected product.

(b) What do I report under this section? You must report any event, and information relevant to the event, associated with the manufacturing, to include testing, processing, packing, labeling, or storage, or with the holding or distribution, of both licensed and unlicensed blood or blood components, including Source Plasma, if that event meets all the following criteria:

(1) Either:

(i) Represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product; or

(ii) Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and

(2) Occurs in your facility or another facility under contract with you; and

(3) Involves distributed blood or blood components.

(c) When do I report under this section? You should report a biological product deviation as soon as possible but you must report at a date not to exceed 45-calendar days from the date you, your agent, or another person who performs a manufacturing, holding, or distribution step under your control, acquire information reasonably suggesting that a reportable event has occurred.

(d) How do I report under this section? You must report on Form FDA-3486.

(e) Where do I report under this section? You must send the completed Form FDA 3486 to the Center for Biologics Evaluation and Research (CBER), either in paper or electronic format.

(1) If you make a paper filing, send the completed form to the CBER Document Control Center (see mailing address in § 600.2(a) of this chapter), and identify on the envelope that a BPDR (biological product deviation report) is enclosed; or

(2) If you make an electronic filing, send the completed Form FDA3486 electronically using CBER's electronic Web-based application.

(f) How does this regulation affect other FDA regulations? This part supplements and does not supersede other provisions of the regulations in this chapter. All biological product deviations, whether or not they are required to be reported under this section, should be investigated in accordance with the applicable provisions of parts 211, 606, and 820 of this chapter.

[65 FR 66635, Nov. 7, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

§ 607.1 Scope.

(a) This part establishes establishment registration and product listing requirements for manufacturers of human blood and blood products.

(b) This part establishes establishment registration and product listing requirements for manufacturers of products that meet the definition of a device under the Federal Food, Drug, and Cosmetic Act and that are licensed under section 351 of the Public Health Service Act, as well as licensed biological products used in the manufacture of a licensed device.

[81 FR 60221, Aug. 31, 2016]

§ 607.3 Definitions.

(a) The term act means the Federal Food, Drug, and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 301-392).

(b) Blood and blood product means a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma, or serum, hereinafter referred to as “blood product.” For the purposes of this part only, blood and blood product also means those products that meet the definition of a device under the Federal Food, Drug, and Cosmetic Act and that are licensed under section 351 of the Public Health Service Act, as well as licensed biological products used in the manufacture of a licensed device.

(c) Establishment means a place of business under one management at one general physical location. The term includes, among others, human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers and independent laboratories that engage in quality control and testing for registered blood product establishments.

(d) Manufacture means the collection, preparation, processing or compatibility testing by chemical, physical, biological, or other procedures of any blood product which meets the definition of a drug as defined in section 201(g) of the act, and including manipulation, sampling, testing, or control procedures applied to the final product or to any part of the process. The term includes packaging, labeling, repackaging or otherwise changing the container, wrapper, or labeling of any blood product package in furtherance of the distribution of the blood product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.

(e) Commercial distribution means any distribution of a blood product except under the investigational use provisions of part 312 of this chapter, but does not include internal or interplant transfer of a bulk product substance between registered establishments within the same parent, subsidiary, and/or affiliate company. For foreign establishments, the term “commercial distribution” shall have the same meaning except that the term shall not include distribution of any blood or blood product that is neither imported nor offered for import into the United States.

(f) Any material change includes but is not limited to any change in the name of the blood product, in the quantity or identity of the active ingredient(s) or in the quantity or identity of the inactive ingredient(s) where quantitative listing of all ingredients is required pursuant to § 607.31(a)(2) and any significant change in the labeling of a blood product. Changes that are not significant include changes in arrangement or printing or changes of an editorial nature.

(g) Bulk product substance means any substance that is represented for use in a blood product and when used in the manufacturing of a blood product becomes an active ingredient or a finished dosage form of such product.

(h) Advertising and labeling include the promotional material described in § 202.1(l) (1) and (2) of this chapter, respectively.

(i) The definitions and interpretations contained in sections 201 and 510 of the act shall be applicable to such terms when used in this part 607.

(j) United States agent means a person residing or maintaining a place of business in the United States whom a foreign establishment designates as its agent. This definition excludes mailboxes, answering machines or services, or other places where an individual acting as the foreign establishment's agent is not physically present.

(k) Importer means a person in the United States that is an owner, consignee, or recipient, at the time of entry, of a foreign establishment's blood product that is imported into the United States.

(l) Foreign for the purpose of registration and listing under this part when used to modify the term “establishment” refers to an establishment that is located in a foreign country and is the site where a blood product that is imported or offered for import into the United States was manufactured.

[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990; 66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]

§ 607.7 Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.

All owners or operators of establishments that engage in the manufacturing of blood products are required to register, pursuant to section 510 of the Federal Food, Drug, and Cosmetic Act. Registration and listing of blood products must comply with this part. Registration does not permit any blood bank or similar establishment to ship blood products in interstate commerce.

[81 FR 60222, Aug. 31, 2016]

§ 607.20 Who must register and submit a blood product list.

(a) Owners or operators of all establishments, not exempt under section 510(g) of the act or subpart D of this part, that engage in the manufacture of blood products shall register and submit a list of every blood product in commercial distribution (except that registration and listing information may be submitted by the parent, subsidiary, and/or affiliate company for all establishments when operations are conducted at more than one establishment and there exists joint ownership and control among all the establishments). Blood products manufactured, prepared, propagated, compounded, or processed in any State as defined in section 201(a)(1) of the act must be listed whether or not the output of such blood product establishment or any particular blood product so listed enters interstate commerce.

(b) Preparatory to engaging in the manufacture of blood products, owners or operators of establishments who are submitting a biologics license application to manufacture blood products are required to register before the biologics license application is approved.

(c) Except in the case of licensed device manufacturers, no registration fee is required. Establishment registration and blood product listing do not constitute an admission or agreement or determination that a blood product is a “drug” within the meaning of section 201(g) of the act.

[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56452, Oct. 20, 1999; 66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]

§ 607.21 Times for establishment registration and blood product listing.

The owner or operator of an establishment entering into an operation defined in § 607.3(d) shall register such establishment within 5 days after the beginning of such operation and submit a list of every blood product in commercial distribution at the time. If the owner or operator of the establishment has not previously entered into such operation (defined in § 607.3(d) of this chapter) for which a license is required, registration shall follow within 5 days after the submission of a biologics license application in order to manufacture blood products. Owners or operators of all establishments so engaged must register annually between October 1 and December 31 and must update their blood product listing every June and December.

[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56453, Oct. 20, 1999; 81 FR 60222, Aug. 31, 2016]

§ 607.22 How to register establishments and list blood products.

(a) Initial and subsequent registrations and product listings must be submitted electronically through the Blood Establishment Registration and Product Listing system, or any future superseding electronic system. This information must be submitted in accordance with part 11 of this chapter, except for the requirements in § 11.10(b), (c), and (e), and the corresponding requirements in § 11.30. All information submitted under this part must be transmitted to FDA electronically unless FDA has granted a request for waiver of this requirement prior to the date on which the information is due. Submission of a request for waiver does not excuse timely compliance with the registration and listing requirements. FDA will grant a waiver request if FDA determines that the use of electronic means for submission of registration and listing information is not reasonable for the registrant making the waiver request.

(b) Waiver requests under this section must be submitted in writing and must include the specific reasons why electronic submission is not reasonable for the registrant and a U.S. telephone number and mailing address where FDA can contact the registrant. All waiver requests must be sent to the Director of FDA's Center for Biologics Evaluation and Research through the Document Control Center (see addresses in § 600.2).

(c) If FDA grants the waiver request, FDA may limit its duration and will specify terms of the waiver and provide information on how to submit establishment registration, drug listings, other information, and updates, as applicable.

[81 FR 60222, Aug. 31, 2016]

§ 607.25 Information required for establishment registration and blood product listing.

(a) The Blood Establishment Registration and Product Listing system requires furnishing or confirming registration information required by the Federal Food, Drug, and Cosmetic Act. This information includes the name and street address of the establishment, including post office code; a registration number if previously assigned by FDA and a Unique Facility Identifier in accordance with the system specified under section 510 of the Federal Food, Drug, and Cosmetic Act; all trade names used by the establishment; the kind of ownership or operation (that is, individually owned partnership, or corporation); and the name of the owner or operator of such establishment. The term “name of the owner or operator” must include, in the case of a partnership, the name of each partner and, in the case of a corporation, the name and title of each corporate officer and director and the name of the State of incorporation. The information required must be given separately for each establishment, as defined in § 607.3(c).

(b) The following information must also be provided:

(1) A list of blood products by established name as defined in section 502(e) of the Federal Food, Drug, and Cosmetic Act and by proprietary name, if any, which are being manufactured for commercial distribution at the identified establishment and which have not been included in any list previously submitted to FDA through the Blood Establishment Registration and Product Listing system or any future superseding electronic system.

(2) For each blood product so listed that is subject to section 351 of the Public Health Service Act, the license number of the manufacturer issued by the Center for Biologics Evaluation and Research, Food and Drug Administration.

(3) For each blood product listed, the registration number if previously assigned by FDA and the Unique Facility Identifier of the parent establishment. An establishment not owned, operated, or controlled by another firm or establishment is its own parent establishment.

[81 FR 60222, Aug. 31, 2016]

§ 607.26 Amendments to establishment registration.

Changes in individual ownership, corporate or partnership structure, location, or blood product handling activity must be submitted electronically through the Blood Establishment Registration and Product Listing system, or any future superseding electronic system, as an amendment to registration within 5 calendar days of such changes. Changes in the names of officers and directors of the corporations do not require such amendment but must be shown at time of annual registration.

[40 FR 52788, Nov. 12, 1975, as amended at 66 FR 59158, Nov. 27, 2001; 81 FR 60222, Aug. 31, 2016]

§ 607.30 Updating blood product listing information.

(a) After submission of the initial blood product listing information, every person who is required to list blood products under § 607.20 must submit electronically through the Blood Establishment Registration and Product Listing system, or any future superseding electronic system, at a minimum once in June and December of every year, the following information:

(1) A list of each blood product introduced by the registrant for commercial distribution which has not been included in any list previously submitted. All of the information required by § 607.25(b) shall be provided for each such blood product.

(2) A list of each blood product formerly listed pursuant to § 607.25(b) for which commercial distribution has been discontinued, including for each blood product so listed the identity by established name and proprietary name, and date of discontinuance. It is requested but not required that the reason for discontinuance of distribution be included with this information.

(3) A list of each blood product for which a notice of discontinuance was submitted pursuant to paragraph (a)(2) of this section and for which commercial distribution has been resumed, including for each blood product so listed the identity by established name as defined in section 502(e) of the act and by any proprietary name, the date of resumption, and any other information required by § 607.25(b) not previously submitted.

(4) Any material change in any information previously submitted.

(b) When no changes have occurred since the previously submitted list, no listing information is required.

[40 FR 52788, Nov. 12, 1975, as amended at 81 FR 60222, Aug. 31, 2016]

§ 607.31 Additional blood product listing information.

(a) In addition to the information routinely required by §§ 607.25 and 607.30, the Director of the Center for Biologics Evaluation and Research may require submission of the following information by letter or by Federal Register notice:

(1) For a particular blood product so listed, upon request made by the Director of the Center for Biologics Evaluation and Research for good cause, a copy of all advertisements.

(2) For a particular blood product so listed, upon a finding by the Director of the Center for Biologics Evaluation and Research that it is necessary to carry out the purposes of the act, a quantitative listing of all ingredients.

(3) For each registrant, upon a finding by the Director of the Center for Biologics Evaluation and Research that it is necessary to carry out the purposes of the act, a list of each listed blood product containing a particular ingredient.

(b) [Reserved]

[66 FR 59158, Nov. 27, 2001]

§ 607.35 Blood product establishment registration number.

An establishment registration number will be assigned to each blood product establishment registered in accordance with this part.

[81 FR 60223, Aug. 31, 2016]

§ 607.37 Public disclosure of establishment registration and blood product listing information.

(a) Except as provided in paragraph (b) of this section, all registration and listing information obtained under §§ 607.25, 607.26, and 607.30 will be made available for public disclosure through the Center for Biologics Evaluation and Research (CBER) Blood Establishment Registration Database Web site by using the CBER electronic Web-based application or by going in person to the Food and Drug Administration, Division of Freedom of Information Public Reading Room (see addresses in § 20.120(a) of this chapter).

(b) FDA may find, in limited circumstances and on a case-by-case basis, that it would be consistent with the protection of the public health to exempt from public disclosure specific listing information obtained under § 607.25 or § 607.30.

(c) Other requests for information regarding blood establishment registrations and blood product listings should be directed to the Food and Drug Administration, Center for Biologics Evaluation and Research Office of Communication, Outreach, and Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.

[81 FR 60223, Aug. 31, 2016]

§ 607.39 Misbranding by reference to establishment registration, validation of registration, or to registration number.

Registration of an establishment, validation of registration, or assignment of a registration number does not in any way denote approval of the firm or its products nor does it mean that the products may be legally marketed. Any representation that creates an impression of official approval because of establishment registration, validation of registration, or possession of a registration number is misleading and constitutes misbranding.

[81 FR 60223, Aug. 31, 2016]

§ 607.40 Establishment registration and blood product listing requirements for foreign blood product establishments.

(a) Every foreign establishment shall comply with the establishment registration and blood product listing requirements contained in subpart B of this part, unless exempt under subpart D of this part or unless the blood product enters a foreign trade zone and is re-exported from that foreign trade zone without having entered U. S. commerce.

(b) No blood product may be imported or offered for import into the United States unless it is the subject of a blood product listing as required under subpart B of this part and is manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment; however, this restriction does not apply to a blood product imported or offered for import under the investigational use provisions of part 312 of this chapter or to a blood product imported under section 801(d)(4) of the act. The establishment registration and blood product listing information shall be in the English language.

(c) Each foreign establishment required to register under paragraph (a) of this section shall, as part of the establishment registration and blood product listing, submit the name and address of the establishment and the name of the individual responsible for submitting establishment registration and blood product listing information. Any changes in this information shall be reported to the Food and Drug Administration at the intervals specified for updating establishment registration information in § 607.26 and blood product listing information in § 607.30(a).

(d) Each foreign establishment required to register under paragraph (a) of this section must submit the name, address, telephone number, and email address of its United States agent as part of its initial and updated registration information in accordance with subpart B of this part. Each foreign establishment must designate only one United States agent.

(1) The United States agent shall reside or maintain a place of business in the United States.

(2) Upon request from FDA, the United States agent shall assist FDA in communications with the foreign establishment, respond to questions concerning the foreign establishment's products that are imported or offered for import into the United States, and assist FDA in scheduling inspections of the foreign establishment. If the agency is unable to contact the foreign establishment directly or expeditiously, FDA may provide information or documents to the United States agent, and such an action shall be considered to be equivalent to providing the same information or documents to the foreign establishment.

(3) The foreign establishment or the United States agent must report changes in the United States agent's name, address, telephone number, or email address to FDA within 30 calendar days of the change.

(e) Each foreign establishment required to register under paragraph (a) of this section must register and list blood products using the Blood Establishment Registration and Product Listing system, or any superseding electronic system, unless FDA waives the electronic submission requirement in accordance with § 607.22.

[66 FR 59159, Nov. 27, 2001, as amended at 81 FR 60223, Aug. 31, 2016]

§ 607.65 Exemptions for blood product establishments.

The following classes of persons are exempt from registration and blood product listing in accordance with this part 607 under the provisions of section 510(g)(1), (g)(2), and (g)(3) of the act, or because the Commissioner of Food and Drugs has found, under section 510(g)(5), that such registration is not necessary for the protection of the public health. The exemptions in paragraphs (a), (b), (f), and (g) of this section are limited to those classes of persons located in any State as defined in section 201(a)(1) of the act.

(a) Pharmacies that are operating under applicable local laws regulating dispensing of prescription drugs and that are not manufacturing blood products for sale other than in the regular course of the practice of the profession of pharmacy including the business of dispensing and selling blood products at retail. The supplying by such pharmacies of blood products to a practitioner licensed to administer such blood products for his use in the course of his professional practice or to other pharmacies to meet temporary inventory shortages are not acts which require such pharmacies to register.

(b) Practitioners who are licensed by law to prescribe or administer drugs and who manufacture blood products solely for use in the course of their professional practice.

(c) Persons who manufacture blood products which are not for sale, rather, are solely for use in research, teaching, or analysis, including laboratory samples.

(d) Carriers, by reason of their receipt, carriage, holding, or delivery of blood products in the usual course of business as carriers.

(e) Persons who engage solely in the manufacture of in vitro diagnostic blood products and reagents not subject to licensing under section 351 of the Public Health Service Act (42 U.S.C. 262). This paragraph does not exempt such persons from registration and listing for medical devices required under part 807 of this chapter.

(f) Transfusion services which are a part of a facility that is certified under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493 or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services and which are engaged in the compatibility testing and transfusion of blood and blood components, but which neither routinely collect nor process blood and blood components. The collection and processing of blood and blood components in an emergency situation as determined by a responsible person and documented in writing, therapeutic collection of blood or plasma, the preparation of recovered human plasma for further manufacturing use, or preparation of red blood cells for transfusion are not acts requiring such transfusion services to register.

(g) Persons who engage solely in the production of any plasma derivative, including, but not limited to, albumin, Immune Globulin, Factor VIII and Factor IX, bulk product substances such as fractionation intermediates or pastes, or recombinant versions of plasma derivatives or animal derived plasma derivatives. These persons must register and list under part 207 of this chapter.

[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978; 45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984; 66 FR 31162, June 11, 2001; 66 FR 59159, Nov. 27, 2001; 72 FR 45886, Aug. 16, 2007; 81 FR 60223, Aug. 31, 2016]

§ 607.80 Applicability of part 607 to licensed devices.

Manufacturers of products that meet the definition of a device under the Federal Food, Drug, and Cosmetic Act and that are licensed under section 351 of the Public Health Service Act, as well as licensed biological products used in the manufacture of a licensed device, must register and list following the procedures under this part, with respect to their manufacture of those products, unless otherwise noted in this section.

[81 FR 60223, Aug. 31, 2016]

§ 610.1 Tests prior to release required for each lot.

No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standard to which the test applies. The results of all tests performed shall be considered in determining whether or not the test results meet the test objective, except that a test result may be disregarded when it is established that the test is invalid due to causes unrelated to the product.

§ 610.2 Requests for samples and protocols; official release.

(a) Licensed biological products regulated by CBER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter). Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: Provided, That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.

(b) Licensed biological products regulated by CDER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter) for official release. Upon notification by the Director, Center for Drug Evaluation and Research, a manufacturer shall not distribute a lot of a biological product until the lot is released by the Director, Center for Drug Evaluation and Research: Provided, That the Director, Center for Drug Evaluation and Research shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.

[40 FR 31313, July 25, 1975, as amended at 49 FR 23834, June 8, 1984; 50 FR 10941, Mar. 19, 1985; 55 FR 11013, 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 610.9 Equivalent methods and processes.

Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions:

(a) The applicant presents evidence, in the form of a license application, or a supplement to the application submitted in accordance with § 601.12(b) or (c), demonstrating that the modification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standards or additional standards for the biological product; and

(b) Approval of the modification is received in writing from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.

[62 FR 39903, July 24, 1997, as amended at 70 FR 14984, Mar. 24, 2005]

§ 610.10 Potency.

Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter.

§ 610.11-610.11a [Reserved]

§ 610.12 Sterility.

(a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and as approved in the biologics license application or supplement for that product.

(b) Test requirements. (1) The sterility test must be appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test.

(2) The sterility test must be validated to demonstrate that the test is capable of reliably and consistently detecting the presence of viable contaminating microorganisms.

(3) The sterility test and test components must be verified to demonstrate that the test method can consistently detect the presence of viable contaminating microorganisms.

(c) Written procedures. Manufacturers must establish, implement, and follow written procedures for sterility testing that describe, at a minimum, the following:

(1) The sterility test method to be used;

(i) If culture-based test methods are used, include, at a minimum:

(A) Composition of the culture media;

(B) Growth-promotion test requirements; and

(C) Incubation conditions (time and temperature).

(ii) If non-culture-based test methods are used, include, at a minimum:

(A) Composition of test components;

(B) Test parameters, including acceptance criteria; and

(C) Controls used to verify the method's ability to detect the presence of viable contaminating microorganisms.

(2) The method of sampling, including the number, volume, and size of articles to be tested;

(3) Written specifications for the acceptance or rejection of each lot; and

(4) A statement of any other function critical to the particular sterility test method to ensure consistent and accurate results.

(d) The sample. The sample must be appropriate to the material being tested, considering, at a minimum:

(1) The size and volume of the final product lot;

(2) The duration of manufacturing of the drug product;

(3) The final container configuration and size;

(4) The quantity or concentration of inhibitors, neutralizers, and preservatives, if present, in the tested material;

(5) For a culture-based test method, the volume of test material that results in a dilution of the product that is not bacteriostatic or fungistatic; and

(6) For a non-culture-based test method, the volume of test material that results in a dilution of the product that does not inhibit or otherwise hinder the detection of viable contaminating microorganisms.

(e) Verification. (1) For culture-based test methods, studies must be conducted to demonstrate that the performance of the test organisms and culture media are suitable to consistently detect the presence of viable contaminating microorganisms, including tests for each lot of culture media to verify its growth-promoting properties over the shelf-life of the media.

(2) For non-culture-based test methods, within the test itself, appropriate controls must be used to demonstrate the ability of the test method to continue to consistently detect the presence of viable contaminating microorganisms.

(f) Repeat test procedures. (1) If the initial test indicates the presence of microorganisms, the product does not comply with the sterility test requirements unless a thorough investigation by the quality control unit can ascribe definitively the microbial presence to a laboratory error or faulty materials used in conducting the sterility testing.

(2) If the investigation described in paragraph (f)(1) of this section finds that the initial test indicated the presence of microorganisms due to laboratory error or the use of faulty materials, a sterility test may be repeated one time. If no evidence of microorganisms is found in the repeat test, the product examined complies with the sterility test requirements. If evidence of microorganisms is found in the repeat test, the product examined does not comply with the sterility test requirements.

(3) If a repeat test is conducted, the same test method must be used for both the initial and repeat tests, and the repeat test must be conducted with comparable product that is reflective of the initial sample in terms of sample location and the stage in the manufacturing process from which it was obtained.

(g) Records. The records related to the test requirements of this section must be prepared and maintained as required by §§ 211.167 and 211.194 of this chapter.

(h) Exceptions. Sterility testing must be performed on final container material or other appropriate material as defined in the approved biologics license application or supplement and as described in this section, except as follows:

(1) This section does not require sterility testing for Whole Blood, Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, and Blood Grouping Reagents.

(2) A manufacturer is not required to comply with the sterility test requirements if the Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research, as appropriate, determines that data submitted in the biologics license application or supplement adequately establish that the route of administration, the method of preparation, or any other aspect of the product precludes or does not necessitate a sterility test to assure the safety, purity, and potency of the product.

[77 FR 26174, May 3, 2012]

§ 610.13 Purity.

Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved biologics license application. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section.

(a)(1) Test for residual moisture. Each lot of dried product shall be tested for residual moisture and shall meet and not exceed established limits as specified by an approved method on file in the biologics license application. The test for residual moisture may be exempted by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, when deemed not necessary for the continued safety, purity, and potency of the product.

(2) Records. Appropriate records for residual moisture under paragraph (a)(1) of this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.

(b) Test for pyrogenic substances. Each lot of final containers of any product intended for use by injection shall be tested for pyrogenic substances by intravenous injection into rabbits as provided in paragraphs (b) (1) and (2) of this section: Provided, That notwithstanding any other provision of Subchapter F of this chapter, the test for pyrogenic substances is not required for the following products: Products containing formed blood elements; Cryoprecipitate; Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts; venoms; diagnostic substances and trivalent organic arsenicals.

(1) Test dose. The test dose for each rabbit shall be at least 3 milliliters per kilogram of body weight of the rabbit and also shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended, but need not exceed 10 milliliters per kilogram of body weight of the rabbit, except that: (i) Regardless of the human dose recommended, the test dose per kilogram of body weight of each rabbit shall be at least 1 milliliter for immune globulins derived from human blood; (ii) for Streptokinase, the test dose shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended.

(2) Test procedure, results, and interpretation; standards to be met. The test for pyrogenic substances shall be performed according to the requirements specified in United States Pharmacopeia XX.

(3) Retest. If the lot fails to meet the test requirements prescribed in paragraph (b)(2) of this section, the test may be repeated once using five other rabbits. The temperature rises recorded for all eight rabbits used in testing shall be included in determining whether the requirements are met. The lot meets the requirements for absence of pyrogens if not more than three of the eight rabbits show individual rises in temperature of 0.6 °C or more, and if the sum of the eight individual maximum temperature rises does not exceed 3.7 °C.

[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975; 41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289, July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984; 50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990; 64 FR 56453, Oct. 20, 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]

§ 610.14 Identity.

The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations shall have been completed. The identity test shall be specific for each product in a manner that will adequately identify it as the product designated on final container and package labels and circulars, and distinguish it from any other product being processed in the same laboratory. Identity may be established either through the physical or chemical characteristics of the product, inspection by macroscopic or microscopic methods, specific cultural tests, or in vitro or in vivo immunological tests.

§ 610.15 Constituent materials.

(a) Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume (v/v) glycerin. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:

(1) 0.85 milligrams if determined by assay;

(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or

(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter).

(b) Extraneous protein; cell culture produced vaccines. Extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection. If serum is used at any stage, its calculated concentration in the final medium shall not exceed 1:1,000,000.

(c) Antibiotics. A minimum concentration of antibiotics, other than penicillin, may be added to the production substrate of viral vaccines.

(d) The Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research may approve an exception or alternative to any requirement in this section. Requests for such exceptions or alternatives must be in writing.

[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981; 48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834, June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 76 FR 20518, Apr. 13, 2011; 80 FR 18093, Apr. 3, 2015]

§ 610.16 Total solids in serums.

Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.

§ 610.17 Permissible combinations.

Licensed products may not be combined with other licensed products either therapeutic, prophylactic or diagnostic, except as a license is obtained for the combined product. Licensed products may not be combined with nonlicensable therapeutic, prophylactic, or diagnostic substances except as a license is obtained for such combination.

§ 610.18 Cultures.

(a) Storage and maintenance. Cultures used in the manufacture of products shall be stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics of the organisms and insure freedom from contamination and deterioration.

(b) Identity and verification. Each culture shall be clearly identified as to source strain. A complete identification of the strain shall be made for each new stock culture preparation. Primary and subsequent seed lots shall be identified by lot number and date of preparation. Periodic tests shall be performed as often as necessary to verify the integrity of the strain characteristics and freedom from extraneous organisms. Results of all periodic tests for verification of cultures and determination of freedom from extraneous organisms shall be recorded and retained.

(c) Cell lines used for manufacturing biological products—(1) General requirements. Cell lines used for manufacturing biological products shall be:

(i) Identified by history;

(ii) Described with respect to cytogenetic characteristics and tumorigenicity;

(iii) Characterized with respect to in vitro growth characteristics and life potential; and

(iv) Tested for the presence of detectable microbial agents.

(2) Tests. Tests that are necessary to assure the safety, purity, and potency of a product may be required by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.

(3) Applicability. This paragraph applies to diploid and nondiploid cell lines. Primary cell cultures that are not subcultivated and primary cell cultures that are subsequently subcultivated for only a very limited number of population doublings are not subject to the provisions of this paragraph (c).

(d) Records. The records appropriate for cultures under this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.

[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986; 55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]

§ 610.39 Definitions.

The definitions set out in § 630.3 of this chapter apply to this subpart.

[80 FR 29896, May 22, 2015]

§ 610.40 Test requirements.

(a) Human blood and blood components. Except as specified in paragraphs (c) and (d) of this section, you, an establishment that collects blood and blood components for transfusion or for use in manufacturing a product, including donations intended as a component of, or used to manufacture, a medical device, must comply with the following requirements:

(1) Test each donation for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(i) through (iii) of this chapter (HIV, HBV, and HCV).

(2) Test each donation for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv) through (vii) of this chapter (HTLV, syphilis, West Nile virus, and Chagas disease). The following exceptions apply:

(i) To identify evidence of infection with syphilis in donors of Source Plasma, you must test donors for evidence of such infection in accordance with § 640.65(b) of this chapter, and not under this section.

(ii) You are not required to test donations of Source Plasma for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv), (vi), and (vii) of this chapter (HTLV, West Nile virus, and Chagas disease).

(iii) For each of the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv) through (vii) of this chapter (HTLV, syphilis, West Nile virus, and Chagas disease):

(A) If, based on evidence related to the risk of transmission of that relevant transfusion-transmitted infection, testing each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood or a blood component, you may adopt an adequate and appropriate alternative testing procedure that has been found acceptable for this purpose by FDA.

(B) If, based on evidence related to the risk of transmission of that relevant transfusion-transmitted infection, testing previously required for that infection is no longer necessary to reduce adequately and appropriately the risk of transmission of such infection by blood or a blood component, you may stop such testing in accordance with procedures found acceptable for this purpose by FDA.

(3) For each of the relevant transfusion-transmitted infections described in § 630.3(h)(1)(viii) through (x) of this chapter (CJD, vCJD, malaria) and § 630.3(h)(2) of this chapter (other transfusion-transmitted infections):

(i) You must test for evidence of infection when the following conditions are met:

(A) A test(s) for the relevant transfusion-transmitted infection is licensed, approved or cleared by FDA for use as a donor screening test and is available for such use; and

(B) Testing for the relevant transfusion-transmitted infection is necessary to reduce adequately and appropriately the risk of transmission of the relevant transfusion-transmitted infection by blood, or blood component, or blood derivative product manufactured from the collected blood or blood component.

(ii) You must perform this testing on each donation, unless one of the following exceptions applies:

(A) Testing of each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood, blood component, or blood derivative product manufactured from the collected blood or blood component. When evidence related to the risk of transmission of such infection supports this determination, you may adopt an adequate and appropriate alternative testing procedure that has been found acceptable for this purpose by FDA.

(B) Testing of each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood, blood component, or blood derivative product manufactured from the collected blood or blood component. When evidence related to the risk of transmission of such infection supports this determination, you may stop such testing in accordance with procedures found acceptable for this purpose by FDA.

(4) Evidence related to the risk of transmission of a relevant transfusion-transmitted infection that would support a determination that testing is not necessary, or that testing of each donation is not necessary, to reduce adequately and appropriately the risk of transmission of such infection by blood or blood component, as described in paragraphs (a)(2)(iii)(A) and (B) of this section, or by blood, blood component, or blood derivative, as described in paragraphs (a)(3)(ii)(A) and (B) of this section, includes epidemiological or other scientific evidence. It may include evidence related to the seasonality or geographic limitation of risk of transmission of such infection by blood or blood component, or other information related to when and how a donation is at risk of transmitting a relevant transfusion-transmitted infection. It may also include evidence related to the effectiveness of manufacturing steps (for example, the use of pathogen reduction technology) that reduce the risk of transmission of the relevant transfusion-transmitted infection by blood, blood components, or blood derivatives, as applicable.

(b) Testing using one or more licensed, approved, or cleared screening tests. To perform testing for evidence of infection due to relevant transfusion-transmitted infections as required in paragraph (a) of this section, you must use screening tests that FDA has licensed, approved, or cleared for such use, in accordance with the manufacturer's instructions. You must perform one or more such tests as necessary to reduce adequately and appropriately the risk of transmission of relevant transfusion-transmitted infections.

(c) Exceptions to testing for dedicated donations, medical devices, and samples.—(1) Dedicated donations. (i) You must test donations of human blood and blood components from a donor whose donations are dedicated to and used solely by a single identified recipient under paragraphs (a), (b), and (e) of this section; except that, if the donor makes multiple donations for a single identified recipient, you may perform such testing only on the first donation in each 30-day period. If an untested dedicated donation is made available for any use other than transfusion to the single, identified recipient, then this exemption from the testing required under this section no longer applies.

(ii) Each donation must be labeled as required under § 606.121 of this chapter and with a label entitled “INTENDED RECIPIENT INFORMATION LABEL” containing the name and identifying information of the recipient. Each donation must also have the following label, as appropriate:

Donor Testing Status | Label

Tests negative | Label as required under § 606.121

Tested negative within the last 30 days | “DONOR TESTED WITHIN THE LAST 30 DAYS”

(2) Medical device. (i) You are not required to test donations of human blood or blood components intended solely as a component of, or used to prepare, a medical device for evidence of infection due to the relevant transfusion-transmitted infections listed in § 630.3(h)(iv) of this chapter unless the final device contains viable leukocytes.

(ii) Donations of human blood and blood components intended solely as a component of, or used to prepare, a medical device must be labeled “Caution: For Further Manufacturing Use as a Component of, or to Prepare, a Medical Device.”

(3) Samples. You are not required to test samples of blood, blood components, plasma, or sera if used or distributed for clinical laboratory testing or research purposes and not intended for administration to humans or in the manufacture of a product.

(d) Autologous donations. You, an establishment that collects human blood or blood components from autologous donors, or you, an establishment that is a consignee of a collecting establishment, are not required to test donations of human blood or blood components from autologous donors for evidence of infection due to relevant transfusion-transmitted infections listed in paragraph (a) of this section, except:

(1) If you allow any autologous donation to be used for allogeneic transfusion, you must assure that all autologous donations are tested under this section.

(2) If you ship autologous donations to another establishment that allows autologous donations to be used for allogeneic transfusion, you must assure that all autologous donations shipped to that establishment are tested under this section.

(3) If you ship autologous donations to another establishment that does not allow autologous donations to be used for allogeneic transfusion, you must assure that, at a minimum, the first donation in each 30-day period is tested under this section.

(4) Each autologous donation must be labeled as required under § 606.121 of this chapter and with the following label, as appropriate:

Donor Testing Status | Label

Untested | “DONOR UNTESTED”

Tests negative | Label as required under § 606.121

Reactive on current collection/reactive in the last 30 days | “BIOHAZARD” legend in § 610.40(h)(2)(ii)(B)

Tested negative within the last 30 days | “DONOR TESTED WITHIN THE LAST 30 DAYS”

(e) Further testing. You must further test each donation, including autologous donations, found to be reactive by a donor screening test performed under paragraphs (a) and (b) of this section using a licensed, approved, or cleared supplemental test, when available. If no such supplemental test is available, you must perform one or more licensed, approved, or cleared tests as adequate and appropriate to provide additional information concerning the reactive donor's infection status. Except:

(1) For autologous donations:

(i) You must further test under this section, at a minimum, the first reactive donation in each 30 calendar day period; or

(ii) If you have a record for that donor of a positive result on further testing performed under this section, you do not have to further test an autologous donation.

(2) You are not required to perform further testing of a donation found to be reactive by a treponemal donor screening test for syphilis.

(f) Testing responsibility. Required testing under this section, must be performed by a laboratory registered in accordance with part 607 of this chapter and either certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services in accordance with those provisions.

(g) Release or shipment prior to testing. Human blood or blood components that are required to be tested for evidence of infection due to relevant transfusion-transmitted infections designated in paragraph (a) of this section may be released or shipped prior to completion of testing in the following circumstances provided that you label the blood or blood components under § 606.121(h) of this chapter, you complete the tests for evidence of infection due to relevant transfusion-transmitted infections as soon as possible after release or shipment, and that you provide the results promptly to the consignee:

(1) Only in appropriately documented medical emergency situations; or

(2) For further manufacturing use as approved in writing by FDA.

(h) Restrictions on shipment or use—(1) Reactive screening test. You must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section or that are collected from a donor with a previous record of a reactive screening test for evidence of infection due to relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section, except as provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this section.

(2) Exceptions. (i) You may ship or use blood or blood components intended for autologous use, including reactive donations, as described in paragraph (d) of this section.

(ii) You must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to a relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section or that are collected from a donor deferred under § 610.41(a) unless you meet the following conditions:

(A) Except for autologous donations, you must obtain from FDA written approval for the shipment or use;

(B) You must appropriately label such blood or blood components as required under § 606.121 of this chapter, and with the “BIOHAZARD” legend;

(C) Except for autologous donations, you must label such human blood and blood components as reactive for the appropriate screening test for evidence of infection due to the identified relevant transfusion-transmitted infection(s);

(D) If the blood or blood components are intended for further manufacturing use into injectable products, you must include a statement on the container label indicating the exempted use specifically approved by FDA.

(E) Each blood or blood component with a reactive screening test and intended solely as a component of, or used to prepare a medical device, must be labeled with the following label, as appropriate:

Type of Medical Device | Label

A medical device other than an in vitro diagnostic reagent | “Caution: For Further Manufacturing Use as a Component of a Medical Device For Which There Are No Alternative Sources”

An in vitro diagnostic reagent | “Caution: For Further Manufacturing Into In Vitro Diagnostic Reagents For Which There Are No Alternative Sources”

(iii) The restrictions on shipment or use do not apply to samples of blood, blood components, plasma, or sera if used or distributed for clinical laboratory testing or research purposes, and not intended for administration in humans or in the manufacture of a product.

(iv) You may use human blood or blood components from a donor with a previous record of a reactive screening test(s) for evidence of infection due to a relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section, if:

(A) At the time of donation, the donor is shown or was previously shown to be eligible by a requalification method or process found acceptable for such purposes by FDA under § 610.41(b); and

(B) tests performed under paragraphs (a) and (b) of this section are nonreactive.

(v) Anti-HBc reactive donations, otherwise nonreactive when tested as required under this section, may be used for further manufacturing into plasma derivatives without prior FDA approval or a “BIOHAZARD” legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of this section.

(vi) You may use human blood or blood components, excluding Source Plasma, that test reactive by a screening test for syphilis as required under paragraph (a) of this section if, the donation is further tested by an adequate and appropriate test which demonstrates that the reactive screening test is a biological false positive. You must label the blood or blood components with both test results.

(vii) You may use Source Plasma from a donor who tests reactive by a screening test for syphilis as required under § 640.65(b)(1)(i) of this chapter, if the donor meets the requirements of § 640.65(b)(2)(ii) through (iv) of this chapter.

[66 FR 31162, June 11, 2001, as amended at 77 FR 18, Jan. 3, 2012; 80 FR 29896, May 22, 2015; 86 FR 49922, July 9, 2021]

§ 610.41 Donor deferral.

(a) You, an establishment that collects human blood or blood components, must defer donors testing reactive by a screening test for evidence of infection due to a relevant transfusion-transmitted infection(s) under § 610.40(a), from future donations of human blood and blood components, except:

(1) You are not required to defer a donor who tests reactive for anti-HBc or anti-HTLV, types I and II, on only one occasion. However, you must defer the donor if further testing for HBV or HTLV has been performed under § 610.40(e) and the donor is found to be positive, or if a second, licensed, cleared, or approved screening test for HBV or HTLV has been performed on the same donation under § 610.40(a) and is reactive, or if the donor tests reactive for anti-HBc or anti-HTLV, types I and II, on more than one occasion;

(2) A deferred donor who tests reactive for evidence of infection due to a relevant transfusion-transmitted infection(s) under § 610.40(a) may serve as a donor for blood or blood components shipped or used under § 610.40(h)(2)(ii);

(3) A deferred donor who showed evidence of infection due to hepatitis B surface antigen (HBsAg) when previously tested under § 610.40(a), (b), and (e) subsequently may donate Source Plasma for use in the preparation of Hepatitis B Immune Globulin (Human) provided the current donation tests nonreactive for HBsAg and the donor is otherwise determined to be eligible;

(4) A deferred donor, who otherwise is determined to be eligible for donation and tests reactive for anti-HBc or for evidence of infection due to HTLV, types I and II, may serve as a donor of Source Plasma;

(5) A deferred donor who tests reactive for a relevant transfusion-transmitted infections(s) under § 610.40(a), may serve as an autologous donor under § 610.40(d).

(b) A deferred donor subsequently may be found to be eligible as a donor of blood or blood components by a requalification method or process found acceptable for such purposes by FDA. Such a donor is considered no longer deferred.

(c) You must comply with the requirements under §§ 610.46 and 610.47 when a donor tests reactive by a screening test for HIV or HCV required under § 610.40(a) and (b), or when you are aware of other reliable test results or information indicating evidence of HIV or HCV infection.

[66 FR 31164, June 11, 2001, as amended at 72 FR 48798, Aug. 24, 2007; 80 FR 29897, May 22, 2015]

§ 610.42 Restrictions on use for further manufacture of medical devices.

(a) In addition to labeling requirements in subchapter H of this chapter, when a medical device contains human blood or a blood component as a component of the final device, and the human blood or blood component was found to be reactive by a screening test performed under § 610.40(a) and (b), then you must include in the device labeling a statement of warning indicating that the product was manufactured from a donation found to be reactive by a screening test for evidence of infection due to the identified relevant transfusion-transmitted infection(s).

(b) FDA may approve an exception or alternative to the statement of warning required in paragraph (a) of this section based on evidence that the reactivity of the human blood or blood component in the medical device presents no significant health risk through use of the medical device.

[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]

§ 610.44 Use of reference panels by manufacturers of test kits.

(a) When available and appropriate to verify acceptable sensitivity and specificity, you, a manufacturer of test kits, must use a reference panel you obtain from FDA or from an FDA designated source to test lots of the following products. You must test each lot of the following products, unless FDA informs you that less frequent testing is appropriate, based on your consistent prior production of products of acceptable sensitivity and specificity:

(1) A test kit approved for use in testing donations of human blood and blood components for evidence of infection due to relevant transfusion-transmitted infections under § 610.40(a); and

(2) Human immunodeficiency virus (HIV) test kit approved for use in the diagnosis, prognosis, or monitoring of this relevant transfusion-transmitted infection.

(b) You must not distribute a lot that is found to be not acceptable for sensitivity and specificity under § 610.44(a). FDA may approve an exception or alternative to this requirement. Applicants must submit such requests in writing. However, in limited circumstances, such requests may be made orally and permission may be given orally by FDA. Oral requests and approvals must be promptly followed by written requests and written approvals.

[66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015]

§ 610.46 Human immunodeficiency virus (HIV) “lookback” requirements.

(a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:

(1) Within 3 calendar days after a donor tests reactive for evidence of human immunodeficiency virus (HIV) infection when tested under § 610.40(a) and (b) or when you are made aware of other reliable test results or information indicating evidence of HIV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected:

(i) Twelve months and less before the donor's most recent nonreactive screening tests, or

(ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test or HIV p24 antigen test, and nonreactive antibody screening test, whichever is the lesser period, you must:

(A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and

(B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;

(2) You must perform further testing for HIV as required under § 610.40(e) of this chapter on the reactive donation.

(3) You must notify consignees of the results of further testing for HIV, or the results of the reactive screening test if further testing under paragraph (a)(2) of this section is not available, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HIV infection under § 610.40(a) and (b) of this chapter. Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HIV infection.

(4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the further testing performed under paragraph (a)(2) of this section or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, exempted for such use by FDA.

(b) If you are a consignee of Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:

(1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment.

(2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA.

(3) When further testing for HIV is positive or when the screening test is reactive and further testing is not available, or if under an IND or IDE is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HIV infection, or the recipient's physician of record, of the need for recipient HIV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, deceased, adjudged incompetent by a State court, or, if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the results of further testing for evidence of HIV infection from the collecting establishment, or after receiving the donor's reactive screening test result for HIV if further testing is not available, or if under an IND or IDE is exempted for such use by FDA.

(c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter.

[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]

§ 610.47 Hepatitis C virus (HCV) “lookback” requirements.

(a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:

(1) Within 3 calendar days after a donor tests reactive for evidence of hepatitis C virus (HCV) infection when tested under § 610.40(a) and (b) of this chapter or when you are made aware of other reliable test results or information indicating evidence of HCV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected:

(i) Twelve months and less before the donor's most recent nonreactive screening tests, or

(ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test and nonreactive antibody screening test, whichever is the lesser period, you must:

(A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and

(B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;

(2) You must perform further testing for HCV as required under § 610.40(e) on the reactive donation.

(3) You must notify consignees of the results of further testing for HCV, or the results of the reactive screening test if further testing is not available, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HCV infection under § 610.40(a) and (b). Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HCV infection.

(4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, exempted for such use by FDA.

(b) If you are a consignee of Whole Blood or blood components, including Source Plasma or Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:

(1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment.

(2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA.

(3) When the further testing for HCV is positive or when the screening test is reactive and further testing is not available, or if under an IND or IDE, is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HCV infection, or the recipient's physician of record, of the need for recipient HCV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, adjudged incompetent by a State court, or if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the results of further testing for evidence of HCV infection from the collecting establishment, or after receiving the donor's reactive screening test result for HCV if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA.

(c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter.

[72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015]

§ 610.48 [Reserved]

§ 610.50 Date of manufacture for biological products.

(a) When the dating period begins. The dating period for a product must begin on the date of manufacture as described in paragraphs (b) and (c) of this section. The dating period for a combination of two or more products must be no longer than the dating period of the component with the shortest dating period.

(b) Determining the date of manufacture for biological products other than Whole Blood and blood components. The date of manufacture for biological products, other than Whole Blood and blood components, must be identified in the approved biologics license application as one of the following, whichever is applicable: The date of:

(1) Potency test or other specific test as described in a biologics license application or supplement to the application;

(2) Removal from animals or humans;

(3) Extraction;

(4) Solution;

(5) Cessation of growth;

(6) Final sterile filtration of a bulk solution;

(7) Manufacture as described in part 660 of this chapter; or

(8) Other specific manufacturing activity described in a biologics license application or supplement to the biologics license application.

(c) Determining the date of manufacture for Whole Blood and blood components. (1) The date of manufacture for Whole Blood and blood components must be one of the following, whichever is applicable:

(i) Collection date and/or time;

(ii) Irradiation date;

(iii) The time the red blood cell product was removed from frozen storage for deglycerolization;

(iv) The time the additive or rejuvenation solution was added;

(v) The time the product was entered for washing or removing plasma (if prepared in an open system);

(vi) As specified in the instructions for use by the blood collection, processing, and storage system approved or cleared for such use by FDA; or

(vii) As approved by the Director, Center for Biologics Evaluation and Research, in a biologics license application or supplement to the application.

(2) For licensed Whole Blood and blood components, the date of manufacture must be identified in the approved biologics license application or supplement to the application.

[81 FR 26691, May 4, 2016]

§ 610.53 Dating periods for Whole Blood and blood components.

(a) General. Dating periods for Whole Blood and blood components are specified in the table in paragraph (b) of this section.

(b) Table of dating periods. In using the table in this paragraph, when a product in column A is stored at the storage temperature prescribed in column B, storage of a product must not exceed the dating period specified in column C, unless a different dating period is specified in the instructions for use by the blood collection, processing and storage system approved or cleared for such use by FDA. Container labels for each product must include the recommended storage temperatures.

Whole Blood and Blood Components Storage Temperatures and Dating Periods

A | B | C

Product | Storage temperature | Dating period

Whole Blood

ACD, CPD, CP2D | Between 1 and 6 °C | 21 days from date of collection.

CPDA-1 | do 1 | 35 days from date of collection.

Red Blood Cells

ACD, CPD, CP2D | Between 1 and 6 °C | 21 days from date of collection.

CPDA-1 | do | 35 days from date of collection.

Additive solutions | do | 42 days from date of collection.

Open system (e.g., deglycerolized, washed) | do | 24 hours after entering bag.

Deglycerolized in closed system with additive solution added | do | 14 days after entering bag.

Irradiated | do | 28 days from date of irradiation or original dating, whichever is shorter.

Frozen | −65 °C or colder | 10 years from date of collection.

Platelets

Platelets | Between 20 and 24 °C | 5 days from date of collection.

Platelets | Other temperatures according to storage bag instructions | As specified in the instructions for use by the blood collection, processing and storage system approved or cleared for such use by FDA.

Plasma

Fresh Frozen Plasma | −18 °C or colder | 1 year from date of collection.

Plasma Frozen Within 24 Hours After Phlebotomy | do | 1 year from date of collection.

Plasma Frozen Within 24 Hours After Phlebotomy Held at Room Temperature Up To 24 Hours After Phlebotomy | do | 1 year from date of collection.

Plasma Cryoprecipitate Reduced | do | 1 year from date of collection.

Plasma | do | 5 years from date of collection.

Liquid Plasma | Between 1 and 6 °C | 5 days from end of Whole Blood dating period.

Source Plasma (frozen injectable) | −20 °C or colder | 10 years from date of collection.

Source Plasma Liquid (injectable) | 10 °C or colder | According to approved biologics license application.

Source Plasma (noninjectable) | Temperature appropriate for final product | 10 years from date of collection.

Therapeutic Exchange Plasma | −20 °C or colder | 10 years from date of collection.

Cryoprecipitated AHF

Cryoprecipitated AHF | −18 °C or colder | 1 year from date of collection of source blood or from date of collection of oldest source blood in pre-storage pool.

Source Leukocytes

Source Leukocytes | Temperature appropriate for final product | In lieu of expiration date, the collection date must appear on the label.

1 The abbreviation “do.” for ditto is used in the table to indicate that the previous line is being repeated.

[81 FR 26691, May 4, 2016]

§ 610.60 Container label.

(a) Full label. The following items shall appear on the label affixed to each container of a product capable of bearing a full label:

(1) The proper name of the product;

(2) The name, address, and license number of manufacturer;

(3) The lot number or other lot identification;

(4) The expiration date;

(5) The recommended individual dose, for multiple dose containers.

(6) The statement: “ ‘Rx only’ ” for prescription biologicals.

(7) If a Medication Guide is required under part 208 of this chapter, the statement required under § 208.24(d) of this chapter instructing the authorized dispenser to provide a Medication Guide to each patient to whom the drug is dispensed and stating how the Medication Guide is provided, except where the container label is too small, the required statement may be placed on the package label.

(b) Package label information. If the container is not enclosed in a package, all the items required for a package label shall appear on the container label.

(c) Partial label. If the container is capable of bearing only a partial label, the container shall show as a minimum the name (expressed either as the proper or common name), the lot number or other lot identification and the name of the manufacturer; in addition, for multiple dose containers, the recommended individual dose. Containers bearing partial labels shall be placed in a package which bears all the items required for a package label.

(d) No container label. If the container is incapable of bearing any label, the items required for a container label may be omitted, provided the container is placed in a package which bears all the items required for a package label.

(e) Visual inspection. When the label has been affixed to the container a sufficient area of the container shall remain uncovered for its full length or circumference to permit inspection of the contents.

[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 63 FR 66400, Dec. 1, 1998; 67 FR 4907, Feb. 1, 2002]

§ 610.61 Package label.

The following items shall appear on the label affixed to each package containing a product:

(a) The proper name of the product;

(b) The name, address, and license number of manufacturer;

(c) The lot number or other lot identification;

(d) The expiration date;

(e) The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words “no preservative”;

(f) The number of containers, if more than one;

(g) The amount of product in the container expressed as (1) the number of doses, (2) volume, (3) units of potency, (4) weight, (5) equivalent volume (for dried product to be reconstituted), or (6) such combination of the foregoing as needed for an accurate description of the contents, whichever is applicable;

(h) The recommended storage temperature;

(i) The words “Shake Well”, “Do not Freeze” or the equivalent, as well as other instructions, when indicated by the character of the product;

(j) The recommended individual dose if the enclosed container(s) is a multiple-dose container;

(k) The route of administration recommended, or reference to such directions in an enclosed circular;

(l) Known sensitizing substances, or reference to an enclosed circular containing appropriate information;

(m) The type and calculated amount of antibiotics added during manufacture;

(n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;

(o) The adjuvant, if present;

(p) The source of the product when a factor in safe administration;

(q) The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information;

(r) Minimum potency of product expressed in terms of official standard of potency or, if potency is a factor and no U.S. standard of potency has been prescribed, the words “No U.S. standard of potency.”

(s) The statement: “ ‘Rx only’ ” for prescription biologicals.

[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55 FR 10423, Mar. 21, 1990; 67 FR 4907, Feb. 1, 2002]

§ 610.62 Proper name; package label; legible type.

(a) Position. The proper name of the product on the package label shall be placed above any trademark or trade name identifying the product and symmetrically arranged with respect to other printing on the label.

(b) Prominence. The point size and typeface of the proper name shall be at least as prominent as the point size and typeface used in designating the trademark and trade name. The contrast in color value between the proper name and the background shall be at least as great as the color value between the trademark and trade name and the background. Typography, layout, contrast, and other printing features shall not be used in a manner that will affect adversely the prominence of the proper name.

(c) Legible type. All items required to be on the container label and package label shall be in legible type. “Legible type” is type of a size and character which can be read with ease when held in a good light and with normal vision.

§ 610.63 Divided manufacturing responsibility to be shown.

If two or more licensed manufacturers participate in the manufacture of a biological product, the name, address, and license number of each must appear on the package label, and on the label of the container if capable of bearing a full label.

[64 FR 56453, Oct. 20, 1999]

§ 610.64 Name and address of distributor.

The name and address of the distributor of a product may appear on the label provided that the name, address, and license number of the manufacturer also appears on the label and the name of the distributor is qualified by one of the following phrases: “Manufactured for _____”, “Distributed by ______”, “Manufactured by _____ for _____”, “Manufactured for _____ by ____”, “Distributor: _____”, or “Marketed by _____”. The qualifying phrases may be abbreviated.

[61 FR 57330, Nov. 6, 1996]

§ 610.65 Products for export.

Labels on packages or containers of products for export may be adapted to meet specific requirements of the regulations of the country to which the product is to be exported provided that in all such cases the minimum label requirements prescribed in § 610.60 are observed.

§ 610.67 Bar code label requirements.

Biological products must comply with the bar code requirements at § 201.25 of this chapter. However, the bar code requirements do not apply to devices regulated by the Center for Biologics Evaluation and Research or to blood and blood components intended for transfusion. For blood and blood components intended for transfusion, the requirements at § 606.121(c)(13) of this chapter apply instead.

[69 FR 9171, Feb. 26, 2004]

§ 610.68 Exceptions or alternatives to labeling requirements for biological products held by the Strategic National Stockpile.

(a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of a biological product, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such product that is or will be included in the Strategic National Stockpile.

(b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores a biological product that is or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director.

(ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative.

(2) A written request for an exception or alternative described in paragraph (a) of this section must:

(i) Identify the specified lots, batches, or other units of the biological product that would be subject to the exception or alternative;

(ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request;

(iii) Explain why compliance with such labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of the biological product that are or will be included in the Strategic National Stockpile;

(iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the product includes appropriate information necessary for the safe and effective use of the product, given the anticipated circumstances of use of the product;

(v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the biological product subject to the exception or alternative; and

(vi) Provide any other information requested by the Center Director in support of the request.

(c) The Center Director must respond in writing to all requests under this section.

(d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director so that the labeling of product subject to the exception or alternative includes the information necessary for the safe and effective use of the product, given the anticipated circumstances of use.

(e) If you are a sponsor receiving a grant of a request for an exception or alternative to the labeling requirements under this section:

(1) You need not submit a supplement under § 601.12(f)(1) through (f)(2) of this chapter; however,

(2) You must report any grant of a request for an exception or alternative under this section as part of your annual report under § 601.12(f)(3) of this chapter.

(f) The Center Director may grant an exception or alternative under this section to the following provisions of this chapter, to the extent that the requirements in these provisions are not explicitly required by statute:

(1) § 610.60;

(2) § 610.61(c) and (e) through (r);

(3) § 610.62;

(4) § 610.63;

(5) § 610.64;

(6) § 610.65; and

(7) § 312.6.

[72 FR 73600, Dec. 28, 2007]

§ 630.1 Purpose and scope.

(a) What is the purpose of subparts A, B, and C of this part? The purpose of these subparts, together with §§ 610.40 and 610.41 of this chapter, is to provide certain minimum criteria for each donation of blood and blood components, for:

(1) Determining the eligibility of a donor of blood and blood components;

(2) Determining the suitability of the donation of blood and blood components; and

(3) Notifying a donor who is deferred from donation.

(b) Who must comply with subparts A, B, and C of this part? Blood establishments that manufacture blood and blood components, as defined in § 630.3(a) and (b), must comply with subparts A, B, and C of this part.

§ 630.3 Definitions.

As used in this part and in part 610, subpart E, and part 640 of this chapter:

(a) Blood means a product that is a fluid containing dissolved and suspended elements which was collected from the vascular system of a human.

(b) Blood component means a product containing a part of blood separated by physical or mechanical means.

(c) Donor means a person who: (1) Donates blood or blood components for transfusion or for further manufacturing use; or

(2) Presents as a potential candidate for such donation.

(d) Eligibility of a donor means the determination that the donor is qualified to donate blood and blood components.

(e) Infrequent plasma donor means a donor who has:

(1) Not donated plasma by plasmapheresis or a co-collection of plasma with another blood component in the preceding 4 weeks; and

(2) Not donated more than 12.0 liters of plasma (14.4 liters of plasma for donors weighing more than 175 pounds) in the past year.

(f) Intimate contact with risk for a relevant transfusion-transmitted infection means having engaged in an activity that could result in the transfer of potentially infectious body fluids from one person to another.

(g) Physician substitute means a trained and qualified person(s) who is:

(1) A graduate of an education program for health care workers that includes clinical training;

(2) Currently licensed or certified as a health care worker in the jurisdiction where the collection establishment is located;

(3) Currently certified in cardiopulmonary resuscitation; and

(4) Trained and authorized under State law, and/or local law when applicable, to perform the specified functions under the direction of the responsible physician.

(h) Relevant transfusion-transmitted infection means:

(1) Any of the following transfusion-transmitted infections:

(i) Human immunodeficiency virus, types 1 and 2 (referred to, collectively, as HIV);

(ii) Hepatitis B virus (referred to as HBV);

(iii) Hepatitis C virus (referred to as HCV);

(iv) Human T-lymphotropic virus, types I and II (referred to, collectively, as HTLV);

(v) Treponema pallidum (referred to as syphilis);

(vi) West Nile virus;

(vii) Trypanosoma cruzi (referred to as Chagas disease);

(viii) Creutzfeldt-Jakob disease (referred to as CJD);

(ix) Variant Creutzfeldt-Jakob disease (referred to as vCJD); and

(x) Plasmodium species (referred to as malaria).

(2) A transfusion-transmitted infection not listed in paragraph (h)(1) of this section when the following conditions are met:

(i) Appropriate screening measures for the transfusion-transmitted infection have been developed and/or an appropriate screening test has been licensed, approved, or cleared for such use by FDA and is available; and

(ii) The disease or disease agent:

(A) May have sufficient incidence and/or prevalence to affect the potential donor population; or

(B) May have been released accidentally or intentionally in a manner that could place potential donors at risk of infection.

(i) Responsible physician means an individual who is:

(1) Licensed to practice medicine in the jurisdiction where the collection establishment is located;

(2) Adequately trained and qualified to direct and control personnel and relevant procedures concerning the determination of donor eligibility; collection of blood and blood components; the immunization of a donor; and the return of red blood cells or other blood components to the donor during collection of blood component(s) by apheresis; and

(3) Designated by the collection establishment to perform the activities described in paragraph (i)(2) of this section.

(j) Suitability of the donation means a determination of whether the donation is acceptable for transfusion or for further manufacturing use.

(k) Trained person means an individual, including a physician substitute, who is authorized under State law, and/or local law when applicable, and adequately instructed and qualified to perform the specified functions under the direction of the responsible physician.

(l) Transfusion-transmitted infection means a disease or disease agent:

(1) That could be fatal or life-threatening, could result in permanent impairment of a body function or permanent damage to a body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of body function or permanent damage to a body structure; and

(2) For which there may be a risk of transmission by blood or blood components, or by a blood derivative product manufactured from blood or blood components, because the disease or disease agent is potentially transmissible by that blood, blood component, or blood derivative product.

§ 630.5 Medical supervision.

(a) Who must determine the eligibility of a donor? The responsible physician must determine the eligibility of a donor of blood or blood components in accordance with this subchapter.

(b) Which activities related to the collection of blood and blood components, other than Source Plasma and plasma collected by plasmapheresis, may the responsible physician delegate?

(1) The responsible physician may delegate the following activities to a physician substitute or other trained person:

(i) Determining the eligibility of a donor and documenting assessments related to that determination, except the responsible physician must not delegate:

(A) The examination and determination of the donor's health required in § 630.10(f)(2) for donors with blood pressure measurements outside specified limits, or for certain more frequent donations under § 630.15(a)(1)(ii);

(B) The determination of the health of the donor required in §§ 630.10(f)(4), 630.20(a), and 640.21(e)(4) of this chapter. The responsible physician may make this determination by telephonic or other offsite consultation; or

(C) The determination of the health of the donor and the determination that the blood or blood component collected would present no undue medical risk to the transfusion recipient, as required in § 630.20(c). The responsible physician may make these determinations by telephonic or other offsite consultation.

(ii) Collecting blood or blood components;

(iii) Returning red blood cells to the donor during apheresis;

(iv) Obtaining the informed consent of a plateletpheresis donor as described in § 640.21(g) of this chapter; or

(v) Other activities provided that the Director, Center for Biologics Evaluation and Research, determines that delegating the activities would present no undue medical risk to the donor or to the transfusion recipient, and authorizes the delegation of such activities.

(2) The responsible physician need not be present at the collection site when activities delegated under paragraph (b)(1) of this section are performed, provided that the responsible physician has delegated oversight of these activities to a trained person who is adequately trained and experienced in the performance of these activities and is also adequately trained and experienced in the recognition of and response to the known adverse responses associated with blood collection procedures.

(c) Which activities related to the collection of Source Plasma and plasma collected by plasmapheresis may the responsible physician delegate?

(1) Donor eligibility and blood component collection activities. (i) The responsible physician may delegate to a physician substitute or other trained person any of the activities described in paragraph (c)(1)(i)(A) of this section, provided that the responsible physician or a physician substitute is on the premises at the collection site:

(A) The activities listed in paragraphs (b)(1)(i) through (iii) and (b)(1)(v) of this section, with respect to Source Plasma and plasma collected by plasmapheresis. However, the responsible physician must not delegate:

(1) The examination and determination of the donor's health required in § 630.10(f)(2) for donors with blood pressure measurements outside specified limits, or in § 630.15(b)(7) for certain donors who have experienced red blood cell loss;

(2) The determination of the health of the donor required in §§ 630.10(f)(4) and 630.20(a) and (b). The responsible physician may make this determination by telephonic or other offsite consultation;

(3) The determination of the health of the donor and the determination that the blood component would present no undue medical risk to the transfusion recipient, as required in § 630.20(c). The responsible physician may make this determination by telephonic or other offsite consultation.

(4) The determination related to a donor's false-positive reaction to a serologic test for syphilis in accordance with § 640.65(b)(2)(iii) of this chapter; and

(5) The determination to permit plasmapheresis of a donor with a reactive serological test for syphilis in accordance with § 640.65(b)(2)(iv) of this chapter.

(B) The collection of Source Plasma in an approved collection program from a donor who is otherwise determined to be ineligible.

(C) The collection of a blood sample in accordance with § 640.65(b)(1)(i) of this chapter.

(ii) The responsible physician, who may or may not be present when these activities are performed, may delegate to a physician substitute the following activities:

(A) Approval and signature for a plasmapheresis procedure as provided in § 640.65(b)(1)(ii) of this chapter; and

(B) Review and signature for accumulated laboratory data, the calculated values of each component, and the collection records in accordance with § 640.65(b)(2)(i) of this chapter. However, the responsible physician must not delegate the decision to reinstate the deferred donor in accordance with that provision.

(2) Donor immunization. The responsible physician must not delegate activities performed in accordance with § 640.66 of this chapter, except that:

(i) The responsible physician may delegate to a physician substitute or other trained person the administration of an immunization other than red blood cells to a donor in an approved collection program, provided that the responsible physician or a physician substitute is on the premises at the collection site when the immunization is administered.

(ii) The responsible physician may delegate to a physician substitute the administration of red blood cells to a donor in an approved collection program, provided that the responsible physician has approved the procedure and is on the premises at the collection site when the red blood cells are administered.

(3) Medical history, physical examination, informed consent, and examination before immunization. Provided that such activities are performed under the supervision of the responsible physician, the responsible physician may delegate to a physician substitute the activities described in § 630.15(b)(1), (2), and (5). The responsible physician is not required to be present at the collection site when the physician substitute performs these activities under supervision.

(4) Infrequent plasma donors. (i) For infrequent plasma donors other than those described in paragraph (c)(4)(ii) of this section, the responsible physician may delegate to a trained person the activities listed in paragraphs (b)(1)(i) through (iii) and (b)(1)(v) of this section and the informed consent requirements described in § 630.15(b)(2). The responsible physician or a physician substitute need not be present at the collection site when any of these activities are performed, provided that the responsible physician has delegated oversight of these activities to a trained person who is not only adequately trained and experienced in the performance of these activities but also adequately trained and experienced in the recognition of and response to the known adverse responses associated with blood collection procedures. However, the responsible physician must not delegate:

(A) The examination and determination of the donor's health required in § 630.10(f)(2) for donors with blood pressure measurements outside specified limits, or in § 630.15(b)(7) for certain donors who have experienced red blood cell loss; or

(B) The determination of the health of the donor required in § 630.10(f)(4).

(ii) For infrequent plasma donors who are otherwise ineligible or are participating in an approved immunization program, the responsible physician may delegate only in accordance with paragraphs (c)(1) through (3) of this section.

(d) Must rapid emergency medical services be available? Establishments that collect blood or blood components must establish, maintain, and follow standard operating procedures for obtaining rapid emergency medical services for donors when medically necessary. In addition, establishments must assure that an individual (responsible physician, physician substitute, or trained person) who is currently certified in cardiopulmonary resuscitation is located on the premises whenever collections of blood or blood components are performed.

§ 630.10 General donor eligibility requirements.

(a) What factors determine the eligibility of a donor? You, an establishment that collects blood or blood components, must not collect blood or blood components before determining that the donor is eligible to donate or before determining that an exception to this provision applies. To be eligible, the donor must be in good health and free from transfusion-transmitted infections as can be determined by the processes in this subchapter. A donor is not eligible if the donor is not in good health or if you identify any factor(s) that may cause the donation to adversely affect:

(1) The health of the donor; or

(2) The safety, purity, or potency of the blood or blood component.

(b) What educational material must you provide to the donor before determining eligibility? You must provide educational material concerning relevant transfusion-transmitted infections to donors before donation when donor education about that relevant transfusion-transmitted infection, such as HIV, is necessary to assure the safety, purity, and potency of blood and blood components. The educational material must include an explanation of the readily identifiable risk factors closely associated with exposure to the relevant transfusion-transmitted infection. You must present educational material in an appropriate form, such as oral, written or multimedia, and in a manner designed to be understood by the donor. The educational material must instruct the donor not to donate blood and blood components when a risk factor is present. When providing educational material to donors under this section, you may include in those materials the information required to be provided to donors under paragraph (g)(2)(ii)(E) of this section.

(c) When must you determine the eligibility of a donor? You must determine donor eligibility on the day of donation, and before collection. Except:

(1) When a donor is donating blood components that cannot be stored for more than 24 hours, you may determine the donor's eligibility and collect a sample for testing required under § 610.40 of this chapter, no earlier than 2 calendar days before the day of donation, provided that your standard operating procedures address these activities.

(2) In the event that, upon review, you find that a donor's responses to the donor questions before collection were incomplete, within 24 hours of the time of collection, you may clarify a donor's response or obtain omitted information required under paragraph (e) of this section, provided that your standard operating procedures address these activities.

(d) How must you determine the eligibility of a donor? You must determine the donor's eligibility before collection of blood or blood components, by the following procedures:

(1) You must consult the records of deferred donors maintained under § 606.160(e)(1) and (2) of this chapter. Exception: If pre-collection review of the record described in § 606.160(e)(2) of this chapter is not feasible because you cannot consult the cumulative record at the collection site, you must consult the cumulative record prior to release of any blood or blood component prepared from the collection.

(2) Assure that the interval since the donor's last donation is appropriate;

(3) Assess the donor's medical history; and

(4) Perform a physical assessment of the donor.

(e) How do you assess the donor's medical history? Before collection you must conduct a medical history interview as described in this section to determine if the donor is in good health; to identify risk factors closely associated with exposure to, or clinical evidence of a relevant transfusion-transmitted infection; and to determine if there are other conditions that may adversely affect the health of the donor or the safety, purity, or potency of the blood or blood components or any product manufactured from the blood or blood components. Your assessment must include each of the following factors:

(1) Factors that make the donor ineligible to donate because of an increased risk for, or evidence of, a relevant transfusion-transmitted infection. A donor is ineligible to donate when information provided by the donor or other reliable evidence indicates possible exposure to a relevant transfusion-transmitted infection if that risk of exposure is still applicable at the time of donation. Information and evidence indicating possible exposure to a relevant transfusion-transmitted infection include:

(i) Behaviors associated with a relevant transfusion-transmitted infection;

(ii) Receipt of blood or blood components or other medical treatments and procedures associated with possible exposure to a relevant transfusion-transmitted infection;

(iii) Signs and/or symptoms of a relevant transfusion-transmitted infection;

(iv) Institutionalization for 72 hours or more consecutively in the past 12 months in a correctional institution;

(v) Intimate contact with risk for a relevant transfusion-transmitted infection; and

(vi) Nonsterile percutaneous inoculation.

(2) Other factors that make the donor ineligible to donate. A donor is ineligible to donate when donating could adversely affect the health of the donor, or when the safety, purity, or potency of the blood or blood component could be affected adversely. Your assessment of the donor must include each of the following factors:

(i) Symptoms of a recent or current illness;

(ii) Certain medical treatments or medications;

(iii) Travel to, or residence in, an area endemic for a transfusion-transmitted infection, when such screening is necessary to assure the safety, purity, and potency of blood and blood components due to the risks presented by donor travel and the risk of transmission of that transfusion-transmitted infection by such donors;

(iv) Exposure or possible exposure to an accidentally or intentionally released disease or disease agent relating to a transfusion-transmitted infection, if you know or suspect that such a release has occurred;

(v) Pregnancy at the time of, or within 6 weeks prior to, donation;

(vi) Whether, in the opinion of the interviewer, the donor appears to be under the influence of any drug, alcohol or for any reason does not appear to be providing reliable answers to medical history questions, or if the donor says that the purpose of donating is to obtain test results for a relevant transfusion-transmitted infection; and

(vii) The donor is a xenotransplantation product recipient.

(f) How do you perform a physical assessment of the donor? You must determine on the day of donation, and before collection that the donor is in good health based on the following, at a minimum:

(1) Temperature. The donor's oral body temperature must not exceed 37.5 °C (99.5 °F), or the equivalent if measured at another body site;

(2) Blood pressure. The donor's systolic blood pressure must not measure above 180 mm of mercury, or below 90 mm of mercury, and the diastolic blood pressure must not measure above 100 mm of mercury or below 50 mms of mercury. A donor with measurements outside these limits may be permitted to donate only when the responsible physician examines the donor and determines and documents that the health of the donor would not be adversely affected by donating.

(3) Hemoglobin or hematocrit determination. You must determine the donor's hemoglobin level or hematocrit value by using a sample of blood obtained by fingerstick, venipuncture, or by a method that provides equivalent results. Blood obtained from the earlobe is not acceptable.

(i) Allogeneic donors must have a hemoglobin level or hematocrit value that is adequate to assure donor safety and product potency. The following minimum standards apply.

(A) Female allogeneic donors must have a hemoglobin level that is equal to or greater than 12.5 grams of hemoglobin per deciliter of blood, or a hematocrit value that is equal to or greater than 38 percent. Recognizing that lower levels are also within normal limits for female donors, you may collect blood from female allogeneic donors who have a hemoglobin level between 12.0 and 12.5 grams per deciliter of blood, or a hematocrit value between 36 and 38 percent, provided that you have taken additional steps to assure that this alternative standard is adequate to ensure that the health of the donor will not be adversely affected due to the donation, in accordance with a procedure that has been found acceptable for this purpose by FDA.

(B) Male allogeneic donors must have a hemoglobin level that is equal to or greater than 13.0 grams of hemoglobin per deciliter of blood, or a hematocrit value that is equal to or greater than 39 percent.

(ii) An autologous donor must have a hemoglobin level no less than 11.0 grams of hemoglobin per deciliter of blood, or a hematocrit value no less than 33 percent.

(4) Pulse. The donor's pulse must be regular and between 50 and 100 beats per minute. A donor with an irregular pulse or measurements outside these limits may be permitted to donate only when the responsible physician determines and documents that the health of the donor would not be adversely affected by donating.

(5) Weight. The donor must weigh a minimum of 50 kilograms (110 pounds).

(6) Skin examination. (i) The donor's phlebotomy site must be free of infection, inflammation, and lesions; and

(ii) The donor's arms and forearms must be free of punctures and scars indicative of injected drugs of abuse.

(g) Are there additional requirements for determining the eligibility of the donor? You must obtain the following from the donor on the day of donation:

(1) Proof of identity and postal address. You must obtain proof of identity of the donor and a postal address where the donor may be contacted for 8 weeks after donation; and

(2) Donor's acknowledgement. (i) Prior to each donation, you must provide information to the donor addressing the elements specified in paragraphs (g)(2)(ii)(A) through (E) of this section and obtain the donor's acknowledgement that the donor has reviewed the information. You must establish procedures in accordance with § 606.100 of this chapter to assure that the donor has reviewed this material, and provide for a signature or other documented acknowledgement.

(ii) The donor acknowledgement must not include any exculpatory language through which the donor is made to waive or appear to waive any of the donor's legal rights. It must, at a minimum clearly address the following:

(A) The donor has reviewed the educational material provided under paragraph (b) of this section regarding relevant transfusion-transmitted infections;

(B) The donor agrees not to donate if the donation could result in a potential risk to recipients as described in the educational material;

(C) A sample of the donor's blood will be tested for specified relevant transfusion-transmitted infections;

(D) If the donation is determined to be not suitable under § 630.30(a) or if the donor is deferred from donation under § 610.41 of this chapter, the donor's record will identify the donor as ineligible to donate and the donor will be notified under § 630.40 of the basis for the deferral and the period of deferral;

(E) The donor has been provided and reviewed information regarding the risks and hazards of the specific donation procedure; and

(F) The donor has the opportunity to ask questions and withdraw from the donation procedure.

(h) What must you do when a donor is not eligible? You must not collect blood or blood components from a donor found to be ineligible prior to collection based on criteria in §§ 630.10 or 630.15, or deferred under § 610.41 of this chapter or § 630.30(b)(2), unless this subchapter provides an exception. You must defer donors found to be ineligible and you must notify the donor of their deferral under § 630.40.

§ 630.15 Donor eligibility requirements specific to Whole Blood, Red Blood Cells and Plasma collected by apheresis.

(a) What additional donor eligibility requirements apply when you, an establishment that collects blood or blood components, collect Whole Blood or Red Blood Cells by apheresis?

(1) Donation frequency must be consistent with protecting the health of the donor.

(i) For a collection resulting in a single unit of Whole Blood or Red Blood Cells collected by apheresis, donation frequency must be no more than once in 8 weeks, and for apheresis collections resulting in two units of Red Blood Cells, the donor must not donate more than once in 16 weeks.

(ii) The limitations in paragraph (a)(1)(i) of this section apply unless the responsible physician examines the donor at the time of donation and one of the following conditions exists:

(A) The donation is for autologous use as prescribed by the donor's physician and the responsible physician determines and documents that the donation may proceed; or

(B) The donation is a dedicated donation based on the intended recipient's documented exceptional medical need and the responsible physician determines and documents that the health of the donor would not be adversely affected by donating.

(2) Therapeutic phlebotomy. When a donor who is determined to be eligible under § 630.10 undergoes a therapeutic phlebotomy under a prescription to promote the donor's health, you may collect from the donor more frequently than once in 8 weeks for collections resulting in a single unit of Whole Blood or Red Blood Cells, or once in 16 weeks for apheresis collections resulting in two units of Red Blood Cells, provided that the container label conspicuously states the disease or condition of the donor that necessitated phlebotomy. However, no labeling for the disease or condition is required under this section if:

(i) The donor meets all eligibility criteria;

(ii) The donor undergoes a therapeutic phlebotomy as prescribed by a licensed health care provider treating the donor for:

(A) Hereditary hemochromatosis; or

(B) Another disease or condition, when the health of a donor with that disease or condition will not be adversely affected by donating, and the donor's disease or condition will not adversely affect the safety, purity, and potency of the blood and blood components, or any products manufactured from them, and the collection is in accordance with a procedure that has been found acceptable for this purpose by FDA; and

(iii) You perform without charge therapeutic phlebotomies for all individuals with that disease or condition.

(b) What additional donor eligibility requirements apply when you, an establishment that collects blood or blood components, collect Source Plasma or plasma by plasmapheresis?

(1) Medical history and physical examination. Except as provided in § 630.25:

(i) The responsible physician must conduct an appropriate medical history and physical examination of the donor on the day of the first donation or no more than 1 week before the first donation and at subsequent intervals of no longer than 1 year.

(ii) The responsible physician must examine the donor for medical conditions that would place the donor at risk from plasmapheresis. If the donor is determined to be at risk, you must defer the donor from donating.

(iii) The responsible physician must conduct a new medical history and physical examination of a donor who does not return for 6 months.

(2) What requirements apply to obtaining informed consent?

(i) The responsible physician must obtain the informed consent of a plasma donor on the first day of donation or no more than 1 week before the first donation, and at subsequent intervals of no longer than 1 year.

(ii) The responsible physician must obtain the informed consent of a plasma donor who does not return within 6 months of the last donation.

(iii) The responsible physician must explain the risks and hazards of the procedure to the donor. The explanation must include the risks of a hemolytic transfusion reaction if the donor is given the cells of another donor and the risks involved if the donor is immunized. The explanation must be made in such a manner that the donor may give their consent and has a clear opportunity to refuse the procedure.

(iv) If a donor is enrolled in a new program, such as an immunization or special collection program, the responsible physician must again obtain an informed consent specific for that program.

(3) Weight. You must weigh a donor at each donation.

(4) Total protein level. You must determine the donor's total plasma protein level before each plasmapheresis procedure. The donor must have a total plasma protein level of no less than 6.0 grams per deciliter and no more than 9.0 grams per deciliter in a plasma sample or a serum sample.

(5) Examination before immunization. (i) No more than 1 week before the first immunization injection for the production of high-titer antibody plasma, the responsible physician must conduct an appropriate medical history and physical examination, as described in paragraph (b)(1) of this section, in addition to assessing the general donor eligibility requirements under § 630.10. It is not necessary to repeat the medical history and physical examination requirement in paragraph (b)(1) of this section, if the immunized donor's plasma is collected within 3 weeks of the first immunization injection.

(ii) You are not required to repeat the medical history and physical examination required under paragraph (b)(1) of this section for a donor currently participating in a plasmapheresis collection program and determined to be eligible under § 630.10 unless the medical history and physical examination are due under paragraph (b)(1)(i) or (b)(1)(iii) of this section.

(6) Deferral of donors due to red blood cell loss. (i) You must defer a donor from donating plasma by plasmapheresis for 8 weeks if the donor has donated a unit of Whole Blood, or a single unit of Red Blood Cells by apheresis. However, you may collect plasma by plasmapheresis after a donation of Whole Blood or a single unit of Red Blood Cells by apheresis after at least 2 calendar days have passed, provided that the extracorporeal volume of the apheresis device is less than 100 milliliters.

(ii) You must defer a donor from donating plasma by plasmapheresis for a period of 16 weeks if the donor donates two units of Red Blood Cells during a single apheresis procedure;

(iii) You must defer a donor for 8 weeks or more if the cumulative red blood cell loss in any 8 week period could adversely affect donor health.

(7) Exceptions to deferral due to red blood cell loss. You are not required to defer a Source Plasma donor from donating plasma by plasmapheresis due to red blood cell loss if the following conditions are met:

(i) The responsible physician examines the donor at the time of the current donation and determines and documents that the donor is in good health and the donor's health permits the plasmapheresis;

(ii) The donor's plasma possesses a property, such as an antibody, antigen, or protein deficiency that is transitory, of a highly unusual or infrequent specificity, or of an unusually high titer;

(iii) The special characteristics of the donor's plasma and the need for plasmapheresis of the donor under § 630.20(b) are documented at your establishment; and

(iv) The extracorporeal volume of the apheresis device is less than 100 milliliters.

(8) Malaria. Freedom from risk of malaria is not required for a donor of Source Plasma.

(9) You must comply with other requirements for collection of plasma in part 640 of this chapter and this part including restrictions on frequency of collection as specified in §§ 640.32 and 640.65 of this chapter.

§ 630.20 Exceptions for certain ineligible donors.

After assessing donor eligibility under §§ 630.10 and 630.15, an establishment may collect blood and blood components from a donor who is determined to be not eligible to donate under any provision of § 630.10(e) and (f) or § 630.15(a) if one of the following sets of conditions are met:

(a) The donation is for autologous use only as prescribed by the donor's physician, the donor has a hemoglobin level no less than 11.0 grams of hemoglobin per deciliter of blood or a hematocrit value no less than 33 percent, and the responsible physician determines and documents that the donor's health permits the collection procedure; or

(b) The donation is collected under a Source Plasma collection program which has received prior written approval from the Director, Center for Biologics Evaluation and Research, to collect plasma for further manufacturing use into in vitro products for which there are no alternative sources, the donor meets the criteria in § 630.10(f)(1) through (6), and the responsible physician determines and documents for each donation that the donor's health permits the collection procedure, and the collection takes place under the medical oversight specified in the approved plasmapheresis program.

(c) The donation is restricted for use solely by a specific transfusion recipient based on documented exceptional medical need, and the responsible physician determines and documents that the donor's health permits the collection procedure, and that the donation presents no undue medical risk to the transfusion recipient.

§ 630.25 Exceptions from certain donor eligibility requirements for infrequent plasma donors.

For an infrequent plasma donor who is not participating in an immunization program, establishments are not required to:

(a) Perform a medical history and physical examination of the donor under § 630.15(b)(1);

(b) Perform a test for total protein under § 630.15(b)(4);

(c) Determine the total plasma or serum protein and immunoglobulin composition under § 640.65(b)(1)(i) of this chapter; or

(d) Review the data and records as required in § 640.65(b)(2)(i) of this chapter.

§ 630.30 Donation suitability requirements.

(a) When is a donation suitable? A donation is suitable when:

(1) The donor is not currently deferred from donation as determined by review of the records of deferred donors required under § 606.160(e) of this chapter;

(2) The results in accordance with §§ 630.10 through 630.25 indicate that the donor is in good health and procedures were followed to ensure that the donation would not adversely affect the health of the donor;

(3) The results in accordance with § 630.10(e) indicate that the donor is free from risk factors for, or evidence of, relevant transfusion-transmitted infections and other factors that make the donor ineligible to donate;

(4) The donor's blood is tested in accordance with § 610.40 of this chapter, and is negative or nonreactive, unless an exception applies under § 610.40(h) of this chapter; and

(5) The donation meets other requirements in this subchapter.

(b) What must you do when the donation is not suitable? (1) You must not release the donation for transfusion or further manufacturing use unless it is an autologous donation, or an exception is provided in this chapter.

(2) You must defer the donor when a donation is determined to be unsuitable based on the criteria in paragraphs (a)(1) through (4) of this section.

(3) You must defer the donor of bacterially contaminated platelets when the contaminating organism is identified in accordance with § 606.145(d) of this chapter as likely to be associated with a bacterial infection that is endogenous to the bloodstream of the donor.

(4) You must notify the deferred donor in accordance with the notification requirements in § 630.40.

§ 630.35 Requalification of previously deferred donors.

Establishments may determine a deferred donor to be eligible as a donor of blood and blood components if, at the time of the current collection, the donor meets the eligibility criteria in this part, except for the record of the previous deferral, and you determine that the criteria that were the basis for the previous deferral are no longer applicable. Criteria for the previous deferral are no longer applicable if the following conditions are met:

(a) The previous deferral was for a defined period of time and that time period has passed, or the deferral was otherwise temporary, such as a deferral based on eligibility criteria described in §§ 630.10(f)(1) through (5) or 630.15(b)(4); or

(b) For a donor deferred for reasons other than under § 610.41(a) of this chapter, you determine that the donor has met criteria for requalification by a method or process found acceptable for such purpose by FDA.

§ 630.40 Requirements for notifying deferred donors.

(a) Notification of donors. You, an establishment that collects blood or blood components, must make reasonable attempts to notify any donor, including an autologous donor, who has been deferred based on the results of tests for evidence of infection with a relevant transfusion-transmitted infection(s) as required by § 610.41(a) of this chapter; any donor who has been deferred as required under § 630.30(b)(3) because their donated platelets have been determined under § 606.145(d) of this chapter to be contaminated with an organism that is identified as likely to be associated with a bacterial infection that is endogenous to the bloodstream of the donor; and any donor who has been determined not to be eligible as a donor based on eligibility criteria under §§ 630.10 and 630.15. You must attempt to obtain the results of further testing required under § 610.40(e) of this chapter prior to notifying a donor of the deferral. If notification occurs prior to receipt of such results, you must also notify a deferred donor of the results of the further testing. You must notify a donor as described in paragraph (b) of this section.

(b) Content of notification. You must provide the following information to a donor deferred or determined not to be eligible as a donor as described in paragraph (a) of this section:

(1) That the donor is deferred or determined not to be eligible for donation and the reason for that decision;

(2) Where appropriate, the types of donation of blood or blood components that the donor should not donate in the future;

(3) Where applicable, the results of tests for evidence of infection due to relevant transfusion-transmitted infection(s) that were a basis for deferral under § 610.41 of this chapter, including results of further testing as required in § 610.40(e) of this chapter; and,

(4) Where appropriate, information concerning medical followup and counseling.

(c) Time period for notification. You must make reasonable attempts to notify the donor within 8 weeks after determining that the donor is deferred or determined not to be eligible for donation as described in paragraph (a) of this section. You must document that you have successfully notified the donor or when you are unsuccessful that you have made reasonable attempts to notify the donor.

(d) Autologous donors. (1) You also must provide the following information to the referring physician of an autologous donor who is deferred based on the results of tests for evidence of infection with a relevant transfusion-transmitted infection(s) or whose platelets indicate evidence of a bacterial infection that is endogenous to the bloodstream of the donor as described in paragraph (a) of this section:

(i) Information that the autologous donor is deferred based on the results of tests for evidence of infection due to relevant transfusion-transmitted infection(s), as required under § 610.41 of this chapter, and the reason for that decision;

(ii) Where appropriate, the types of donation of blood or blood components that the autologous donor should not donate in the future; and

(iii) The results of tests for evidence of infection due to relevant transfusion-transmitted infection(s), that were a basis for deferral under § 610.41 of this chapter, including results of further testing as required in § 610.40(e) of this chapter.

(2) You must make reasonable attempts to notify the autologous donor's referring physician within 8 weeks after determining that the autologous donor is deferred as described in paragraph (a) of this section. You must document that you have successfully notified the autologous donor's referring physician or when you are unsuccessful that you have made reasonable attempts to notify the physician.

[66 FR 31176, June 11, 2001. Redesignated and amended at 80 FR 29898, May 22, 2015]

§ 640.1 Whole Blood.

The proper name of this product shall be Whole Blood. Whole Blood is defined as blood collected from human donors for transfusion to human recipients.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]

§ 640.2 General requirements.

(a) Manufacturing responsibility. All manufacturing of Whole Blood, including donor examination, blood collection, laboratory tests, labeling, storage and issue, shall be done under the supervision and control of the same licensed establishment except that the Director, Center for Biologics Evaluation and Research, may approve arrangements, upon joint request of two or more licensed establishments, which he finds are of such a nature as to assure compliance otherwise with the provisions of this subchapter.

(b) Blood container. The blood container shall not be entered prior to issue for any purpose except for blood collection or when the method of processing requires use of a different container. The container shall be uncolored and transparent to permit visual inspection of the contents and any closure shall be such as will maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, or potency of the blood.

(c) Reissue of blood. Blood that has been removed from storage controlled by a licensed establishment shall not be reissued by a licensed establishment unless the following conditions are observed:

(1) The container has a tamper-proof seal when originally issued and this seal remains unbroken;

(2) A segment is properly attached and has not been removed, except that blood lacking a properly attached segment may be reissued in an emergency provided it is accompanied by instructions for sampling and for use within 6 hours after entering the container for sampling;

(3) The blood has been stored continuously at 1 to 6 °C and shipped between 1 and 10 °C;

(4) The blood is held for observation until a significant inspection consistent with the requirements of § 640.5(e) can be made.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR 116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4, 2002]

§ 640.4 Collection of the blood.

(a) [Reserved]

(b) The donor center. The pertinent requirements of §§ 600.10 and 600.11 of this chapter shall apply at both the blood establishment and at any other place where the bleeding is performed.

(c) Blood containers. Blood containers and donor sets shall be pyrogen-free, sterile and identified by lot number. The amount of anticoagulant required for the quantity of blood to be collected shall be in the blood container when it is sterilized. In addition, all container and donor set surfaces that come in contact with blood used in the processing of Heparin Whole Blood shall be water repellent.

(d) The anticoagulant solution. The anticoagulant solution shall be sterile and pyrogen-free. Anticoagulant solutions shall be compounded and used according to a formula approved by the Director, Center for Biologics Evaluation and Research.

(e) Donor identification. Each unit of blood shall be so marked or identified by number or other symbol as to relate it to the individual donor whose identity shall be established to the extent necessary for compliance with § 630.10 of this chapter.

(f) Prevention of contamination of the blood. The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected by aseptic methods in a sterile system which may be closed or may be vented if the vent protects the blood against contamination.

(g) Samples and segments for laboratory tests. Samples and segments for laboratory tests shall meet the following standards:

(1) One or more segments shall be provided with each unit of blood when issued or reissued except as provided in § 640.2(c)(2) and all segments shall be from the donor who is the source of the unit of blood.

(2) All samples for laboratory tests performed by the manufacturer and all segments accompanying a unit of blood shall be collected at the time of filling the original blood container.

(3) All containers for all samples shall bear the donor's identification before collecting the samples.

(4) All segments accompanying a unit of blood shall be attached to the whole blood container before blood collection, in a tamperproof manner that will conspicuously indicate removal and reattachment.

(5) Segments for compatibility testing shall contain blood mixed with the appropriate anticoagulant.

(h) Storage. Whole Blood must be placed in storage at a temperature between 1 and 6 °C immediately after collection unless the blood is to be further processed into another component or the blood must be transported from the donor center to the processing laboratory. If transported, the blood must be placed in temporary storage having sufficient refrigeration capacity to cool the blood continuously toward a temperature range between 1 and 10 °C until arrival at the processing laboratory. At the processing laboratory, the blood must be stored at a temperature between 1 and 6 °C. Blood from which a component is to be prepared must be held in an environment maintained at a temperature range specified for that component in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, CBER.

[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May 22, 2015]

§ 640.5 Testing the blood.

All laboratory tests shall be made on a specimen of blood taken from the donor, and these tests shall include the following:

(a) [Reserved]

(b) Determination of blood group. Each container of Whole Blood shall be classified as to ABO blood group. At least two blood group tests shall be made and the unit shall not be issued until grouping tests by different methods or with different lots of antiserums are in agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, the regulations of this subchapter shall be used, and the technique used shall be that for which the serum is specifically designed to be effective.

(c) Determination of the Rh factors. Each container of Whole Blood shall be classified as to Rh type on the basis of tests done on the sample. The label shall indicate the extent of typing and the results of all tests performed. If the test, using Anti-D Blood Grouping Reagent, is positive, the container may be labeled “Rh Positive.” If the test is negative, the results shall be confirmed by further testing which shall include tests for the “weak D (formerly D u).” Blood may be labeled “Rh Negative” if further testing is negative. Units testing positive after additional more specific testing shall be labeled as “Rh Positive.” Only Anti-Rh Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, this subchapter shall be used, and the technique used shall be that for which the reagent is specifically designed to be effective.

(d) Sterility test. Whole Blood intended for transfusion shall not be tested for sterility by a method that entails entering the final container before the blood is used for transfusion.

(e) Inspection. Whole Blood shall be inspected visually during storage and immediately prior to issue. If the color or physical appearance is abnormal or there is any indication or suspicion of microbial contamination the unit of Whole Blood shall not be issued for transfusion.

(f) Test for relevant transfusion-transmitted infections. Whole Blood shall be tested for evidence of infection due to relevant transfusion-transmitted infections as required under § 610.40 of this chapter.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 80 FR 29904, May 22, 2015]

§ 640.6 Modifications of Whole Blood.

Upon approval by the Director, Center for Biologics Evaluation and Research, of a supplement to the biologics license application for Whole Blood a manufacturer may prepare Whole Blood from which the antihemophilic factor has been removed, provided the Whole Blood meets the applicable requirements of this subchapter and the following conditions are met:

(a) The antihemophilic factor shall be removed in accordance with paragraphs (a), (b), and (c) of § 640.52.

(b) Although the closed system between the red blood cells and plasma shall be maintained, the red blood cells shall be maintained between 1 and 6 °C at all times, including that time when the plasma is being frozen for removal of the antihemophilic factor.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]

§ 640.10 Red Blood Cells.

The proper name of this product shall be Red Blood Cells. The product is defined as red blood cells remaining after separating plasma from human blood.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]

§ 640.11 General requirements.

(a) Storage. Immediately after processing, the Red Blood Cells shall be placed in storage and maintained at a temperature between 1 and 6 °C.

(b) Inspection. The product shall be inspected immediately after separation of the plasma, periodically during storage, and at the time of issue. The product shall not be issued if there is any abnormality in color or physical appearance or if there is any indication of microbial contamination.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42 FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]

§ 640.12 Eligibility of donor.

Establishments must determine the eligibility of donors of the source blood for Red Blood Cells in accordance with §§ 630.10 and 630.15 of this chapter.

[80 FR 29904, May 22, 2015]

§ 640.13 Collection of the blood.

(a) The source blood shall be collected as prescribed in § 640.4.

(b) Source blood may also be derived from Whole Blood manufactured in accordance with applicable provisions of this subchapter.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999]

§ 640.14 Testing the blood.

Blood from which Red Blood Cells are prepared shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) and (c).

[53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015]

§ 640.15 Segments for testing.

Segments collected in integral tubing shall meet the following standards:

(a) One or more segments shall be provided with each unit of Whole Blood or Red Blood Cells when issued or reissued.

(b) Before they are filled, all segments shall be marked or identified so as to relate them to the donor of that unit of red cells.

(c) All segments accompanying a unit of Red Blood Cells shall be filled at the time the blood is collected or at the time the final product is prepared.

[66 FR 40890, Aug. 6, 2001]

§ 640.16 Processing.

(a) Separation. Within the timeframe specified in the directions for use for the blood collecting, processing, and storage system used, Red Blood Cells may be prepared either by centrifugation, done in a manner that will not tend to increase the temperature of the blood, or by normal undisturbed sedimentation. A portion of the plasma sufficient to insure optimal cell preservation shall be left with the red cells except when a cryoprotective substance or additive solution is added for prolonged storage.

(b) Sterile system. All surfaces that come in contact with the red cells shall be sterile and pyrogen-free.

(c) Final containers. Final containers used for Red Blood Cells shall be the original blood containers unless the method of processing requires a different container. The final container shall meet the requirements for blood containers prescribed in § 640.2(c). At the time of filing, if a different container is used, it shall be marked or identified by number or other symbol so as to relate it to the donor of that unit of red cells.

[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]

§ 640.17 Modifications for specific products.

Red Blood Cells Frozen: A cryophylactic substance may be added to the Red Blood Cells for extended manufacturers' storage at −65 °C or colder, provided the manufacturer submits data considered by the Director, Center for Biologics Evaluation and Research, as adequately demonstrating through in vivo cell survival and other appropriate tests that the addition of the substance, the materials used and the processing methods results in a final product that meets the required standards of safety, purity, and potency for Red Blood Cells, and that the frozen product will maintain those properties for the prescribed dating period. Section 640.11 (a) and (b) do not apply while a cryophylactic substance is present.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]

§ 640.20 Platelets.

(a) Proper name and definition. The proper name of this product shall be Platelets. The product is defined as platelets collected from one unit of blood and resuspended in an appropriate volume of original plasma, as prescribed in § 640.24(d).

(b) Source. The source material for Platelets is plasma which may be obtained by whole blood collection or by plateletpheresis.

[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007]

§ 640.21 Eligibility of donors.

(a) Establishments must determine the eligibility of donors of platelets derived from Whole Blood and donors of platelets collected by plateletpheresis in accordance with §§ 630.10 and 630.15 of this chapter, except as provided in this section.

(b) A plateletpheresis donor must not serve as the source of platelets for transfusion if the donor has recently ingested a drug that adversely affects platelet function.

(c) A Whole Blood donor must not serve as the source of platelets for transfusion if the donor has recently ingested a drug that adversely affects platelet function unless the unit is labeled to identify the ingested drug that adversely affects platelet function.

(d) If you are collecting platelets by plateletpheresis, you must assess and monitor the donor's platelet count.

(1) You must take adequate and appropriate steps to assure that the donor's platelet count is at least 150,000 platelets per microliter (/µL) before plateletpheresis begins. Exception: If you do not have records of a donor's platelet count from prior donations and you are not able to assess the donor's platelet count either prior to or immediately following the initiation of the collection procedure, you may collect platelets by plateletpheresis, but you must not collect 9.0 × 10 11 or more platelets from that donor.

(2) You must defer from platelet donation a donor whose pre-donation platelet count is less than 150,000 platelets/µL until a subsequent pre-donation platelet count indicates that the donor's platelet count is at least 150,000 platelets/µL; and

(3) You must take appropriate steps to assure that the donor's intended post-donation platelet count will be no less than 100,000 platelets/µL.

(e) Frequency of plateletpheresis collection. (1) The donor may donate no more than a total of 24 plateletpheresis collections during a 12-month rolling period.

(2) When you collect fewer than 6 × 10 11 platelets, you must wait at least 2 calendar days before any subsequent plateletpheresis collection. You must not attempt to collect more than 2 collections within a 7 calendar day period.

(3) When you collect 6 × 10 11 or more platelets, you must wait at least 7 calendar days before any subsequent plateletpheresis collection.

(4) Exception. For a period not to exceed 30 calendar days, a donor may serve as a dedicated plateletpheresis donor for a single recipient, in accordance with § 610.40(c)(1) of this chapter, as often as is medically necessary, provided that the donor is in good health, as determined and documented by the responsible physician, and the donor's platelet count is at least 150,000 platelets/µL, measured at the conclusion of the previous donation or before initiating plateletpheresis for the current donation.

(f) Deferral of plateletpheresis donors due to red blood cell loss. (1) You must defer a donor from donating platelets by plateletpheresis or a co-collection of platelets and plasma by apheresis for 8 weeks if the donor has donated a unit of Whole Blood, or a single unit of Red Blood Cells by apheresis unless at least 2 calendar days have passed and the extracorporeal volume of the apheresis device is less than 100 milliliters.

(2) You must defer a donor from donating platelets for a period of 16 weeks if the donor donates two units of Red Blood Cells during a single apheresis procedure.

(3) You must defer a donor for 8 weeks or more if the cumulative red blood cell loss in any 8 week period could adversely affect donor health.

(g) The responsible physician must obtain the informed consent of a plateletpheresis donor on the first day of donation, and at subsequent intervals no longer than 1 year.

(1) The responsible physician must explain the risks and hazards of the procedure to the donor; and

(2) The explanation must be made in such a manner that the donor may give consent, and has a clear opportunity to refuse the procedure.

[80 FR 29904, May 22, 2015]

§ 640.22 Collection of source material.

(a) Whole blood used as the source of Platelets shall be collected as prescribed in § 640.4.

(b) [Reserved]

(c) If plateletpheresis is used, the procedure for collection must be as prescribed in §§ 640.21, 640.64 (except paragraph (c)), and 640.65, or as described in an approved biologics license application (BLA) or an approved supplement to a BLA.

(d) The phlebotomy shall be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue.

[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22, 2015]

§ 640.23 Testing the blood.

(a) Blood from which plasma is separated for the preparation of Platelets shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) and (c).

(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.

[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015]

§ 640.24 Processing.

(a) Separation of plasma and platelets and resuspension of the platelets must be in a closed system. Platelets must not be pooled during processing unless the platelets are pooled as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluation and Research.

(b) Immediately after collection, the whole blood or plasma shall be held in storage between 20 and 24 °C unless it must be transported from the collection center to the processing laboratory. During such transport, all reasonable methods shall be used to maintain the temperature as close as possible to a range between 20 and 24 °C until it arrives at the processing laboratory where it shall be held between 20 and 24 °C until the platelets are separated. The platelet concentrate shall be separated within 4 hours or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system.

(c) The time and speed of centrifugation must have been demonstrated to produce an unclumped product, without visible hemolysis, that yields a count of not less than 5.5 × 10 10 platelets per unit in at least 75 percent of the units tested.

(d) The volume of original plasma used for resuspension of the platelets shall be determined by the maintenance of a pH of not less than 6.2 during the storage period. The pH shall be measured on a sample of platelets which has been stored for the maximum dating period at the selected storage temperature. One of the following storage temperatures shall be used continuously:

(1) 20 to 24 °C.

(2) 1 to 6 °C.

(e) Final containers used for Platelets shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, or efficacy of the product. At the time of filling, the final container shall be marked or identified by number so as to relate it to the donor.

[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, 2008]

§ 640.25 General requirements.

(a) Storage. Immediately after resuspension, Platelets shall be placed in storage at the selected temperature range. If stored at 20 to 24 °C, a continuous gentle agitation of the platelet concentrate shall be maintained throughout the storage period. Agitation is optional if stored at a temperature between 1 and 6 °C.

(b) Quality control testing. Each month four units prepared from different donors shall be tested at the end of the storage period as follows:

(1) Platelet count.

(2) pH of not less than 6.2 measured at the storage temperature of the unit.

(3) Measurement of actual plasma volume.

(4) If the results of the quality control testing indicate that the product does not meet the prescribed requirements, immediate corrective action shall be taken and a record maintained of such action.

(c) Manufacturing responsibility. All manufacturing of Platelets shall be performed at the same licensed establishment, except that the quality control testing under paragraph (b) of this section may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and is qualified to perform platelet counts. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of this chapter, provided the following conditions are met:

(1) The results of each test are received within 10 days of the preparation of the platelet concentrate, and are maintained by the establishment licensed for Platelets so that they may be reviewed by an authorized representative of the Food and Drug Administration.

(2) The licensed Platelets manufacturer has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 66 FR 1836, Jan. 10, 2001; 72 FR 45888, Aug. 16, 2007]

§ 640.30 Plasma.

(a) Proper name and definition. The proper name of this component is Plasma. The component is defined as:

(1) The fluid portion of one unit of human blood intended for intravenous use which is collected in a closed system, stabilized against clotting, and separated from the red cells; or

(2) The fluid portion of human blood intended for intravenous use which is prepared by apheresis methods as specified in the directions for use for the blood collecting, processing, and storage system including closed and open systems.

(b) Source. (1) Plasma shall be obtained by separating plasma from blood collected from blood donors or by plasmapheresis.

(2) Plasma may be obtained from a unit of Whole Blood collected by another licensed establishment.

[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 50 FR 4139, Jan. 29, 1985; 72 FR 45888, Aug. 16, 2007]

§ 640.31 Eligibility of donors.

(a) Whole Blood donors must meet the criteria for donor eligibility prescribed in §§ 630.10 and 630.15 of this chapter.

(b) Collection establishments must determine the eligibility of plasmapheresis donors in accordance with §§ 630.10 and 630.15 of this chapter.

[80 FR 29904, May 22, 2015]

§ 640.32 Collection of source material.

(a) Whole Blood must be collected, transported, and stored as prescribed in § 640.4. When whole blood is intended for Plasma, Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the whole blood must be maintained at a temperature between 1 and 6 °C or as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluations and Research. Whole blood intended for Platelet Rich Plasma must be maintained as prescribed in § 640.24 until the plasma is removed. The red blood cells must be placed in storage at a temperature between 1 and 6 °C immediately after the plasma is separated.

(b) Plasma obtained by plasmapheresis shall be collected as prescribed in § 640.64 (except that paragraph (c)(3) of § 640.64 shall not apply), and § 640.65.

[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980; 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, Aug. 16, 2007; 80 FR 29905, May 22, 2015]

§ 640.33 Testing the blood.

(a) Blood from which plasma is separated shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) and (c).

(b) Manufacturers of Plasma collected by plasmapheresis shall have testing and recordkeeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.

[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015]

§ 640.34 Processing.

(a) Plasma. Plasma shall be separated from the red blood cells and shall be stored at −18 °C or colder within 6 hours after transfer to the final container or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system unless the product is to be stored as Liquid Plasma.

(b) Fresh Frozen Plasma. Fresh frozen plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and minimal manipulation of the donor's tissue. The plasma must be separated from the red blood cells or collected by an apheresis procedure, and placed in a freezer within 8 hours or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system, and stored at −18 °C or colder.

(c) Liquid Plasma. Liquid Plasma shall be separated from the red blood cells and shall be stored at a temperature of 1 to 6 °C within 4 hours after filling the final container or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system.

(d) Platelet Rich Plasma. Platelet rich plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and manipulation of the donor's tissue. The plasma shall be separated from the red blood cells by centrifugation within 4 hours after completion of the phlebotomy or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. The time and speed of the centrifugation shall have been shown to produce a product with at least 250,000 platelets per microliter. The plasma shall be stored at a temperature between 20 and 24 °C immediately after filling the final container. A gentle and continuous agitation of the product shall be maintained throughout the storage period, if stored at a temperature of 20 to 24 °C.

(e) Modifications of Plasma. It is possible to separate Platelets and/or Cryoprecipitated AHF from Plasma. When these components are to be separated, the plasma shall be collected as described in § 640.32 for Plasma.

(1) Platelets shall be separated as prescribed in subpart C of part 640, prior to freezing the plasma. The remaining plasma may be labeled as “Fresh Frozen Plasma,” if frozen within 6 hours after filling the final container or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system.

(2) Cryoprecipitated AHF shall be removed as prescribed in subpart F of part 640. The remaining plasma shall be labeled “Plasma, Cryoprecipitate Reduced.”

(3) Plasma remaining after both Platelets and Cryoprecipitated AHF have been removed may be labeled “Plasma, Cryoprecipitate Reduced.”

(f) The final container. (1) The final container shall have no color added to the plastic and shall be transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents.

(2) The final container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, and effectiveness of the product.

(3) Prior to filling, the final container shall be identified by number so as to relate it to the donor.

(g) The final product. (1) The final product shall be inspected immediately after separation of the plasma and shall not be issued for transfusion if there is (i) any abnormality in color or physical appearance, or (ii) any indication of contamination.

(2) With the exception of Platelet Rich Plasma and Liquid Plasma the final product shall be inspected for evidence of thawing or breakage at the time of issuance, however, the containers need not be stored in a manner that shows evidence of thawing if records of continuous monitoring of the storage temperature establish that the temperature remained at −18 °C or colder. If continuous monitoring of the product is not available, the final product shall be stored in a manner that will show evidence of thawing and shall not be issued if there is any evidence of thawing.

(3) No preservative shall be added to the final product.

[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4, 1978; 48 FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR 45888, Aug. 16, 2007]

§ 640.50 Cryoprecipitated AHF.

(a) Proper name and definition. The proper name of this product shall be Cryoprecipitated AHF. The product is defined as a preparation of antihemophilic factor, which is obtained from a single unit of plasma collected and processed in a closed system.

(b) Source. The source material for Cryoprecipitated AHF shall be plasma which may be obtained by whole blood collection or by plasmapheresis.

[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 50 FR 4139, Jan. 29, 1985]

§ 640.51 Eligibility of donors.

(a) Whole blood donors must meet the criteria for eligibility prescribed in §§ 630.10 and 630.15 of this chapter.

(b) Collection establishments must determine the eligibility of plasmapheresis donors in accordance with §§ 630.10 and 630.15 of this chapter.

[80 FR 29905, May 22, 2015]

§ 640.52 Collection of source material.

(a) Whole blood used as a source of Cryoprecipitated AHF shall be collected as prescribed in § 640.4. Whole blood from which both Platelets and Cryoprecipitated AHF is derived shall be maintained as required under § 640.24 until the platelets are removed.

(b) If plasmapheresis is used, the procedure for collection shall be as prescribed in § 640.64 (except that paragraph (c)(3) of that section shall not apply), and 640.65.

[42 FR 21774, Apr. 29, 1977, as amended at 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 80 FR 29905, May 22, 2015]

§ 640.53 Testing the blood.

(a) Blood from which plasma is separated for the preparation of Cryoprecipitated AHF shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) and (c).

(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.

(c) Manufacturers of Cryoprecipitated AHF obtained from plasma collected by plasmapheresis shall have testing and record-keeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.

[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977; 42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015]

§ 640.54 Processing.

(a) Processing the plasma. (1) The plasma shall be separated from the red blood cells by centrifugation to obtain essentially cell-free plasma.

(2) The plasma shall be placed in a freezer within 8 hours after blood collection or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. A combination of dry ice and organic solvent may be used for freezing: Provided, That the procedure has been shown not to cause the solvent to penetrate the container or leach plasticizer from the container into the plasma.

(3) Immediately after separation and freezing of the plasma, the plasma shall be stored and maintained at −18 °C or colder until thawing of the plasma for further processing to remove the Cryoprecipitated AHF.

(b) Processing the final product. (1) The Cryoprecipitated AHF shall be separated from the plasma by a procedure that has been shown to produce an average of no less than 80 units of antihemophilic factor per final container.

(2) No diluent shall be added to the product by the manufacturer prior to freezing.

(3) The final container used for Cryoprecipitated AHF shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents under customary conditions of storage and use in such a manner as to have an adverse effect upon the safety, purity, potency and effectiveness of the product. At the time of filling, the final container shall be identified by a number so as to relate it to the donor.

[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]

§ 640.55 U.S. Standard preparation.

A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may be obtained from the Center for Biologics Evaluation and Research, (HFM-407) (see mailing addresses in § 600.2 of this chapter) for use in the preparation of a working reference to be employed in a quality control potency test of Cryoprecipitated AHF.

[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005]

§ 640.56 Quality control test for potency.

(a) Quality control tests for potency of antihemophilic factor shall be conducted each month on at least four representative containers of Cryoprecipitated AHF.

(b) The results of each test are received by the establishment licensed for Cryoprecipitated AHF within 30 days of the preparation of the cryoprecipitated antihemophilic factor and are maintained at that establishment so that they may be reviewed by an authorized representative of the Food and Drug Administration.

(c) The quality control test for potency may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and is qualified to perform potency tests for antihemophilic factor. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of this chapter, provided the following conditions are met:

(1) The establishment licensed for Cryoprecipitated AHF has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

(d) If the average potency level of antihemophilic factor in the containers tested is less than 80 units of antihemophilic factor per container, immediate corrective actions shall be taken and a record maintained of such action.

[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001]

§ 640.60 Source Plasma.

The proper name of the product shall be Source Plasma. The product is defined as the fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use. The definition excludes single donor plasma products intended for intravenous use.

[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]

§ 640.64 Collection of blood for Source Plasma.

(a) [Reserved]

(b) Blood containers. Blood containers and donor sets must be pyrogen-free, sterile, and identified by lot number.

(c) The anticoagulant solution. The anticoagulant solution must be sterile and pyrogen-free. Anticoagulant solutions must be compounded and used according to a formula that has been approved for the applicant by the Director, Center for Biologics Evaluation and Research.

(d) Donor identification. Each unit of blood and plasma shall be so marked or identified by number or other symbol so as to relate it directly to the donor.

(e) Prevention of contamination of the blood and plasma. The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected, the plasma separated, and the cells returned to the donor by aseptic methods in a sterile system which may be closed, or may be vented if the vent protects the blood cells and plasma against contamination.

[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at 41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16, 2007; 80 FR 29905, May 22, 2015]

§ 640.65 Plasmapheresis.

(a) Procedure-general. The plasmapheresis procedure is a procedure in which, during a single visit to the establishment, blood is removed from a donor, the plasma separated from the formed elements, and at least the red blood cells returned to the donor. This procedure shall be described in detail in the biologics license application.

(b) Procedures-specific requirements. The plasmapheresis procedure shall meet the following requirements:

(1)(i) Except as provided under § 630.25 of this chapter, the responsible physician must draw a sample of blood from each donor on the day of the initial physical examination or plasmapheresis, whichever comes first, and at least every 4 months thereafter. A serologic test for syphilis, a total plasma or serum protein determination, and a plasma or serum protein electrophoresis or quantitative immuno-diffusion test or an equivalent test to determine immunoglobulin composition of the plasma or serum shall be performed on the sample.

(ii) A repeat donor who does not return for plasmapheresis at the time the 4-month sample is due to be collected may be plasmapheresed on the day he appears: Provided, That no longer than 6 months has elapsed since the last sample was collected, and the responsible physician approves the plasmapheresis procedure and so indicates by signing the donor's record before such procedure is performed. The sample for the 4-month tests shall be collected on the day of the donor's return.

(iii) A repeat donor from whom the plasmapheresis center is unable to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of this section for a total period exceeding 6 months shall be processed as a new donor.

(2)(i) Except as provided under § 630.25 of this chapter, the responsible physician must review the accumulated laboratory data, including any tracings of the plasma or serum protein electrophoresis pattern, the calculated values of the protein composition of each component, and the collection records within 14 calendar days after the sample is drawn to determine whether or not the donor should be deferred from further donation. If a determination is not made within 14 calendar days, the donor must be deferred pending such a determination. The responsible physician must sign the review. If the protein composition is not within normal limits established by the testing laboratory, or if the total protein level is less than 6.0 grams per deciliter or more than 9.0 grams per deciliter in a plasma sample or serum sample, the donor must be deferred from donation until the protein composition returns to acceptable levels. Reinstatement of the donor into the plasmapheresis program when the donor's protein composition values have returned to an acceptable level must first be approved by the responsible physician.

(ii) A donor with a reactive serologic test for syphilis shall not be plasmapheresed again until the donor's serum is tested and found to be nonreactive to a serologic test for syphilis, except as provided in paragraph (b)(2) (iii) and (iv) of this section.

(iii) A donor whose serum is determined to have a biologic false-positive reaction to a serologic test for syphilis may be plasmapheresed: Provided, That the donor's file identifies the serologic test for syphilis and results used to confirm the biologic false-positive reaction and indicates that the responsible physician has determined the false-positive reaction is not the result of an underlying disorder that would disqualify the donor from participation in the plasmapheresis program. If the serologic test for syphilis is performed at a facility other than the plasmapheresis center, all applicable provisions of § 640.71 shall be met.

(iv) A donor with a reactive serologic test for syphilis may be plasmapheresed only to obtain plasma to be used for further manufacturing into control serum for the serologic test for syphilis: Provided, That the responsible physician approves the donation, the donor's file contains a signed statement from a physician or clinic establishing that treatment for syphilis has been initiated and that continuance in the plasmapheresis program will not interfere with or jeopardize the treatment of the syphilitic donor.

(3) A donor identification system shall be established that positively identifies each donor and relates such donor directly to his blood and its components as well as to his accumulated records and laboratory data. Such system shall include either a photograph of each donor which shall be used on each visit to confirm the donor's identity, or some other method that provides equal or greater assurance of positively identifying the donor.

(4) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure or in any 2-day period shall not exceed 1,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from the donor during a manual plasmapheresis procedure or in any 2-day period shall not exceed 1,200 milliliters.

(5) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure within a 7-day period shall not exceed 2,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure within a 7-day period shall not exceed 2,400 milliliters.

(6) No more than 500 milliliters of whole blood shall be removed from a donor at one time, unless the donor's weight is 175 pounds or greater, in which case no more than 600 milliliters of whole blood shall be removed from the donor at one time.

(7) The plasma shall be separated from the red blood cells immediately after blood collection. The maximum feasible volume of red blood cells shall be returned to the donor before another unit is collected.

(8) The volume of plasma collected during an automated plasmapheresis collection procedure shall be consistent with the volumes specifically approved by the Director, Center for Biologics Evaluation and Research, and collection shall not occur less than 2 days apart or more frequently than twice in a 7-day period.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, May 22, 2015]

§ 640.66 Immunization of donors.

If specific immunization of a donor is to be performed, the selection, scheduling and administration of the antigen, and the evaluation of each donor's clinical response, shall be by the responsible physician. Any material used for immunization shall be either a product licensed under section 351 of the Public Health Service Act for such purpose or one specifically approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Immunization procedures shall be on file at each plasmapheresis center where immunizations are performed.

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 80 FR 29905, May 22, 2015]

§ 640.67 Laboratory tests.

Each unit of Source Plasma shall be tested for evidence of infection due to relevant transfusion-transmitted infections as required under § 610.40 of this chapter.

[66 FR 31165, June 11, 2001, as amended at 80 FR 29905, May 22, 2015]

§ 640.68 Processing.

(a) Sterile system. All administration and transfer sets inserted into blood containers used for processing Source Plasma intended for manufacturing into injectable or noninjectable products and all interior surfaces of plasma containers used for processing Source Plasma intended for manufacturing into injectable products shall be sterile, pyrogen-free, nontoxic, and compatible with the contents under normal conditions of use. Only Sodium Chloride Injection USP shall be used as a red blood cell diluent. If the method of separation of the plasma intended for injectable products involves a system in which an airway must be inserted into the plasma container, the airway shall be sterile and constructed so as to exclude microorganisms and maintain a sterile system.

(b) Final containers. Final containers used for Source Plasma, whether integrally attached or separated from the original blood container, shall not be entered prior to issuance for any purpose except for filling with the plasma. Such containers shall be uncolored and hermetically sealed, and shall permit clear visibility of the contents. Final containers and their components shall not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination. Prior to filling, the final container shall be marked or identified by number or other symbol which will relate it directly to the donor.

(c) Preservative. Source Plasma shall not contain a preservative.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29, 1985]

§ 640.69 General requirements.

(a) Pooling. Two units of Source Plasma from the same donor may be pooled if such units are collected during one plasmapheresis procedure: Provided, That the pooling is done by a procedure that does not introduce a risk of contamination of the red blood cells and, for plasma intended for injectable products, gives maximum assurance of a sterile container of plasma.

(1) The pooling of plasma from two or more donors is not permitted in the manufacture of Source Plasma intended for manufacturing into injectable products.

(2) The pooling of plasma from two or more donors by the manufacturer of Source Plasma intended for manufacturing into noninjectable products is permitted: Provided, That the plasma from two or more donors is pooled after the plasma has been removed from the red blood cells, and after the red blood cell containers are sealed.

(b) Storage. Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than −20 °C, except for plasma collected as provided in § 640.74. Plasma intended for manufacturing into noninjectable products may be stored at temperatures appropriate for the intended use of the final product, provided these temperatures are included in the Source Plasma license application.

(c) Inspection. Source Plasma intended for manufacturing into injectable products shall be inspected for evidence of thawing at the time of issuance, except that inspection of individual plasma containers need not be made if the records of continuous monitoring of the storage temperature establish that the temperature remained at −20 °C or colder. If there is evidence that the storage temperature has not been maintained at −20 °C or colder, the plasma may be relabeled and issued as provided in § 640.76(a).

(d) Samples. If samples are provided, they shall meet the following standards:

(1) Prior to filling, all samples shall be marked or identified so as to relate them directly to the donor of that unit of plasma.

(2) All samples shall be filled at the time the final product is prepared by the person who prepares the final product.

(3) All samples shall be representative of the contents of the final product or be collected from the donor at the time of filling the collection container.

(4) All samples shall be collected in a manner that does not contaminate the contents of the final container.

(e) Restrictions on distribution. Establishments must ensure that Source Plasma donated by paid donors not be used for further manufacturing into injectable products until the donor has a record of being found eligible to donate in accordance with § 630.10 of this chapter and a record of negative test results on all tests required under § 610.40(a) of this chapter on two occasions in the past 6 months.

(f) Hold. Source Plasma donated by paid donors determined to be suitable for further manufacturing into injectable products must be held in quarantine for a minimum of 60 calendar days before it is released for further manufacturing. If, after placing a donation in quarantine under this section, the donor is subsequently deferred under § 610.41 of this chapter, or you subsequently determine a donor to be ineligible under § 630.10 of this chapter due to risk factors closely associated with exposure to, or clinical evidence of, infection due to a relevant transfusion-transmitted infection, you must not distribute quarantined donations from that donor for further manufacturing use to make an injectable product.

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR 29905, May 22, 2015]

§ 640.71 Manufacturing responsibility.

(a) All steps in the manufacturing of Source Plasma, including donor examination, blood collection, plasmapheresis, laboratory testing, labeling, storage, and issuing shall be performed by personnel of the establishment licensed to manufacture Source Plasma, except that testing performed in accordance with § 610.40 of this chapter and § 640.65(b) may be performed by personnel of an establishment licensed for blood and blood derivatives under section 351(a) of the Public Health Service Act, or by a clinical laboratory that meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a): Provided, The establishment or clinical laboratory is qualified to perform the assigned test(s).

(b) Such testing shall not be considered divided manufacturing, which requires two biologics licenses for Source Plasma: Provided, That

(1) The results of such tests are maintained by the licensed manufacturer of the Source Plasma whereby such results may be reviewed by a responsible physician as required in § 640.65(b)(2) of this chapter and by an authorized representative of the Food and Drug Administration.

(2) The Source Plasma manufacturer has obtained a written agreement that the testing laboratory will permit authorized representatives of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR 1837, Jan. 10, 2001; 80 FR 29905, May 22, 2015]

§ 640.72 Records.

(a) In addition to the recordkeeping requirements of this subchapter, the following records shall be maintained:

(1) Documentation shall be available to ensure that the shipping temperature requirements of § 600.15 of this title and of § 640.74(b)(2) are being met for Source Plasma intended for manufacture into injectable products.

(2)(i) For each donor, establishments must maintain records including a separate and complete record of initial and periodic examinations, tests, laboratory data, and interviews, etc., as required in §§ 630.10 and 630.15 of this chapter and §§ 640.65, 640.66, and 640.67, except as provided in paragraph (a)(2)(ii) of this section.

(ii) Negative results for testing for evidence of infection due to relevant transfusion-transmitted infections required in § 610.40 of this chapter, and the volume or weight of plasma withdrawn from a donor need not be recorded on the individual donor record if such information is maintained on the premises of the plasmapheresis center where the donor's plasma has been collected.

(3) The original or a clear copy or other durable record which may be electronic of the donor's consent for participation in the plasmapheresis program or for immunization.

(4) Records of the medical history and physical examination of the donor conducted in accordance with § 630.15(b)(1) of this chapter and, where applicable, § 630.15(b)(5) of this chapter must document the eligibility of the donor as a plasmapheresis donor and, when applicable, as an immunized donor.

(5) If plasma that is reactive to a serologic test for syphilis is issued as prescribed in § 640.65(b)(2)(iv), the distribution records shall indicate by number those units that are reactive.

(b) Each donor record must be directly cross-referenced to the unit(s) of Source Plasma associated with the donor.

(c) If a repeat donor is rejected or a donor's plasma is found unsuitable, the donor's record shall contain a full explanation for the rejection.

(d) If a donor has a reaction while on the plasmapheresis premises, or a donor reaction is reported to the center after the donor has left the premises, the donor's record shall contain a full explanation of the reaction, including the measures taken to assist the donor and the outcome of the incident.

[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4, 2002; 80 FR 29905, May 22, 2015]

§ 640.73 Reporting of fatal donor reactions.

If a donor has a fatal reaction which, in any way, may be associated with plasmapheresis the Director of the Center for Biologics Evaluation and Research shall be notified by telephone as soon as possible. If the facility is located outside of the continental United States, notification by cable or telegram shall be acceptable.

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

§ 640.74 Modification of Source Plasma.

(a) Upon approval by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, of a supplement to the biologics license application for Source Plasma, a manufacturer may prepare Source Plasma as a liquid product for a licensed blood derivative manufacturer who has indicated a need for a liquid product.

(b) Source Plasma Liquid shall meet all standards of the frozen Source Plasma except:

(1) Source Plasma Liquid shall be stored in nonleachable containers so that the containers and their components will not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination.

(2) Source Plasma Liquid shall be shipped, stored and labeled for storage at a temperature of 10 °C or colder. An exception to the shipping or storage temperature shall be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, based upon his receipt of substantial evidence to support another temperature. Such evidence may be submitted by either the licensed manufacturer of the Source Plasma Liquid or the manufacturer of the final blood derivative product who has requested the Source Plasma Liquid.

(3) The label for the Source Plasma Liquid shall be easily distinguished from that of the frozen product. Color coding shall not be used for this purpose.

(4) The label affixed to each container of Source Plasma Liquid shall contain, in addition to the information required by § 606.121 of this chapter, but excluding § 606.121(e)(5)(ii) of this chapter, the name of the manufacturer of the final blood derivative product for whom it was prepared.

(5) Source Plasma Liquid shall be inspected immediately prior to issuance. If the color or physical appearance is abnormal, or there is any indication or suspicion of microbial contamination, the unit of Source Plasma Liquid shall not be issued.

[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012]

§ 640.76 Products stored or shipped at unacceptable temperatures.

(a) Storage temperature. (1) Except as provided in paragraph (a)(2) of this section, Source Plasma intended for manufacture into injectable products that is inadvertently exposed (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a storage temperature warmer than −20 °C and colder than + 10 °C may be issued only if labeled as “Source Plasma Salvaged.” The label shall be revised before issuance, and appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining fully the conditions that caused the inadvertent temperature exposure.

(2) Source Plasma intended for manufacture into injectable products that is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to one episode of storage temperature fluctuation that is warmer than −20 °C and colder than −5 °C for not more than 72 hours is exempt from the labeling requirements of paragraph (a)(1) of this section, provided that the plasma has been and remains frozen solid. Appropriate records shall be maintained identifying the units involved, describing their disposition, explaining fully the conditions that caused the inadvertent temperature exposure, and documenting that the episode of temperature elevation did not exceed 72 hours, that the temperature did not rise to warmer than −5 °C in storage, and that the plasma remained frozen solid throughout the period of elevated temperature. When requested, copies of the records shall be provided to the plasma derivative manufacturer.

(b) Shipping temperature. If Source Plasma for manufacture into injectable products is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a shipping temperature warmer than −5 °C and colder than + 10 °C, the plasma derivative manufacturer shall label it “Source Plasma Salvaged.” Appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining fully the conditions that caused the inadvertent temperature exposure.

(c) Relabeling. If Source Plasma is required to be relabeled as “Source Plasma Salvaged” under paragraph (a)(1) or (b) of this section, the person responsible for the relabeling shall cover the original label with either (1) a complete new label containing the appropriate information or (2) a partial label affixed to the original label and containing the appropriate new information, which covers the incorrect information regarding storage temperature.

[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]

§ 640.80 Albumin (Human).

(a) Proper name and definition. The proper name of the product shall be Albumin (Human). The product is defined as a sterile solution of the albumin derived from human plasma.

(b) Source material. The source material of Albumin (Human) shall be plasma recovered from Whole Blood prepared as prescribed in §§ 640.1 through 640.5, or Source Plasma prepared as prescribed in §§ 640.60 through 640.76.

(c) Additives in source material. Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.

[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, 1999]

§ 640.81 Processing.

(a) Date of manufacture. The date of manufacture shall be the date of final sterile filtration of a uniform pool of bulk solution.

(b) Processing method. The processing method shall not affect the integrity of the product, and shall have been shown to yield consistently a product which is safe for intravenous injection.

(c) Microbial contamination. All processing steps shall be conducted in a manner to minimize the risk of contamination from microorganisms, pyrogens, or other impurities. Preservatives to inhibit growth of microorganisms shall not be used during processing.

(d) Storage of bulk fraction. Bulk concentrate to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of −5 °C or colder. Any other bulk form of the product, exclusive of the sterile bulk solution, to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk fraction to be held one week or less prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder.

(e) Heat treatment. Heating of the final containers of Albumin (Human) shall begin within 24 hours after completion of filling. Heat treatment shall be conducted so that the solution is heated continuously for not less than 10, or more than 11 hours, at an attained temperature of 60±0.5 °C.

(f) Stabilizer. Either 0.08±0.016 millimole sodium caprylate, or 0.08±0.016 millimole sodium acetyltryptophanate and 0.08±0.016 millimole sodium caprylate per gram of protein shall be present as a stabilizer(s). Calculations of the stabilizer concentration may employ the labeled value for the protein concentration of the product as referred to in § 640.84(d).

(g) Incubation. All final containers of Albumin (Human) shall be incubated at 20 to 35 °C for at least 14 days following the heat treatment prescribed in paragraph (e) of this section. At the end of this incubation period, each final container shall be examined and all containers showing any indication of turbidity or microbial contamination shall not be issued. The contents of turbid final containers shall be examined microscopically and tested for sterility. If growth occurs, organisms shall be identified as to genus, and the material from such containers shall not be used for further manufacturing.

[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000]

§ 640.82 Tests on final product.

Tests shall be performed on the final product to determine that it meets the following standards:

(a) Protein concentration. Final product shall conform to one of the following concentrations: 4.0 ±0.25 percent; 5.0 ±0.30 percent; 20.0 ±1.2 percent; and 25.0 ±1.5 percent solution of protein.

(b) Protein composition. At least 96 percent of the total protein in the final product shall be albumin, as determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(c) pH. The pH shall be 6.9 ±0.5 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.

(d) Sodium concentration. The sodium concentration of the final product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the final product shall not exceed 2 milliequivalents per liter.

(f) Heat stability. A final container sample of Albumin (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.

[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 1999]

§ 640.83 General requirements.

(a) Preservative. The final product shall not contain a preservative.

(b) Storage of bulk solution. After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.

[42 FR 27582, May 31, 1977]

§ 640.84 Labeling.

In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:

(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter;

(b) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More Than 4 Hours After the Container Has Been Entered.”;

(c) The need for additional fluids when 20 percent or 25 percent albumin is administered to a patient with marked dehydration;

(d) The protein concentration, expressed as a 4 percent, 5 percent, 20 percent, or 25 percent solution.

[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, 1999]

§ 640.90 Plasma Protein Fraction (Human).

(a) Proper name and definition. The proper name of the product shall be Plasma Protein Fraction (Human). The product is defined as a sterile solution of protein composed of albumin and globulin, derived from human plasma.

(b) Source material. The source material of Plasma Protein Fraction (Human) shall be plasma recovered from Whole Blood prepared as prescribed in §§ 640.1 through 640.5, or Source Plasma prepared as prescribed in §§ 640.60 through 640.76.

(c) Additives in source material. Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.

[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]

§ 640.91 Processing.

(a) Date of manufacture. The date of manufacture shall be the date of final sterile filtration of a uniform pool of bulk solution.

(b) Processing method. The processing method shall not affect the integrity of the product, and shall have been shown to yield consistently a product which:

(1) After the heating prescribed in paragraph (e) of this section does not show an increase in the components with electrophoretic mobility similar to that of alpha globulin that amounts to more than 5 percent of the total protein.

(2) Contains less than 5 percent protein with a sedimentation coefficient greater than 7.0 S.

(3) Is safe for intravenous injection.

(c) Microbial contamination. All processing steps shall be conducted in a manner to minimize the risk of contamination from microorganisms, pyrogens, or other impurities. Preservatives to inhibit growth of microorganisms shall not be used during processing.

(d) Storage of bulk fraction. Bulk concentrate to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of −5 °C or colder. Any other bulk form of the product (exclusive of the sterile bulk solution) to be held more than 1 week prior to further processing, shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk fraction to be held one week or less prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder.

(e) Heat treatment. Heating of the final containers of Plasma Protein Fraction (Human) shall begin within 24 hours after completion of filling. Heat treatment shall be conducted so that the solution is heated continuously for not less than 10 or more than 11 hours at an attained temperature of 60±0.5 °C.

(f) Stabilizer. Either 0.08±0.016 millimole sodium caprylate, or 0.08±0.016 millimole sodium acetyltryptophanate and 0.08±0.016 millimole sodium caprylate per gram of protein shall be present as a stabilizer(s). Calculations of the stabilizer concentration may employ the labeled value 5 percent for the protein concentration of the product.

(g) Incubation. All final containers of Plasma Protein Fraction (Human) shall be incubated at 20 to 35 °C for at least 14 days following the heat treatment prescribed in paragraph (e) of this section. At the end of this incubation period, each final container shall be examined and all containers showing any indication of turbidity or microbial contamination shall not be issued. The contents of turbid final containers shall be examined microscopically and tested for sterility. If growth occurs, the types of organisms shall be identified as to genus and the material from such containers shall not be used for further manufacturing.

[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]

§ 640.92 Tests on final product.

Tests shall be performed on the final product to determine that it meets the following standards:

(a) Protein concentration. The final product shall be a 5.0 ±0.30 percent solution of protein.

(b) Protein composition. The total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin. The protein composition shall be determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(c) pH. The pH shall be 7.0 ±0.3 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.

(d) Sodium concentration. The sodium concentration of the final product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the final product shall not exceed 2 milliequivalents per liter.

(f) Heat stability. A final container sample of Plasma Protein Fraction (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.

[42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000]

§ 640.93 General requirements.

(a) Preservative. The final product shall not contain a preservative.

(b) Storage of bulk solution. After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.

§ 640.94 Labeling.

In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:

(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter.

(b) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More than 4 Hours After the Container Has Been Entered.”

[42 FR 27583, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, 1999]

§ 640.100 Immune Globulin (Human).

(a) Proper name and definition. The proper name of this product shall be Immune Globulin (Human). The product is defined as a sterile solution containing antibodies derived from human plasma.

(b) Source material. The source material of Immune Globulin (Human) shall be plasma recovered from Whole Blood prepared as prescribed in §§ 640.1 through 640.5, or Source Plasma prepared as prescribed in §§ 640.60 through 640.76.

(c) Additives in source material. The source material shall contain no additives other than citrate or acid citrate dextrose anticoagulant solution, unless it is shown that the processing method yields a product free of the additive to such an extent that the safety, purity, and potency of the product will not be affected adversely.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26287, May 14, 1999]

§ 640.101 General requirements.

(a) Heat stability test. Approximately 2 ml. of completely processed material of each lot shall not show any visible sign of gelation after heating in a 12 × 75 mm. stoppered glass tube at 57 °C for 4 hours.

(b) pH. The pH of final container material shall be 6.8 ±0.4 when measured in a solution diluted to 1 percent protein with 0.15 molar sodium chloride.

(c) Turbidity. The product shall be free of turbidity as determined by visual inspection of final containers.

(d) Date of manufacture. The date of manufacture is the date of initiating the last valid measles or poliomyelitis antibody test (§ 640.104(b) (2) and (3)) whichever date is earlier.

(e) Labeling. In addition to complying with all applicable labeling required in this subchapter, labeling shall indicate that:

(1) There is no prescribed potency for viral hepatitis antibodies.

(2) The product is not recommended for intravenous administration.

[38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. 29, 1983, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999]

§ 640.102 Manufacture of Immune Globulin (Human).

(a) Processing method. The processing method shall be one that has been shown: (1) To be capable of concentrating tenfold from source material at least two different antibodies; (2) not to affect the integrity of the globulins; (3) to consistently yield a product which is safe for subcutaneous and intramuscular injection and (4) not to transmit viral hepatitis.

(b) Microbial contamination. Low temperatures or aseptic techniques shall be used to minimize contamination by microorganisms. Preservatives to inhibit growth of microorganisms shall not be used during processing.

(c) Bulk storage. The globulin fraction may be stored in bulk prior to further processing provided it is stored in clearly identified hermetically closed vessels. Globulin as either a liquid concentrate or a solid and containing alcohol or more than 5 percent moisture shall be stored at a temperature of −10 °C or lower. Globulin as a solid free from alcohol and containing less than 5 percent moisture, shall be stored at a temperature of 0 °C or lower.

(d) Determination of the lot. Each lot of Immune Globulin (Human) shall represent a pooling of approximately equal amounts of material from not less than 1,000 donors.

(e) Sterilization and heating. The final product shall be sterilized promptly after solution. At no time during processing shall the product be exposed to temperatures above 45 °C, and after sterilization the product shall not be exposed to temperatures above 32 °C for more than 72 hours.

[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000]

§ 640.103 The final product.

(a) Final solution. The final product shall be a 16.5 ±1.5 percent solution of globulin containing 0.3 molar glycine and a preservative.

(b) Protein composition. At least 96 percent of the total protein shall be immunoglobulin G (IgG), as determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

[38 FR 32089, Nov. 20, 1973, as amended at 64 FR 26287, May 14, 1999]

§ 640.104 Potency.

(a) Antibody levels and tests. Each lot of final product shall contain at least the minimum levels of antibodies for diphtheria, measles, and for at least one type of poliomyelitis. In the event the final bulk solution is stored at a temperature above 5 °C the antibody level tests shall be performed after such storage with a sample of the stored material.

(b) Minimum levels. The minimum antibody levels are as follows:

(1) No less than 2 units of diphtheria antitoxin per ml.

(2) A measles neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material.

(3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research, Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material.

(c) Reference materials. The following reference materials shall be obtained from the Center for Biologics Evaluation and Research:

(1) Reference Immune Globulin for correlation of measles antibody titers.

(2) Reference Immune Globulin for correlation of poliomyelitis antibody titers, Types 1, 2, and 3.

[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999]

§ 640.120 Alternative procedures.

(a) The Director, Center for Biologics Evaluation and Research, may issue an exception or alternative to any requirement in subchapter F of chapter I of title 21 of the Code of Federal Regulations regarding blood, blood components, or blood products. The Director may issue such an exception or alternative in response to:

(1) A written request from an establishment. Licensed establishments must submit such requests in accordance with § 601.12 of this chapter;

(2) An oral request from an establishment, if there are difficult circumstances and submission of a written request is not feasible. Establishments must follow up such oral request by submitting written requests under paragraph (a)(1) of this section within 5 working days.

(b) To respond to a public health need, the Director may issue a notice of exception or alternative to any requirement in subchapter F of chapter I of title 21 of the Code of Federal Regulations regarding blood, blood components, or blood products, if a variance under this section is necessary to assure that blood, blood components, or blood products will be available in a specified location or locations to address an urgent and immediate need for blood, blood components, or blood products or to provide for appropriate donor screening and testing.

(c) If the Director issues such an exception or alternative orally, the Director will follow up by issuing a written notice of the exception or alternative. Periodically, FDA will provide a list of approved exceptions and alternative procedures on the FDA Center for Biologics Evaluation and Research Web site.

[80 FR 29906, May 22, 2015]

§ 640.125 Definitions.

The definitions set out in § 630.3 of this chapter apply to the use of those defined terms in this part.

§ 640.130 Medical supervision.

The requirements for medical supervision established in § 630.5 of this chapter supplement the regulations in this part.

§ 660.1 Antibody to Hepatitis B Surface Antigen.

(a) Proper name and definition. The proper name of this product shall be Antibody to Hepatitis B Surface Antigen. The product is defined as a preparation of serum containing antibody to hepatitis B surface antigen.

(b) Source. The source of this product shall be plasma or blood, obtained aseptically from animals immunized with hepatitis B surface antigen, which have met the applicable requirements of § 600.11 of this chapter, or from human donor whose blood is positive for hepatitis B surface antigen.

[40 FR 29711, July 15, 1975]

§ 660.2 General requirements.

(a) Processing. The processing method shall be one that has been shown to consistently yield a specific and potent final product free of properties which would adversely affect the test results when the product is tested by the methods recommended by the manufacturer in the package enclosure.

(b) Ancillary reagents and materials. All ancillary reagents and materials supplied in the package with the product shall meet generally accepted standards of purity and quality and shall be effectively segregated and otherwise manufactured in a manner (such as heating at 60 °C. for 10 hours) that will reduce the risk of contaminating the product and other biological products. Ancillary reagents and materials accompanying the product which are used in the performance of the test as described by the manufacturer's recommended test procedures shall have been shown not to adversely affect the product within the prescribed dating period.

(c) Labeling. (1) In addition to the items required by other applicable labeling provisions of this subchapter, the following shall also be included:

(i) Indication of the source of the product immediately following the proper name on both the final container and package label, e.g., human, guinea pig.

(ii) Name of the test method(s) recommended for the product on the package label and on the final container label when capable of bearing a full label (see § 610.60(a) of this chapter).

(iii) A warning on the package label and on the final container label if capable of bearing a full label (see § 610.60(a) of this chapter) indicating that the product and antigen if supplied, shall be handled as if capable of transmitting hepatitis.

(iv) If the product is dried, the final container label shall indicate “Reconstitution date: ___” and a statement indicating the period within which the product may be used after reconstitution.

(v) The package shall include a package enclosure providing:

(A) Adequate instructions for use;

(B) A description of all recommended test methods; and

(C) Warnings as to possible hazards, including hepatitis, in handling the product and any ancillary reagents and materials accompanying the product.

(2) The applicant may provide the labeling information referenced in paragraph (c)(1) of this section in the form of:

(i) A symbol accompanied by explanatory text adjacent to the symbol;

(ii) A symbol not accompanied by adjacent explanatory text that:

(A) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;

(B) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(C) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(iii) A symbol not accompanied by adjacent explanatory text that:

(A) Is established in a standard developed by a standards development organization (SDO);

(B) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(C) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act;

(D) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(E) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used.

(3) The use of symbols to provide the labeling information referenced in paragraph (c)(1) of this section which do not meet the requirements of paragraph (c)(2) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act.

(4) For purposes of paragraph (c)(2) of this section:

(i) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(ii) The term “symbols glossary” means a compiled listing of:

(A) Each SDO-established symbol used in the labeling for the device;

(B) The title and designation number of the SDO-developed standard containing the symbol;

(C) The title of the symbol and its reference number, if any, in the standard; and

(D) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

(d) Final container. A final container shall be sufficiently transparent to permit visual inspection of the contents for presence of particulate matter and increased turbidity. The effectiveness of the contents of a final container shall be maintained throughout its dating period.

(e) Date of manufacture. The date of manufacture of Antibody to Hepatitis B surface Antigen that has been iodinated with radioactive iodine ( 125I) shall be the day of labeling the antibody with the radionuclide.

(f) Retention samples. Each manufacturer shall retain representative samples of the product in accordance with § 600.13 of this chapter except for that which has been iodinated with radioactive iodine. Retention samples of Antibody to Hepatitis B Surface Antigen iodinated with 125I shall consist of a minimum of two complete finished packages of each lot of the diagnostic test kit and shall be retained for a period of at least 90 days from the date of manufacture.

[38 FR 32098, Nov. 20, 1973, as amended at 40 FR 29711, July 15, 1975; 46 FR 36134, July 14, 1981; 49 FR 1684, Jan. 13, 1984; 81 FR 38924, June 15, 2016]

§ 660.3 Reference panel.

A Reference Hepatitis B Surface Antigen Panel shall be obtained from the Food and Drug Administration, Center for Biologics Evaluation and Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002 and shall be used for determining the potency and specificity of Antibody to Hepatitis B Surface Antigen.

[40 FR 29711, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.4 Potency test.

To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent to detect the antigen in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert.

[40 FR 29711, July 15, 1975]

§ 660.5 Specificity.

Each filling of the product shall be specific for antibody to hepatitis B surface antigen, as determined by specificity tests found acceptable by the Director, Center for Biologics Evaluation and Research.

[40 FR 29712, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

§ 660.6 Samples; protocols; official release.

(a) Samples. (1) For the purposes of this section, a sample of product not iodinated with 125I means a sample from each filling of each lot packaged as for distribution, including all ancillary reagents and materials; and a sample of product iodinated with 125I means a sample from each lot of diagnostic test kits in a finished package, including all ancillary reagents and materials.

(2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:

(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.

(ii) One sample at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture.

(iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product.

(b) Protocols. For each sample submitted as required in paragraph (a)(1) of this section, the manufacturer shall send a protocol that consists of a summary of the history of manufacture of the product, including all results of each test for which test results are requested by the Director, Center for Biologics Evaluation and Research. The protocols submitted with the samples at periodic intervals as provided in paragraph (a)(2)(ii) of this section shall be identified by the manufacturer as “surveillance test results.”

(c) Official release. (1) The manufacturer shall not distribute the product until written notification of official release is received from the Director, Center for Biologics Evaluation and Research, except as provided in paragraph (c)(2) of this section. Official release is required for samples from at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product.

(2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter.

(3) The manufacturer shall not distribute lots or fillings, as applicable, of products that required sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research.

[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.20 Blood Grouping Reagent.

(a) Proper name and definition. The proper name of this product shall be Blood Grouping Reagent and it shall consist of an antibody-containing fluid containing one or more of the blood grouping antibodies listed in § 660.28(a)(4).

(b) Source. The source of this product shall be blood, plasma, serum, or protein-rich fluids, such as those derived from stable immunoglobulin-secreting cell lines maintained either in tissue cultures or in secondary hosts.

[53 FR 12764, Apr. 19, 1988, as amended at 65 FR 77499, Dec. 12, 2000; 81 FR 38925, June 15, 2016]

§ 660.21 Processing.

(a) Processing method. (1) The processing method shall be one that has been shown to yield consistently a specific, potent final product, free of properties that would affect adversely the intended use of the product throughout its dating period. Stability testing shall be performed on an adequate number of representative samples of each group of products manufactured in the same fashion.

(2) Only that material that has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot.

(3) A lot may be subdivided into sublots. If lots are to be subdivided, the manufacturer shall include this information in the biologics license application. The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot.

(4) Each lot of Blood Grouping Reagent shall be identified by a lot number. Each sublot shall be identified by that lot number to which a distinctive prefix or suffix shall be added. Final container and package labels shall bear the lot number and all distinctive prefixes and suffixes that have been applied to identify the sublot from which filling was accomplished.

(b) Color coding of reagents. Blood Grouping Reagents may be colored provided the added colorant does not adversely affect the safety, purity, or potency of the product and the colorant is approved by the Director, Center for Biologics Evaluation and Research.

(c) Final containers and dropper assemblies. Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents to detect particulate matter or increased turbidity during use.

(d) Volume of final product. Each manufacturer shall identify the possible final container volumes in the biologics license application.

(e) Date of manufacture. The date of manufacture shall be the date the manufacturer begins the last entire group of potency tests.

[53 FR 12764, Apr. 19, 1988, as amended at 64 FR 56454, Oct. 20, 1999; 65 FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]

§ 660.22 Potency requirements with reference preparations.

(a) Potency requirements. Products for which reference Blood Grouping Reagents are available shall have a potency titer value at least equal to that of the reference preparation.

(b) Reference preparations. Reference Blood Grouping Reagents shall be obtained from the Food and Drug Administration, Center for Biologics Evaluation and Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002, and shall be used as described in the accompanying package insert for determining the potency of Blood Grouping Reagents.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.25 Potency tests without reference preparations.

Products for which Reference Blood Grouping Reagents are not available shall be tested for potency by a method approved by the Director, Center for Biologics Evaluation and Research.

(a) Potency requirements. Blood Grouping Reagents recommended for the test tube methods, including the indirect antiglobulin tests, shall have the following potency titer values, unless other values are approved by the Director, Center for Biologics Evaluation and Research.

(1) For Anti-K, Anti-k , Anti-Jk a, Anti-Fy a, Anti-C w, at least 1 + reaction with a 1:8 dilution of the reagent.

(2) For Anti-S, Anti-s , Anti-P1, Anti-M, Anti-I, Anti-e (saline), Anti-c (saline), and Anti-A1, at least 1 + reaction with a 1:4 dilution of the reagent.

(3) For Anti-U, Anti-Kp a, Anti-Kp b, Anti-Js a, Anti-Js b, Anti-Fy b, Anti-N, Anti-Le a, Anti-Le b, Anti-Lu a, Anti-Lu b, Anti-Di a, Anti-M g, Anti-Jk b, Anti-Co b, Anti-Wr a, and Anti-Xg a, at least 2 + reaction with undiluted reagent.

(b) Products recommended for slide tests or microplate techniques. Blood Grouping Reagent recommended for slide test methods or microplate techniques shall produce clearly positive macroscopic results when both undiluted reagent and reagent diluted with an equal volume of diluent are tested by all methods recommended in the manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the corresponding antigen. The dilution shall be made with an equal volume of compatible serum or approved diluent.

(c) Products recomended for use in an automated system. The manufacturer of Blood Grouping Reagent that is recommended for use in an automated system shall demonstrate that its product when used both undiluted and diluted with an equal volume of diluent satisfactorily performs when tested with cells representing heterozygous or diminished expression of the corresponding antigen.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]

§ 660.26 Specificity tests and avidity tests.

Specificity and avidity tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research.

[53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]

§ 660.28 Labeling.

(a) In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10 of this chapter, and in lieu of the requirements in §§ 610.60 and 610.61 of this chapter, the following requirements shall be met:

(1) Final container label—(i) Color coding. The final container label of all Blood Grouping Reagents shall be completely white, except that all or a portion of the final container label of the following Blood Grouping Reagents may be color coded with the specified color which shall be a visual match to a specific color sample designated by the Director, Center for Biologics Evaluation and Research. Printing on all final container labels shall be in solid black. A logo or company name may be placed on the final container label; however, the logo or company name shall be located along the bottom or end of the label, outside the main panel.

Blood grouping reagent | Color of label paper

Anti-A | Blue.

Anti-B | Yellow.

Slide and rapid tube test blood grouping reagents only:

Anti-C | Pink.

Anti-D | Gray.

Anti-E | Brown.

Anti-CDE | Orange.

Anti-c | Lavender.

Anti-e | Green.

(ii) Required information. The proper name “Blood Grouping Reagent” need not appear on the final container label provided the final container is distributed in a package and the package label bears the proper name. The final container label shall bear the following information:

(A) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section.

(B) Name, address (including ZIP code), and license number of the manufacturer.

(C) Lot number, including sublot designations.

(D) Expiration date.

(E) Source of product if other than human plasma or serum.

(F) Test method(s) recommended.

(G) Recommended storage temperature in degrees Celsius.

(H) Volume of product if a liquid, or equivalent volume for a dried product if it is to be reconstituted.

(I) If a dried product, to remind users to record the reconstitution date on the label, the statement “RECONSTITUTION DATE ___. EXPIRES 1 YEAR AFTER RECONSTITUTION DATE.”

(iii) Lettering size. The type size for the specificity of the antibody designation on the labels of a final container with a capacity of less than 5 milliliters shall be not less than 12 point. The type size for the specificity of the antibody designations on the label of a container with a capacity of 5 milliliters or more shall be not less than 18 point.

(iv) Visual inspection. When the label has been affixed to the final container, a sufficient area of the container shall remain uncovered for its full length or no less than 5 millimeters of the lower circumference to permit inspection of the contents. The label on a final product container for antibodies Anti-c, Anti-k, or Anti-s shall display a bar immediately over the specificity letter used in the name, i.e., Anti-c , Anti-k , or Anti-s .

(2) Package label. The following information shall appear either on the package label or on the final container label if it is visible within the package.

(i) Proper name of the product.

(ii) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section.

(iii) Name, address (including ZIP Code), and license number of the manufacturer.

(iv) Lot number, including sublot designations.

(v) Expiration date.

(vi) Preservative used and its concentration.

(vii) Number of containers, if more than one.

(viii) Volume or equivalent volume for dried products when reconstituted, and precautions for adequate mixing when reconstituting.

(ix) Recommended storage temperature in degrees Celsius.

(x) Source of the product if other than human serum or plasma.

(xi) Reference to enclosed package insert.

(xii) If a dried product, a statement indicating the period within which the product may be used after reconstitution.

(xiii) The statement: “FOR IN VITRO DIAGNOSTIC USE.”

(xiv) The statement: “MEETS FDA POTENCY REQUIREMENTS.”

(xv) If human blood was used in manufacturing the product, the statement: “CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.”

(xvi) A statement of an observable indication of an alteration of the product, e.g., turbidity, color change, precipitate, that may indicate possible deterioration of the product.

(3) Package insert. Each final container of Blood Grouping Reagent shall be accompanied by a package insert meeting the requirements of § 809.10. If two or more final containers requiring identical package inserts are placed in a single package, only one package insert per package is required.

(4) Names of antibodies.

Blood Group Designation for Container Label

Anti-A | Anti-Jk b

Anti-A1 | Anti-Js a

Anti-A, B | Anti-Js b

Anti-A and B | Anti-K

Anti-B | Anti-k

Anti-C | Anti-Kp a

Anti-C w | Anti-Kp b

Anti- c | Anti-Le a

Anti-CD | Anti-Le b

Anti-CDE | Anti-Lu a

Anti-Co b | Anti-Lu b

Anti-D | Anti-M

Anti-DE | Anti-M g

Anti-Di a | Anti-N

Anti-E | Anti-P1

Anti-e | Anti-S

Anti-Fy a | Anti-s

Anti-Fy b | Anti-U

Anti-I | Anti-Wr a

Anti-Jk a | Anti-Xg a

(b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of:

(1) A symbol accompanied by explanatory text adjacent to the symbol;

(2) A symbol not accompanied by adjacent explanatory text that:

(i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;

(ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(3) A symbol not accompanied by adjacent explanatory text that:

(i) Is established in a standard developed by a standards development organization (SDO);

(ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act;

(iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used.

(c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements in paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act.

(d) For purposes of paragraph (b) of this section:

(1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(2) The term “symbols glossary” means a compiled listing of:

(i) Each SDO-established symbol used in the labeling for the device;

(ii) The title and designation number of the SDO-developed standard containing the symbol;

(iii) The title of the symbol and its reference number, if any, in the standard; and

(iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

[81 FR 38925, June 15, 2016]

§ 660.30 Reagent Red Blood Cells.

(a) Proper name and definition. The proper name of the product shall be Reagent Red Blood Cells, which shall consist of a preparation of human red blood cells used to detect or identify human blood-group antibodies.

(b) Source. Reagent Red Blood Cells shall be prepared from human peripheral blood meeting the criteria of §§ 660.31 and 660.32 of this chapter, or from umbilical cord cells which shall be collected and prepared according to the manufacturer's biologics license application.

[52 FR 37450, Oct. 7, 1987, as amended at 64 FR 56454, Oct. 20, 1999]

§ 660.31 Eligibility of donor.

Donors of peripheral blood for Reagent Red Blood Cells must meet all the criteria for donor eligibility under §§ 630.10 and 630.15 of this chapter.

[80 FR 29906, May 22, 2015]

§ 660.32 Collection of source material.

Blood for Reagent Red Blood Cells from donors of peripheral blood shall be collected as prescribed under § 640.4 of this chapter, except that paragraphs (c), (d), (g), and (h) of § 640.4 shall not apply.

§ 660.33 Testing of source material.

Except as provided in this section, a sample of each blood incorporated into the Reagent Red Blood Cell product shall be individually tested, with no fewer than two donor sources of each antibody specificity employed, to confirm the identification of all blood group antigens specified in the labeling as present or absent. The manufacturer shall perform at least one of the required tests for each factor. The Reagent Red Blood Cell product may be tested with a single donor source of antibody specificity if only one source of antibody is available, and the Director, Center for Biologics Evaluation and Research, has approved the use of a single donor source of antiserum. Each of these tests shall be conducted and interpreted independently, and any discrepancy between the results of these two tests shall be resolved by testing with at least one additional antiserum before concluding that the antigen is present or absent. Where fewer than three donor sources of an antibody specificity are available, test discrepancies shall be resolved in accordance with the manufacturer's biologics license application. Group O Reagent Red Blood Cells used in the detection or identification of unexpected antibodies shall include at least the following common antigens in each lot of the product: D, C, E, c , e, K, k , Fy a, Fy b, Jk a, Jk b, Le a, Le b, P1, M, N, S, and s .

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 64 FR 56454, Oct. 20, 1999]

§ 660.34 Processing.

(a) Processing method. The processing method shall be one that has been shown to yield consistently a product that is capable of detecting, throughout the dating period, alloantibodies corresponding to all required blood group antigens specified in the labeling as present.

(b) Products prepared from pooled red blood cells. If the product is recommended for the detection of unexpected antibodies, the pool shall be prepared by combining equal amounts of cells from no more than two donors. Umbilical cord cells are exempt from this requirement. Pooled cells shall not be recommended for pretransfusion tests, done in lieu of a major crossmatch, to detect unexpected antibodies in patients' samples.

(c) Absence of antibodies. Each lot of final product shall be free of demonstrable antibodies, including anti-A and anti-B, unless the package insert and container lable include instructions to wash the cells before use. The final product shall also be direct antiglobulin test negative when tested with polyspecific anti-human globulin.

(d) Final container. The final containers used for each lot of product shall be clean and shall permit observation of the contents for hemolysis or a change in color. The final container label, container cap, and dropper bulb of a Reagent Red Blood Cell product may be color-coded with a visual match to a specific color approved by the Director, Center for Biologics Evaluation and Research.

(e) Date of manufacture. The date of manufacture of the product shall be the date that the blood is withdrawn from the donor or obtained from umbilical cords. The period during which the reagent red blood cell source material is kept by the manufacturer in storage in a frozen state at −65 °C or colder is excluded from the dating period. If the product consists of red blood cells from two or more donors, the date of manufacture of the final product shall be the date of withdrawal of blood from the donor of the oldest constituent blood. When a product consists of more than one container, e.g., cell panel, the date of manufacture of each container of the product shall be the earliest date that blood was withdrawn from a donor for any container of the product.

(f) Retention samples. Retention samples shall be maintained as required by § 600.13 of this chapter, except that samples must be retained only throughout the dating period of the product.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002]

§ 660.35 Labeling.

(a) In addition to the items required by § 809.10 of this chapter and other applicable labeling provisions of this chapter, the following information shall be included in the labeling:

(1)(i) A logo or company name may be placed on the final container label, however, the logo or company name shall be located along the bottom or end of the label, outside of the main panel.

(ii) If washing the cells is required by the manufacturer, the container label shall include appropriate instructions; if the cells should not be washed before use, e.g., if washing will adversely affect the product, the package insert shall explain.

(2) The container label of Group O cells shall state:

“FOR USE IN DETECTION OF UNEXPECTED ANTIBODIES” or “FOR USE IN IDENTIFICATION OF UNEXPECTED ANTIBODIES” or “NOT FOR USE IN DETECTION OR IDENTIFICATION OF UNEXPECTED ANTIBODIES”.

(3) Except as provided in this section, the container and package labels shall state the percentage of red blood cells in the suspension either as a discrete figure with a variance of more than [±] 1 percentage unit or as a range the extremes of which differ by no more than 2 percentage units. If the stated red blood cell concentration is less than 2 percent, the variance shall be no more than [±] 0.5 percentage unit.

(4) The words “pooled cells” shall appear on the container and package labels of products prepared from pooled cells. The package label or package insert shall state that pooled cells are not recommended for pre-transfusion tests, done in lieu of a major crossmatch, to detect unexpected antibodies in patients' samples.

(5) The package insert of a pooled product intended for detection of unexpected antibodies shall identify the number of donors contributing to the pool. Products designed exclusively for ABO Serum Grouping and umbilical cord cells need not identify the number of donors in the pool.

(6) When the product is a multicontainer product, e.g., a cell panel, the container label and package label shall be assigned the same identifying lot number, and shall also bear a number or symbol to distinguish one container from another. Such number or symbol shall also appear on the antigenic constitution matrix.

(7) The package label or package insert shall state the blood group antigens that have been tested for and found present or absent on the cells of each donor, or refer to such information in an accompanying antigenic constitution matrix. Cells for ABO Serum Grouping are exempt from this requirement. The package insert or antigen constitution matrix shall list each of the antigens tested with only one source of antibody.

(8) The package label or package insert shall bear the cautionary statement: “The reactivity of the product may decrease during the dating period.”

(9) The package insert of a product intended for the detection or identification of unexpected antibodies shall note that the rate at which antigen reactivity (e.g., agglutinability) is lost is partially dependent upon individual donor characteristics that are neither controlled nor predicted by the manufacturer.

(10) The package insert shall provide adequate directions for use.

(11) The package insert shall bear the statement:

“CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.”

(12) The package insert or the antigenic constitution matrix for each lot of product shall specify the date of manufacture or the length of the dating period.

(13) Manufacturers shall identify with a permanent donor code in the product labeling each donor of peripheral blood used for detection or identification of unexpected antibodies.

(b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of:

(1) A symbol accompanied by explanatory text adjacent to the symbol;

(2) A symbol not accompanied by adjacent explanatory text that:

(i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;

(ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(3) A symbol not accompanied by adjacent explanatory text that:

(i) Is established in a standard developed by a standards development organization (SDO);

(ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act;

(iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used.

(c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act.

(d) For purposes of paragraph (b) of this section:

(1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(2) The term “symbols glossary” means a compiled listing of:

(i) Each SDO-established symbol used in the labeling for the device;

(ii) The title and designation number of the SDO-developed standard containing the symbol;

(iii) The title of the symbol and its reference number, if any, in the standard; and

(iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

[81 FR 38926, June 15, 2016]

§ 660.36 Samples and protocols.

(a) The following shall be submitted to the Center for Biologics Evaluation and Research Sample Custodian (see mailing addresses in § 600.2(c) of this chapter), within 30 days after each routine establishment inspection by FDA.

(1) From a lot of final product, samples from a cell panel intended for identification of unexpected antibodies. The sample shall be packaged as for distribution and shall have at least 14 days remaining in the dating period when shipped to the Center for Biologics Evaluation and Research.

(2) A protocol which shall include the following:

(i) Complete test records of at least two donors of the samples submitted, including original and confirmation phenotyping records.

(ii) Bleeding records or receipt records which indicate collection date, volume, and HBsAg test results.

(iii) Manufacturing records which document all steps involved in the preparation of the product.

(iv) Test results which verify that the final product meets specifications.

(v) Identity test results.

(b) A copy of the antigenic constitution matrix specifying the antigens present or absent shall be submitted to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), at the time of initial distribution of each lot of Reagent Red Blood Cells for detection or identification of unexpected antibodies. Products designed exclusively to identify Anti-A, Anti-A1, and Anti-B, as well as products composed entirely of umbilical cord cells, are excluded from this requirement.

(c) Except for umbilical cord samples, whenever a new donor is used, a sample of red blood cells from each new donor used in a cell panel intended for the identification of unexpected antibodies shall be submitted by the manufacturer to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter). The sample should contain a minimum volume of 0.5 milliliter of red blood cells.

[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.40 Hepatitis B Surface Antigen.

(a) Proper name and definition. The proper name of this product shall be Hepatitis B Surface Antigen (HBsAg), which shall consist of a serum or tissue preparation containing one or more subtypes of the Hepatitis B Surface Antigen.

(b) Source. The source of the product shall be blood, plasma, serum, or tissue, obtained aseptically from nonhuman primates that have met the applicable requirements of § 600.11 of this chapter, or from human donors whose blood is positive for the Hepatitis B Surface Antigen.

§ 660.41 Processing.

(a) Method. The processing method shall be one that has been shown to yield consistently a specific and potent final product, free of properties which would adversely affect the test results when the product is tested by the methods recommended by the manufacturer in the package insert. The product and all ancillary reagents and materials supplied in the package with the product shall be manufactured in a manner that will reduce the risk of transmitting type B viral hepatitis.

(b) Ancillary reagents and materials. All ancillary reagents and materials supplied in the package with the product shall meet generally accepted standards of purity and quality and shall be effectively segregated and otherwise manufactured in a manner that will reduce the risk of contaminating the product and other biological products. Ancillary reagents and materials accompanying the product, which are used in the performance of the test as described by the manufacturer's recommended test procedures, shall have been shown not to affect adversely the product within the prescribed dating period.

(c) Final container. A final container shall be sufficiently transparent to permit visual inspection of the contents for presence of particulate matter and increased turbidity. The effectiveness of the contents of a final container shall be maintained throughout its dating period.

(d) Date of manufacture. The date of manufacture of Hepatitis B Surface Antigen that has been iodinated with radioactive iodine ( 125I) shall be the day of labeling the antibody with the radionuclide.

[44 FR 36382, June 22, 1979, as amended at 49 FR 1685, Jan. 13, 1984]

§ 660.43 Potency test.

To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the antibody in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert.

§ 660.44 Specificity.

Each filling of the product shall be specific for Hepatitis B Surface Antigen as determined by specificity tests found acceptable to the Director, Center for Biologics Evaluation and Research.

[44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

§ 660.45 Labeling.

(a) In addition to the requirements of §§ 610.60, 610.61, and 809.10 of this chapter, the labeling shall bear the following:

(1) The “d and y” antigen subtype and the source of the product to follow immediately the proper name on both the final container label and the package label. If the product is intended to identify antibodies to the “r and w” antigen subtype, the antigen subtype designation shall include the “r and w” antigen subtype.

(2) The name of the test method(s) recommended for use of the product on the package label and on the final container label, when capable of bearing a full label (see § 610.60(a) of this chapter).

(3) A warning on the package label and on the final container label stating that the product is capable of transmitting hepatitis and should be handled accordingly.

(4) The package shall include a package insert providing:

(i) Detailed instructions for use,

(ii) An adequate description of all recommended test methods, and

(iii) Warnings as to possible hazards, including hepatitis transmitted in handling the product and any ancillary reagents and materials accompanying the product.

(b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of:

(1) A symbol accompanied by explanatory text adjacent to the symbol;

(2) A symbol not accompanied by adjacent explanatory text that:

(i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;

(ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(3) A symbol not accompanied by adjacent explanatory text that:

(i) Is established in a standard developed by a standards development organization (SDO);

(ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act;

(iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used.

(c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act.

(d) For purposes of paragraph (b) of this section:

(1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(2) The term “symbols glossary” means a compiled listing of:

(i) Each SDO-established symbol used in the labeling for the device;

(ii) The title and designation number of the SDO-developed standard containing the symbol;

(iii) The title of the symbol and its reference number, if any, in the standard; and

(iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

[81 FR 38928, June 15, 2016]

§ 660.46 Samples; protocols; official release.

(a) Samples. (1) For the purposes of this section, a sample of product not iodinated with 125I means a sample from each filling of each lot packaged as for distribution, including all ancillary reagents and materials; and a sample of product iodinated with 125I or unlyophilized HBsAg-coated red blood cells means a sample from each lot of diagnostic test kits in a finished package, including all ancillary reagents and materials.

(2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:

(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.

(ii) One sample of product at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by the manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture.

(iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product.

(b) Protocols. For each sample submitted as required in paragraph (a)(1) of this section, the manufacturer shall send a protocol that consists of a summary of the history of manufacture of the product, including all results of each test for which test results are requested by the Director, Center for Biologics Evaluation and Research. The protocols submitted with the samples at periodic intervals as provided in paragraph (a)(2)(ii) of this section shall be identified by the manufacturer as “surveillance test results.”

(c) Official release. (1) The manufacturer shall not distribute the product until written notification of official release is received from the Director, Center for Biologics Evaluation and Research, except as provided in paragraph (c)(2) of this section. Official release is required for at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product.

(2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings manufactured after licensure of the products, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter.

(3) The manufacturer shall not distribute lots or fillings, as applicable, of products that require sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research.

[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.50 Anti-Human Globulin.

(a) Proper name and definition. The proper name of this product shall be Anti-Human Globulin which shall consist of one or more antiglobulin antibodies identified in § 660.55(a)(4).

(b) Source. The source of this product shall be either serum from animals immunized with one or more human serum globulins or protein-rich fluids derived from stable immunoglobulin-secreting cell lines maintained either in tissue cultures or in secondary hosts.

[50 FR 5579, Feb. 11, 1985, as amended at 65 FR 77499, Dec. 12, 2000; 81 FR 38928, June 15, 2016]

§ 660.51 Processing.

(a) Processing method. (1) The processing method shall be one that has been shown to yield consistently a specific, potent final product, free of properties that would adversely affect the product for its intended use throughout its dating period.

(2) Anti-IgG, -C3d (polyspecific) reagents and anti-IgG products may be colored green.

(3) Only that material which has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot. Each lot shall be identified by a lot number.

(4) A lot may be subdivided into sublots which shall be identified by the lot number to which has been added a distinctive prefix or suffix. If lots are to be subdivided, the manufacturer shall include this information in the license application . The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot.

(b) Final containers and dropper assemblies. (1) Final containers and dropper assemblies shall be clean.

(2) Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents for presence of particulate matter or increased turbidity.

(c) Date of manufacture. The date of manufacture shall be the date the manufacturer begins the last entire group of potency tests.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 65 FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002]

§ 660.52 Reference preparations.

Reference Anti-Human Globulin preparations shall be obtained from the Food and Drug Administration, Center for Biologics Evaluation and Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002, and shall be used as described in the accompanying package insert for determining the potency of Anti-Human Globulin.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 660.53 Controls for serological procedures.

Red blood cells sensitized with complement shall be tested with appropriate positive and negative control antisera. All tests shall be performed in accordance with serological testing procedures approved by the Director, Center for Biologics Evaluation and Research.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005]

§ 660.54 Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.

The following tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research:

(a) Potency tests for determining anti-IgG and anti-complement activity.

(b) Specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.

[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005]

§ 660.55 Labeling.

(a) In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10 of this chapter, and in lieu of the requirements in §§ 610.60 and 610.61 of this chapter, the following requirements shall be met:

(1) Final container label—(i) Color coding. The main panel of the final container label of all Anti-IgG, -C3d (polyspecific) reagents shall be white or colorless and printing shall be solid dark contrasting lettering. The main panel of the final container label of all other Anti-Human Globulin reagents shall be black with solid white lettering. A logo or company name may be placed on the final container label; however, the logo or company name shall be located along the bottom or end of the label, outside of the main panel.

(ii) Required information. The proper name “Anti-Human Globulin” need not appear on the final container label provided the final container is distributed in a package and the package label bears the proper name. The final container label shall bear the following information:

(A) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section. Anti-Human Globulin may contain one or more antibodies to either immunoglobulins or complement components but the name of each significant antibody must appear on the final container label (e.g., anti-C3b, -C3d, -C4d). The final container labels of polyspecific Anti-Human Globulin are not required to identify antibody specificities other than anti-IgG and anti-C3d but the reactivity of the Anti-Human Globulin shall be accurately described in the package insert.

(B) Name, address, and license number of the manufacturer.

(C) Lot number, including any sublot designations.

(D) Expiration date.

(E) Source of the product.

(F) Recommended storage temperature in degrees Celsius.

(G) Volume of product.

(H) Appropriate cautionary statement if the Anti-Human Globulin is not polyspecific. For example, “DOES NOT CONTAIN ANTIBODIES TO IMMUNOGLOBULINS” or “DOES NOT CONTAIN ANTIBODIES TO COMPLEMENT COMPONENTS.”

(I) If the final container is not enclosed in a package, all items required for a package label shall appear on the container label.

(iii) Lettering size. The type size for the designation of the specific antibody on the label of a final container shall be not less than 12 point, unless otherwise approved by the Director, Center for Biologics Evaluation and Research. The prefix anti- and other parts of the name such as polyspecific may appear in smaller type.

(iv) Visual inspection. When the label has been affixed to the final container, a sufficient area of the container shall remain uncovered for its full length or for no less than 5 millimeters of the lower circumference to permit inspection of the contents.

(2) Package label. The following items shall appear either on the package label or on the final container label if see-through packaging is used:

(i) Proper name of the product, and the name of the antibody or antibodies as listed in paragraph (a)(4) of this section.

(ii) Name, address (including ZIP code), and license number of the manufacturer.

(iii) Lot number, including any sublot designations.

(iv) Expiration date.

(v) Preservative(s) used and its concentration.

(vi) Number of containers, if more than one.

(vii) Recommended storage temperature in degrees Celsius.

(viii) Source of the product.

(ix) Reference to enclosed package insert.

(x) The statement: “For In Vitro Diagnostic Use.”

(xi) The statement: “Meets FDA Potency Requirements.”

(xii) A statement of an observable indication of an alteration of the product, e.g., turbidity, color change, precipitate, that may indicate possible deterioration of the product.

(xiii) Appropriate cautions.

(3) Package insert. Each final container of Anti-Human Globulin shall be accompanied by a package insert meeting the requirements of § 809.10 of this chapter. If two or more final containers requiring identical package inserts are placed in a single package, only one package insert per package is required.

(4) Names of antibodies. Anti-Human Globulin preparations may contain one or more of the antibody specificities listed in this paragraph as described in paragraph (a)(1)(ii)(A) of this section.

Antibody designation on container label | Definition

(1) Anti-IgG, -C3d; Polyspecific | Contains anti-IgG and anti-C3d (may contain other anticomplement and anti-immunoglobulin antibodies).

(2) Anti-IgG | Contains anti-IgG with no anti-complement activity (not necessarily gamma chain specific).

(3) Anti-IgG; heavy chains | Contains only antibodies reactive against human gamma chains.

(4) Anti-C3b | Contains only C3b antibodies with no anti-immunoglobulin activity. Note: The antibody produced in response to immunization is usually directed against the antigenic determinant which is located in the C3c subunit; some persons have called this antibody “anti-C3c.” In product labeling, this antibody should be designated anti-C3b.

(5) Anti-C3d | Contains only C3d antibodies with no anti-immunoglobulin activity.

(6) Anti-C4b | Contains only C4b antibodies with no anti-immunoglobulin activity.

(7) Anti-C4d | Contains only C4d antibodies with no anti-immunoglobulin activity.

(b) The applicant may provide the labeling information referenced in this section in the form of:

(1) A symbol accompanied by explanatory text adjacent to the symbol;

(2) A symbol not accompanied by adjacent explanatory text that:

(i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act;

(ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(3) A symbol not accompanied by adjacent explanatory text that:

(i) Is established in a standard developed by a standards development organization (SDO);

(ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act;

(iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used.

(c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act.

(d) For purposes of paragraph (b) of this section:

(1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(2) The term “symbols glossary” means a compiled listing of:

(i) Each SDO-established symbol used in the labeling for the device;

(ii) The title and designation number of the SDO-developed standard containing the symbol;

(iii) The title of the symbol and its reference number, if any, in the standard; and

(iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

[81 FR 38928, June 15, 2016]

§ 680.1 Allergenic Products.

(a) Definition. Allergenic Products are products that are administered to man for the diagnosis, prevention or treatment of allergies.

(b) Source materials—(1) Criteria for source material. Only specifically identified allergenic source materials that contain no more than a total of 1.0 percent of detectable foreign materials shall be used in the manufacture of Allergenic Products, except that this requirement shall not apply to molds and animals described under paragraphs (b) (2) and (3) of this section, respectively. Source materials such as pelts, feathers, hairs, and danders shall be collected in a manner that will minimize contamination of the source material.

(2) Molds. (i) Molds (excluding rusts and smuts) used as source material in the manufacture of Allergenic Products shall meet the requirements of § 610.18 of this chapter and § 680.2 (a) and (b).

(ii) Mold cultures shall be free of contaminating materials (including microorganisms) prior to harvest, and care shall be taken to minimize contamination during harvest and subsequent processing.

(iii) Mold manufacturers shall maintain written standard operating procedures, developed by a qualified individual, that will ensure the identity of the seed culture, prescribe adequate processing of the mold, and specify the acceptable limits and kinds of contamination. These limits shall be based on results of appropriate tests performed by the manufacturer on at least three consecutive lots of a mold that is a representative species of mold subject to the standard operating procedures. The tests shall be performed at each manufacturing step during and subsequent to harvest, as specified in the standard operating procedures. Before use of the mold as a source material for Allergenic Products, in accordance with 21 CFR 601.2, the standard operating procedures and test data from the three representative lots described above shall be submitted to and approved by the Director, Center for Biologics Evaluation and Research (see mailing address in § 600.2(a) of this chapter).

(3) Mammals and birds—(i) Care of animals. Animals intended as a source material for Allergenic Products shall be maintained by competent personnel in facilities or designated areas that will ensure adequate care. Competent veterinary care shall be provided as needed.

(ii) Health of animals. Only animals in good health and free from detectable skin diseases shall be used as a source material for Allergenic Products. The determination of good health prior to collection of the source material shall be made by a licensed veterinarian or a competent individual under the supervision and instruction of a licensed veterinarian provided that the licensed veterinarian certifies in writing that the individual is capable of determining the good health of the animals.

(iii) Immunization against tetanus. Animals of the equine genus intended as a source material for Allergenic Products shall be treated to maintain immunity to tetanus.

(iv) Reporting of certain diseases. In cases of actual or suspected infection with foot and mouth disease, glanders, tetanus, anthrax, gas gangrene, equine infectious anemia, equine encephalomyelitis, or any of the pock diseases among animals intended for use or used as source material in the manufacture of Allergenic Products, the manufacturer shall immediately notify the Director, Center for Biologics Evaluation and Research (see mailing address in § 600.2(a) of this chapter).

(v) Dead animals. Dead animals may be used as source material in the manufacture of Allergenic Products: Provided, That (a) the carcasses shall be frozen or kept cold until the allergen can be collected, or shall be stored under other acceptable conditions so that the postmortal decomposition processes do not adversely affect the allergen, and (b) when alive, the animal met the applicable requirements prescribed in paragraphs (b)(3) (i), (ii), and (iii) of this section.

(vi) Mammals and birds inspected by the U.S. Department of Agriculture. Mammals and birds, subject to inspection by the U.S. Department of Agriculture at the time of slaughter and found suitable as food, may be used as a source material, and the requirements of paragraph (b)(3) (i) through (iv) of this section do not apply in such a case. Notwithstanding U.S. Department of Agriculture inspection, the carcasses of such inspected animals shall be frozen or kept cold until the allergen is collected, or shall be stored under other acceptable conditions so that the postmortal decomposition processes do not adversely affect the allergen.

(c) Listing of source materials and suppliers. Each licensed manufacturer shall initially list with the Director, Center for Biologics Evaluation and Research (see mailing address in § 600.2(a) of this chapter), the name and address of each of the manufacturer's source material suppliers. The listing shall identify each source material obtained from each source material supplier. The licensed manufacturers shall update the listing annually to include new source material suppliers or to delete those no longer supplying source materials.

(d) Exemptions. (1) Exemptions or modifications from the requirements under paragraph (b) of this section shall be made only upon written approval by the Director, Center for Biologics Evaluation and Research.

(2) Nonlicensed source material suppliers are exempt from drug registration.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25432, June 21, 1984; 49 FR 31395, Aug. 7, 1984; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015]

§ 680.2 Manufacture of Allergenic Products.

(a) Extraneous allergenic substances. All manufacturing steps shall be performed so as to insure that the product will contain only the allergenic and other substances intended to be included in the final product.

(b) Cultures derived from microorganisms. Culture media into which organisms are inoculated for the manufacture of Allergenic Products shall contain no allergenic substances other than those necessary as a growth requirement. Neither horse protein nor any allergenic derivative of horse protein shall be used in culture media.

(c) Liquid products for oral administration. Liquid products intended for oral administration that are filled in multiple dose final containers shall contain a preservative in a concentration adequate to inhibit microbial growth.

(d) Residual pyridine. Products for which pyridine is used in manufacturing shall have no more residual pyridine in the final product than 25 micrograms per milliliter.

(e) [Reserved]

(f) Records. A record of the history of the manufacture or propagation of each lot of source material intended for manufacture of final Allergenic Products shall be available at the establishment of the manufacturer of the source material, as required by § 211.188 of this chapter. A summary of the history of the manufacture or propagation of the source material shall be available at the establishment of the manufacturer of the final product.

[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25433, June 21, 1984; 67 FR 9587, Mar. 4, 2002]

§ 680.3 Tests.

(a) Identity. When a specific identity test meeting the provisions of § 610.14 of this chapter cannot be performed, the manufacture of each lot shall be separated from the manufacture of other products in a manner that will preclude adulteration, and records made in the course of manufacture shall be in sufficient detail to verify the identity of the product.

(b) [Reserved]

(c) Sterility. A sterility test shall be performed on each lot of each Allergenic Product as required by § 610.12 of this chapter.

(d) [Reserved]

(e) Potency. The potency of each lot of each Allergenic Product shall be determined as prescribed in § 610.10 of this chapter. Except as provided in this section, the potency test methods shall measure the allergenic activity of the product. Until manufacturers are notified by the Director, Center for Biologics Evaluation and Research, of the existence of a potency test that measures the allergenic activity of an allergenic product, manufacturers may continue to use unstandardized potency designations.

(f) Records. The records related to the testing requirements of this section shall be prepared and maintained as required by §§ 211.165, 211.167, 211.188, and 211.194 of this chapter.

[38 FR 32100, Nov. 20, 1973, as amended at 39 FR 19777, June 6, 1974; 41 FR 4015, Jan. 28, 1976; 52 FR 37607, Oct. 8, 1987; 55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 77 FR 26175, May 3, 2012; 77 FR 30884, May 24, 2012; 80 FR 37974, July 2, 2015]

§ 700.3 Definitions.

As used in this subchapter:

(a) The term act means the Federal Food, Drug, and Cosmetic Act.

(b) The term cosmetic product means a finished cosmetic the manufacture of which has been completed. Any cosmetic product which is also a drug or device or component thereof is also subject to the requirements of Chapter V of the act.

(c) The term flavor means any natural or synthetic substance or substances used solely to impart a taste to a cosmetic product.

(d) The term fragrance means any natural or synthetic substance or substances used solely to impart an odor to a cosmetic product.

(e) The term ingredient means any single chemical entity or mixture used as a component in the manufacture of a cosmetic product.

(f) The term proprietary ingredient means any cosmetic product ingredient whose name, composition, or manufacturing process is protected from competition by secrecy, patent, or copyright.

(g) The term chemical description means a concise definition of the chemical composition using standard chemical nomenclature so that the chemical structure or structures of the components of the ingredient would be clear to a practicing chemist. When the composition cannot be described chemically, the substance shall be described in terms of its source and processing.

(h) The term cosmetic raw material means any ingredient, including an ingredient that is a mixture, which is used in the manufacture of a cosmetic product for commercial distribution and is supplied to a cosmetic product manufacturer, packer, or distributor by a cosmetic raw material manufacturer or supplier.

(i) The term commercial distribution of a cosmetic product means annual gross sales in excess of $1,000 for that product.

(j) Establishment means a place of business where cosmetic products are manufactured or packaged.

(k) The term manufacture of a cosmetic product means the making of any cosmetic product by chemical, physical, biological, or other procedures, including manipulation, sampling, testing, or control procedures applied to the product.

(l) The term packaging of a cosmetic product means filling or labeling the product container, including changing the immediate container or label (but excluding changing other labeling) at any point in the distribution of the cosmetic product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.

(m) The term all business trading names used by the establishment means any name which is used on a cosmetic product label and owned by the cosmetic product manufacturer or packer, but is different from the principal name under which the cosmetic product manufacturer or packer is registered.

(n) The definitions and interpretations contained in sections 201, 601, and 602 of the act shall be applicable to such terms when used in the regulations in this subchapter.

(o) System of commercial distribution of a cosmetic product means any distribution outside the establishment manufacturing the product, whether for sale, to promote future sales (including free samples of the product), or to gage consumer acceptance through market testing, in excess of $1,000 in cost of goods.

(p) Filed screening procedure means a procedure that is:

(1) On file with the Food and Drug Administration and subject to public inspection;

(2) Designed to determine that there is a reasonable basis for concluding that an alleged injury did not occur in conjunction with the use of the cosmetic product; and

(3) Which is subject, upon request by the Food and Drug Administration, to an audit conducted by the Food and Drug Administration at reasonable times and, where an audit is conducted, such audit shows that the procedure is consistently being applied and that the procedure is not disregarding reportable information.

(q) Reportable experience means an experience involving any allergic reaction, or other bodily injury, alleged to be the result of the use of a cosmetic product under the conditions of use prescribed in the labeling of the product, under such conditions of use as are customary or reasonably foreseeable for the product or under conditions of misuse, that has been reported to the manufacturer, packer, or distributor of the product by the affected person or any other person having factual knowledge of the incident, other than an alleged experience which has been determined to be unfounded or spurious when evaluated by a filed screening procedure.

[39 FR 10054, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981]

§ 700.11 Cosmetics containing bithionol.

(a) Bithionol has been used to some extent as an antibacterial agent in cosmetic preparations such as detergent bars, shampoos, creams, lotions, and bases used to hide blemishes. New evidence of clinical experience and photopatch tests indicate that bithionol is capable of causing photosensitivity in man when used topically and that in some instances the photosensitization may persist for prolonged periods as severe reactions without further contact with sensitizing articles. Also, there is evidence to indicate that bithionol may produce cross-sensitization with other commonly used chemicals such as certain halogenated salicylanilides and hexachlorophene. It is, therefore, the view of the Food and Drug Administration that bithionol is a deleterious substance which may render any cosmetic product that contains it injurious to users. Accordingly, any cosmetic containing bithionol is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.

(b) Regulatory proceedings may be initiated with respect to any cosmetic preparation containing bithionol shipped within the jurisdiction of the act after March 15, 1968.

§ 700.13 Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic preparations also regarded as drugs.

(a) Mercury-containing cosmetic preparations have been represented for many years as skin-bleaching agents or as preparations to remove or prevent freckles and/or brown spots (so-called age spots). Preparations intended for such use are regarded as drugs as well as cosmetics. In addition to such use as skin-bleaching agents, mercury compounds have also been widely used as preservatives in cosmetics such as hand and body creams and lotions; hair shampoos, hair sets and rinses, hair straighteners, hair coloring, and other preparations; bath oils, bubble bath, and other bath preparations; makeup; antiperspirants and deodorants; and eye-area cosmetics.

(b) The toxicity of mercury compounds is extensively documented in scientific literature. It is well known that mercury compounds are readily absorbed through the unbroken skin as well as through the lungs by inhalation and by intestinal absorption after ingestion. Mercury is absorbed from topical application and is accumulated in the body, giving rise to numerous adverse effects. Mercury is a potent allergen and sensitizer, and skin irritation is common after topical application. Cosmetic preparations containing mercury compounds are often applied with regularity and frequency for prolonged periods. Such chronic use of mercury-containing skin-bleaching preparations has resulted in the accumulation of mercury in the body and the occurrence of severe reactions. Recently it has also been determined that microorganisms in the environment can convert various forms of mercury into highly toxic methyl mercury which has been found in the food supply and is now considered to be a serious environmental problem.

(c) The effectiveness of mercury-containing preparations as skin-bleaching agents is questionable. The Food and Drug Administration has not been provided with well controlled studies to document the effectiveness of these preparations. Although mercurial preservatives are recognized as highly effective, less toxic and satisfactory substitutes are available except in the case of certain eye-area cosmetics.

(d) Because of the known hazards of mercury, its questionable efficacy as a skin-bleaching agent, and the availability of effective and less toxic nonmercurial preservatives, there is no justification for the use of mercury in skin-bleaching preparations or its use as a preservative in cosmetics, with the exception of eye-area cosmetics for which no other effective and safe nonmercurial preservative is available. The continued use of mercurial preservatives in such eye-area cosmetics is warranted because mercury compounds are exceptionally effective in preventing Pseudomonas contamination of cosmetics and Pseudomonas infection of the eye can cause serious injury, including blindness. Therefore:

(1) The Food and Drug Administration withdraws the opinion expressed in trade correspondence TC-9 (issued May 13, 1939) and concludes that any product containing mercury as a skin-bleaching agent and offered for sale as skin-bleaching, beauty, or facial preparation is misbranded within the meaning of sections 502(a), 502(f)(1) and (2), and 502(j), and may be a new drug without approval in violation of section 505 of the Federal Food, Drug, and Cosmetic Act. Any such preparation shipped within the jurisdiction of the Act after January 5, 1973 will be the subject of regulatory action.

(2) The Food and Drug Administration withdraws the opinion expressed in trade correspondence TC-412 (issued Feb. 11, 1944) and will regard as adulterated within the meaning of section 601(a) of the Act any cosmetic containing mercury unless the cosmetic meets the conditions of paragraph (d)(2) (i) or (ii) of this section.

(i) It is a cosmetic containing no more than a trace amount of mercury and such trace amount is unavoidable under conditions of good manufacturing practice and is less than 1 part per million (0.0001 percent), calculated as the metal; or

(ii) It is a cosmetic intended for use only in the area of the eye, it contains no more than 65 parts per million (0.0065 percent) of mercury, calculated as the metal, as a preservative, and there is no effective and safe nonmercurial substitute preservative available for use in such cosmetic.

§ 700.14 Use of vinyl chloride as an ingredient, including propellant of cosmetic aerosol products.

(a) Vinyl chloride has been used as an ingredient in cosmetic aerosol products including hair sprays. Where such aerosol products are used in the confines of a small room, as is often the case, the level of vinyl chloride to which the individual may be exposed could be significantly in excess of the safe level established in connection with occupational exposure. Evidence indicates that vinyl chloride inhalation can result in acute toxicity, manifested by dizziness, headache, disorientation, and unconsciousness where inhaled at high concentrations. Studies also demonstrate carcinogenic effects in animals as a result of inhalation exposure to vinyl chloride. Furthermore, vinyl chloride has recently been linked to liver disease, including liver cancer, in workers engaged in the polymerization of vinyl chloride. It is the view of the Commissioner that vinyl chloride is a deleterious substance which may render any cosmetic aerosol product that contains it as an ingredient injurious to users. Accordingly, any cosmetic aerosol product containing vinyl chloride as an ingredient is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.

(b) Any cosmetic aerosol product containing vinyl chloride as an ingredient shipped within the jurisdiction of the Act is subject to regulatory action.

[39 FR 30830, Aug. 26, 1974]

§ 700.15 Use of certain halogenated salicylanilides as ingredients in cosmetic products.

(a) Halogenated salicylanilides (tribromsalan (TBS,3,4′,5-tribromosalicylanilide), dibromsalan (DBS,4′5-dibromosalicylanilide), metabromsalan (MBS, 3,5-dibromosalicylanilide) and 3,3′,4,5′-tetrachlorosalicylanilide (TCSA)) have been used as antimicrobial agents for a variety of purposes in cosmetic products. These halogenated salicylanilides are potent photosensitizers and cross-sensitizers and can cause disabling skin disorders. In some instances, the photosensitization may persist for prolonged periods as a severe reaction without further exposure to these chemicals. Safer alternative antimicrobial agents are available.

(b) These halogenated salicylanilides are deleterious substances which render any cosmetic that contains them injurious to users. Therefore, any cosmetic product that contains such a halogenated salicylanilide as an ingredient at any level for any purpose is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.

(c) Any cosmetic product containing these halogenated salicylanilides as an ingredient that is initially introduced into interstate commerce after December 1, 1975, that is not in compliance with this section is subject to regulatory action.

[40 FR 50531, Oct. 30, 1975]

§ 700.16 Use of aerosol cosmetic products containing zirconium.

(a) Zirconium-containing complexes have been used as an ingredient in cosmetics and/or cosmetics that are also drugs, as, for example, aerosol antiperspirants. Evidence indicates that certain zirconium compounds have caused human skin granulomas and toxic effects in the lungs and other organs of experimental animals. When used in aerosol form, some zirconium will reach the deep portions of the lungs of users. The lung is an organ, like skin, subject to the development of granulomas. Unlike the skin, the lung will not reveal the presence of granulomatous changes until they have become advanced and, in some cases, permanent. It is the view of the Commissioner that zirconium is a deleterious substance that may render any cosmetic aerosol product that contains it injurious to users.

(b) Any aerosol cosmetic product containing zirconium is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.

(c) Any such cosmetic product introduced in interstate commerce after September 15, 1977 is subject to regulatory action.

[42 FR 41376, Aug. 16, 1977]

§ 700.18 Use of chloroform as an ingredient in cosmetic products.

(a) Chloroform has been used as an ingredient in cosmetic products. Recent information has become available associating chloroform with carcinogenic effects in animals. Studies conducted by the National Cancer Institute have demonstrated that the oral administration of chloroform to mice and rats induced hepatocellular carcinomas (liver cancer) in mice and renal tumors in male rats. Scientific literature indicates that chloroform is absorbed from the gastrointestinal tract, through the respiratory system, and through the skin. The Commissioner concludes that, on the basis of these findings, chloroform is a deleterious substance which may render injurious to users any cosmetic product that contains chloroform as an ingredient.

(b) Any cosmetic product containing chloroform as an ingredient is adulterated and is subject to regulatory action under sections 301 and 601(a) of the Federal Food, Drug, and Cosmetic Act. Any cosmetic product containing chloroform in residual amounts from its use as a processing solvent during manufacture, or as a byproduct from the synthesis of an ingredient, is not, for the purpose of this section, considered to contain chloroform as an ingredient.

[41 FR 26845, June 29, 1976]

§ 700.19 Use of methylene chloride as an ingredient of cosmetic products.

(a) Methylene chloride has been used as an ingredient of aerosol cosmetic products, principally hair sprays, at concentrations generally ranging from 10 to 25 percent. In a 2-year animal inhalation study sponsored by the National Toxicology Program, methylene chloride produced a significant increase in benign and malignant tumors of the lung and liver of male and female mice. Based on these findings and on estimates of human exposure from the customary use of hair sprays, the Food and Drug Administration concludes that the use of methylene chloride in cosmetic products poses a significant cancer risk to consumers, and that the use of this ingredient in cosmetic products may render these products injurious to health.

(b) Any cosmetic product that contains methylene chloride as an ingredient is deemed adulterated and is subject to regulatory action under sections 301 and 601(a) of the Federal Food, Drug, and Cosmetic Act.

[54 FR 27342, June 29, 1989]

§ 700.23 Chlorofluorocarbon propellants.

The use of chlorofluorocarbons in cosmetics as propellants in self-pressurized containers is prohibited as provided in § 2.125 of this chapter.

[43 FR 11317, Mar. 17, 1978]

§ 700.25 Tamper-resistant packaging requirements for cosmetic products.

(a) General. Because most cosmetic liquid oral hygiene products and vaginal products are not now packaged in tamper-resistant retail packages, there is the opportunity for the malicious adulteration of those cosmetic products with health risks to individuals who unknowingly purchase adulterated products and with loss of consumer confidence in the security of cosmetic product packages. The Food and Drug Administration has the authority and responsibility under the Federal Food, Drug, and Cosmetic Act (the act) to establish a uniform national requirement for tamper-resistant packaging of cosmetic liquid oral hygiene products or products used vaginally that will improve the packaging security and help assure the safety of those products. Such a cosmetic product for retail sale that is not packaged in a tamper-resistant package or that is not properly labeled under this section is adulterated under section 601 of the act or misbranded under section 602 of the act, or both.

(b) Requirement for tamper-resistant package. Each manufacturer and packer who packages a cosmetic liquid oral hygiene product or vaginal product for retail sale shall package the product in a tamper-resistant package, if this product is accessible to the public while held for sale. A tamper-resistant package is one having an indicator or barrier to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of substitution of a tamper-resistant feature after tampering, the indicator or barrier to entry is required to be distinctive by design (e.g., an aerosol product container) or by the use of an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture). For purposes of this section, the term “distinctive by design” means the packaging cannot be duplicated with commonly available materials or through commonly available processes. For purposes of this section, the term “aerosol product” means a product which depends upon the power of a liquified or compressed gas to expel the contents from the container. A tamper-resistant package may involve an immediate-container and closure system or secondary-container or carton system or any combination of systems intended to provide a visual indication of package integrity. The tamper-resistant feature shall be designed to and shall remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.

(c) Labeling. Each retail package of a cosmetic product covered by this section, except aerosol products as defined in paragraph (b) of this section, is required to bear a statement that is prominently placed so that consumers are alerted to the specific tamper-resistant feature of the package. The labeling statement is also required to be so placed that it will be unaffected if the tamper-resistant feature of the package is breached or missing. If the tamper-resistant feature chosen to meet the requirement in paragraph (b) of this section is one that uses an identifying characteristic, that characteristic is required to be referred to in the labeling statement. For example, the labeling statement on a bottle with a shrink band could say “For your protection, this bottle has an imprinted seal around the neck.”

(d) Requests for exemptions from packaging and labeling requirements. A manufacturer or packer may request an exemption from the packaging and labeling requirements of this section. A request for an exemption is required to be submitted in the form of a citizen petition under § 10.30 of this chapter and should be clearly identified on the envelope as a “Request for Exemption from Tamper-resistant Rule.” The petition is required to contain the following:

(1) The name of the product.

(2) The reasons that the product's compliance with the tamper-resistant packaging or labeling requirements of this section is unnecessary or cannot be achieved.

(3) A description of alternative steps that are available, or that the petitioner has already taken, to reduce the likelihood that the product will be the subject of malicious adulteration.

(4) Other information justifying an exemption.

This information collection requirement has been approved by the Office of Management and Budget under number 0910-0149.

(e) Effective date. Cosmetic products covered by this section are required to comply with the requirements of this section on the dates listed below except to the extent that a product's manufacturer or packer has obtained an exemption from a packaging or labeling requirement.

(1) Initial effective date for packaging requirements. (i) The packaging requirement in paragraph (b) of this section is effective on Feburary 7, 1983 for each affected cosmetic product (except vaginal tablets) packaged for retail sale on or after that date, except for the requirement in paragraph (b) of this section for a distinctive indicator or barrier to entry.

(ii) The packaging requirement in paragraph (b) of this section is effective on May 5, 1983 for each cosmetic product that is a vaginal tablet packaged for retail sale on or after that date.

(2) Initial effective date for labeling requirements. The requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design and the requirement in paragraph (c) of this section for a labeling statement are effective on May 5, 1983 for each affected cosmetic product packaged for retail sale on or after that date, except that the requirement for a specific label reference to any identifying characteristic is effective on February 6, 1984 for each affected cosmetic product packaged for retail sale on or after that date.

(3) Retail level effective date. The tamper-resistant packaging requirement of paragraph (b) of this section is effective February 6, 1984 for each affected cosmetic product held for sale on or after that date that was packaged for retail sale before May 5, 1983. This does not include the requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design. Products packaged for retail sale after May 5, 1983, as required to be in compliance with all aspects of the regulations without regard to the retail level effective date.

[47 FR 50451, Nov. 5, 1982; 48 FR 1707, Jan. 14, 1983; 48 FR 11427, Mar. 18, 1983, as amended at 48 FR 16664, Apr. 19, 1983; 48 FR 37624, Aug. 19, 1983]

Effective Date Note:See 48 FR 41579, Sept. 16, 1983, for a document announcing an interim stay of the effective date of certain provisions in paragraph (e)(3) of § 700.25.

§ 700.27 Use of prohibited cattle materials in cosmetic products.

(a) Definitions. The definitions and interpretations of terms contained in section 201 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) apply to such terms when used in this part. The following definitions also apply:

(1) Prohibited cattle materials mean specified risk materials, small intestine of all cattle except as provided in paragraph (b)(2) of this section, material from nonambulatory disabled cattle, material from cattle not inspected and passed, or mechanically separated (MS) (Beef). Prohibited cattle materials do not include the following:

(i) Tallow that contains no more than 0.15 percent insoluble impurities, tallow derivatives, gelatin, hides and hide-derived products, and milk and milk products, and

(ii) Cattle materials inspected and passed from a country designated under paragraph (e) of this section.

(2) Inspected and passed means that the product has been inspected and passed for human consumption by the appropriate regulatory authority, and at the time it was inspected and passed, it was found to be not adulterated.

(3) Mechanically separated (MS) (Beef) means a meat food product that is finely comminuted, resulting from the mechanical separation and removal of most of the bone from attached skeletal muscle of cattle carcasses and parts of carcasses that meets the specifications contained in 9 CFR 319.5, the U.S. Department of Agriculture regulation that prescribes the standard of identity for MS (Species).

(4) Nonambulatory disabled cattle means cattle that cannot rise from a recumbent position or that cannot walk, including, but not limited to, those with broken appendages, severed tendons or ligaments, nerve paralysis, fractured vertebral column, or metabolic conditions.

(5) Specified risk material means the brain, skull, eyes, trigeminal ganglia, spinal cord, vertebral column (excluding the vertebrae of the tail, the transverse processes of the thoracic and lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia of cattle 30 months of age and older and the tonsils and distal ileum of the small intestine of all cattle.

(6) Tallow means the rendered fat of cattle obtained by pressing or by applying any other extraction process to tissues derived directly from discrete adipose tissue masses or to other carcass parts and tissues. Tallow must be produced from tissues that are not prohibited cattle materials or must contain no more than 0.15 percent insoluble impurities as determined by the method entitled “Insoluble Impurities” (AOCS Official Method Ca 3a-46), American Oil Chemists' Society (AOCS), 5th Edition, 1997, incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method equivalent in accuracy, precision, and sensitivity to AOCS Official Method Ca 3a-46. You may obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. Bradley Ave. Champaign, IL 61821. Copies may be examined at the Food and Drug Administration's Main Library, 10903 New Hampshire Ave., Bldg. 2, Third Floor, Silver Spring, MD 20993, 301-796-2039 or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

(7) Tallow derivative means any chemical obtained through initial hydrolysis, saponification, or trans-esterification of tallow; chemical conversion of material obtained by hydrolysis, saponification, or trans-esterification may be applied to obtain the desired product.

(8) Gelatin means a product that has been obtained by the partial hydrolysis of collagen derived from hides, connective tissue, and/or bone bones of cattle and swine. Gelatin may be either Type A (derived from an acid-treated precursor) or Type B (derived from an alkali-treated precursor) that has gone through processing steps that include filtration and sterilization or an equivalent process in terms of infectivity reduction.

(b) Requirements. (1) No cosmetic shall be manufactured from, processed with, or otherwise contain, prohibited cattle materials.

(2) The small intestine is not considered prohibited cattle material if the distal ileum is removed by a procedure that removes at least 80 inches of the uncoiled and trimmed small intestine, as measured from the caeco-colic junction and progressing proximally towards the jejunum, or by a procedure that the establishment can demonstrate is equally effective in ensuring complete removal of the distal ileum.

(c) Records. (1) Manufacturers and processors of a cosmetic that is manufactured from, processed with, or otherwise contains, material from cattle must establish and maintain records sufficient to demonstrate that the cosmetic is not manufactured from, processed with, or does not otherwise contain, prohibited cattle materials.

(2) Records must be retained for 2 years after the date they were created.

(3) Records must be retained at the manufacturing or processing establishment or at a reasonably accessible location.

(4) The maintenance of electronic records is acceptable. Electronic records are considered to be reasonably accessible if they are accessible from an onsite location.

(5) Records required by this section and existing records relevant to compliance with this section must be available to FDA for inspection and copying.

(6) When filing entry with U.S. Customs and Border Protection, the importer of record of a cosmetic manufactured from, processed with, or otherwise containing, cattle material must affirm that the cosmetic was manufactured from, processed with, or otherwise contains, cattle material and must affirm that the cosmetic was manufactured in accordance with this section. If a cosmetic is manufactured from, processed with, or otherwise contains, cattle material, then the importer of record must, if requested, provide within 5 days records sufficient to demonstrate that the cosmetic is not manufactured from, processed with, or does not otherwise contain, prohibited cattle material.

(7) Records established or maintained to satisfy the requirements of this subpart that meet the definition of electronic records in § 11.3(b)(6) of this chapter are exempt from the requirements of part 11 of this chapter. Records that satisfy the requirements of this subpart but that are also required under other applicable statutory provisions or regulations remain subject to part 11 of this chapter.

(d) Adulteration. Failure of a manufacturer or processor to operate in compliance with the requirements of paragraph (b) or (c) of this section renders a cosmetic adulterated under section 601(c) of the act.

(e) Process for designating countries. A country seeking designation must send a written request to the Director, Office of the Center Director, Center for Food Safety and Applied Nutrition, Food and Drug Administration, at the address designated in 21 CFR 5.1100. The request shall include information about a country's bovine spongiform encephalopathy (BSE) case history, risk factors, measures to prevent the introduction and transmission of BSE, and any other information relevant to determining whether specified risk materials, the small intestine of cattle except as provided in paragraph (b)(2) of this section, material from nonambulatory disabled cattle, or MS (Beef) from cattle from the country should be considered prohibited cattle materials. FDA shall respond in writing to any such request and may impose conditions in granting any such request. A country designation granted by FDA under this paragraph will be subject to future review by FDA, and may be revoked if FDA determines that it is no longer appropriate.

[70 FR 53068, Sept. 7, 2005, as amended at 71 FR 59668, Oct. 11, 2006; 73 FR 20794, Apr. 17, 2008; 81 FR 5596, Feb. 3, 2016; 81 FR 14732, Mar. 18, 2016]

§ 700.35 Cosmetics containing sunscreen ingredients.

(a) A product that includes the term “sunscreen” in its labeling or in any other way represents or suggests that it is intended to prevent, cure, treat, or mitigate disease or to affect a structure or function of the body comes within the definition of a drug in section 201(g)(1) of the act. Sunscreen active ingredients affect the structure or function of the body by absorbing, reflecting, or scattering the harmful, burning rays of the sun, thereby altering the normal physiological response to solar radiation. These ingredients also help to prevent diseases such as sunburn and may reduce the chance of premature skin aging, skin cancer, and other harmful effects due to the sun when used in conjunction with limiting sun exposure and wearing protective clothing. When consumers see the term “sunscreen” or similar sun protection terminology in the labeling of a product, they expect the product to protect them in some way from the harmful effects of the sun, irrespective of other labeling statements. Consequently, the use of the term “sunscreen” or similar sun protection terminology in a product's labeling generally causes the product to be subject to regulation as a drug. However, sunscreen ingredients may also be used in some products for nontherapeutic, nonphysiologic uses (e.g., as a color additive or to protect the color of the product). To avoid consumer misunderstanding, if a cosmetic product contains a sunscreen ingredient and uses the term “sunscreen” or similar sun protection terminology anywhere in its labeling, the term must be qualified by describing the cosmetic benefit provided by the sunscreen ingredient.

(b) The qualifying information required under paragraph (a) of this section shall appear prominently and conspicuously at least once in the labeling in conjunction with the term “sunscreen” or other similar sun protection terminology used in the labeling. For example: “Contains a sunscreen—to protect product color.”

[64 FR 27693, May 21, 1999]

§ 701.1 Misbranding.

(a) Among representations in labeling of a cosmetic which render such cosmetic misbranded is a false or misleading representation with respect to another cosmetic or a food, drug, or device.

(b) The labeling of a cosmetic which contains two or more ingredients may be misleading by reason (among other reasons) of the designation of such cosmetic in such labeling by a name which includes or suggests the name of one or more but not all such ingredients, even though the names of all such ingredients are stated elsewhere in the labeling.

§ 701.2 Form of stating labeling requirements.

(a) A word, statement, or other information required by or under authority of the Act to appear on the label may lack that prominence and conspicuousness required by section 602(c) of the Act by reason (among other reasons) of:

(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;

(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;

(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;

(4) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the Act to appear on the label;

(5) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device;

(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.

(b)(1) All words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.

(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the Act to appear on the label shall appear thereon in the foreign language.

(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear on the labeling in the foreign language.

§ 701.3 Designation of ingredients.

(a) The label on each package of a cosmetic shall bear a declaration of the name of each ingredient in descending order of predominance, except that fragrance or flavor may be listed as fragrance or flavor. An ingredient which is both fragrance and flavor shall be designated by each of the functions it performs unless such ingredient is identified by name. No ingredient may be designated as fragrance or flavor unless it is within the meaning of such term as commonly understood by consumers. Where one or more ingredients is accepted by the Food and Drug Administration as exempt from public disclosure pursuant to the procedure established in § 720.8(a) of this chapter, in lieu of label declaration of identity the phrase “and other ingredients” may be used at the end of the ingredient declaration.

(b) The declaration of ingredients shall appear with such prominence and conspicuousness as to render it likely to be read and understood by ordinary individuals under normal conditions of purchase. The declaration shall appear on any appropriate information panel in letters not less than 1/16 of an inch in height and without obscuring design, vignettes, or crowding. In the absence of sufficient space for such declaration on the package, or where the manufacturer or distributor wishes to use a decorative container, the declaration may appear on a firmly affixed tag, tape, or card. In those cases where there is insufficient space for such declaration on the package, and it is not practical to firmly affix a tag, tape, or card, the Commissioner may establish by regulation an acceptable alternate, e.g., a smaller type size. A petition requesting such a regulation as an amendment to this paragraph shall be submitted pursuant to part 10 of this chapter.

(c) A cosmetic ingredient shall be identified in the declaration of ingredients by:

(1) The name specified in § 701.30 as established by the Commissioner for that ingredient for the purpose of cosmetic ingredient labeling pursuant to paragraph (e) of this section;

(2) In the absence of the name specified in § 701.30, the name adopted for that ingredient in the following editions and supplements of the following compendia, listed in order as the source to be utilized:

(i) CTFA (Cosmetic, Toiletry and Fragrance Association, Inc.) Cosmetic Ingredient Dictionary, Second Ed., 1977 (available from the Cosmetic, Toiletry and Fragrance Association, Inc. 1110 Vermont Ave. NW., Suite 800, Washington, DC 20005, or at the National Archives and Records Administration (NARA), which is incorporated by reference, except for the following deletions and revisions. (For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.)

(a) The following names are not adopted for the purpose of cosmetic ingredient labeling:

Acid Black 58 Acid Black 107 Acid Black 139 Acid Blue 168 Acid Blue 170 Acid Blue 188 Acid Blue 209 Acid Brown 19 Acid Brown 30 Acid Brown 44 Acid Brown 45 Acid Brown 46 Acid Brown 48 Acid Brown 224 Acid Orange 80 Acid Orange 85 Acid Orange 86 Acid Orange 88 Acid Orange 89 Acid Orange 116 Acid Red 131 Acid Red 213 Acid Red 252 Acid Red 259 Acid Violet 73 Acid Violet 76 Acid Violet 99 Acid Yellow 114 Acid Yellow 127 Direct Yellow 81 Solvent Black 5 Solvent Brown 43 Solvent Yellow 63 Solvent Yellow 90

(b) The following names are adopted for the purpose of cosmetic ingredient labeling, provided the respective monographs are revised to describe their otherwise disclosed chemical compositions, or describe their chemical compositions more precisely, and such revised monographs are published in supplements to this dictionary edition by July 18, 1980.

Acid Black 2 Benzophenone-11 Carbomer 934 Carbomer 934P Carbomer 940 Carbomer 941 Carbomer 960 Carbomer 961 Chlorofluorocarbon 11S Dimethicone Copolyol Disperse Red 17 Pigment Green 7 Polyamino Sugar Condensate SD Alcohol (all 27 alphanumeric designations) Sodium Chondroitin Sulfate Synthetic Beeswax

(c) The following names are adopted for the purpose of cosmetic ingredient labeling until January 19, 1981.

Amphoteric (all 20 numeric designations) Quaternium (all 49 numeric designations)

(ii) United States Pharmacopeia, 19th Ed., 1975, and Second Supplement to the USP XIX and NF XIV, 1976. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.).

(iii) National Formulary, 14th Ed., 1975, and Second Supplement to the USP XIX and NF XIV, 1976. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.).

(iv) Food Chemicals Codex, 2d Ed., 1972; First Supplement, 1974, and Second Supplement, 1975, which are incorporated by reference. Copies are available from the Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

(v) USAN and the USP dictionary of drug names, USAN 1975, 1961-1975 cumulative list. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.)

(3) In the absence of such a listing, the name generally recognized by consumers.

(4) In the absence of any of the above, the chemical or other technical name or description.

(d) Where a cosmetic product is also an over-the-counter drug product, the declaration shall declare the active drug ingredients as set forth in § 201.66(c)(2) and (d) of this chapter, and the declaration shall declare the cosmetic ingredients as set forth in § 201.66(c)(8) and (d) of this chapter.

(e) Interested persons may submit a petition requesting the establishment of a specific name for a cosmetic ingredient pursuant to part 10 of this chapter. The Commissioner may also propose such a name on his own initiative.

(f) As an alternative to listing all ingredients in descending order of predominance, ingredients may be grouped and the groups listed in the following manner and order:

(1) Ingredients, other than color additives, present at a concentration greater than 1 percent, in descending order of predominance; followed by

(2) Ingredients, other than color additives, present at a concentration of not more than 1 percent, without respect to order of predominance; followed by

(3) Color additives, without respect to order of predominance. Ingredients specified in paragraph (f)(2) of this section may be included with those specified in paragraph (f)(1) of this section and listed in descending order of predominance.

(g) A declaration of ingredients may include an ingredient not in the product if the ingredient is identified by the phrase “may contain” and:

(1) It is a color additive added to some batches of the product for purposes of color matching; or

(2)(i) The same declaration of ingredients is also used for other products similar in composition and intended for the same use, including products which may be assortments of products similar in composition and intended for the same use; and

(ii) Such products are “shaded” products, i.e., those falling within the product categories identified in § 720.4 (c)(3), (7) and (8)(v) of this chapter; and

(iii) All products sharing the common declaration of ingredients are sold by the labeler under a common trade name or brand designation, and no trade name or brand designation not common to all such products appears in the labeling of any of them; and

(iv) The ingredient is a color additive.

(h) As an alternative to a declaration of color additive ingredients for each product, the color additives of an assortment of cosmetic products that are sold together in the same package may be declared in a single composite list in a manner that is not misleading and that indicates that the list pertains to all the products.

(i) As an alternative to the declaration of ingredients specified in paragraph (b) of this section, the declaration of ingredients may appear in letters not less than 1/16 of an inch in height in labeling accompanying the product, as for example, on padded sheets or in leaflets, if the total surface area of the package is less than 12 square inches. This paragraph is inapplicable to any packaged cosmetic product enclosed in an outer container, e.g., a folding carton. In addition, this paragraph is applicable only to cosmetic products meeting one of the following requirements:

(1) The cosmetic products are held and displayed for sale in tightly compartmented trays or racks of a display unit. The holder of the labeling bearing the declaration of ingredients shall be attached to the display unit; or

(2) The cosmetic products are “shaded” products, i.e., those falling within the product categories identified in § 720.4 (c)(3), (7) and (8)(v) of this chapter, and are held for sale in tightly compartmented trays or racks. The holder of the labeling bearing the declaration of ingredients shall be attached to a display chart bearing samples of the product shades, which is displayed to purchasers. Such a display chart shall be of such construction and design as to permit its continuous use as a display, such as on a counter, and shall be designed for the primary purpose of displaying samples of the shades of the products.

(j) The holder of labeling bearing a declaration of ingredients and used in accordance with paragraph (i) of this section shall be attached to the display unit or chart and shall meet one of the following conditions:

(1) The labeling is on the front of the display unit or chart and can be read in full by a purchaser facing the display unit or chart under customary conditions of retail sale; or

(2) The labeling is on the front of the display unit or chart, is partially visible, and is accompanied by a conspicuous notice on the front of the display unit or chart describing the location of such labeling in letters not less than 3/16 of an inch in height, e.g., “Ingredient lists above”, that can be read by a purchaser facing the display unit or chart under customary conditions of retail sale, or by the notice required by provisions in paragraph (k)(3) of this section, if conspicuous at all times; or

(3) The labeling is on a side of the display unit or chart, but not on the top, back, or bottom, and is accompanied by a conspicuous notice on the front of the display unit or chart describing the location of such labeling in letters not less than 3/16 of an inch in height, e.g., “Ingredient lists located on right side of display”, that can be read by a purchaser facing the display unit or chart under customary conditions of retail sale.

(k) Any use of a display unit or chart bearing labeling under the provisions of paragraph (i) of this section shall meet the following requirements:

(1) All articles of labeling bearing ingredient declarations and used in conjunction with any one display unit or chart shall be identical and shall declare the ingredients of all products sold in conjunction with the display unit or chart for which the ingredient declaration is made pursuant to paragraph (i) of this section.

(2) Any display unit or chart intended for such use shall be shipped together with the labeling intended to be attached to it.

(3) Every display unit or chart and/or labeling system shall be designed so that the words “Federal law requires ingredient lists to be displayed here” in letters not less than 3/16 of an inch in height (i) become conspicuous when no ingredient declarations are displayed and when the last list has been taken, or (ii) are conspicuous at all times adjacent to the place where ingredient declarations are to be attached.

(4) Any labeling containing a declaration of ingredients which reflects a formulation change and not shipped accompanying a display unit or chart shall be dated. Whenever any formulation change is made, and the labeling containing the declaration of ingredients is thereby required to be used in conjunction with products of both the old and new formulations, the labeling shall declare the ingredients of both the old and new formulations separately in a way that is not misleading and in a way that permits the purchaser to identify the ingredient declaration applicable to each package, or which clearly advises the purchaser that the formulation has been changed and that either declaration may be applicable.

(5) Sufficient copies of the declaration of ingredients shall be provided with each shipment of a cosmetic so that a purchaser may obtain a copy of the declaration with each purchase. Display units and replacement labeling for display units shall be accompanied by instructions to the retailer, which when followed will result in compliance with the requirements of this section. Copies of the declaration accompanying refills shall be attached to the specific refill items to which they pertain, or shall be packed with the specific refill items to which they pertain, in a container that does not contain other cosmetic products.

(6) The firm whose name appears on a product pursuant to § 701.12 shall promptly mail a copy of the declaration of ingredients to any person requesting it.

(7) The display unit or chart shall be designed and located such that the labeling is easily accessible to a purchaser facing the display unit or chart under customary conditions of retail sale.

(l) The provisions of this section do not require the declaration of incidental ingredients that are present in a cosmetic at insignificant levels and that have no technical or functional effect in the cosmetic. For the purpose of this paragraph, incidental ingredients are:

(1) Substances that have no technical or functional effect in the cosmetic but are present by reason of having been incorporated into the cosmetic as an ingredient of another cosmetic ingredient.

(2) Processing aids, which are as follows:

(i) Substances that are added to a cosmetic during the processing of such cosmetic but are removed from the cosmetic in accordance with good manufacturing practices before it is packaged in its finished form.

(ii) Substances that are added to a cosmetic during processing for their technical or functional effect in the processing, are converted to substances the same as constituents of declared ingredients, and do not significantly increase the concentration of those constituents.

(iii) Substances that are added to a cosmetic during the processing of such cosmetic for their technical and functional effect in the processing but are present in the finished cosmetic at insignificant levels and do not have any technical or functional effect in that cosmetic.

(m) In the event that there is a current or anticipated shortage of a cosmetic ingredient, the declaration required by this section may specify alternatives to any ingredients that may be affected. An alternative ingredient shall be declared either (1) immediately following the normally used ingredient for which it substitutes, in which case it shall be identified as an alternative ingredient by the word “or” following the name of the normally used ingredient and any other alternative ingredient, or (2) following the declaration of all normally used ingredients, in which case the alternative ingredients in the group so listed shall be listed in expected descending order of predominance or in accordance with the provisions of paragraph (f) of this section and shall be identified as alternative ingredients by the phrase “may also contain”. This paragraph is inapplicable to any ingredient mentioned in advertising, or in labeling other than in the declaration of ingredients required by this section.

(n) In the event that the shortage of a cosmetic ingredient necessitates a formulation change, packages bearing labels declaring the ingredients of the old formulation may be used if the revised ingredient declaration appears (1) on a firmly affixed tag, tape, card, or sticker or similar overlabeling attached to the package and bearing the conspicuous words “new ingredient list” in letters not less than 1/16 of an inch in height, or (2) on labeling inside an unsealed package and the package bears the conspicuous words, on a sticker or similar overlabeling, “new ingredient list inside” in letters not less than 1/16 of an inch in height.

(o) The ingredients of products that are similar in composition and intended for the same use may be declared as follows:

(1) The declaration of ingredients for an assortment of such products that are sold together in the same package, e.g., eyeshadows of different colors, may declare the ingredients that are common to all the products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients and identifying the products in which they are present. The color additive ingredients of all the products in such an assortment, whether or not common to all the products, may be declared in a single composite list following the declaration of the other ingredients without identifying the products in which they are present.

(2) The ingredients of an assortment of such products that are sold together in the same package, e.g., eyeshadows of different colors, may be declared in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, if the package is designed such that it has a total surface area available to bear labeling of less than 12 square inches. For the purpose of this paragraph, surface area is not available for labeling if physical characteristics of the package surface, e.g., decorative relief, make application of a label impractical.

(3) The declaration of ingredients for such a product that is individually packaged and bears a label that is shared with other products pursuant to the provisions of paragraph (g)(2) of this section, e.g., one lipstick in a line of lipsticks, may declare the ingredients that are common to all such products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients in such products, and identifying the products in which they are present. The color additive ingredients shall be declared in accordance with the provisions of paragraph (g) of this section.

(4) The declaration of ingredients for an assortment of such cosmetic products that bears a label that is shared with other products pursuant to the provisions of paragraph (g)(2) of this section, e.g., one of several compacts in a line of compacts, may declare the ingredients that are common to all such products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients in such products and identifying the products in which they are present. The color additive ingredients shall be declared in accordance with the provisions of paragraph (g) of this section.

(p) As an alternative to the declaration of ingredients in letters not less than 1/16 of an inch in height, letters may be not less than 1/32 of an inch in height if the package is designed such that it has a total surface area available to bear labeling of less than 12 square inches. For the purpose of this paragraph, surface area is not available for labeling if physical characteristics of the package surface, e.g., decorative relief, make application of a label impractical.

(q) The inside containers in a multiunit or multicomponent retail cosmetic package are not required to bear a declaration of ingredients when the labeling of the multiunit or multicomponent retail cosmetic package meets all the requirements of this section and the inside containers are not intended to be, and are not customarily, separated from the retail package for retail sale.

(r) In the case of cosmetics distributed to the consumers by direct mail, as an alternative to the declaration of ingredients on an information panel, the declaration of ingredients may appear in letters not less than 1/16 of an inch in height in labeling that accompanies and specifically relates to the cosmetic(s) mailed, or in labeling furnished to each consumer for his personal use and from which he orders cosmetics through the mail, e.g., a direct mail sales catalog or brochure, provided all of the following additional requirements are met:

(1) The declarations of ingredients are conspicuous and presented in a way that permits the consumer to identify the declaration of ingredients applicable to each cosmetic.

(2) The package mailed to the consumer is accompanied by a notice located on, or affixed to, the top of the package or on top of the contents inside the package, or on the face of the package platform surrounding and holding the product(s), readily visible to the consumer on opening of the package, and provides the following information in letters not less than 3/16 of an inch in height:

(i) The location of the declarations of ingredients, e.g., in an accompanying brochure, or in a sales catalog used for ordering;

(ii) A statement that a copy of the declaration of ingredients will be mailed promptly to any person requesting it; and

(iii) The name and place of business of the mail order distributor,

(3) The mail order distributor promptly mails a copy of the declaration of ingredients to any person requesting it.

[39 FR 10056, Mar. 15, 1974, as amended at 40 FR 8922, Mar. 3, 1975; 40 FR 18426, Apr. 28, 1975; 42 FR 4718, Jan. 25, 1977; 42 FR 15676, Mar. 22, 1977; 42 FR 24255, May 31, 1977; 42 FR 46516, Sept. 16, 1977; 42 FR 61257, Dec. 2, 1977; 45 FR 3577, Jan. 18, 1980; 47 FR 9397, Mar. 5, 1982; 54 FR 24900, June 12, 1989; 64 FR 13297, Mar. 17, 1999; 69 FR 18803, Apr. 9, 2004; 81 FR 49897, July 29, 2016]

§ 701.9 Exemptions from labeling requirements.

(a) Except as provided by paragraphs (b) and (c) of this section, a shipment or other delivery of a cosmetic which is, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling requirements of sections 601(a) and 602(b) of the act if:

(1) The person who introduced such shipment or delivery into interstate commerce is the operator of the establishment where such cosmetic is to be processed, labeled, or repacked; or

(2) In case such person is not such operator, such shipment or delivery is made to such establishment under a written agreement, signed by and containing the post office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such cosmetic in such establishment as will insure, if such specifications are followed, that such cosmetic will not be adulterated or misbranded within the meaning of the act upon completion of such processing, labeling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such cosmetic from such establishment, and shall make such copies available for inspection at any reasonable hour to any officer or employee of the Department who requests them.

(b) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment, become void ab initio if the cosmetic comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed.

(c) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(2) of this section shall become void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by such clause.

(d) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(2) of this section shall expire:

(1) At the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment if the cosmetic comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or

(2) Upon refusal by the operator of the establishment where such cosmetic is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement, as required by such clause.

§ 701.10 Principal display panel.

The term principal display panel as it applies to cosmetics in package form and as used in this part, means the part of a label that is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accommodate all the mandatory label information required to be placed thereon by this part with clarity and conspicuousness and without obscuring designs, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents of all packages of substantially the same size, the term “area of the principal display panel” means the area of the side or surface that bears the principal display panel, which area shall be:

(a) In the case of a rectangular package where one entire side properly can be considered to be the principal display panel side, the product of the height times the width of that side;

(b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the container times the circumference; and

(c) In the case of any other shape of container, 40 percent of the total surface of the container: Provided, however, That where such container presents an obvious “principal display panel” such as the top of a triangular or circular package, the area shall consist of the entire top surface.

In determining the area of the principal display panel, exclude tops, bottoms, flanges at the tops and bottoms of cans, and shoulders and necks of bottles or jars. In the case of cylindrical or nearly cylindrical containers, information required by this part to appear on the principal display panel shall appear within that 40 percent of the circumference which is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale.

§ 701.11 Identity labeling.

(a) The principal display panel of a cosmetic in package form shall bear as one of its principal features a statement of the identity of the commodity.

(b) Such statement of identity shall be in terms of:

(1) The common or usual name of the cosmetic; or

(2) An appropriately descriptive name or, when the nature of the cosmetic is obvious, a fanciful name understood by the public to identify such cosmetic; or

(3) An appropriate illustration or vignette representing the intended cosmetic use.

(c) The statement of identity shall be presented in bold type on the principal display panel, shall be in a size reasonably related to the most prominent printed matter on such panel, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.

§ 701.12 Name and place of business of manufacturer, packer, or distributor.

(a) The label of a cosmetic in package form shall specify conspicuously the name and place of business of the manufacturer, packer, or distributor.

(b) The requirement for declaration of the name of the manufacturer, packer, or distributor shall be deemed to be satisfied in the case of a corporation only by the actual corporate name, which may be preceded or followed by the name of the particular division of the corporation. Abbreviations for “Company,” “Incorporated,” etc., may be used and “The” may be omitted. In the case of an individual, partnership, or association, the name under which the business is conducted shall be used.

(c) Where the cosmetic is not manufactured by the person whose name appears on the label, the name shall be qualified by a phrase that reveals the connection such person has with such cosmetic; such as, “Manufactured for _______”, “Distributed by ________”, or any other wording that expresses the facts.

(d) The statement of the place of business shall include the street address, city, State, and ZIP Code; however, the street address may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclusion of the ZIP Code shall apply only to consumer commodity labels developed or revised after the effective date of this section. In the case of nonconsumer packages, the ZIP Code shall appear either on the label or the labeling (including the invoice).

(e) If a person manufactures, packs, or distributes a cosmetic at a place other than his principal place of business, the label may state the principal place of business in lieu of the actual place where such cosmetic was manufactured or packed or is to be distributed, unless such statement would be misleading.

§ 701.13 Declaration of net quantity of contents.

(a) The label of a cosmetic in package form shall bear a declaration of the net quantity of contents. This shall be expressed in terms of weight, measure, numerical count, or a combination of numerical count and weight or measure. The statement shall be in terms of fluid measure if the cosmetic is liquid or in terms of weight if the cosmetic is solid, semisolid, or viscous, or a mixture of solid and liquid. If there is a firmly established, general consumer usage and trade custom of declaring the net quantity of a cosmetic by numerical count, linear measure, or measure of area, such respective term may be used. If there is a firmly established, general consumer usage and trade custom of declaring the contents of a liquid cosmetic by weight, or a solid, semisolid, or viscous cosmetic by fluid measure, it may be used. Whenever the Commissioner determines for a specific packaged cosmetic that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a combination of these does not facilitate value comparisons by consumers, he shall by regulation designate the appropriate term or terms to be used for such cosmetic.

(b) Statements of weight shall be in terms of avoirdupois pound and ounce. Statements of fluid measure shall be in terms of the U.S. gallon of 231 cubic inches and quart, pint, and fluid-ounce subdivisions thereof and shall express the volume at 68 °F. (20 °C.).

(c) When the declaration of quantity of contents by numerical count, linear measure, or measure of area does not give accurate information as to the quantity of cosmetic in the package, it shall be augmented by such statement of weight, measure, or size of the individual units or the total weight or measure of the cosmetic as will give such information.

(d) The declaration may contain common or decimal fractions. A common fraction shall be in terms of halves, quarters, eighths, sixteenths, or thirty-seconds; except that if there exists a firmly established, general consumer usage and trade custom of employing different common fractions in the net quantity declaration of a particular commodity they may be employed. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than two places. A statement that includes small fractions of an ounce shall be deemed to permit smaller variations than one which does not include such fractions.

(e) The declaration shall be located on the principal display panel of the label; with respect to packages bearing alternate principal display panels, it shall be duplicated on each principal display panel: Provided, That:

(1) The principal display panel of a cosmetic marketed in a “boudoir-type” container including decorative cosmetic containers of the “cartridge,” “pill box,” “compact,” or “pencil” variety, and those with a capacity of one-fourth ounce or less, may be considered to be a tear-away tag or tape affixed to the decorative container and bearing the mandatory label information as required by this part, but the type size of the net quantity of contents statement shall be governed by the dimensions of the decorative container; and

(2) The principal display panel of a cosmetic marketed on a display card to which the immediate container is affixed may be considered to be the display panel of the card, and the type size of the net quantity of content statement is governed by the dimensions of the display card.

(f) The declaration shall appear as a distinct item on the principal display panel, shall be separated (by at least a space equal to the height of the lettering used in the declaration) from other printed label information appearing above or below the declaration and (by at least a space equal to twice the width of the letter “N” of the style of type used in the quantity of contents statement) from other printed label information appearing to the left or right of the declaration. It shall not include any term qualifying a unit of weight, measure, or count (such as “giant pint” and “full quart”) that tends to exaggerate the amount of the cosmetic in the container. It shall be placed on the principal display panel within the bottom 30 percent of the area of the label panel in line generally parallel to the base on which the package rests as it is designed to be displayed: Provided, That:

(1) On packages having a principal display panel of 5 square inches or less, the requirement for placement within the bottom 30 percent of the area of the label panel shall not apply when the declaration of net quantity of contents meets the other requirements of this part; and

(2) In the case of a cosmetic that is marketed with both outer and inner retail containers bearing the mandatory label information required by this part, and the inner container is not intended to be sold separately, the net quantity of contents placement requirement of this section applicable to such inner containers is waived.

(g) The declaration shall accurately reveal the quantity of cosmetic in the package exclusive of wrappers and other material packed therewith: Provided, That:

(1) In the case of cosmetics packed in containers designed to deliver the cosmetic under pressure, the declaration shall state the net quantity of the contents that will be expelled when the instructions for use as shown on the container are followed. The propellant is included in the net quantity declaration; and

(2) In the case of a package which contains the integral components making up a complete kit, and which is designed to deliver the components in the manner of an application (for example, a home permanent wave kit), the declaration may state the net quantity of the contents in nondeceptive terms of the number of applications available in the kit when the instructions for use as shown on the container are followed.

(h) The declaration shall appear in conspicuous and easily legible boldface print or type in distinct contrast (by typography, layout, color, embossing, or molding) to other matter on the package; except that a declaration of net quantity blown, embossed, or molded on a glass or plastic surface is permissible when all label information is so formed on the surface. Requirements of conspicuousness and legibility shall include the specifications that:

(1) The ratio of height to width (of the letter) shall not exceed a differential of 3 units to 1 unit (no more than 3 times as high as it is wide).

(2) Letter heights pertain to upper case or capital letters. When upper and lower case or all lower case letters are used, it is the lower case letter “o” or its equivalent that shall meet the minimum standards.

(3) When fractions are used, each component numeral shall meet one-half the minimum height standards.

(i) The declaration shall be in letters and numerals in a type size established in relationship to the area of the principal display panel of the package and shall be uniform for all packages of substantially the same size by complying with the following type specifications:

(1) Not less than one-sixteenth inch in height on packages the principal display panel of which has an area of 5 square inches or less.

(2) Not less than one-eighth inch in height on packages the principal display panel of which has an area of more than 5 but not more than 25 square inches.

(3) Not less than three-sixteenths inch in height on packages the principal display panel of which has an area of more than 25 but not more than 100 square inches.

(4) Not less than one-fourth inch in height on packages the principal display panel of which has an area of more than 100 square inches, except not less than one-half inch in height if the area is more than 400 square inches.

Where the declaration is blown, embossed, or molded on a glass or plastic surface rather than by printing, typing, or coloring, the lettering sizes specified in paragraphs (i)(1) through (4) of this section shall be increased by one-sixteenth of an inch.

(j) On packages containing less than 4 pounds or 1 gallon and labeled in terms of weight or fluid measure:

(1) The declaration shall be expressed both in ounces, with identification by weight or by liquid measure and, if applicable (1 pound or 1 pint or more), followed in parentheses by a declaration in pounds for weight units, with any remainder in terms of ounces or common or decimal fractions of the pound (as set forth in paragraphs (m)(1) and (2) of this section), or in the case of liquid measure, in the largest whole units (quarts, quarts and pints, or pints, as appropriate) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (as set forth in paragraphs (m)(3) and (4) of this section). Net weight or fluid measure of less than 1 ounce shall be expressed in common or decimal fractions of the respective ounce and not in drams.

(2) The declaration may appear in more than one line. The term “net weight” shall be used when stating the net quantity of contents in terms of weight. Use of the terms “net” or “net contents” in terms of fluid measure or numerical count is optional. It is sufficient to distinguish avoirdupois ounce from fluid ounce through association of terms; for example, “Net wt. 6 oz.” or “6 oz. net wt.” and “Net contents 6 fl. oz.” or “6 fl. oz.”

(k) On packages containing 4 pounds or 1 gallon or more and labeled in terms of weight or fluid measure, the declaration shall be expressed in pounds for weight units with any remainder in terms of ounces or common or decimal fractions of the pound; in the case of fluid measure, it shall be expressed in the largest whole unit (gallons, followed by common or decimal fractions of a gallon or by the next smaller whole unit or units (quarts or quarts and pints)) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (as set forth in paragraph (m)(5) of this section).

(l) [Reserved]

(m) Examples: (1) A declaration of 1 1/2 pounds weight shall be expressed as “Net wt. 24 oz. (1 lb. 8 oz.)”, “Net wt. 24 oz. (1 1/2 lb.)”, or “Net wt. 24 oz. (1.5 lb.)”.

(2) A declaration of three-fourths pound avoirdupois weight shall be expressed as “Net wt. 12 oz.”

(3) A declaration of 1 quart liquid measure shall be expressed as “Net contents 32 fl. oz. (1 qt.)”.

(4) A declaration of 1 3/4 quarts liquid measure shall be expressed as “Net contents 56 fl. oz. (1 qt. 1 1/2 pt.)” or “Net contents 56 fl. oz. (1 qt. 1 pt. 8 oz.)” but not in terms of quart and ounce such as “Net content 56 fl. oz. (1 qt. 24 oz.)”.

(5) A declaration of 2 1/2 gallons liquid measure shall be expressed in the alternative as “Net contents 2 gal. 2 qt.” and not as “2 gal. 4 pt.”

(n) For quantities, the following abbreviations and none other may be employed (periods and plural forms are optional):

weight wt.

square sq.

fluid fl.

yard yd.

feet or foot ft.

inch in.

gallon gal.

quart qt.

pint pt.

ounce oz.

pound lb.

(o) On packages labeled in terms of linear measure, the declaration shall be expressed both in terms of inches and, if applicable (1 foot or more), the largest whole units (yards, yards and feet, feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of inches and any remainder shall be in terms of inches or common or decimal fractions of the foot or yard. Examples are “86 inches (2 yd. 1 ft. 2 inches)”, “90 inches (2 1/2 yd.)”, “30 inches (2.5 ft.)”, etc.

(p) On packages labeled in terms of area measure, the declaration shall be expressed in terms of square inches and, if applicable (1 square foot or more), the largest whole square unit (square yards, square yards and square feet, square feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of square inches and any remainder shall be in terms of square inches or common or decimal fractions of the square foot or square yard; for example, “158 sq. inches (1 sq. ft. 14 sq. inches)”, etc.

(q) Nothing in this section shall prohibit supplemental statements at locations other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents, provided that such supplemental statements of net quantity of contents shall not include any term qualifying a unit of weight, measure, or count that tends to exaggerate the amount of the cosmetic contained in the package; for example, “giant pint” and “full quart.” Dual or combination declarations of net quantity of contents as provided for in paragraphs (a), (c), and (j) of this section (for example, a combination of net weight plus numerical count) are not regarded as supplemental net quantity statements and shall be located on the principal display panel.

(r) A separate statement of the net quantity of contents in terms of the metric system is not regarded as a supplemental statement and an accurate statement of the net quantity of contents in terms of the metric system of weight or measure may also appear on the principal display panel or on other panels.

(s) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large.

§ 701.20 Detergent substances, other than soap, intended for use in cleansing the body.

(a) In its definition of the term cosmetic, the Federal Food, Drug, and Cosmetic Act specifically excludes soap. The term soap is nowhere defined in the act. In administering the act, the Food and Drug Administration interprets the term “soap” to apply only to articles that meet the following conditions:

(1) The bulk of the nonvolatile matter in the product consists of an alkali salt of fatty acids and the detergent properties of the article are due to the alkali-fatty acid compounds; and

(2) The product is labeled, sold, and represented only as soap.

(b) Products intended for cleansing the human body and which are not “soap” as set out in paragraph (a) of this section are “cosmetics,” and accordingly they are subject to the requirements of the act and the regulations thereunder. For example, such a product in bar form is subject to the requirement, among others, that it shall bear a label containing an accurate statement of the weight of the bar in avoirdupois pounds and ounces, this statement to be prominently and conspicuously displayed so as to be likely to be read under the customary conditions of purchase and use.

§ 701.30 Ingredient names established for cosmetic ingredient labeling.

The Commissioner establishes the following names for the purpose of cosmetic ingredient labeling pursuant to paragraph (e) of § 701.3:

Chemical name or description | Chemical formula | Established label name

Trichlorofluoromethane | CCl3F | Chlorofluorocarbon 11.

Trichlorofluoromethane and 0.3 pct nitromethane | CCl3F + CH3NO2 | Chlorofluorocarbon 11 S.

Dichlorodifluoromethane | CCl2F2 | Chlorofluorocarbon 12.

Chlorodifluoromethane | CHClF2 | Hydrochlorofluorocarbon 22.

1, 2-dichloro-1, 1, 2, 2-tetrafluoroethane | CClF2CClF2 | Chlorofluorocarbon 114.

1-Chloro-1, 1-difluoroethane | CH3CClF2 | Hydrochlorofluorocarbon 142 B.

1, 1-difluoroethane | CH3CHF2 | Hydrofluorocarbon 152 A.

Ethyl ester of hydrolyzed animal protein is the ester of ethyl alcohol and the hydrolysate of collagen or other animal protein, derived by acid, enzyme, or other form of hydrolysis | Ethyl ester of hydrolyzed animal protein.

[42 FR 24255, May 13, 1977, as amended at 45 FR 3577, Jan. 18, 1980]

§ 710.1 Who should register.

The owner or operator of a cosmetic product establishment which is not exempt under § 710.9 and engages in the manufacture or packaging of a cosmetic product is requested to register for each such establishment, whether or not the product enters interstate commerce. This request extends to any foreign cosmetic product establishment whose products are exported for sale in any State as defined in section 201(a)(1) of the act. No registration fee is required.

§ 710.2 Time for registration.

The owner or operator of an establishment entering into the manufacture or packaging of a cosmetic product should register his establishment within 30 days after the operation begins.

§ 710.3 How and where to register.

Form FD-2511 (“Registration of Cosmetic Product Establishment”) is obtainable on request from the Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, or at any Food and Drug Administration district office. The completed form should be mailed to Cosmetic Product Establishment Registration, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003; 81 FR 49897, July 29, 2016]

§ 710.4 Information requested.

Form FD-2511 requests information on the name and address of the cosmetic product establishment, including post office ZIP code; all business trading names used by the establishment; and the type of business (manufacturer and/or packer). The information requested should be given separately for each establishment as defined in § 700.3(j) of this chapter.

[39 FR 10059, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 54 FR 39640, Sept. 27, 1989]

§ 710.5 Amendments to registration.

Within 30 days after a change in any of the information contained on a submitted Form FD-2511, a new Form FD-2511 should be submitted to amend the registration. This amendment is also necessary when a registration is to be canceled because an establishment has changed its name and no longer conducts business under the original name.

§ 710.6 Notification of registrant; cosmetic product establishment registration number.

The Commissioner of Food and Drugs will provide the registrant with a validated copy of Form FD-2511 as evidence of registration. This validated copy will be sent only to the location shown for the registering establishment. A permanent registration number will be assigned to each cosmetic product establishment registered in accordance with the regulations in this part.

§ 710.7 Inspection of registrations.

A copy of the Form FD-2511 filed by the registrant will be available for inspection at the Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740.

[39 FR 10059, Mar. 15, 1974, as amended at 68 FR 15355, Mar. 31, 2003; 81 FR 49897, July 29, 2016]

§ 710.8 Misbranding by reference to registration or to registration number.

Registration of a cosmetic product establishment or assignment of a registration number does not in any way denote approval of the firm or its products by the Food and Drug Administration. Any representation in labeling or advertising that creates an impression of official approval because of registration or possession of a registration number will be considered misleading.

§ 710.9 Exemptions.

The following classes of persons are not requested to register in accordance with this part 710 because the Commissioner has found that such registration is not justified:

(a) Beauty shops, cosmetologists, retailers, pharmacies, and other persons and organizations that compound cosmetic products at a single location and administer, dispense, or distribute them at retail from that location and who do not otherwise manufacture or package cosmetic products at that location.

(b) Physicians, hospitals, clinics, and public health agencies.

(c) Persons who manufacture, prepare, compound, or process cosmetic products solely for use in research, pilot plant production, teaching, or chemical analysis, and who do not sell these products.

§ 720.1 Who should file.

Either the manufacturer, packer, or distributor of a cosmetic product is requested to file Form FDA 2512 (“Cosmetic Product Ingredient Statement”), whether or not the cosmetic product enters interstate commerce. This request extends to any foreign manufacturer, packer, or distributor of a cosmetic product exported for sale in any State as defined in section 201(a)(1) of the Federal Food, Drug, and Cosmetic Act. No filing fee is required.

[57 FR 3129, Jan. 28, 1992]

§ 720.2 Times for filing.

Within 180 days after forms are made available to the industry, Form FDA 2512 should be filed for each cosmetic product being commercially distributed as of the effective date of this part. Form FDA 2512 should be filed within 60 days after the beginning of commercial distribution of any product not covered within the 180-day period.

[57 FR 3129, Jan. 28, 1992]

§ 720.3 How and where to file.

Forms FDA 2512 and FDA 2514 (“Discontinuance of Commercial Distribution of Cosmetic Product Formulation”) are obtainable on request from the Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, or at any Food and Drug Administration district office. The completed form should be mailed or delivered to: Cosmetic Product Statement, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, according to the instructions provided with the forms.

[57 FR 3129, Jan. 28, 1992, as amended at 68 FR 15355, Mar. 31, 2003; 81 FR 49897, July 29, 2016]

§ 720.4 Information requested about cosmetic products.

(a) Form FDA-2512 requests information on:

(1) The name and address, including post office ZIP code of the person (manufacturer, packer, or distributor) designated on the label of the product.

(2) The name and address, including post office ZIP code, of the manufacturer or packer of the product if different from the person designated on the label of the product, when the manufacturer or packer submits the information requested under this paragraph.

(3) The brand name or names of the cosmetic product.

(4) The cosmetic product category or categories.

(5) The ingredients in the product.

(b) The person filing Form FDA-2512 should:

(1) Provide the information requested in paragraph (a) of this section.

(2) Have the form signed by an authorized individual.

(3) Provide poison control centers with ingredient information and/or adequate diagnostic and therapeutic procedures to permit rapid evaluation and treatment of accidental ingestion or other accidental use of the cosmetic product.

(4) Provide ingredient information (and, when requested, ingredient samples) to a licensed physician who, in connection with the treatment of a patient, requests assistance in determining whether an ingredient in the cosmetic product is the cause of the problem for which the patient is being treated.

(c) One or more of the following cosmetic product categories should be cited to indicate the product's intended use.

(1) Baby products. (i) Baby shampoos.

(ii) Lotions, oils, powders, and creams.

(iii) Other baby products.

(2) Bath preparations. (i) Bath oils, tablets, and salts.

(ii) Bubble baths.

(iii) Bath capsules.

(iv) Other bath preparations.

(3) Eye makeup preparations. (i) Eyebrow pencil.

(ii) Eyeliner.

(iii) Eye shadow.

(iv) Eye lotion.

(v) Eye makeup remover.

(vi) Mascara.

(vii) Other eye makeup preparations.

(4) Fragrance preparations. (i) Colognes and toilet waters.

(ii) Perfumes.

(iii) Powders (dusting and talcum) (excluding aftershave talc).

(iv) Sachets.

(v) Other fragrance preparations.

(5) Hair preparations (noncoloring). (i) Hair conditioners.

(ii) Hair sprays (aerosol fixatives).

(iii) Hair straighteners.

(iv) Permanent waves.

(v) Rinses (noncoloring).

(vi) Shampoos (noncoloring).

(vii) Tonics, dressings, and other hair grooming aids.

(viii) Wave sets.

(ix) Other hair preparations.

(6) Hair coloring preparations. (i) Hair dyes and colors (all types requiring caution statement and patch test).

(ii) Hair tints.

(iii) Hair rinses (coloring).

(iv) Hair shampoos (coloring).

(v) Hair color sprays (aerosol).

(vi) Hair lighteners with color.

(vii) Hair bleaches.

(viii) Other hair coloring preparations.

(7) Makeup preparations (not eye). (i) Blushers (all types).

(ii) Face powders.

(iii) Foundations.

(iv) Leg and body paints.

(v) Lipstick.

(vi) Makeup bases.

(vii) Rouges.

(viii) Makeup fixatives.

(ix) Other makeup preparations.

(8) Manicuring preparations. (i) Basecoats and undercoats.

(ii) Cuticle softeners.

(iii) Nail creams and lotions.

(iv) Nail extenders.

(v) Nail polish and enamel.

(vi) Nail polish and enamel removers.

(vii) Other manicuring preparations.

(9) Oral hygiene products. (i) Dentifrices (aerosol, liquid, pastes, and powders).

(ii) Mouthwashes and breath fresheners (liquids and sprays).

(iii) Other oral hygiene products.

(10) Personal cleanliness. (i) Bath soaps and detergents.

(ii) Deodorants (underarm).

(iii) Douches.

(iv) Feminine hygiene deodorants.

(v) Other personal cleanliness products.

(11) Shaving preparations. (i) Aftershave lotions.

(ii) Beard softeners.

(iii) Men's talcum.

(iv) Preshave lotions (all types).

(v) Shaving cream (aerosol, brushless, and lather).

(vi) Shaving soap (cakes, sticks, etc.).

(vii) Other shaving preparation products.

(12) Skin care preparations, (creams, lotions, powder, and sprays). (i) Cleansing (cold creams, cleansing lotions, liquids, and pads).

(ii) Depilatories.

(iii) Face and neck (excluding shaving preparations).

(iv) Body and hand (excluding shaving preparations).

(v) Foot powders and sprays.

(vi) Moisturizing.

(vii) Night.

(viii) Paste masks (mud packs).

(ix) Skin fresheners.

(x) Other skin care preparations.

(13) Suntan preparations. (i) Suntan gels, creams, and liquids.

(ii) Indoor tanning preparations.

(iii) Other suntan preparations.

(d) Ingredients in the product should be listed as follows:

(1) A list of each ingredient of the cosmetic product in descending order of predominance by weight (except that the fragrance and/or flavor may be designated as such without naming each individual ingredient when the manufacturer or supplier of the fragrance and/or flavor refuses to disclose ingredient data).

(2) An ingredient should be listed by the name adopted by the Food and Drug Administration (FDA) for the ingredient pursuant to § 701.3(c) of this chapter.

(3) In the absence of a name adopted by FDA pursuant to § 701.3(c) of this chapter, its common or usual name, if it has one, or its chemical or technical name should be listed.

(4) If an ingredient is a mixture, each ingredient of the mixture should be listed in accordance with paragraphs (d)(2) and (d)(3) of this section, unless such mixture is a formulation voluntarily registered on Form FDA 2512, in which case such mixture should be identified as “fragrance,” “flavor,” “fragrance and flavor” or “base formulation,” as appropriate, and by stating its FDA-assigned cosmetic product ingredient statement number.

(5) When the manufacturer or supplier of a fragrance and/or flavor refuses to disclose ingredient data, the fragrance and/or flavor should be listed as such. The nonconfidential listing of the product name and/or trade name or name of the manufacturer or supplier of each proprietary fragrance and/or flavor mixture is optional.

(e) A separate Form FDA-2512 should be filed for each different formulation of a cosmetic product. However, except for the hair coloring preparations listed in paragraph (c)(6) of this section for which a statement for each shade of such product is required, a single Form FDA-2512 may be filed for two or more shades of a cosmetic product where only the amounts of the color additive ingredient used are varied or in the case of flavors and fragrances where only the amounts of the flavors and fragrances used are varied.

(Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0030)

[39 FR 10060, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 57 FR 3129, Jan. 28, 1992]

§ 720.5 [Reserved]

§ 720.6 Amendments to statement.

Changes in the information requested under §§ 720.4 (a)(3) and (a)(5) on the ingredients or brand name of a cosmetic product should be submitted by filing an amended Form FDA 2512 within 60 days after the product is entered into commercial distribution. Other changes do not justify immediate amendment, but should be shown by filing an amended Form FDA 2512 within a year after such changes. Notice of discontinuance of commercial distribution of a cosmetic product formulation should be submitted by Form FDA 2514 within 180 days after discontinuance of commercial distribution becomes known to the person filing.

[57 FR 3130, Jan. 28, 1992, as amended at 67 FR 9587, Mar. 4, 2002]

§ 720.7 Notification of person submitting cosmetic product ingredient statement.

When Form FDA 2512 is received, FDA will either assign a permanent cosmetic product ingredient statement number or a Food and Drug Administration (FDA) reference number in those cases where a permanent number cannot be assigned. Receipt of the form will be acknowledged by sending the individual signing the statement an appropriate notice bearing either the FDA reference number or the permanent cosmetic product ingredient statement number. If the person submitting Form FDA 2512 has not complied with §§ 720.4 (b)(1) and (b)(2), the person will be notified as to the manner in which the statement is incomplete.

[57 FR 3130, Jan. 28, 1992]

§ 720.8 Confidentiality of statements.

(a) Data and information contained in, attached to, or included with Forms FDA 2512 and FDA 2514, and amendments thereto are submitted voluntarily to the Food and Drug Administration (FDA). Any request for confidentiality of a cosmetic ingredient submitted with such forms or separately will be handled in accordance with the procedure set forth in this section. The request for confidentiality will also be subject to the provisions of § 20.111 of this chapter, as well as to the exemptions in subpart D of part 20 of this chapter and to the limitations on exemption in subpart E of part 20 of this chapter.

(b) Any request for confidentiality of the identity of a cosmetic ingredient should contain a full statement, in a well-organized format, of the factual and legal grounds for that request, including all data and other information on which the petitioner relies, as well as representative information known to the petitioner that is unfavorable to the petitioner's position. The statement of the factual grounds should include, but should not be limited to, scientific or technical data, reports, tests, and other relevant information addressing the following factors that FDA will consider in determining whether the identity of an ingredient qualifies as a trade secret:

(1) The extent to which the identity of the ingredient is known outside petitioner's business;

(2) The extent to which the identity of the ingredient is known by employees and others involved in petitioner's business;

(3) The extent of measures taken by the petitioner to guard the secrecy of the information;

(4) The value of the information about the identity of the claimed trade secret ingredient to the petitioner and to its competitors;

(5) The amount of effort or money expended by petitioner in developing the ingredient; and

(6) The ease or difficulty with which the identity of the ingredient could be properly acquired or duplicated by others.

(c) The request for confidentiality should also be accompanied by a statement that the identity of the ingredient for which confidentiality is requested has not previously been published or disclosed to anyone other than as provided in § 20.81(a) of this chapter.

(d) FDA will return to the petitioner any request for confidentiality that contains insufficient data to permit a review of the merits of the request. FDA will also advise the petitioner about the additional information that is necessary to enable the agency to proceed with its review of the request.

(e) If, after receiving all of the data that are necessary to make a determination about whether the identity of an ingredient is a trade secret, FDA tentatively decides to deny the request, the Agency will inform the person requesting trade secrecy of its tentative determination in writing. FDA will set forth the grounds upon which it relied in making this tentative determination. The petitioner may submit, within 60 days from the date of receipt of the written notice of the tentative denial, additional relevant information and arguments and request that the Agency reconsider its decision in light of both the additional material and the information that it originally submitted.

(f) If the petitioner submits new data in response to FDA's tentative denial of trade secret status, the agency will consider that material together with the information that was submitted initially before making its final determination.

(g) A final determination that an ingredient is not a trade secret within the meaning of § 20.61 of this chapter constitutes final Agency action that is subject to judicial review under 5 U.S.C. Chapter 7. If suit is brought within 30 calendar days after such a determination, FDA will not disclose the records involved or require that the disputed ingredient or ingredients be disclosed in labeling until the matter is finally determined in the courts. If suit is not brought within 30 calendar days after a final determination that an ingredient is not a trade secret within the meaning of § 20.61 of this chapter, the records involved will be available for public disclosure in accordance with part 20 of this chapter.

[51 FR 11444, Apr. 3, 1986, as amended at 57 FR 3130, Jan. 28, 1992; 68 FR 25288, May 12, 2003; 87 FR 55914, Sept. 13, 2022]

§ 720.9 Misbranding by reference to filing or to statement number.

The filing of Form FDA 2512 or assignment of a number to the statement does not in any way denote approval by the Food and Drug Administration of the firm or the product. Any representation in labeling or advertising that creates an impression of official approval because of such filing or such number will be considered misleading.

[57 FR 3130, Jan. 28, 1992]

§ 740.1 Establishment of warning statements.

(a) The label of a cosmetic product shall bear a warning statement whenever necessary or appropriate to prevent a health hazard that may be associated with the product.

(b) The Commissioner of Food and Drugs, either on his own initiative or on behalf of any interested person who has submitted a petition, may publish a proposal to establish or amend, under subpart B of this part, a regulation prescribing a warning for a cosmetic. Any such petition shall include an adequate factual basis to support the petition, shall be in the form set forth in part 10 of this chapter, and will be published for comment if it contains reasonable grounds for the proposed regulation.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977]

§ 740.2 Conspicuousness of warning statements.

(a) A warning statement shall appear on the label prominently and conspicuously as compared to other words, statements, designs, or devices and in bold type on contrasting background to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use, but in no case may the letters and/or numbers be less than 1/16 inch in height, unless an exemption pursuant to paragraph (b) of this section is established.

(b) If the label of any cosmetic package is too small to accommodate the information as required by this section, the Commissioner may establish by regulation an acceptable alternative method, e.g., type size smaller than 1/16 inch in height. A petition requesting such a regulation, as an amendment to this section, shall be submitted to the Dockets Management Staff in the form established in part 10 of this chapter.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977; 69 FR 13717, Mar. 24, 2004; 88 FR 45067, July 14, 2023]

§ 740.10 Labeling of cosmetic products for which adequate substantiation of safety has not been obtained.

(a) Each ingredient used in a cosmetic product and each finished cosmetic product shall be adequately substantiated for safety prior to marketing. Any such ingredient or product whose safety is not adequately substantiated prior to marketing is misbranded unless it contains the following conspicuous statement on the principal display panel:

Warning—The safety of this product has not been determined.

(b) An ingredient or product having a history of use in or as a cosmetic may at any time have its safety brought into question by new information that in itself is not conclusive. The warning required by paragraph (a) of this section is not required for such an ingredient or product if:

(1) The safety of the ingredient or product had been adequately substantiated prior to development of the new information;

(2) The new information does not demonstrate a hazard to human health; and

(3) Adequate studies are being conducted to determine expeditiously the safety of the ingredient or product.

(c) Paragraph (b) of this section does not constitute an exemption to the adulteration provisions of the Act or to any other requirement in the Act or this chapter.

[40 FR 8917, Mar. 3, 1975]

§ 740.11 Cosmetics in self-pressurized containers.

(a)(1) The label of a cosmetic packaged in a self-pressurized container and intended to be expelled from the package under pressure shall bear the following warning:

Warning—Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperature above 120 °F. Keep out of reach of children.

(2) In the case of products intended for use by children, the phrase “except under adult supervision” may be added at the end of the last sentence in the warning required by paragraph (a)(1) of this section.

(3) In the case of products packaged in glass containers, the word “break” may be substituted for the word “puncture” in the warning required by paragraph (a)(1) of this section.

(4) The words “Avoid spraying in eyes” may be deleted from the warning required by paragraph (a)(1) of this section in the case of a product not expelled as a spray.

(b)(1) In addition to the warning required by paragraph (a)(1) of this section, the label of a cosmetic packaged in a self-pressurized container in which the propellant consists in whole or in part of a halocarbon or a hydrocarbon shall bear the following warning:

Warning—Use only as directed. Intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal.

(2) The warning required by paragraph (b)(1) of this section is not required for the following products:

(i) Products expelled in the form of a foam or cream, which contain less than 10 percent propellant in the container.

(ii) Products in a container with a physical barrier that prevents escape of the propellant at the time of use.

(iii) Products of a net quantity of contents of less than 2 ozs. that are designed to release a measured amount of product with each valve actuation.

(iv) Products of a net quantity of contents of less than 1/2 oz.

(c) Labeling requirements for cosmetics packaged in a self- pressurized container containing or manufactured with a chlorofluorocarbon propellant or other ozone-depleting substance designated by the Environmental Protection Agency (EPA) are set forth in 40 CFR part 82.

[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 22033, Apr. 29, 1977; 54 FR 39640, Sept. 27, 1989; 61 FR 20101, May 3, 1996]

§ 740.12 Feminine deodorant sprays.

(a) For the purpose of this section, the term “feminine deodorant spray” means any spray deodorant product whose labeling represents or suggests that the product is for use in the female genital area or for use all over the body.

(b) The label of a feminine deodorant spray shall bear the following statement:

Caution—For external use only. Spray at least 8 inches from skin. Do not apply to broken, irritated, or itching skin. Persistent, unusual odor or discharge may indicate conditions for which a physician should be consulted. Discontinue use immediately if rash, irritation, or discomfort develops.

The sentence “Spray at least 8 inches from skin” need not be included in the cautionary statement for products whose expelled contents do not contain a liquified gas propellant such as a halocarbon or hydrocarbon propellant.

(c) Use of the word “hygiene” or “hygienic” or a similar word or words renders any such product misbranded under section 602(a) of the Federal Food, Drug, and Cosmetic Act. The use of any word or words which represent or suggest that such products have a medical usefulness renders such products misbranded under section 502(a) of the Act and illegal new drugs marketed in violation of section 505 of the Act.

[40 FR 8929, Mar. 3, 1975]

§ 740.17 Foaming detergent bath products.

(a) For the purpose of this section, a foaming detergent bath product is any product intended to be added to a bath for the purpose of producing foam that contains a surface-active agent serving as a detergent or foaming ingredient.

(b) The label of foaming detergent bath products within the meaning of paragraph (a) of this section, except for those products that are labeled as intended for use exclusively by adults, shall bear adequate directions for safe use and the following caution:

Caution—Use only as directed. Excessive use or prolonged exposure may cause irritation to skin and urinary tract. Discontinue use if rash, redness, or itching occurs. Consult your physician if irritation persists. Keep out of reach of children.

(c) In the case of products intended for use by children, the phrase “except under adult supervision” may be added at the end of the last sentence in the caution required by paragraph (b) of this section.

[51 FR 20475, June 5, 1986]

§ 740.18 Coal tar hair dyes posing a risk of cancer.

(a) The principal display panel of the label and any labeling accompanying a coal tar hair dye containing any ingredient listed in paragraph (b) of this section shall bear, in accordance with the requirements of § 740.2, the following:

Warning—Contains an ingredient that can penetrate your skin and has been determined to cause cancer in laboratory animals.

(b) Hair dyes containing any of the following ingredients shall comply with the requirements of this section: (1) 4-methoxy-m-phenylenediamine (2,4-diaminoanisole) and (2) 4-methoxy-m-phenylenediamine sulfate (2,4-diaminoanisole sulfate).

[44 FR 59522, Oct. 16, 1979]

Effective Date Note:At 47 FR 7829, Feb. 23, 1982, § 740.18 was stayed until further notice, effective Sept. 18, 1980.

§ 740.19 Suntanning preparations.

The labeling of suntanning preparations that do not contain a sunscreen ingredient must display the following warning: “Warning—This product does not contain a sunscreen and does not protect against sunburn. Repeated exposure of unprotected skin while tanning may increase the risk of skin aging, skin cancer, and other harmful effects to the skin even if you do not burn.” For purposes of this section, the term “suntanning preparations” includes gels, creams, liquids, and other topical products that are intended to provide cosmetic effects on the skin while tanning through exposure to UV radiation (e.g., moisturizing or conditioning products), or to give the appearance of a tan by imparting color to the skin through the application of approved color additives (e.g., dihydroxyacetone) without the need for exposure to UV radiation. The term “suntanning preparations” does not include products intended to provide sun protection or otherwise intended to affect the structure or any function of the body.

[64 FR 27693, May 21, 1999]

§ 800.10 Contact lens solutions; sterility.

(a)(1) Informed medical opinion is in agreement that all preparations offered or intended for ophthalmic use, including contact lens solutions, should be sterile. It is further evident that such preparations purport to be of such purity and quality as to be suitable for safe use in the eye.

(2) The Food and Drug Administration concludes that all such preparations, if they are not sterile, fall below their professed standard of purity or quality and may be unsafe. In a statement of policy issued on September 1, 1964, the Food and Drug Administration ruled that liquid preparations offered or intended for ophthalmic use that are not sterile may be regarded as adulterated within the meaning of section 501(c) of the Federal Food, Drug, and Cosmetic Act (the act), and, further, may be deemed misbranded within the meaning of section 502(j) of the act. By this regulation, this ruling is applicable to all preparations for ophthalmic use that are regulated as medical devices, i.e., contact lens solutions. By the regulation in § 200.50 of this chapter, this ruling is applicable to ophthalmic preparations that are regulated as drugs.

(3) The containers shall be sterile at the time of filling and closing, and the container or individual carton shall be so sealed that the contents cannot be used without destroying the seal. The packaging and labeling of these solutions shall also comply with § 800.12 on tamper-resistant packaging requirements.

(b) Liquid ophthalmic preparations packed in multiple-dose containers should:

(1) Contain one or more suitable and harmless substances that will inhibit the growth of microorganisms; or

(2) Be so packaged as to volume and type of container and so labeled as to duration of use and with such necessary warnings as to afford adequate protection and minimize the hazard of injury resulting from contamination during use.

(c) Eye cups, eye droppers, and other dispensers intended for ophthalmic use should be sterile, and may be regarded as falling below their professed standard of purity or quality if they are not sterile. These articles, which are regulated as medical devices unless packaged with the drugs with which they are to be used, should be packaged so as to maintain sterility until the package is opened and be labeled, on or within the retail package, so as to afford adequate directions and necessary warnings to minimize the hazard of injury resulting from contamination during use.

[47 FR 50455, Nov. 5, 1982]

§ 800.12 Contact lens solutions and tablets; tamper-resistant packaging.

(a) General. Unless contact lens solutions used, for example, to clean, disinfect, wet, lubricate, rinse, soak, or store contact lenses and salt tablets or other dosage forms to be used to make any such solutions are packaged in tamper-resistant retail packages, there is the opportunity for the malicious adulteration of these products with risks both to individuals who unknowingly purchase adulterated products and with loss of consumer confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug Administration has the authority and responsibility under the Federal Food, Drug, and Cosmetic Act (the act) to establish a uniform national standard for tamper-resistant packaging of those OTC products vulnerable to malicious adulteration that will improve the security of OTC packaging and help assure the safety and effectiveness of the products contained therein. A contact lens solution or tablet or other dosage form to be used to make such a solution for retail sale that is not packaged in a tamper-resistant package and labeled in accordance with this section is adulterated under section 501 of the act or misbranded under section 502 of the act, or both.

(b) Requirement for tamper-resistant package. Each manufacturer and packer who packages for retail sale a product regulated as a medical device that is a solution intended for use with contact lenses, e.g., for cleaning, disinfecting, wetting, lubricating, rinsing, soaking, or storing contact lenses or tablets or other dosage forms to be used to make any such solution shall package the product in a tamper-resistant package, if this product is accessible to the public while held for sale. A tamper-resistant package is one having an indicator or barrier to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of substitution of a tamper-resistant feature after tampering, the indicator or barrier to entry is required to be distinctive by design or by the use of an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture). For purposes of this section, the term “distinctive by design” means the package cannot be duplicated with commonly available material or through commonly available processes. A tamper-resistant package may involve an immediate-container and closure system or secondary-container or carton system or any combination of systems intended to provide a visual indication of package integrity. The tamper-resistant feature shall be designed to and shall remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.

(c) Labeling. Each retail package of a product covered by this section is required to bear a statement that is prominently placed so that consumers are alerted to the tamper-resistant feature of the package. The labeling statement is also required to be so placed that it will be unaffected if the tamper-resistant feature of the package is breached or missing. If the tamper-resistant feature chosen to meet the requirement in paragraph (b) of this section is one that uses an identifying characteristic, that characteristic is required to be referred to in the labeling statement. For example, the labeling statement on a bottle with a shrink band could say “For your protection, this bottle has an imprinted seal around the neck.”

(d) Requests for exemptions from packaging and labeling requirements. A manufacturer or packer may request an exemption from the packaging and labeling requirements of this section. A request for an exemption is required to be submitted in the form of a citizen petition under § 10.30 of this chapter and should be clearly identified on the envelope as a “Request for Exemption from Tamper-resistant Rule.” A petition for an exemption from a requirement of this section is required to contain the same kind of information about the product as is specified for OTC drugs in § 211.132(d) of this chapter.

(e) Products subject to approved premarket approval applications. Holders of approved premarket approval applications for products subject to this section are required to submit supplements to provide for changes in packaging to comply with the requirement of paragraph (b) of this section unless these changes do not affect the composition of the container, the torque (tightness) of the container, or the composition of the closure component in contact with the contents (cap liner or innerseal) as these features are described in the approved premarket approval application. Any supplemental premarket approval application under this paragraph is required to include data sufficient to show that these changes do not adversely affect the product.

(f) Effective date. Each product subject to this section is required to comply with the requirements of this section on the dates listed below except to the extent that a product's manufacturer or packer has obtained an exemption from a packaging or labeling requirement:

(1) Initial effective date for packaging requirements. (i) The packaging requirement in paragraph (b) of this section is effective on February 7, 1983 for each contact lens solution packaged for retail sale on or after that date, except for the requirement in paragraph (b) of this section for a distinctive indicator or barrier to entry.

(ii) The packaging requirement in paragraph (b) of this section is effective on May 5, 1983 for each tablet that is to be used to make a contact lens solution and that is packaged for retail sale on or after that date.

(2) Initial effective date for labeling requirements. The requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design and the requirement in paragraph (c) of this section for a labeling statement are effective on May 5, 1983 for each product subject to this section packaged for retail sale on or after that date, except that the requirement for a specific label reference to any identifying characteristic is effective on February 6, 1984 for each affected product subject to this section packaged for retail sale on or after that date.

(3) Retail level effective date. The tamper-resistant packaging requirement of paragraph (b) of this section is effective on February 6, 1984 for each product subject to this section that is held for sale at retail level on or after that date that was packaged for retail sale before May 5, 1983. This does not include the requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design. Products packaged for retail sale after May 5, 1983, are required to be in compliance with all aspects of the regulations without regard to the retail level effective date.

[47 FR 50455, Nov. 5, 1982; 48 FR 1706, Jan. 14, 1983, as amended at 48 FR 16666, Apr. 19, 1983; 48 FR 37625, Aug. 19, 1983; 53 FR 11252, Apr. 6, 1988; 73 FR 34859, June 19, 2008]

Effective Date Note:A document published at 48 FR 41579, Sept. 16, 1983, stayed the effective date of § 800.12(f)(3) until further notice.

§ 800.20 Patient examination gloves and surgeons' gloves; sample plans and test method for leakage defects; adulteration.

(a) Purpose. The prevalence of human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS), and its risk of transmission in the health care context, have caused the Food and Drug Administration (FDA) to look more closely at the quality control of barrier devices, such as surgeons' gloves and patient examination gloves (collectively known as medical gloves) to reduce the risk of transmission of HIV and other blood-borne infectious diseases. The Centers for Disease Control (CDC) recommend that health care workers wear medical gloves to reduce the risk of transmission of HIV and other blood-borne infectious deseases. The CDC recommends that health care workers wear medical gloves when touching blood or other body fluids, mucous membranes, or nonintact skin of all patients; when handling items or surfaces soiled with blood or other body fluids; and when performing venipuncture and other vascular access procedures. Among other things, CDC's recommendation that health care providers wear medical gloves demonstrates the proposition that devices labeled as medical gloves purport to be and are represented to be effective barriers against the transmission of blood- and fluid-borne pathogens. Therefore, FDA, through this regulation, is defining adulteration for patient examination and surgeons' gloves as a means of assuring safe and effective devices.

(1) For a description of a patient examination glove, see § 880.6250. Finger cots, however, are excluded from the test method and sample plans in paragraphs (b) and (c) of this section.

(2) For a description of a surgeons' glove, see § 878.4460 of this chapter.

(b)(1) General test method. For the purposes of this part, FDA's analysis of gloves for leaks and visual defects will be conducted by a visual examination and by a water leak test method, using 1,000 milliliters (ml) of water.

(i) Units examined. Each medical glove will be analyzed independently. When packaged as pairs, each glove is considered separately, and both gloves will be analyzed.

(ii) Identification of defects. For this test, defects include leaks detected when tested in accordance with paragraph (b)(3) of this section. A leak is defined as the appearance of water on the outside of the glove. This emergence of water from the glove constitutes a watertight barrier failure. Other defects include tears, embedded foreign objects, extrusions of glove material on the exterior or interior surface of the glove, gloves that are fused together so that individual glove separation is impossible, gloves that adhere to each other and tear when separated, or other visual defects that are likely to affect the barrier integrity.

(iii) Factors for counting defects. One defect in one glove is counted as one defect. A defect in both gloves in a pair of gloves is counted as two defects. If multiple defects, as defined in paragraph (b)(1)(ii) of this section, are found in one glove, they are counted as one defect. Visual defects and leaks that are observed in the top 40 millimeters (mm) of a glove will not be counted as a defect for the purposes of this part.

(2) Leak test materials. FDA considers the following to be the minimum materials required for this test :

(i) A 60 mm by 380 mm (clear) plastic cylinder with a hook on one end and a mark scored 40 mm from the other end (a cylinder of another size may be used if it accommodates both cuff diameter and any water above the glove capacity);

(ii) Elastic strapping with velcro or other fastening material;

(iii) Automatic water-dispensing apparatus or manual device capable of delivering 1,000 ml of water;

(iv) Stand with horizontal rod for hanging the hook end of the plastic tube. The horizontal support rod must be capable of holding the weight of the total number of gloves that will be suspended at any one time, e.g., five gloves suspended will weigh about 5 kilograms (kg);

(v) Timer capable of measuring two minute intervals.

(3) Visual defects and leak test procedures. Examine the sample and identify code/lot number, size, and brand as appropriate. Continue the visual examination using the following procedures:

(i) Visual defects examination. Inspect the gloves for visual defects by carefully removing the glove from the wrapper, box, or package. Visually examine each glove for defects. As noted in paragraph (b)(1)(iii) of this section, a visual defect observed in the top 40 mm of a glove will not be counted as a defect for the purpose of this part. Visually defective gloves do not require further testing, although they must be included in the total number of defective gloves counted for the sample.

(ii) Leak test set-up. (A) During this procedure, ensure that the exterior of the glove remains dry. Attach the glove to the plastic fill tube by bringing the cuff end to the 40 mm mark and fastening with elastic strapping to make a watertight seal.

(B) Add 1,000 ml of room temperature water (i.e., 20 (deg)C to 30 (deg)C) into the open end of the fill tube. The water should pass freely into the glove. (With some larger sizes of long-cuffed surgeons' gloves, the water level may reach only the base of the thumb. With some smaller gloves, the water level may extend several inches up the fill tube.)

(iii) Leak test examination. Immediately after adding the water, examine the glove for water leaks. Do not squeeze the glove; use only minimum manipulation to spread the fingers to check for leaks. Water drops may be blotted to confirm leaking.

(A) If the glove does not leak immediately, keep the glove/filling tube assembly upright and hang the assembly vertically from the horizontal rod, using the wire hook on the open end of the fill tube (do not support the filled glove while transferring).

(B) Make a second observation for leaks 2 minutes after the water is added to the glove. Use only minimum manipulation of the fingers to check for leaks.

(C) Record the number of defective gloves.

(c) Sampling, inspection, acceptance, and adulteration. In performing the test for leaks and other visual defects described in paragraph (b) of this section, FDA will collect and inspect samples of medical gloves, and determine when the gloves are acceptable as set out in paragraphs (c)(1) through (c)(3) of this section.

(1) Sample plans. FDA will collect samples from lots of medical gloves in accordance with agency sampling plans. These plans are based on sample sizes, levels of sample inspection, and acceptable quality levels (AQLs) found in the International Standard Organization's standard ISO 2859, “Sampling Procedures For Inspection By Attributes.”

(2) Sample sizes, inspection levels, and minimum AQLs. FDA will use single normal sampling for lots of 1,200 gloves or less and multiple normal sampling for all larger lots. FDA will use general inspection level II in determining the sample size for any lot size. As shown in the tables following paragraph (c)(3) of this section, FDA considers a 1.5 AQL to be the minimum level of quality acceptable for surgeons' gloves and a 2.5 AQL to be the minimum level of quality acceptable for patient examination gloves.

(3) Adulteration levels and accept/reject criteria. FDA considers a lot of medical gloves to be adulterated when the number of defective gloves found in the tested sample meets or exceeds the applicable rejection number at the 1.5 AQL for surgeons' gloves or the 2.5 AQL for patient examination gloves. These acceptance and rejection numbers are identified in the tables following paragraph (c)(3) of this section as follows:

Accept/Reject Criteria at 1.5 AQL for Surgeons' Gloves

Lot Size | Sample | Sample Size | Number Examined | Number Defective

Accept | Reject

8 to 90 | Single sample | 8 | 0 | 1

91 to 280 | Single sample | 32 | 1 | 2

281 to 500 | Single sample | 50 | 2 | 3

501 to 1,200 | Single sample | 80 | 3 | 4

1,201 to 3,200 | First | 32 | 32 | — | 4

Second | 32 | 64 | 1 | 5

Third | 32 | 96 | 2 | 6

Fourth | 32 | 128 | 3 | 7

Fifth | 32 | 160 | 5 | 8

Sixth | 32 | 192 | 7 | 9

Seventh | 32 | 224 | 9 | 10

3,201 to 10,000 | First | 50 | 50 | 0 | 4

Second | 50 | 100 | 1 | 6

Third | 50 | 150 | 3 | 8

Fourth | 50 | 200 | 5 | 10

Fifth | 50 | 250 | 7 | 11

Sixth | 50 | 300 | 10 | 12

Seventh | 50 | 350 | 13 | 14

10,001 to 35,000 | First | 80 | 80 | 0 | 5

Second | 80 | 160 | 3 | 8

Third | 80 | 240 | 6 | 10

Fourth | 80 | 320 | 8 | 13

Fifth | 80 | 400 | 11 | 15

Sixth | 80 | 480 | 14 | 17

Seventh | 80 | 560 | 18 | 19

35,000 | First | 125 | 125 | 1 | 7

Second | 125 | 250 | 4 | 10

Third | 125 | 375 | 8 | 13

Fourth | 125 | 500 | 12 | 17

Fifth | 125 | 625 | 17 | 20

Sixth | 125 | 750 | 21 | 23

Seventh | 125 | 875 | 25 | 26

Accept/Reject Criteria at 2.5 AQL for Patient Examination Gloves

Lot Size | Sample | Sample Size | Number Examined | Number Defective

Accept | Reject

5 to 50 | Single sample | 5 | 0 | 1

51 to 150 | Single sample | 20 | 1 | 2

151 to 280 | Single sample | 32 | 2 | 3

281 to 500 | Single sample | 50 | 3 | 4

501 to 1,200 | Single sample | 80 | 5 | 6

1,201 to 3,200 | First | 32 | 32 | 0 | 4

Second | 32 | 64 | 1 | 6

Third | 32 | 96 | 3 | 8

Fourth | 32 | 128 | 5 | 10

Fifth | 32 | 160 | 7 | 11

Sixth | 32 | 192 | 10 | 12

Seventh | 32 | 224 | 13 | 14

3,201 to 10,000 | First | 50 | 50 | 0 | 5

Second | 50 | 100 | 3 | 8

Third | 50 | 150 | 6 | 10

Fourth | 50 | 200 | 8 | 13

Fifth | 50 | 250 | 11 | 15

Sixth | 50 | 300 | 14 | 17

Seventh | 50 | 350 | 18 | 19

10,001 to 35,000 | First | 80 | 80 | 1 | 7

Second | 80 | 160 | 4 | 10

Third | 80 | 240 | 8 | 13

Fourth | 80 | 320 | 12 | 17

Fifth | 80 | 400 | 17 | 20

Sixth | 80 | 480 | 21 | 23

Seventh | 80 | 560 | 25 | 26

35,000 and above | First | 125 | 125 | 2 | 9

Second | 125 | 250 | 7 | 14

Third | 125 | 375 | 13 | 19

Fourth | 125 | 500 | 19 | 25

Fifth | 125 | 625 | 25 | 29

Sixth | 125 | 750 | 31 | 33

Seventh | 125 | 875 | 37 | 38

(d) Compliance. Lots of gloves that are sampled, tested, and rejected using procedures in paragraphs (b) and (c) of this section, are considered adulterated within the meaning of section 501(c) of the act.

(1) Detention and seizure. Lots of gloves that are adulterated under section 501(c) of the act are subject to administrative and judicial action, such as detention of imported products and seizure of domestic products.

(2) Reconditioning. FDA may authorize the owner of the product, or the owner's representative, to attempt to recondition, i.e., bring into compliance with the act, a lot or part of a lot of foreign gloves detained at importation, or a lot or part of a lot of seized domestic gloves.

(i) Modified sampling, inspection, and acceptance. If FDA authorizes reconditioning of a lot or portion of a lot of adulterated gloves, testing to confirm that the reconditioned gloves meet AQLs must be performed by an independent testing facility. The following tightened sampling plan must be followed, as described in ISO 2859 “Sampling Procedures for Inspection by Attributes:”

(A) General inspection level II,

(B) Single sampling plans for tightened inspection,

(C) 1.5 AQL for surgeons' gloves, and

(D) 2.5 AQL for patient examination gloves.

(ii) Adulteration levels and acceptance criteria for reconditioned gloves. (A) FDA considers a lot or part of a lot of adulterated gloves, that is reconditioned in accordance with paragraph (d)(2)(i) of this section, to be acceptable when the number of defective gloves found in the tested sample does not exceed the acceptance number in the appropriate tables in paragraph (d)(2)(ii)(B) of this section for reconditioned surgeons' gloves or patient examination gloves.

(B) FDA considers a reconditioned lot of medical gloves to be adulterated within the meaning of section 501(c) of the act when the number of defective gloves found in the tested sample meets or exceeds the applicable rejection number in the tables following paragraph (d)(2)(ii)(B) of this section:

Accept/Reject Criteria at 1.5 AQL for Reconditioned Surgeons' Gloves

Lot Size | Sample | Sample Size | Number Defective

Accept | Reject

13 to 90 | Single sample | 13 | 0 | 1

91 to 500 | Single sample | 50 | 1 | 2

501 to 1,200 | Single sample | 80 | 2 | 3

1,201 to 3,200 | Single sample | 125 | 3 | 4

3,201 to 10,000 | Single sample | 200 | 5 | 6

10,001 to 35,000 | Single sample | 315 | 8 | 9

35,000 and above | Single sample | 500 | 12 | 13

Accept/Reject Criteria at 2.5 AQL for Reconditioned Patient Examination Gloves

Lot Size | Sample | Sample Size | Number Defective

Accept | Reject

8 to 50 | Single sample | 8 | 0 | 1

51 to 280 | Single sample | 32 | 1 | 2

281 to 500 | Single sample | 50 | 2 | 3

501 to 1,200 | Single sample | 80 | 3 | 4

1,201 to 3,200 | Single sample | 125 | 5 | 6

3,201 to 10,000 | Single sample | 200 | 8 | 9

10,001 to 35,000 | Single sample | 315 | 12 | 13

35,000 and above | Single sample | 500 | 18 | 19

[55 FR 51256, Dec. 12, 1990, as amended at 71 FR 75876, Dec. 19, 2006]

§ 800.30 Over-the-counter hearing aid controls.

(a) Scope. This section specifies the requirements for over-the-counter (OTC) air-conduction hearing aids. Air-conduction hearing aids that satisfy the requirements in paragraphs (c) through (f) of this section are considered “available” over the counter as section 520(q)(1)(A)(v) of the Federal Food, Drug, and Cosmetic Act uses the term. Air-conduction hearing aids that do not meet the definition in section 520(q) of the Federal Food, Drug, and Cosmetic Act or do not satisfy the following requirements are prescription hearing aids. Unless otherwise specified, the requirements in this section are in addition to other applicable requirements, including but not limited to special controls found in the applicable classification regulation in part 874 of this chapter.

(b) Definitions for the purposes of this section. This section uses the following definitions:

Air-conduction hearing aid. An air-conduction hearing aid is a hearing aid that conducts sound to the ear through the air.

Hearing aid. A hearing aid is any wearable device designed for, offered for the purpose of, or represented as aiding persons with or compensating for, impaired hearing.

Licensed person. A licensed person is a person as defined in section 201(e) of the Federal Food, Drug, and Cosmetic Act that holds a license or degree for the diagnosis, assessment, or treatment of hearing loss; or that holds a license to sell or distribute hearing aids. A person that must meet generally applicable licensing or operating requirements such as annual health and safety inspections, provided the generally applicable licensing or operating requirement is consistent with this section and other applicable requirements under the Federal Food, Drug, and Cosmetic Act, is not a “licensed person” solely for that reason. A person that represents as a marketer, seller, dispenser, distributor, or customer support representative (or an equivalent description) is not a “licensed person” solely by making such representations.

Over-the-counter hearing aid. An over-the-counter (OTC) hearing aid is an air-conduction hearing aid that does not require implantation or other surgical intervention, and is intended for use by a person age 18 or older to compensate for perceived mild to moderate hearing impairment. The device, through tools, tests, or software, allows the user to control the hearing aid and customize it to the user's hearing needs. The device may use wireless technology or may include tests for self-assessment of hearing loss. The device is available over-the-counter, without the supervision, prescription, or other order, involvement, or intervention of a licensed person, to consumers through in-person transactions, by mail, or online, provided that the device satisfies the requirements in this section.

Prescription hearing aid. A prescription hearing aid is a hearing aid that is not an OTC hearing aid as defined in this section or a hearing aid that does not satisfy the requirements in this section.

Rebuilt hearing aid. An OTC hearing aid is “rebuilt” if the manufacturer has inspected and tested the device, made any necessary modifications to ensure it meets applicable regulatory requirements, including the requirements in this section to be available OTC, and adequately reprocessed the device for the next user.

Sale. Sale includes a lease, rental, or any other purchase or exchange for value.

Tools, tests, or software. Tools, tests, or software are components of the device that, individually or in combination, allow a lay user to control the device and customize it sufficiently, such as the device's output, to meet the user's hearing needs.

Used hearing aid. A hearing aid is “used” if a user has worn it for any period of time. However, a hearing aid shall not be “used” merely because a prospective user wore it as part of a bona fide hearing aid evaluation to determine whether to select that particular hearing aid for that prospective user. A hearing aid evaluation is “bona fide” if it was conducted in the presence of the dispenser or a hearing health professional selected by the dispenser to assist the prospective user in making a determination.

(c) Labeling. An OTC hearing aid shall bear all of the following in the labeling:

(1) Outside package labeling. The outside package of an OTC hearing aid shall bear all of the following:

(i) Warnings and other important information. All of the following shall appear on the outside package:

(A) (A) Warning against use in people younger than 18.

(B) Symptoms suggesting perceived mild to moderate hearing loss.

(C) Advice of availability of professional services.

(D) “Red flag” conditions.

(E) Notice of contact information.

(F) Notice of manufacturer's return policy.

(ii) Statement of build condition. If the OTC hearing aid is used or rebuilt, the outside package shall declare that fact. A sticker under and visible through the outer wrapper will suffice to declare such fact.

(iii) Statement of OTC availability. The principal display panel shall bear the marks “OTC” and “hearing aid” with the same prominence required under § 801.61(c) of this chapter for the device's statement of identity. The device's common name on the principal display panel may satisfy all or part of this requirement to the extent the common name includes the marks.

(iv) Indication of battery information. The outside package shall indicate the type and number of batteries and whether batteries are included in the package.

(v) Indication of control platform. The outside package shall indicate whether a mobile device or other non-included control platform is required. The indication must include the type of platform and how the platform connects to the device.

(2) Labeling, inside the package. The manufacturer or distributor of an OTC hearing aid shall include a user instructional brochure inside the package and shall make an electronic version available for download without site or customer registration and without requiring purchase of any product or service. The user instructional brochure shall include all of the following:

(i) The following warnings, which shall appear in the following order and prior to any content except the cover page:

(A) Warning against use in people younger than 18.

(B) “Red flag” conditions.

(C) Warning about pain from device placement.

(ii) Any additional warnings the manufacturer may include prior to the cautions and notices to users in paragraph (c)(2)(iii) of this section.

(iii) The following cautions and notices for users, which shall appear prior to any content except the cover page and the warnings under paragraphs (c)(2)(i) and (ii) of this section:

(A) Caution about hearing protection.

(B) Caution about excessive sound output.

(C) Caution about components lodging in ear.

(D) Advice to seek professional services.

(E) Note about user expectations.

(E) Note about reporting adverse events to FDA.

(iv) An illustration(s) of the OTC hearing aid that indicates operating controls, user adjustments, and the battery compartment.

(v) Information on the function of all controls intended for user adjustment.

(vi) A description of any accessory that accompanies the OTC hearing aid, including but not limited to wax guards and accessories for use with a computer, television, or telephone.

(vii) Specific instructions for all of the following:

(A) Instructions for sizing or inserting the eartip of the OTC hearing aid to prevent insertion past the depth limit and damage to the tympanic membrane.

(B) The tools, tests, or software that allow the user to control the OTC hearing aid, including self-selection and self-checking the performance of the OTC hearing aid, and customize it to the user's hearing needs, including information about properly fitting eartips.

(C) Use of the OTC hearing aid with any accompanying accessories.

(D) Maintenance and care of the OTC hearing aid, including how a lay user can clean, disinfect, and replace parts or how to seek replacements, as well as how to store the hearing aid when it will not be used for an extended period of time.

(E) If the battery is replaceable or rechargeable, how to replace or recharge the battery, including a generic designation of replacement batteries.

(F) Expected battery life.

(G) Any other information necessary for adequate directions for use as defined in § 801.5 of this chapter.

(viii) Identification of any known physiological side effects associated with the use of the OTC hearing aid that may warrant consultation with a physician, referring to an ear-nose-throat doctor when preferable, including if applicable, skin irritation and accelerated accumulation of cerumen (ear wax).

(ix) The technical specifications required by paragraph (c)(4) of this section.

(x) A description of commonly occurring, avoidable events that could adversely affect or damage the OTC hearing aid, including but not limited to, as applicable, ear wax buildup, drops, immersion in water, or exposure to excessive heat.

(xi) If the hearing aid incorporates wireless technology in its programming or use, appropriate warnings, instructions, and information relating to electromagnetic compatibility and wireless technology and human exposure to non-ionizing radiation.

(xii) Information on how and where to obtain repair service or replacements, including at least one specific address where the user can go or send the OTC hearing aid to obtain such repair service or replacements.

(xiii) If clinical or non-clinical studies were conducted by or for the manufacturer to support the performance of the OTC hearing aid, a summary of all such studies.

(3) Labeling on the device. The labeling on an OTC hearing aid itself shall bear all of the following clearly and permanently, except as provided in paragraph (c)(3)(iii) of this section:

(i) The serial number.

(ii) If the battery is removable, a “+” symbol to indicate the positive terminal for battery insertion unless the battery's physical design prevents inserting the battery in the reversed position.

(iii) If the OTC hearing aid is used or rebuilt, the manufacturer shall physically attach a removable tag to the hearing aid declaring that fact.

(4) Technical specifications. All of the following technical specifications shall appear in the user instructional brochure that accompanies the device. You may additionally include it on the outside package:

(i) The maximum output limit value (Output Sound Pressure Level 90 (OSPL90)).

(ii) The full-on gain value, which is the gain with a 50 decibel (dB) Sound Pressure Level (SPL) pure-tone input and volume set to full on.

(iii) The total harmonic distortion value.

(iv) The self-generated noise value.

(v) The latency value.

(vi) The upper and lower cutoff frequencies for bandwidth.

(5) Software device labeling. OTC hearing aid software that is not distributed with the hearing aid or amplification platform shall meet all of the following labeling requirements. With respect to the information required under paragraphs (c)(1) through (4) of this section, the information must be provided in the software device labeling, as specified in paragraphs (c)(5)(i) through (v) of this section, rather than the locations (e.g., outside package labeling) specified in paragraphs (c)(1) through (4):

(i) Prior to first use of the software or obtaining payment information for the software, whichever occurs first, the labeling must clearly and prominently present all of the following to the prospective user. For each, the labeling must remain visible until the user dismisses it or proceeds to the next step:

(A) Compatibility and minimum operating requirements for the software device.

(B) Disclosures of any fees or payments after first use or initial payment, including but not limited to any fees or payments relating to subscriptions, add-on features, or continued access to features or services. The disclosures must name and briefly describe what each fee or payment covers.

(C) The information required under paragraphs (c)(1)(i), (iii), and (v) of this section.

(ii) Prior to first use of the software, the labeling must clearly and prominently present all of the following to the prospective user:

(A) The information required under paragraph (c)(2)(i)(A) of this section, and it must remain visible until the user acknowledges it.

(B) The information required under paragraphs (c)(2)(i)(B) and (C), (c)(2)(ii), (iii), and (v), (c)(2)(vii)(B) and (G), and (c)(2)(viii) and (ix) of this section, and the information must remain visible until the user dismisses it or proceeds to the next step.

(C) All other information required under paragraph (c)(2) of this section, to the extent applicable, and the information must remain visible until the user dismisses it or proceeds to the next step.

(iii) The software device labeling must include the information required under paragraphs (c)(3)(i) and (c)(4) of this section.

(iv) All of the software device labeling must be accessible for review after acknowledgment, dismissal, or proceeding to the next step.

(v) If there are changes to any of the labeling required under paragraph (c)(5) of this section, the labeling with the changed information must be presented to the user until the user dismisses it.

(d) Output limits. The output limit for an OTC hearing aid shall be the device maximum acoustic output sound pressure level (SPL) with an acoustic coupler as described in paragraph (e)(6) of this section when the device input is a 90 dB SPL pure-tone, and the gain/volume control is full on. An OTC hearing aid shall not exceed the following limits at any of the frequencies at which the device is intended to operate:

(1) General output limit. An OTC hearing aid shall not exceed an output limit of 111 dB SPL at any frequency except as provided in paragraph (d)(2) of this section.

(2) Output limit for a device with activated input-controlled compression. An OTC hearing aid that has input-controlled compression activated shall not exceed an output limit of 117 dB SPL at any frequency.

(e) Electroacoustic performance limits. An OTC hearing aid shall perform within all of the following electroacoustic limits. Measure each electroacoustic performance characteristic using an acoustic coupler as described in paragraph (e)(6) of this section, where applicable:

(1) Output distortion control limits. Test the output distortion of the OTC hearing aid as follows to ensure that it does not exceed the limit specified in paragraphs (e)(1)(i) through (iii) of this section.

(i) The total harmonic distortion plus noise shall not exceed 5 percent for output levels within one of the following sets of levels, depending on the test method:

(A) Using sine wave-based testing, measure at 70 dB SPL and 100 dB SPL; or

(B) Using a 500-hertz (Hz) one-third-octave pulsed-noise signal, measure at 67 dB SPL and 97 dB SPL.

(ii) You must measure the total harmonic distortion using a 500-Hz input tone with an analyzer that has a bandwidth at least as wide as the frequency limits of the OTC hearing aid.

(iii) You must measure the output distortion at the OTC hearing aid's maximum volume and the input sound level to the OTC hearing aid adjusted to produce the required outputs.

(2) Self-generated noise level limits. Self-generated noise shall not exceed 32 dBA. You must disable any methods that artificially lower the apparent noise floor for the measurement. Such methods would include but are not limited to auto-muting and downward expansion.

(3) Latency. Latency shall not exceed 15 ms. You must measure the latency with a method that is accurate and repeatable to within 1.5 ms.

(4) Frequency response bandwidth. The lower cutoff frequency shall extend to 250 Hz or below, and the upper cutoff frequency shall extend to 5 kHz or greater. You must measure the frequency response bandwidth as specified in the Method for clause 4.1 in ANSI/CTA-2051:2017.

(5) Frequency response smoothness. No single peak in the one-third-octave frequency response shall exceed 12 dB relative to the average levels of the one-third-octave bands, two-thirds octave above and below the peak. You must measure the frequency response smoothness using values for a diffuse field and the corrected one-third-octave frequency insertion response as specified in the Method for clause 4.1 in ANSI/CTA-2051:2017.

(6) Acoustic coupler choice. Where applicable, use one of the following acoustic couplers to measure electroacoustic performance:

(i) When compatible with the device design, a 2-cubic centimeter (cm 3) acoustic coupler; or

(ii) When a 2-cm 3 acoustic coupler is not compatible with the device design, an acoustic coupler that is a scientifically valid and technically equivalent alternative. You must document the rationale for using an alternative acoustic coupler.

(f) Design requirements. An OTC hearing aid must conform to all of the following design requirements:

(1) Insertion depth. The design of an OTC hearing aid shall limit the insertion of the most medial component so that, when inserted, the component is reasonably expected to remain at least 10 millimeters (mm) from the tympanic membrane.

(2) Use of atraumatic materials. The material for the eartip of an OTC hearing aid shall be atraumatic.

(3) Proper physical fit. The design of an OTC hearing aid shall enable consumers to readily achieve a safe, customized, acoustically favorable, and comfortable physical fit in the ear canal and/or external ear.

(4) Tools, tests, or software. The OTC hearing aid shall, through tools, tests, or software, permit a lay user to control the device and customize it to the user's hearing needs.

(5) User-adjustable volume control. The OTC hearing aid shall have a user-adjustable volume control.

(6) Adequate reprocessing. If the OTC hearing aid is used or rebuilt, it must be adequately reprocessed for the next user prior to sale.

(g) Conditions for sale of an OTC hearing aid. The sale of an OTC hearing aid is subject to all of the following conditions:

(1) Age minimum. Sale to or for a person younger than 18 years of age is prohibited.

(2) Statement of OTC availability. Sale of an OTC hearing aid is prohibited unless its labeling bears the statement of OTC availability required under paragraph (c)(1)(iii) of this section.

(h) Effect on State law. Any State or local government requirement for an OTC hearing aid is preempted to the following extent:

(1) Preemption. No State or local government shall establish or continue in effect any law, regulation, order, or other requirement specifically related to hearing products that would restrict or interfere with the servicing, marketing, sale, dispensing, use, customer support, or distribution of OTC hearing aids through in-person transactions, by mail, or online, that is different from, in addition to, or otherwise not identical to, the regulations promulgated under section 709(b) of the FDA Reauthorization Act of 2017, including any State or local requirement for the supervision, prescription, or other order, involvement, or intervention of a licensed person for consumers to access OTC hearing aids.

(2) Professional requirements—(i) General rule. The servicing, marketing, sale, dispensing, customer support, or distribution of OTC hearing aids, or an equivalent activity, whether through in-person transactions, by mail, or online, shall not cause, require, or otherwise obligate a person providing such services to obtain specialized licensing, certification, or any other State or local sanction unless such requirement is generally applicable to the sale of any product or to all places of business regardless of whether they sell OTC hearing aids. However, although a State or local government may not require the order, involvement, or intervention of a licensed person for consumers to access OTC hearing aids, a licensed person may service, market, sell, dispense, provide customer support for, or distribute OTC hearing aids.

(ii) Sale of OTC hearing aids is not an exemption. The servicing, marketing, sale, dispensing, customer support, or distribution of OTC hearing aids does not exempt a person from any State or local government's professional or establishment requirements that are consistent with this section.

(iii) Representations may create professional obligations. A person shall not incur specialized obligations by representing as a servicer, marketer, seller, dispenser, customer support representative, or distributor (or an equivalent description) of OTC hearing aids. However, a person representing as any other defined professional or establishment, or as a State licensed dispenser, is subject to applicable State and local requirements even if the person undertakes commercial or professional activities only in relation to OTC hearing aids.

(3) Private remedies. This section does not modify or otherwise affect the ability of any person to exercise a private right of action under any State or Federal product liability, tort, warranty, contract, or consumer protection law.

(i) Incorporation by reference. ANSI/CTA-2051, “Personal Sound Amplification Performance Criteria,” dated January 2017 (ANSI/CTA-2051:2017), is incorporated by reference into this section with the approval of the Director of the Office of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. This material is available for inspection at the Food and Drug Administration and at the National Archives and Records Administration (NARA). Contact the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500. For information on the availability of this material at NARA, email: fr.inspection@nara.gov, or go to: www.archives.gov/federal-register/cfr/ibr-locations.html. The material may be obtained from Consumer Technology Association (CTA), Technology & Standards Department, 1919 S Eads Street, Arlington, VA 22202; phone: 703-907-7600; fax: (703) 907-7693; email: standards@ce.org, website: www.cta.tech.

[87 FR 50748, Aug. 17, 2022]

§ 800.55 Administrative detention.

(a) General. This section sets forth the procedures for detention of medical devices intended for human use believed to be adulterated or misbranded. Administrative detention is intended to protect the public by preventing distribution or use of devices encountered during inspections that may be adulterated or misbranded, until the Food and Drug Administration (FDA) has had time to consider what action it should take concerning the devices, and to initiate legal action, if appropriate. Devices that FDA orders detained may not be used, moved, altered, or tampered with in any manner by any person during the detention period, except as authorized under paragraph (h) of this section, until FDA terminates the detention order under paragraph (j) of this section, or the detention period expires, whichever occurs first.

(b) Criteria for ordering detention. Administrative detention of devices may be ordered in accordance with this section when an authorized FDA representative, during an inspection under section 704 of the Federal Food, Drug, and Cosmetic Act (the act), has reason to believe that a device, as defined in section 201(h) of the act, is adulterated or misbranded.

(c) Detention period. The detention is to be for a reasonable period that may not exceed 20 calendar days after the detention order is issued, unless the FDA Division Director in whose division the devices are located determines that a greater period is required to seize the devices, to institute injunction proceedings, or to evaluate the need for legal action, in which case the Division Director may authorize detention for 10 additional calendar days. The additional 10-calendar-day detention period may be ordered at the time the detention order is issued or at any time thereafter. The entire detention period may not exceed 30 calendar days, except when the detention period is extended under paragraph (g)(6) of this section. An authorized FDA representative may, in accordance with paragraph (j) of this section, terminate a detention before the expiration of the detention period.

(d) Issuance of detention order. (1) The detention order shall be issued in writing, in the form of a detention notice, signed by the authorized FDA representative who has reason to believe that the devices are adulterated or misbranded, and issued to the owner, operator, or agent in charge of the place where the devices are located. If the owner or the user of the devices is different from the owner, operator, or agent in charge of the place where the devices are detained, a copy of the detention order shall be provided to the owner or user of the devices if the owner's or user's identity can be readily determined.

(2) If detention of devices in a vehicle or other carrier is ordered, a copy of the detention order shall be provided to the shipper of record and the owner of the vehicle or other carrier, if their identities can be readily determined.

(3) The detention order shall include the following information:

(i) A statement that the devices identified in the order are detained for the period shown;

(ii) A brief, general statement of the reasons for the detention;

(iii) The location of the devices;

(iv) A statement that these devices are not to be used, moved, altered, or tampered with in any manner during that period, except as permitted under paragraph (h) of this section, without the written permission of an authorized FDA representative;

(v) Identification of the detained devices;

(vi) The detention order number;

(vii) The date and hour of the detention order;

(viii) The period of the detention;

(ix) The text of section 304(g) of the act and paragraph (g) (1) and (2) of this section;

(x) A statement that any informal hearing on an appeal of a detention order shall be conducted as a regulatory hearing under part 16 of this chapter, with certain exceptions described in paragraph (g)(3) of this section; and

(xi) The mailing address, telephone number, and name of the FDA Division Director.

(e) Approval of detention order. A detention order, before issuance, shall be approved by the FDA Division Director in whose division the devices are located. If prior written approval is not feasible, prior oral approval shall be obtained and confirmed by written memorandum within FDA as soon as possible.

(f) Labeling or marking a detained device. An FDA representative issuing a detention order under paragraph (d) of this section shall label or mark the devices with official FDA tags that include the following information:

(1) A statement that the devices are detained by the United States Government in accordance with section 304(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 334(g)).

(2) A statement that the devices shall not be used, moved, altered, or tampered with in any manner for the period shown, without the written permission of an authorized FDA representative, except as authorized in paragraph (h) of this section.

(3) A statement that the violation of a detention order or the removal or alteration of the tag is punishable by fine or imprisonment or both (section 303 of the act, 21 U.S.C. 333).

(4) The detention order number, the date and hour of the detention order, the detention period, and the name of the FDA representative who issued the detention order.

(g) Appeal of a detention order. (1) A person who would be entitled to claim the devices, if seized, may appeal a detention order. Any appeal shall be submitted in writing to the FDA Division Director in whose division the devices are located within 5 working days of receipt of a detention order. If the appeal includes a request for an informal hearing, as defined in section 201(x) of the act, the appellant shall request either that a hearing be held within 5 working days after the appeal is filed or that the hearing be held at a later date, which shall not be later than 20 calendar days after receipt of a detention order.

(2) The appellant of a detention order shall state the ownership or proprietary interest the appellant has in the detained devices. If the detained devices are located at a place other than an establishment owned or operated by the appellant, the appellant shall include documents showing that the appellant would have legitimate authority to claim the devices if seized.

(3) Any informal hearing on an appeal of a detention order shall be conducted as a regulatory hearing pursuant to regulation in accordance with part 16 of this chapter, except that:

(i) The detention order under paragraph (d) of this section, rather than the notice under § 16.22(a) of this chapter, provides notice of opportunity for a hearing under this section and is part of the administrative record of the regulatory hearing under § 16.80(a) of this chapter.

(ii) A request for a hearing under this section should be addressed to the FDA Division Director.

(iii) The last sentence of § 16.24(e) of this chapter, stating that a hearing may not be required to be held at a time less than 2 working days after receipt of the request for a hearing, does not apply to a hearing under this section.

(iv) Paragraph (g)(4) of this section, rather than § 16.42(a) of this chapter, describes the FDA employees who preside at hearings under this section.

(4) The presiding officer of a regulatory hearing on an appeal of a detention order, who also shall decide the appeal, shall be an Office of Regulatory Affairs Program Director or another FDA official senior to an FDA Division Director who is permitted by § 16.42(a) of this chapter to preside over the hearing.

(5) If the appellant requests a regulatory hearing and requests that the hearing be held within 5 working days after the appeal is filed, the presiding officer shall, within 5 working days, hold the hearing and render a decision affirming or revoking the detention.

(6) If the appellant requests a regulatory hearing and requests that the hearing be held at a date later than within 5 working days after the appeal is filed, but not later than 20 calendar days after receipt of a detention order, the presiding officer shall hold the hearing at a date agreed upon by FDA and the appellant. The presiding officer shall decide whether to affirm or revoke the detention within 5 working days after the conclusion of the hearing. The detention period extends to the date of the decision even if the 5-working-day period for making the decision extends beyond the otherwise applicable 20-calendar-day or 30-calendar-day detention period.

(7) If the appellant appeals the detention order but does not request a regulatory hearing, the presiding officer shall render a decision on the appeal affirming or revoking the detention within 5 working days after the filing of the appeal.

(8) If the presiding officer affirms a detention order, the devices continue to be detained until FDA terminates the detention under paragraph (j) of this section or the detention period expires, whichever occurs first.

(9) If the presiding officer revokes a detention order, FDA shall terminate the detention under paragraph (j) of this section.

(h) Movement of detained devices. (1) Except as provided in this paragraph (h), no person shall move detained devices within or from the place where they have been ordered detained until FDA terminates the detention under paragraph (j) of this section or the detention period expires, whichever occurs first.

(2) If detained devices are not in final form for shipment, the manufacturer may move them within the establishment where they are detained to complete the work needed to put them in final form. As soon as the devices are moved for the purpose of the preceding sentence, the individual responsible for their movement shall orally notify the FDA representative who issued the detention order, or another responsible division office official, of the movement of the devices. As soon as the devices are put in final form, they shall be segregated from other devices, and the individual responsible for their movement shall orally notify the FDA representative who issued the detention order, or another responsible division office official, of their new location. The devices put in final form shall not be moved further without FDA approval.

(3) The FDA representative who issued the detention order, or another responsible division office official, may approve, in writing, the movement of detained devices for any of the following purposes:

(i) To prevent interference with an establishment's operations or harm to the devices.

(ii) To destroy the devices.

(iii) To bring the devices into compliance.

(iv) For any other purpose that the FDA representative who issued the detention order, or other responsible division office official, believes is appropriate in the case.

(4) If an FDA representative approves the movement of detained devices under paragraph (h)(3) of this section, the detained devices shall remain segregated from other devices and the person responsible for their movement shall immediately orally notify the official who approved the movement of the devices, or another responsible FDA division office official, of the new location of the detained devices.

(5) Unless otherwise permitted by the FDA representative who is notified of, or who approves, the movement of devices under this paragraph, the required tags shall accompany the devices during and after movement and shall remain with the devices until FDA terminates the detention or the detention period expires, whichever occurs first.

(i) Actions involving adulterated or misbranded devices. If FDA determines that the detained devices, including any that have been put in final form, are adulterated or misbranded, or both, it may initiate legal action against the devices or the responsible individuals, or both, or request that the devices be destroyed or otherwise brought into compliance with the act under FDA's supervision.

(j) Detention termination. If FDA decides to terminate a detention or when the detention period expires, whichever occurs first, an FDA representative authorized to terminate a detention will issue a detention termination notice releasing the devices to any person who received the original detention order or that person's representative and will remove, or authorize in writing the removal of, the required labels or tags.

(k) Recordkeeping requirements. (1) After issuance of a detention order under paragraph (d) of this section, the owner, operator, or agent in charge of any factory, warehouse, other establishment, or consulting laboratory where detained devices are manufactured, processed, packed, or held shall have, or establish, and maintain adequate records relating to how the detained devices may have become adulterated or misbranded, records on any distribution of the devices before and after the detention period, records on the correlation of any in-process detained devices that are put in final form under paragraph (h) of this section to the completed devices, records of any changes in, or processing of, the devices permitted under the detention order, and records of any other movement under paragraph (h) of this section. Records required under this paragraph shall be provided to the FDA on request for review and copying. Any FDA request for access to records required under this paragraph shall be made at a reasonable time, shall state the reason or purpose for the request, and shall identify to the fullest extent practicable the information or type of information sought in the records to which access is requested.

(2) Records required under this paragraph shall be maintained for a maximum period of 2 years after the issuance of the detention order or for such other shorter period as FDA directs. When FDA terminates the detention or when the detention period expires, whichever occurs first, FDA will advise all persons required under this paragraph to keep records concerning that detention whether further recordkeeping is required for the remainder of the 2-year, or shorter, period. FDA ordinarily will not require further recordkeeping if the agency determines that the devices are not adulterated or misbranded or that recordkeeping is not necessary to protect the public health, unless the records are required under other regulations in this chapter (e.g., the good manufacturing practice regulation in part 820 of this chapter).

[44 FR 13239, Mar. 9, 1979, as amended at 49 FR 3174, Jan. 26, 1984; 69 FR 17292, Apr. 2, 2004; 79 FR 9412, Feb. 19, 2014; 82 FR 14147, Mar. 17, 2017; 85 FR 16555, Mar. 25, 2020]

§ 800.75 Requests for supervisory review of certain decisions made by the Center for Devices and Radiological Health.

(a) Definitions. The following definitions shall apply to this section:

(1) FDA means the Food and Drug Administration.

(2) 517A decision means a significant decision made by the Center for Devices and Radiological Health, as set forth in section 517A of the Federal Food, Drug, and Cosmetic Act, and includes one of the following decisions:

(i) A substantially equivalent order under § 807.100(a)(1) of this chapter, or a not substantially equivalent order under § 807.100(a)(2) of this chapter;

(ii) An approval order under § 814.44(d) of this chapter, an approvable letter under § 814.44(e) of this chapter, a not approvable letter under § 814.44(f) of this chapter, or an order denying approval under § 814.45 of this chapter;

(iii) An approval order under § 814.116(b) of this chapter, an approvable letter under § 814.116(c) of this chapter, a not approvable letter under § 814.116(d) of this chapter, or an order denying approval under § 814.118 of this chapter;

(iv) A grant or denial of a request for breakthrough device designation under section 515B of the Federal Food, Drug, and Cosmetic Act;

(v) An approval order under § 812.30(a) of this chapter or a disapproval order under § 812.30(c) of this chapter;

(vi) A failure to reach agreement letter under section 520(g)(7) of the Federal Food, Drug, and Cosmetic Act; or

(vii) A clinical hold determination under section 520(g)(8) of the Federal Food, Drug, and Cosmetic Act.

(3) CDRH means the Center for Devices and Radiological Health.

(b) Submission of request—(1) Review of 517A decisions. (i) An initial or sequential request for supervisory review within CDRH of a 517A decision under § 10.75 of this chapter must be addressed to the next organizational level or higher above the individual who made the decision; submitted in electronic format in accordance with section 745A(b) of the Federal Food, Drug, and Cosmetic Act; marked “Appeal: Request for Supervisory Review”; and received by CDRH no later than 30 days after the date of the decision involved. Any such request for supervisory review not received by CDRH within 30 days after the date of the decision involved is not eligible for review. Except as provided in paragraph (b)(1)(ii) or (iii) of this section, FDA will render a decision within 45 days of the request for supervisory review.

(ii) A person requesting supervisory review under paragraph (b)(1)(i) may request an in-person meeting or teleconference with the supervisor reviewing the request for supervisory review. Except as provided in paragraph (b)(1)(iii) of this section, if a request for in-person meeting or teleconference is included in the request for supervisory review to CDRH, CDRH will schedule the meeting or teleconference to occur within 30 days of receipt of the request. Except as provided in paragraph (b)(1)(iii) of this section, a decision will be rendered within 30 days of such meeting or teleconference.

(iii) The timeframes for CDRH to render a decision provided in (b)(1)(i) and (ii) of this section, and the timeframe to schedule an in-person meeting or teleconference review in (b)(1)(ii) of this section, do not apply if a matter related to the 517A decision under review is referred by CDRH to external experts, such as an advisory committee, as provided in § 10.75(b) of this chapter.

(2) Supervisory review. An initial or sequential request for supervisory review within CDRH under § 10.75 of this chapter of a decision other than a 517A decision that is not received by CDRH within 60 days after the date of the decision involved will be denied as untimely, unless CDRH, for good cause, permits the request to be filed after 60 days. An initial or sequential request for supervisory review within CDRH of a decision other than a 517A decision must be addressed to the next organizational level or higher above the individual who made the decision; submitted in electronic format in accordance with section 745A(b) of the Federal Food, Drug, and Cosmetic Act, when applicable; marked, “Appeal: Request for Supervisory Review” in the subject line of the electronic request; and sent to the CDRH Ombudsman at CDRHOmbudsman@fda.hhs.gov.

[84 FR 31477, July 2, 2019]

§ 801.1 Medical devices; name and place of business of manufacturer, packer or distributor.

(a) The label of a device in package form shall specify conspicuously the name and place of business of the manufacturer, packer, or distributor.

(b) The requirement for declaration of the name of the manufacturer, packer, or distributor shall be deemed to be satisfied, in the case of a corporation, only by the actual corporate name which may be preceded or followed by the name of the particular division of the corporation. Abbreviations for “Company,” “Incorporated,” etc., may be used and “The” may be omitted. In the case of an individual, partnership, or association, the name under which the business is conducted shall be used.

(c) Where a device is not manufactured by the person whose name appears on the label, the name shall be qualified by a phrase that reveals the connection such person has with such device; such as, “Manufactured for ___”, “Distributed by _____”, or any other wording that expresses the facts.

(d) The statement of the place of business shall include the street address, city, State, and Zip Code; however, the street address may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclusion of the ZIP Code shall apply only to consumer commodity labels developed or revised after the effective date of this section. In the case of nonconsumer packages, the ZIP Code shall appear on either the label or the labeling (including the invoice).

(e) If a person manufactures, packs, or distributes a device at a place other than his principal place of business, the label may state the principal place of business in lieu of the actual place where such device was manufactured or packed or is to be distributed, unless such statement would be misleading.

§ 801.3 Definitions.

As used in this part:

Automatic identification and data capture (AIDC) means any technology that conveys the unique device identifier or the device identifier of a device in a form that can be entered into an electronic patient record or other computer system via an automated process.

Center Director means the Director of the Center for Devices and Radiological Health or the Director of the Center for Biologics Evaluation and Research, depending on which Center has been assigned lead responsibility for the device.

Combination product has the meaning set forth in § 3.2(e) of this chapter.

Convenience kit means two or more different medical devices packaged together for the convenience of the user.

Device package means a package that contains a fixed quantity of a particular version or model of a device.

Expiration date means the date by which the label of a device states the device must or should be used.

FDA, we, or us means the Food and Drug Administration.

Finished device means any device or accessory to any device that is suitable for use or capable of functioning.

Global Unique Device Identification Database (GUDID) means the database that serves as a repository of information to facilitate the identification of medical devices through their distribution and use.

Human cells, tissues, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

Implantable device means a device that is intended to be placed in a surgically or naturally formed cavity of the human body. A device is regarded as an implantable device for the purpose of this part only if it is intended to remain implanted continuously for a period of 30 days or more, unless the Commissioner of Food and Drugs determines otherwise in order to protect human health.

Label has the meaning set forth in section 201(k) of the Federal Food, Drug, and Cosmetic Act.

Labeler means:

(1) Any person who causes a label to be applied to a device with the intent that the device will be commercially distributed without any intended subsequent replacement or modification of the label; and

(2) Any person who causes the label of a device to be replaced or modified with the intent that the device will be commercially distributed without any subsequent replacement or modification of the label, except that the addition of the name of, and contact information for, a person who distributes the device, without making any other changes to the label, is not a modification for the purposes of determining whether a person is a labeler.

Lot or batch means one finished device or more that consist of a single type, model, class, size, composition, or software version that are manufactured under essentially the same conditions and that are intended to have uniform characteristics and quality within specified limits.

Shipping container means a container used during the shipment or transportation of devices, and whose contents may vary from one shipment to another.

Specification means any requirement with which a device must conform.

Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured;

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

Universal product code (UPC) means the product identifier used to identify an item sold at retail in the United States.

Version or model means all devices that have specifications, performance, size, and composition, within limits set by the labeler.

[78 FR 58817, Sept. 24, 2013]

§ 801.4 Meaning of intended uses.

Link to an amendment published at 82 FR 2217, Jan. 9, 2017.

This amendment was delayed until Mar. 21, 2017, at 82 FR 9501, Feb. 7, 2017.

This amendment was further delayed until Mar. 19, 2018, at 82 FR 14319, Mar. 20, 2017.

This amendment delayed indefinitely at 83 FR 11639, Mar. 16, 2018.

The words intended uses or words of similar import in §§ 801.5, 801.119, 801.122, and 1100.5 of this chapter refer to the objective intent of the persons legally responsible for the labeling of an article (or their representatives). The intent may be shown by such persons' expressions, the design or composition of the article, or by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. Objective intent may be shown, for example, by circumstances in which the article is, with the knowledge of such persons or their representatives, offered or used for a purpose for which it is neither labeled nor advertised; provided, however, that a firm would not be regarded as intending an unapproved new use for a device approved, cleared, granted marketing authorization, or exempted from premarket notification based solely on that firm's knowledge that such device was being prescribed or used by health care providers for such use. The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he or she received the article, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses.

[86 FR 41401, Aug. 2, 2021]

§ 801.5 Medical devices; adequate directions for use.

Adequate directions for use means directions under which the layman can use a device safely and for the purposes for which it is intended. Section 801.4 defines intended use. Directions for use may be inadequate because, among other reasons, of omission, in whole or in part, or incorrect specification of:

(a) Statements of all conditions, purposes, or uses for which such device is intended, including conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral, written, printed, or graphic advertising, and conditions, purposes, or uses for which the device is commonly used; except that such statements shall not refer to conditions, uses, or purposes for which the device can be safely used only under the supervision of a practitioner licensed by law and for which it is advertised solely to such practitioner.

(b) Quantity of dose, including usual quantities for each of the uses for which it is intended and usual quantities for persons of different ages and different physical conditions.

(c) Frequency of administration or application.

(d) Duration of administration or application.

(e) Time of administration or application, in relation to time of meals, time of onset of symptoms, or other time factors.

(f) Route or method of administration or application.

(g) Preparation for use, i.e., adjustment of temperature, or other manipulation or process.

§ 801.6 Medical devices; misleading statements.

Among representations in the labeling of a device which render such device misbranded is a false or misleading representation with respect to another device or a drug or food or cosmetic.

§ 801.15 Medical devices; prominence of required label statements; use of symbols in labeling.

(a) A word, statement, or other information required by or under authority of the act to appear on the label may lack that prominence and conspicuousness required by section 502(c) of the act by reason, among other reasons, of:

(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;

(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;

(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;

(4) Insufficiency of label space for the prominent placing of such word, statement, or information, resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;

(5) Insufficiency of label space for the placing of such word, statement, or information, resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device; or

(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.

(b) No exemption depending on insufficiency of label space, as prescribed in regulations promulgated under section 502(b) of the act, shall apply if such insufficiency is caused by:

(1) The use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;

(2) The use of label space to give greater conspicuousness to any word, statement, or other information than is required by section 502(c) of the act; or

(3) The use of label space for any representation in a foreign language.

(c)(1)(i) All words, statements, and other information required by or under authority of the act to appear on the label or labeling for a device shall appear thereon in one or more of the following formats:

(A) The English language;

(B) In the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English;

(C) A symbol accompanied by adjacent explanatory English text, or text in the predominant language of the Territory, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English;

(D) A symbol not accompanied by adjacent explanatory text that:

(1) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the act;

(2) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(3) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used;

(E) A symbol not accompanied by adjacent explanatory text that:

(1) Is established in a standard developed by a standards development organization (SDO);

(2) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(3) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the act;

(4) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(5) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used;

(F) The symbol statement “Rx only” or “℞ only” may be used as provided under § 801.109(b)(1).

(ii) The use of symbols in device labeling which do not meet the requirements of paragraph (c)(1)(i) of this section renders a device misbranded under section 502(c) of the act.

(iii) For purposes of paragraph (c)(1)(i) of this section:

(A) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(B) The term “symbols glossary” means a compiled listing of:

(1) Each SDO-established symbol used in the labeling for the device;

(2) The title and designation number of the SDO-developed standard containing the symbol;

(3) The title of the symbol and its reference number, if any, in the standard; and

(4) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.

(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear on the labeling in the foreign language.

[41 FR 6896, Feb. 13, 1976, as amended at 81 FR 38930, June 15, 2016]

§ 801.16 Medical devices; Spanish-language version of certain required statements.

If devices restricted to prescription use only are labeled solely in Spanish for distribution in the Commonwealth of Puerto Rico where Spanish is the predominant language, such labeling is authorized under § 801.15(c).

§ 801.18 Format of dates provided on a medical device label.

(a) In general. Whenever the label of a medical device includes a printed expiration date, date of manufacture, or any other date intended to be brought to the attention of the user of the device, the date must be presented in the following format: The year, using four digits; followed by the month, using two digits; followed by the day, using two digits; each separated by hyphens. For example, January 2, 2014, must be presented as 2014-01-02.

(b) Exceptions. (1) A combination product that properly bears a National Drug Code (NDC) number is not subject to the requirements of paragraph (a) of this section.

(2) If the device is an electronic product to which a standard is applicable under subchapter J of this chapter, Radiological Health, the date of manufacture shall be presented as required by § 1010.3(a)(2)(ii) of this chapter.

[78 FR 58818, Sept. 24, 2013]

§ 801.20 Label to bear a unique device identifier.

(a) In general. (1) The label of every medical device shall bear a unique device identifier (UDI) that meets the requirements of this subpart and part 830 of this chapter.

(2) Every device package shall bear a UDI that meets the requirements of this subpart and part 830 of this chapter.

(b) Exceptions. Exceptions to the general rule of paragraph (a) of this section are provided by §§ 801.30, 801.45, and 801.128(f)(2), and § 801.55 provides a means to request an exception or alternative not provided by those provisions.

[78 FR 58818, Sept. 24, 2013]

§ 801.30 General exceptions from the requirement for the label of a device to bear a unique device identifier.

(a) In general. The following types of devices are excepted from the requirement of § 801.20; a device within one or more of the following exceptions is not required to bear a unique device identifier (UDI):

(1) A finished device manufactured and labeled prior to the compliance date established by FDA for § 801.20 regarding the device. This exception expires with regard to a particular device 3 years after the compliance date established by FDA for the device.

(2) A class I device that FDA has by regulation exempted from the good manufacturing practice requirements of part 820 of this chapter, exclusive of any continuing requirement for recordkeeping under § 820.35 of this chapter.

(3) Individual single-use devices, all of a single version or model, that are distributed together in a single device package, intended to be stored in that device package until removed for use, and which are not intended for individual commercial distribution. This exception is not available for any implantable device. The device package containing these individual devices is not excepted from the requirement of § 801.20, and must bear a UDI.

(4) A device used solely for research, teaching, or chemical analysis, and not intended for any clinical use.

(5) A custom device within the meaning of § 812.3(b) of this chapter.

(6) An investigational device within the meaning of part 812 of this chapter.

(7) A veterinary medical device not intended for use in the diagnosis of disease or other conditions in man, in the cure, mitigation, treatment, or prevention of disease in man, or intended to affect the structure or any function of the body of man.

(8) A device intended for export from the United States.

(9) A device held by the Strategic National Stockpile and granted an exception or alternative under § 801.128(f)(2).

(10) A device for which FDA has established a performance standard under section 514(b) of the Federal Food, Drug, and Cosmetic Act and has provided therein an exception from the requirement of § 801.20, or for which FDA has recognized all or part of a performance standard under section 514(c) of the Federal Food, Drug, and Cosmetic Act and has included an exception from the requirement of § 801.20 within the scope of that recognition.

(11) A device packaged within the immediate container of a combination product or convenience kit, provided that the label of the combination product or convenience kit bears a UDI.

(b) National Drug Code (NDC) Numbers. If a combination product properly bears an NDC number on its label—

(1) The combination product is not subject to the requirements of § 801.20.

(2) A device constituent of such a combination product whose components are physically, chemically, or otherwise combined or mixed and produced as a single entity as described by § 3.2(e)(1) of this chapter is not subject to the requirements of § 801.20.

(3) Each device constituent of such a combination product, other than one described by § 3.2(e)(1) of this chapter, must bear a UDI on its label unless paragraph (a)(11) of this section applies.

(c) Exception for shipping containers. This rule does not require a UDI to be placed on any shipping container.

(d) The UDI of a class I device is not required to include a production identifier.

[78 FR 58818, Sept. 24, 2013, as amended at 90 FR 55979, Dec. 4, 2025]

§ 801.35 Voluntary labeling of a device with a unique device identifier.

(a) The labeler of a device that is not required to bear a unique device identifier (UDI) may voluntarily comply with § 801.20. If a labeler voluntarily includes a UDI for a device, the labeler may voluntarily provide information concerning the device under subpart E of part 830 of this chapter.

(b) A device may bear both a Universal Product Code (UPC) and a UDI on its label and packages.

[78 FR 58818, Sept. 24, 2013]

§ 801.40 Form of a unique device identifier.

(a) Every unique device identifier (UDI) must meet the technical requirements of § 830.20 of this chapter. The UDI must be presented in two forms:

(1) Easily readable plain-text, and

(2) Automatic identification and data capture (AIDC) technology.

(b) The UDI must include a device identifier segment. Whenever a device label includes a lot or batch number, a serial number, a manufacturing date, an expiration date, or for a human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device, a distinct identification code as required by § 1271.290(c) of this chapter, the UDI must include a production identifier segment that conveys such information.

(c) If the AIDC technology is not evident upon visual examination of the label or device package, the label or device package must disclose the presence of AIDC technology.

(d) A class I device that bears a Universal Product Code (UPC) on its label and device packages is deemed to meet all requirements of subpart B of this part. The UPC will serve as the unique device identifier required by § 801.20.

[78 FR 58818, Sept. 24, 2013]

§ 801.45 Devices that must be directly marked with a unique device identifier.

(a) In general. A device that must bear a unique device identifier (UDI) on its label must also bear a permanent marking providing the UDI on the device itself if the device is intended to be used more than once and intended to be reprocessed before each use.

(b) UDI for direct marking. The UDI provided through a direct marking on a device may be:

(1) Identical to the UDI that appears on the label of the device, or

(2) A different UDI used to distinguish the unpackaged device from any device package containing the device.

(c) Form of a UDI when provided as a direct marking. When a device must bear a UDI as a direct marking, the UDI may be provided through either or both of the following:

(1) Easily readable plain-text;

(2) Automatic identification and data capture (AIDC) technology, or any alternative technology, that will provide the UDI of the device on demand.

(d) Exceptions. The requirement of paragraph (a) of this section shall not apply to any device that meets any of the following criteria:

(1) Any type of direct marking would interfere with the safety or effectiveness of the device;

(2) The device cannot be directly marked because it is not technologically feasible;

(3) The device is a single-use device and is subjected to additional processing and manufacturing for the purpose of an additional single use.

(4) The device has been previously marked under paragraph (a) of this section.

(e) Exception to be noted in design and development files. A labeler that decides to make use of an exception under paragraph (d) of this section must document the basis of that decision in the design and development files required by § 820.10(c) of this chapter.

[78 FR 58818, Sept. 24, 2013, as amended at 90 FR 55979, Dec. 4, 2025]

§ 801.50 Labeling requirements for stand-alone software.

(a) Stand-alone software that is not distributed in packaged form (e.g., when downloaded from a Web site) is deemed to meet the UDI labeling requirements of this subpart if it complies with the requirements of paragraph (b) of this section and conveys the version number in its production identifier.

(b) Regardless of whether it is or is not distributed in packaged form, stand-alone software regulated as a medical device must provide its unique device identifier through either or both of the following:

(1) An easily readable plain-text statement displayed whenever the software is started;

(2) An easily readable plain-text statement displayed through a menu command (e.g., an “About * * *” command).

(c) Stand-alone software that is distributed in both packaged form and in a form that is not packaged (e.g., when downloaded from a Web site) may be identified with the same device identifier.

[78 FR 58818, Sept. 24, 2013]

§ 801.55 Request for an exception from or alternative to a unique device identifier requirement.

(a) A labeler may submit a request for an exception from or alternative to the requirement of § 801.20 or any other requirement of this subpart for a specified device or a specified type of device. A written request for an exception or alternative must:

(1) Identify the device or devices that would be subject to the exception or alternative;

(2) Identify the provisions of this subpart that are the subject of the request for an exception or alternative;

(3) If requesting an exception, explain why you believe the requirements of this subpart are not technologically feasible;

(4) If requesting an alternative, describe the alternative and explain why it would provide for more accurate, precise, or rapid device identification than the requirements of this subpart or how the alternative would better ensure the safety or effectiveness of the device that would be subject to the alternative;

(5) Provide, if known, the number of labelers and the number of devices that would be affected if we grant the requested exception or alternative; and

(6) Provide other requested information that the Center Director needs to clarify the scope and effects of the requested exception or alternative.

(b) A written request for an exception or alternative must be submitted by sending it:

(1) If the device is regulated by the Center for Biologics Evaluation and Research (CBER), by email to: cberudirequests@fda.hhs.gov or by correspondence to: Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993.

(2) In all other cases, by email to: GUDIDSupport@fda.hhs.gov, or by correspondence to: UDI Regulatory Policy Support, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 3293, Silver Spring, MD 20993-0002.

(c) The Center Director may grant an exception or alternative, either in response to a request or on his or her own initiative, if the Center Director determines that an exception is appropriate because the requirements of this subpart are not technologically feasible, or that an alternative would provide for more accurate, precise, or rapid device identification than the requirements of this subpart or would better ensure the safety or effectiveness of the device that would be subject to the alternative. If we grant an exception or alternative, we may include any safeguards or conditions deemed appropriate to ensure the adequate identification of the device through its distribution and use. Any labeler may make use of an exception or alternative granted under this section, provided that such use satisfies all safeguards or conditions that are part of the exception or alternative.

(d) FDA may initiate and grant an exception or alternative if we determine that the exception or alternative is in the best interest of the public health. Any such exception or alternative will remain in effect only so long as there remains a public health need for the exception or alternative.

(e) The Center Director may rescind an exception or alternative granted under this section if, after providing an opportunity for an informal hearing as defined in section 201(x) of the Federal Food, Drug, and Cosmetic Act and under part 16 of this chapter, the Center Director determines that the exception or alternative no longer satisfies the criteria described in this paragraph (e) or that any safeguard or condition required under this paragraph (e) has not been met.

[78 FR 58818, Sept. 24, 2013, as amended at 80 FR 18093, Apr. 3, 2015; 81 FR 11428, Mar. 4, 2016; 85 FR 18441, Apr. 2, 2020]

§ 801.57 Discontinuation of legacy FDA identification numbers assigned to devices.

(a) On the date your device must bear a unique device identifier (UDI) on its label, any National Health-Related Item Code (NHRIC) or National Drug Code (NDC) number assigned to that device is rescinded, and you may no longer provide an NHRIC or NDC number on the label of your device or on any device package.

(b) If your device is not required to bear a UDI on its label, any NHRIC or NDC number assigned to that device is rescinded as of September 24, 2018, and beginning on that date, you may no longer provide an NHRIC or NDC number of the label of your device or on any device package.

(c) A labeler who has been assigned an FDA labeler code to facilitate use of NHRIC or NDC numbers may continue to use that labeler code under a system for the issuance of UDIs, provided that—

(1) Such use is consistent with the framework of the issuing agency that operates that system; and

(2) No later than September 24, 2014, the labeler submits, and obtains FDA approval of, a request for continued use of the assigned labeler code. A request for continued use of an assigned labeler code must be submitted by email to: GUDIDSupport@fda.hhs.gov, or by correspondence to: UDI Regulatory Policy Support, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 3293, Silver Spring, MD 20993-0002.

(d) Each request for continued use of an assigned labeler code must provide—

(1) The name, mailing address, email address, and phone number of the labeler who is currently using the labeler code;

(2) The owner/operator account identification used by the labeler to submit registration and listing information using FDA's Unified Registration and Listing System (FURLS).

(3) The FDA labeler code that the labeler wants to continue using.

[78 FR 58820, Sept. 24, 2013, as amended at 81 FR 11428, Mar. 4, 2016; 85 FR 18441, Apr. 2, 2020]

§ 801.60 Principal display panel.

The term principal display panel, as it applies to over-the-counter devices in package form and as used in this part, means the part of a label that is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accommodate all the mandatory label information required to be placed thereon by this part with clarity and conspicuousness and without obscuring designs, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents for all packages of substantially the same size, the term area of the principal display panel means the area of the side or surface that bears the principal display panel, which area shall be:

(a) In the case of a rectangular package where one entire side properly can be considered to be the principal display panel side, the product of the height times the width of that side;

(b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the container times the circumference; and

(c) In the case of any other shape of container, 40 percent of the total surface of the container: Provided, however, That where such container presents an obvious “principal display panel” such as the top of a triangular or circular package, the area shall consist of the entire top surface.

In determining the area of the principal display panel, exclude tops, bottoms, flanges at the tops and bottoms of cans, and shoulders and necks of bottles or jars. In the case of cylindrical or nearly cylindrical containers, information required by this part to appear on the principal display panel shall appear within that 40 percent of the circumference which is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale.

§ 801.61 Statement of identity.

(a) The principal display panel of an over-the-counter device in package form shall bear as one of its principal features a statement of the identity of the commodity.

(b) Such statement of identity shall be in terms of the common name of the device followed by an accurate statement of the principal intended action(s) of the device. Such statement shall be placed in direct conjunction with the most prominent display of the name and shall employ terms descriptive of the principal intended action(s). The indications for use shall be included in the directions for use of the device, as required by section 502(f)(1) of the act and by the regulations in this part.

(c) The statement of identity shall be presented in bold face type on the principal display panel, shall be in a size reasonably related to the most prominent printed matter on such panel, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.

§ 801.62 Declaration of net quantity of contents.

(a) The label of an over-the-counter device in package form shall bear a declaration of the net quantity of contents. This shall be expressed in the terms of weight, measure, numerical count, or a combination of numerical count and weight, measure, or size: Provided, That:

(1) In the case of a firmly established general consumer usage and trade custom of declaring the quantity of a device in terms of linear measure or measure of area, such respective term may be used. Such term shall be augmented when necessary for accuracy of information by a statement of the weight, measure, or size of the individual units or of the entire device.

(2) If the declaration of contents for a device by numerical count does not give accurate information as to the quantity of the device in the package, it shall be augmented by such statement of weight, measure, or size of the individual units or of the total weight, measure, or size of the device as will give such information; for example, “100 tongue depressors, adult size”, “1 rectal syringe, adult size”, etc. Whenever the Commissioner determines for a specific packaged device that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a combination of these does not facilitate value comparisions by consumers, he shall by regulation designate the appropriate term or terms to be used for such article.

(b) Statements of weight of the contents shall be expressed in terms of avoirdupois pound and ounce. A statement of liquid measure of the contents shall be expressed in terms of the U.S. gallon of 231 cubic inches and quart, pint, and fluid-ounce subdivisions thereof, and shall express the volume at 68 °F (20 °C). See also paragraph (p) of this section.

(c) The declaration may contain common or decimal fractions. A common fraction shall be in terms of halves, quarters, eighths, sixteenths, or thirty-seconds; except that if there exists a firmly established, general consumer usage and trade custom of employing different common fractions in the net quantity declaration of a particular commodity, they may be employed. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than two places. A statement that includes small fractions of an ounce shall be deemed to permit smaller variations than one which does not include such fractions.

(d) The declaration shall be located on the principal display panel of the label, and with respect to packages bearing alternate principal panels it shall be duplicated on each principal display panel.

(e) The declaration shall appear as a distinct item on the principal display panel, shall be separated, by at least a space equal to the height of the lettering used in the declaration, from other printed label information appearing above or below the declaration and, by at least a space equal to twice the width of the letter “N” of the style of type used in the quantity of contents statement, from other printed label information appearing to the left or right of the declaration. It shall not include any term qualifying a unit of weight, measure, or count, such as “giant pint” and “full quart”, that tends to exaggerate. It shall be placed on the principal display panel within the bottom 30 percent of the area of the label panel in lines generally parallel to the base on which the package rests as it is designed to be displayed: Provided, That:

(1) On packages having a principal display panel of 5 square inches or less the requirement for placement within the bottom 30 percent of the area of the label panel shall not apply when the declaration of net quantity of contents meets the other requirements of this part; and

(2) In the case of a device that is marketed with both outer and inner retail containers bearing the mandatory label information required by this part and the inner container is not intended to be sold separately, the net quantity of contents placement requirement of this section applicable to such inner container is waived.

(3) The principal display panel of a device marketed on a display card to which the immediate container is affixed may be considered to be the display panel of the card, and the type size of the net quantity of contents statement is governed by the dimensions of the display card.

(f) The declaration shall accurately reveal the quantity of device in the package exclusive of wrappers and other material packed therewith.

(g) The declaration shall appear in conspicuous and easily legible boldface print or type in distinct contrast (by typography, layout, color, embossing, or molding) to other matter on the package; except that a declaration of net quantity blown, embossed, or molded on a glass or plastic surface is permissible when all label information is so formed on the surface. Requirements of conspicuousness and legibility shall include the specifications that:

(1) The ratio of height to width of the letter shall not exceed a differential of 3 units to 1 unit, i.e., no more than 3 times as high as it is wide.

(2) Letter heights pertain to upper case or capital letters. When upper and lower case or all lower case letters are used, it is the lower case letter “o” or its equivalent that shall meet the minimum standards.

(3) When fractions are used, each component numeral shall meet one-half the minimum height standards.

(h) The declaration shall be in letters and numerals in a type size established in relationship to the area of the principal display panel of the package and shall be uniform for all packages of substantially the same size by complying with the following type specifications:

(1) Not less than one-sixteenth inch in height on packages the principal display panel of which has an area of 5 square inches or less.

(2) Not less than one-eighth inch in height on packages the principal display panel of which has an area of more than 5 but not more than 25 square inches.

(3) Not less than three-sixteenths inch in height on packages the principal display panel of which has an area of more than 25 but not more than 100 square inches.

(4) Not less than one-fourth inch in height on packages the principal display panel of which has an area of more than 100 square inches, except not less than one-half inch in height if the area is more than 400 square inches.

Where the declaration is blown, embossed, or molded on a glass or plastic surface rather than by printing, typing, or coloring, the lettering sizes specified in paragraphs (h)(1) through (4) of this section shall be increased by one-sixteenth of an inch.

(i) On packages containing less than 4 pounds or 1 gallon and labeled in terms of weight or fluid measure:

(1) The declaration shall be expressed both in ounces, with identification by weight or by liquid measure and, if applicable (1 pound or 1 pint or more) followed in parentheses by a declaration in pounds for weight units, with any remainder in terms of ounces or common or decimal fractions of the pound (see examples set forth in paragraphs (k) (1) and (2) of this section), or in the case of liquid measure, in the largest whole units (quarts, quarts and pints, or pints, as appropriate) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (see examples set forth in paragraphs (k) (3) and (4) of this section). If the net weight of the package is less than 1 ounce avoirdupois or the net fluid measure is less than 1 fluid ounce, the declaration shall be in terms of common or decimal fractions of the respective ounce and not in terms of drams.

(2) The declaration may appear in more than one line. The term “net weight” shall be used when stating the net quantity of contents in terms of weight. Use of the terms “net” or “net contents” in terms of fluid measure or numerical count is optional. It is sufficient to distinguish avoirdupois ounce from fluid ounce through association of terms; for example, “Net wt. 6 oz” or “6 oz net wt.,” and “6 fl oz” or “net contents 6 fl oz.”

(j) On packages containing 4 pounds or 1 gallon or more and labeled in terms of weight or fluid measure, the declaration shall be expressed in pounds for weight units with any remainder in terms of ounces or common or decimal fractions of the pound; in the case of fluid measure, it shall be expressed in the largest whole unit, i.e., gallons, followed by common or decimal fractions of a gallon or by the next smaller whole unit or units (quarts or quarts and pints), with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart; see paragraph (k)(5) of this section.

(k) Examples: (1) A declaration of 1 1/2 pounds weight shall be expressed as “net wt. 24 oz (1 lb 8 oz),” or “Net wt. 24 oz (1 1/2 lb)” or “Net wt. 24 oz (1.5 lb).”

(2) A declaration of three-fourths pound avoirdupois weight shall be expressed as “Net wt. 12 oz.”.

(3) A declaration of 1 quart liquid measure shall be expressed as “Net contents 32 fl oz (1 qt)” or “32 fl oz (1 qt).”

(4) A declaration of 1 3/4 quarts liquid measure shall be expressed as, “Net contents 56 fl oz (1 qt 1 pt 8 oz)” or “Net contents 56 fl oz (1 qt 1.5 pt),” but not in terms of quart and ounce such as “Net contents 56 fl oz (1 qt 24 oz).”

(5) A declaration of 2 1/2 gallons liquid measure shall be expressed as “Net contents 2 gal 2 qt”, “Net contents 2.5 gallons,” or “Net contents 2 1/2 gal” but not as “2 gal 4 pt”.

(l) For quantities, the following abbreviations and none other may be employed. Periods and plural forms are optional:

gallon gal | liter l

milliliter ml | cubic centimeter cc

quart qt | yard yd

pint pt | feet or foot ft

ounce oz | inch in

pound lb | meter m

grain gr | centimeter cm

kilogram kg | millimeter mm

gram g | fluid fl

milligram mg | square sq

microgram mcg | weight wt

(m) On packages labeled in terms of linear measure, the declaration shall be expressed both in terms of inches and, if applicable (1 foot or more), the largest whole units (yards, yards and feet, feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of inches and any remainder shall be in terms of inches or common or decimal fractions of the foot or yard; if applicable, as in the case of adhesive tape, the initial declaration in linear inches shall be preceded by a statement of the width. Examples of linear measure are “86 inches (2 yd 1 ft 2 in)”, “90 inches (2 1/2 yd)”, “30 inches (2.5 ft)”, “ 3/4 inch by 36 in (1 yd)”, etc.

(n) On packages labeled in terms of area measure, the declaration shall be expressed both in terms of square inches and, if applicable (1 square foot or more), the largest whole square unit (square yards, square yards and square feet, square feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of square inches and any remainder shall be in terms of square inches or common or decimal fractions of the square foot or square yard; for example, “158 sq inches (1 sq ft 14 sq in)”.

(o) Nothing in this section shall prohibit supplemental statements at locations other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents, provided that such supplemental statements of net quantity of contents shall not include any term qualifying a unit of weight, measure, or count that tends to exaggerate the amount of the device contained in the package; for example, “giant pint” and “full quart”. Dual or combination declarations of net quantity of contents as provided for in paragraphs (a) and (i) of this section are not regarded as supplemental net quantity statements and shall be located on the principal display panel.

(p) A separate statement of net quantity of contents in terms of the metric system of weight or measure is not regarded as a supplemental statement and an accurate statement of the net quantity of contents in terms of the metric system of weight or measure may also appear on the principal display panel or on other panels.

(q) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large.

§ 801.63 Medical devices; warning statements for devices containing or manufactured with chlorofluorocarbons and other class I ozone-depleting substances.

(a) All over-the-counter devices containing or manufactured with chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or any other class I substance designated by the Environmental Protection Agency (EPA) shall carry one of the following warnings:

(1) The EPA warning statement:

Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a substance which harms public health and environment by destroying ozone in the upper atmosphere.

(2) The alternative statement:

Note:

The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or other class I substance, if applicable]:

Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a substance which harms public health and environment by destroying ozone in the upper atmosphere.

CONSULT WITH YOUR PHYSICIAN, HEALTH PROFESSIONAL, OR SUPPLIER IF YOU HAVE ANY QUESTION ABOUT THE USE OF THIS PRODUCT.

(b) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase. This provision does not replace or relieve a person from any requirements imposed under 40 CFR part 82.

[61 FR 20101, May 3, 1996]

§ 801.109 Prescription devices.

A device which, because of any potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use is not safe except under the supervision of a practitioner licensed by law to direct the use of such device, and hence for which “adequate directions for use” cannot be prepared, shall be exempt from section 502(f)(1) of the act if all the following conditions are met:

(a) The device is:

(1)(i) In the possession of a person, or his agents or employees, regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of such device; or

(ii) In the possession of a practitioner, such as physicians, dentists, and veterinarians, licensed by law to use or order the use of such device; and

(2) Is to be sold only to or on the prescription or other order of such practitioner for use in the course of his professional practice.

(b) The label of the device, other than surgical instruments, bears:

(1) The symbol statement “Rx only” or “℞ only” or the statement “Caution: Federal law restricts this device to sale by or on the order of a ___”, the blank to be filled with the word “physician”, “dentist”, “veterinarian”, or with the descriptive designation of any other practitioner licensed by the law of the State in which the practitioner practices to use or order the use of the device; and

(2) The method of its application or use.

(c) Labeling on or within the package from which the device is to be dispensed bears information for use, including indications, effects, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the device can use the device safely and for the purpose for which it is intended, including all purposes for which it is advertised or represented: Provided, however, That such information may be omitted from the dispensing package if, but only if, the article is a device for which directions, hazards, warnings, and other information are commonly known to practitioners licensed by law to use the device. Upon written request, stating reasonable grounds therefor, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso.

(d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the device is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the device, that furnishes or purports to furnish information for use of the device contains adequate information for such use, including indications, effects, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to employ the device can use the device safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented. This information will not be required on so-called reminder—piece labeling which calls attention to the name of the device but does not include indications or other use information.

(e) All labeling, except labels and cartons, bearing information for use of the device also bears the date of the issuance or the date of the latest revision of such labeling.

[41 FR 6896, Feb. 13, 1976, as amended at 81 FR 38930, June 15, 2016]

§ 801.110 Retail exemption for prescription devices.

A device subject to § 801.109 shall be exempt at the time of delivery to the ultimate purchaser or user from section 502(f)(1) of the act if it is delivered by a licensed practitioner in the course of his professional practice or upon a prescription or other order lawfully issued in the course of his professional practice, with labeling bearing the name and address of such licensed practitioner and the directions for use and cautionary statements, if any, contained in such order.

§ 801.116 Medical devices having commonly known directions.

A device shall be exempt from section 502(f)(1) of the act insofar as adequate directions for common uses thereof are known to the ordinary individual.

§ 801.119 In vitro diagnostic products.

A product intended for use in the diagnosis of disease and which is an in vitro diagnostic product as defined in § 809.3(a) of this chapter shall be deemed to be in compliance with the requirements of this part and section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act if it meets the requirements of subpart B of this part and the requirements of § 809.10 of this chapter.

[78 FR 58820, Sept. 24, 2013]

§ 801.122 Medical devices for processing, repacking, or manufacturing.

A device intended for processing, repacking, or use in the manufacture of another drug or device shall be exempt from section 502(f)(1) of the act if its label bears the statement “Caution: For manufacturing, processing, or repacking”.

§ 801.125 Medical devices for use in teaching, law enforcement, research, and analysis.

A device subject to § 801.109 shall be exempt from section 502(f)(1) of this act if shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis, or physical testing, and is to be used only for such instruction, law enforcement, research, analysis, or testing.

§ 801.127 Medical devices; expiration of exemptions.

(a) If a shipment or delivery, or any part thereof, of a device which is exempt under the regulations in this section is made to a person in whose possession the article is not exempt, or is made for any purpose other than those specified, such exemption shall expire, with respect to such shipment or delivery or part thereof, at the beginning of that shipment or delivery. The causing of an exemption to expire shall be considered an act which results in such device being misbranded unless it is disposed of under circumstances in which it ceases to be a drug or device.

(b) The exemptions conferred by §§ 801.119, 801.122, and 801.125 shall continue until the devices are used for the purposes for which they are exempted, or until they are relabeled to comply with section 502(f)(1) of the act. If, however, the device is converted, or manufactured into a form limited to prescription dispensing, no exemption shall thereafter apply to the article unless the device is labeled as required by § 801.109.

§ 801.128 Exceptions or alternatives to labeling requirements for medical devices held by the Strategic National Stockpile.

(a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of a medical device, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such devices that are or will be included in the Strategic National Stockpile.

(b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores devices that are or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director.

(ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative.

(2) A written request for an exception or alternative described in paragraph (a) of this section must:

(i) Identify the specified lots, batches, or other units of the medical device that would be subject to the exception or alternative;

(ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request;

(iii) Explain why compliance with the labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of a medical device that are or will be held in the Strategic National Stockpile;

(iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the device includes appropriate information necessary for the safe and effective use of the device, given the anticipated circumstances of use of the device;

(v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the medical device subject to the exception or alternative; and

(vi) Provide any other information requested by the Center Director in support of the request.

(c) The Center Director must respond in writing to all requests under this section. The Center Director may impose appropriate conditions when granting such an exception or alternative under this section.

(d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director so that the labeling of devices subject to the exception or alternative includes the information necessary for the safe and effective use of the device, given the anticipated circumstances of use.

(e) If the Center Director grants a request for an exception or alternative to the labeling requirements under this section:

(1) The Center Director may determine that the submission and grant of a written request under this section satisfies the provisions relating to premarket notification submissions under § 807.81(a)(3) of this chapter.

(2)(i) For a Premarket Approval Application (PMA)-approved device, the submission and grant of a written request under this section satisfies the provisions relating to submission of PMA supplements under § 814.39 of this chapter; however,

(ii) The grant of the request must be identified in a periodic report under § 814.84 of this chapter.

(f) The Center Director may grant an exception or alternative under this section to the following provisions of this chapter, to the extent that the requirements in these provisions are not explicitly required by statute:

(1) § 801.1(d);

(2) Subpart B of this part and part 830 of this chapter in its entirety;

(3) § 801.60;

(4) § 801.61;

(5) § 801.62;

(6) § 801.63;

(7) § 801.109; and

(8) Part 801, subpart H.

[72 FR 73601, Dec. 28, 2007, as amended at 78 FR 58820, Sept. 24, 2013]

§ 801.150 Medical devices; processing, labeling, or repacking.

(a) Except as provided by paragraphs (b) and (c) of this section, a shipment or other delivery of a device which is, in accordance with the practice of the trade, to be processed, labeled, or repacked, in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling and packaging requirements of section 502(b) and (f) of the act if:

(1) The person who introduced such shipment or delivery into interstate commerce is the operator of the establishment where such device is to be processed, labeled, or repacked; or

(2) In case such person is not such operator, such shipment or delivery is made to such establishment under a written agreement, signed by and containing the post office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such device in such establishment as will insure, if such specifications are followed, that such device will not be adulterated or misbranded within the meaning of the act upon completion of such processing, labeling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such device from such establishment, and shall make such copies available for inspection at any reasonable hour to any officer or employee of the Department who requests them.

(b) An exemption of a shipment or other delivery of a device under paragraph (a)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment, become void ab initio if the device comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed.

(c) An exemption of a shipment or other delivery of a device under paragraph (a)(2) of this section shall become void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by such paragraph (a)(2).

(d) An exemption of a shipment or other delivery of a device under paragraph (a)(2) of this section shall expire:

(1) At the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment if the device comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or

(2) Upon refusal by the operator of the establishment where such device is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement, as required by such clause.

(e) As it is a common industry practice to manufacture and/or assemble, package, and fully label a device as sterile at one establishment and then ship such device in interstate commerce to another establishment or to a contract sterilizer for sterilization, the Food and Drug Administration will initiate no regulatory action against the device as misbranded or adulterated when the nonsterile device is labeled sterile, provided all the following conditions are met:

(1) There is in effect a written agreement which:

(i) Contains the names and post office addresses of the firms involved and is signed by the person authorizing such shipment and the operator or person in charge of the establishment receiving the devices for sterilization.

(ii) Provides instructions for maintaining proper records or otherwise accounting for the number of units in each shipment to insure that the number of units shipped is the same as the number received and sterilized.

(iii) Acknowledges that the device is nonsterile and is being shipped for further processing, and

(iv) States in detail the sterilization process, the gaseous mixture or other media, the equipment, and the testing method or quality controls to be used by the contract sterilizer to assure that the device will be brought into full compliance with the Federal Food, Drug, and Cosmetic Act.

(2) Each pallet, carton, or other designated unit is conspicuously marked to show its nonsterile nature when it is introduced into and is moving in interstate commerce, and while it is being held prior to sterilization. Following sterilization, and until such time as it is established that the device is sterile and can be released from quarantine, each pallet, carton, or other designated unit is conspicuously marked to show that it has not been released from quarantine, e.g., “sterilized—awaiting test results” or an equivalent designation.

§ 801.405 Labeling of articles intended for lay use in the repairing and/or refitting of dentures.

(a) The American Dental Association and leading dental authorities have advised the Food and Drug Administration of their concern regarding the safety of denture reliners, repair kits, pads, cushions, and other articles marketed and labeled for lay use in the repairing, refitting, or cushioning of ill-fitting, broken, or irritating dentures. It is the opinion of dental authorities and the Food and Drug Administration that to properly repair and properly refit dentures a person must have professional knowledge and specialized technical skill. Laymen cannot be expected to maintain the original vertical dimension of occlusion and the centric relation essential in the proper repairing or refitting of dentures. The continued wearing of improperly repaired or refitted dentures may cause acceleration of bone resorption, soft tissue hyperplasia, and other irreparable damage to the oral cavity. Such articles designed for lay use should be limited to emergency or temporary situations pending the services of a licensed dentist.

(b) The Food and Drug Administration therefore regards such articles as unsafe and misbranded under the Federal Food, Drug, and Cosmetic Act, unless the labeling:

(1)(i) Limits directions for use for denture repair kits to emergency repairing pending unavoidable delay in obtaining professional reconstruction of the denture;

(ii) Limits directions for use for denture reliners, pads, and cushions to temporary refitting pending unavoidable delay in obtaining professional reconstruction of the denture;

(2) Contains in a conspicuous manner the word “emergency” preceding and modifying each indication-for-use statement for denture repair kits and the word “temporary” preceding and modifying each indication-for-use statement for reliners, pads, and cushions; and

(3) Includes a conspicuous warning statement to the effect:

(i) For denture repair kits: “Warning—For emergency repairs only. Long term use of home-repaired dentures may cause faster bone loss, continuing irritation, sores, and tumors. This kit for emergency use only. See Dentist Without Delay.”

(ii) For denture reliners, pads, and cushions: “Warning—For temporary use only. Longterm use of this product may lead to faster bone loss, continuing irritation, sores, and tumors. For Use Only Until a Dentist Can Be Seen.”

(c) Adequate directions for use require full information of the temporary and emergency use recommended in order for the layman to understand the limitations of usefulness, the reasons therefor, and the importance of adhering to the warnings. Accordingly, the labeling should contain substantially the following information:

(1) For denture repair kits: Special training and tools are needed to repair dentures to fit properly. Home-repaired dentures may cause irritation to the gums and discomfort and tiredness while eating. Long term use may lead to more troubles, even permanent changes in bones, teeth, and gums, which may make it impossible to wear dentures in the future. For these reasons, dentures repaired with this kit should be used only in an emergency until a dentist can be seen. Dentures that don't fit properly cause irritation and injury to the gums and faster bone loss, which is permanent. Dentures that don't fit properly cause gum changes that may require surgery for correction. Continuing irritation and injury may lead to cancer in the mouth. You must see your dentist as soon as possible.

(2) For denture reliners, pads, and cushions: Use of these preparations or devices may temporarily decrease the discomfort; however, their use will not make the denture fit properly. Special training and tools are needed to repair a denture to fit properly. Dentures that do not fit properly cause irritation and injury to the gums and faster bone loss, which is permanent and may require a completely new denture. Changes in the gums caused by dentures that do not fit properly may require surgery for correction. Continuing irritation and injury may lead to cancer in the mouth. You must see your dentist as soon as possible.

(3) If the denture relining or repairing material forms a permanent bond with the denture, a warning statement to the following effect should be included: “This reliner becomes fixed to the denture and a completely new denture may be required because of its use.”

(d) Labeling claims exaggerating the usefulness or the safety of the material or failing to disclose all facts relevant to the claims of usefulness will be regarded as false and misleading under sections 201(n) and 502(a) of the Federal Food, Drug, and Cosmetic Act.

(e) Regulatory action may be initiated with respect to any article found within the jurisdiction of the act contrary to the provisions of this policy statement after 90 days following the date of publication of this section in the Federal Register.

§ 801.410 Use of impact-resistant lenses in eyeglasses and sunglasses.

(a) Examination of data available on the frequency of eye injuries resulting from the shattering of ordinary crown glass lenses indicates that the use of such lenses constitutes an avoidable hazard to the eye of the wearer.

(b) The consensus of the ophthalmic community is that the number of eye injuries would be substantially reduced by the use in eyeglasses and sunglasses of impact-resistant lenses.

(c)(1) To protect the public more adequately from potential eye injury, eyeglasses and sunglasses must be fitted with impact-resistant lenses, except in those cases where the physician or optometrist finds that such lenses will not fulfill the visual requirements of the particular patient, directs in writing the use of other lenses, and gives written notification thereof to the patient.

(2) The physician or optometrist shall have the option of ordering glass lenses, plastic lenses, or laminated glass lenses made impact resistant by any method; however, all such lenses shall be capable of withstanding the impact test described in paragraph (d)(2) of this section.

(3) Each finished impact-resistant glass lens for prescription use shall be individually tested for impact resistance and shall be capable of withstanding the impact test described in paragraph (d)(2) of this section. Raised multifocal lenses shall be impact resistant but need not be tested beyond initial design testing. Prism segment multifocal, slab-off prism, lenticular cataract, iseikonic, depressed segment one-piece multifocal, bioconcave, myodisc and minus lenticular, custom laminate and cemented assembly lenses shall be impact resistant but need not be subjected to impact testing. To demonstrate that all other types of impact-resistant lenses, including impact-resistant laminated glass lenses (i.e., lenses other than those described in the three preceding sentences of this paragraph (c)(3)), are capable of withstanding the impact test described in this regulation, the manufacturer of these lenses shall subject to an impact test a statistically significant sampling of lenses from each production batch, and the lenses so tested shall be representative of the finished forms as worn by the wearer, including finished forms that are of minimal lens thickness and have been subjected to any treatment used to impart impact resistance. All nonprescription lenses and plastic prescription lenses tested on the basis of statistical significance shall be tested in uncut-finished or finished form.

(d)(1) For the purpose of this regulation, the impact test described in paragraph (d)(2) of this section shall be the “referee test,” defined as “one which will be utilized to determine compliance with a regulation.” The referee test provides the Food and Drug Administration with the means of examining a medical device for performance and does not inhibit the manufacturer from using equal or superior test methods. A lens manufacturer shall conduct tests of lenses using the impact test described in paragraph (d)(2) of this section or any equal or superior test. Whatever test is used, the lenses shall be capable of withstanding the impact test described in paragraph (d)(2) of this section if the Food and Drug Administration examines them for performance.

(2) In the impact test, a 5/8-inch steel ball weighing approximately 0.56 ounce is dropped from a height of 50 inches upon the horizontal upper surface of the lens. The ball shall strike within a 5/8-inch diameter circle located at the geometric center of the lens. The ball may be guided but not restricted in its fall by being dropped through a tube extending to within approximately 4 inches of the lens. To pass the test, the lens must not fracture; for the purpose of this section, a lens will be considered to have fractured if it cracks through its entire thickness, including a laminar layer, if any, and across a complete diameter into two or more separate pieces, or if any lens material visible to the naked eyes becomes detached from the ocular surface. The test shall be conducted with the lens supported by a tube (1-inch inside diameter, 1 1/4-inch outside diameter, and approximately 1-inch high) affixed to a rigid iron or steel base plate. The total weight of the base plate and its rigidly attached fixtures shall be not less than 27 pounds. For lenses of small minimum diameter, a support tube having an outside diameter of less than 1 1/4 inches may be used. The support tube shall be made of rigid acrylic plastic, steel, or other suitable substance and shall have securely bonded on the top edge a 1/8- by 1/8-inch neoprene gasket having a hardness of 40 ±5, as determined by ASTM Method D 1415-88, “Standard Test Method for Rubber Property—International Hardness” a minimum tensile strength of 1,200 pounds, as determined by ASTM Method D 412-98A, “Standard Test Methods for Vulcanized Rubber and Thermoplastic Elastomers—Tension,” and a minimum ultimate elongation of 400 percent, as determined by ASTM Method D 412-68 (Both methods are incorporated by reference and are available from the American Society for Testing Materials, 100 Barr Harbor Dr., West Conshohocken, Philadelphia, PA 19428, or available for inspection at the Center for Devices and Radiological Health's Library, 9200 Corporate Blvd., Rockville, MD 20850, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. The diameter or contour of the lens support may be modified as necessary so that the 1/8- by 1/8-inch neoprene gasket supports the lens at its periphery.

(e) Copies of invoice(s), shipping document(s), and records of sale or distribution of all impact resistant lenses, including finished eyeglasses and sunglasses, shall be kept and maintained for a period of 3 years; however, the names and addresses of individuals purchasing nonprescription eyeglasses and sunglasses at the retail level need not be kept and maintained by the retailer. The records kept in compliance with this paragraph shall be made available upon request at all reasonable hours by any officer or employee of the Food and Drug Administration or by any other officer or employee acting on behalf of the Secretary of Health and Human Services and such officer or employee shall be permitted to inspect and copy such records, to make such inventories of stock as he deems necessary, and otherwise to check the correctness of such inventories.

(f) In addition, those persons conducting tests in accordance with paragraph (d) of this section shall maintain the results thereof and a description of the test method and of the test apparatus for a period of 3 years. These records shall be made available upon request at any reasonable hour by any officer or employee acting on behalf of the Secretary of Health and Human Services. The persons conducting tests shall permit the officer or employee to inspect and copy the records, to make such inventories of stock as the officer or employee deems necessary, and otherwise to check the correctness of the inventories.

(g) For the purpose of this section, the term “manufacturer” includes an importer for resale. Such importer may have the tests required by paragraph (d) of this section conducted in the country of origin but must make the results thereof available, upon request, to the Food and Drug Administration, as soon as practicable.

(h) All lenses must be impact-resistant except when the physician or optometrist finds that impact-resistant lenses will not fulfill the visual requirements for a particular patient.

(i) This statement of policy does not apply to contact lenses.

[41 FR 6896, Feb. 13, 1976, as amended at 44 FR 20678, Apr. 6, 1979; 47 FR 9397, Mar. 5, 1982; 65 FR 3586, Jan. 24, 2000; 65 FR 44436, July 18, 2000; 69 FR 18803, Apr. 9, 2004]

§ 801.415 Maximum acceptable level of ozone.

(a) Ozone is a toxic gas with no known useful medical application in specific, adjunctive, or preventive therapy. In order for ozone to be effective as a germicide, it must be present in a concentration far greater than that which can be safely tolerated by man and animals.

(b) Although undesirable physiological effects on the central nervous system, heart, and vision have been reported, the predominant physiological effect of ozone is primary irritation of the mucous membranes. Inhalation of ozone can cause sufficient irritation to the lungs to result in pulmonary edema. The onset of pulmonary edema is usually delayed for some hours after exposure; thus, symptomatic response is not a reliable warning of exposure to toxic concentrations of ozone. Since olfactory fatigue develops readily, the odor of ozone is not a reliable index of atmospheric ozone concentration.

(c) A number of devices currently on the market generate ozone by design or as a byproduct. Since exposure to ozone above a certain concentration can be injurious to health, any such device will be considered adulterated and/or misbranded within the meaning of sections 501 and 502 of the act if it is used or intended for use under the following conditions:

(1) In such a manner that it generates ozone at a level in excess of 0.05 part per million by volume of air circulating through the device or causes an accumulation of ozone in excess of 0.05 part per million by volume of air (when measured under standard conditions at 25 °C (77 °F) and 760 millimeters of mercury) in the atmosphere of enclosed space intended to be occupied by people for extended periods of time, e.g., houses, apartments, hospitals, and offices. This applies to any such device, whether portable or permanent or part of any system, which generates ozone by design or as an inadvertent or incidental product.

(2) To generate ozone and release it into the atmosphere in hospitals or other establishments occupied by the ill or infirm.

(3) To generate ozone and release it into the atmosphere and does not indicate in its labeling the maximum acceptable concentration of ozone which may be generated (not to exceed 0.05 part per million by volume of air circulating through the device) as established herein and the smallest area in which such device can be used so as not to produce an ozone accumulation in excess of 0.05 part per million.

(4) In any medical condition for which there is no proof of safety and effectiveness.

(5) To generate ozone at a level less than 0.05 part per million by volume of air circulating through the device and it is labeled for use as a germicide or deodorizer.

(d) This section does not affect the present threshold limit value of 0.10 part per million (0.2 milligram per cubic meter) of ozone exposure for an 8-hour-day exposure of industrial workers as recommended by the American Conference of Governmental Industrial Hygienists.

(e) The method and apparatus specified in 40 CFR part 50, or any other equally sensitive and accurate method, may be employed in measuring ozone pursuant to this section.

§ 801.417 Chlorofluorocarbon propellants.

The use of chlorofluorocarbon in devices as propellants in self-pressurized containers is generally prohibited except as provided in § 2.125 of this chapter.

[43 FR 11318, Mar. 17, 1978]

§ 801.422 Prescription hearing aid labeling.

(a) Scope. This section specifies the labeling requirements for prescription hearing aids. Any hearing aid that does not satisfy the requirements of § 800.30 of this chapter shall be a prescription device. Unless otherwise specified, the requirements in this section are in addition to other applicable requirements, including but not limited to special controls found in the applicable classification regulation in part 874 of this chapter. This section does not apply to group auditory trainers.

(b) Definitions for the purposes of this section. This section uses the following definitions:

Dispenser. A dispenser is any person, as defined in section 201(e) of the Federal Food, Drug, and Cosmetic Act, engaged in the sale of hearing aids to any member of the consuming public or any employee, agent, salesperson, and/or representative of such a person.

Hearing aid. A hearing aid is any wearable device designed for, offered for the purpose of, or represented as aiding persons with or compensating for, impaired hearing.

Prescription hearing aid. A prescription hearing aid is a hearing aid that is not an over-the-counter (OTC) hearing aid as defined in § 800.30 of this chapter or a hearing aid that does not satisfy the requirements in § 800.30 of this chapter.

Rebuilt hearing aid. A prescription hearing aid is “rebuilt” if the manufacturer has inspected and tested the device, made any necessary modifications to ensure it meets applicable regulatory requirements, including the requirements in this section, and adequately reprocessed the device for the next user.

Sale. Sale includes a lease, rental, or any other purchase or exchange for value.

Used hearing aid. A hearing aid is “used” if a user has worn it for any period of time. However, a hearing aid shall not be “used” merely because a prospective user wore it as part of a bona fide hearing aid evaluation to determine whether to select that particular hearing aid for that prospective user. A hearing aid evaluation is “bona fide” if it was conducted in the presence of the dispenser or a hearing health professional selected by the dispenser to assist the prospective user in making a determination.

(c) Labeling. A prescription hearing aid shall bear all of the following labeling:

(1) Outside package labeling. The outside package of a prescription hearing aid shall bear all of the following:

(i) Warnings and other important information. All of the following shall appear on the outside package:

(A) Warning against use in people younger than 18 without prior medical evaluation.

(B) “Red flag” conditions.

(C) Note about device trial options.

(ii) Statement of build condition. If the prescription hearing aid is used or rebuilt, the outside package shall declare that fact. A sticker under and visible through the outer wrapper will suffice to declare such fact.

(iii) Indication of battery information. The outside package shall indicate the type and number of batteries and whether batteries are included in the package.

(iv) Indication of control platform. That outside package shall indicate whether a mobile device or other non-included control platform is required. The indication must include the type of platform and how the platform connects to the device.

(2) Labeling, inside the package. The manufacturer or distributor of a prescription hearing aid shall include a user instructional brochure inside the package and shall make an electronic version available for download without site or customer registration and without requiring purchase of any product or service. The user instructional brochure shall include all of the following:

(i) The following warnings, which shall appear in the following order and prior to any content except the cover page:

(A) Warning against use in people younger than 18 without prior medical evaluation.

(B) “Red flag” conditions, addressed to dispensers.

(C) Warning to dispensers about very high-output devices.

(D) Additional warnings. Any additional warnings the manufacturer may include prior to the cautions and notices to users in paragraph (c)(2)(ii) of this section.

(ii) The following cautions and notices for users, which shall appear prior to any content, except the cover page and the warnings under paragraph (c)(2)(i) of this section:

(A) Caution about hearing protection.

(B) Caution about excessive sound output.

(C) Caution about components lodging in ear.

(D) Note about user expectations.

(E) Note about reporting adverse events to FDA.

(F) Note about hearing loss in people younger than 18 and fitting devices.

(iii) An illustration(s) of the prescription hearing aid that indicates operating controls, user adjustments, and the battery compartment.

(iv) Information on the function of all controls intended for user adjustment.

(v) A description of any accessory that accompanies the prescription hearing aid, including but not limited to wax guards, and accessories for use with a computer, television, or telephone.

(vi) Specific instructions for all of the following:

(A) Use of the prescription hearing aid with any accompanying accessories.

(B) Maintenance and care of the prescription hearing aid, including how a user can clean, disinfect, and replace parts or how to seek replacements, as well as how to store the hearing aid when it will not be used for an extended period of time.

(C) If the battery is replaceable or rechargeable, how to replace or recharge the battery, including a generic designation of replacement batteries.

(D) Expected battery life.

(vii) Identification of any known physiological side effects associated with the use of the prescription hearing aid that may warrant consultation with a physician, referring to an ear-nose-throat doctor when preferable, including if applicable, skin irritation and accelerated accumulation of cerumen (ear wax).

(viii) The technical specifications required by paragraph (c)(4) of this section unless such specifications appear in separate labeling accompanying the prescription hearing aid.

(ix) A description of commonly occurring, avoidable events that could adversely affect or damage the prescription hearing aid, including but not limited to, as applicable, ear wax buildup, drops, immersion in water, or exposure to excessive heat.

(x) If the hearing aid incorporates wireless technology in its programming or use, appropriate warnings, instructions, and information relating to electromagnetic compatibility and wireless technology and human exposure to non-ionizing radiation.

(xi) Information on how and where to obtain repair service or replacements, including at least one specific address where the user can go or send the prescription hearing aid to obtain such repair service or replacements.

(xii) If clinical or non-clinical studies were conducted by or for the manufacturer to support the performance of the prescription hearing aid, a summary of all such studies.

(3) Labeling on the device. The labeling on a prescription hearing aid itself shall bear all of the following clearly and permanently, except as provided in paragraph (c)(3)(iii) of this section:

(i) The serial number.

(ii) If the battery is removable, a “+” symbol to indicate the positive terminal for battery insertion unless the battery's physical design prevents inserting the battery in the reversed position.

(iii) If the prescription hearing aid is used or rebuilt, the manufacturer shall physically attach a removable tag to the hearing aid declaring that fact.

(4) Technical specifications. You must determine the technical specification values for the prescription hearing aid labeling in accordance with the test procedures of ANSI/ASA S3.22-2014 (R2020), except as provided in paragraph (c)(4)(ix) of this section for latency. Technical specifications and their associated values that are useful in selecting, fitting, and checking the performance of the prescription hearing aid shall appear in the user instructional brochure or in separate labeling that accompanies the device, including all of the following:

(i) Saturation output curve (Saturation Sound Pressure Level (SSPL) 90 curve).

(ii) Frequency response curve.

(iii) Average saturation output (High Frequency (HF)-Average SSPL 90).

(iv) Average full-on gain (HF-Average full-on gain).

(v) Reference test gain.

(vi) Frequency range.

(vii) Total harmonic distortion.

(viii) Equivalent input noise.

(ix) Latency, measured using a method that is accurate and repeatable to within 1.5 ms.

(x) Battery current drain.

(xi) Induction coil sensitivity (telephone coil aids only).

(xii) Input-output curve (only for hearing aids with automatic gain control).

(xiii) Attack and release times (only for hearing aids with automatic gain control).

(5) Software device labeling. Prescription hearing aid software that is not distributed with the hearing aid or amplification platform shall meet all of the following labeling requirements. With respect to the information required under paragraphs (c)(1) through (4) of this section, the information must be provided in the software device labeling, as specified in paragraphs (c)(5)(i) through (v) of this section, rather than the locations (e.g., outside package labeling) specified in paragraphs (c)(1) through (4).

(i) Prior to first use of the software or obtaining payment information for the software, whichever occurs first, the labeling must clearly and prominently present all of the following to the prospective user. For each, the labeling must remain visible until the user dismisses it or proceeds to the next step:

(A) Compatibility and minimum operating requirements for the software device.

(B) Disclosures of any fees or payments after first use or initial payment, including but not limited to any fees or payments relating to subscriptions, add-on features, or continued access to features or services. The disclosures must name and briefly describe what each fee or payment covers.

(C) The information required under paragraphs (c)(1)(i) and (iv) of this section.

(ii) Prior to first use of the software, the labeling must clearly and prominently present all of the following to the prospective user:

(A) The information required under paragraph (c)(2)(i)(A) of this section, and it must remain visible until the user acknowledges it.

(B) The information required under paragraphs (c)(2)(i)(B) through (D) and (c)(2)(ii), (iv), (vii), and (viii) of this section, and the information must remain visible until the user dismisses it or proceeds to the next step.

(C) All other information required under paragraph (c)(2) of this section, to the extent applicable, and the information must remain visible until the user dismisses it or proceeds to the next step.

(iii) The software device labeling must include the information required under paragraphs (c)(3)(i) and (c)(4) of this section.

(iv) All of the software device labeling must be accessible for review after acknowledgment, dismissal, or proceeding to the next step.

(v) If there are changes to any of the labeling required under paragraph (c)(5) of this section, the labeling with the changed information must be presented to the user until the user dismisses it.

(6) Misbranding. A prescription hearing aid that is not labeled as required under this section and § 801.109 is misbranded under sections 201(n), 502(a), and/or 502(f) of the Federal Food, Drug, and Cosmetic Act.

(d) Incorporation by reference. ANSI/ASA S3.22-2014 (R2020), “AMERICAN NATIONAL STANDARD Specification of Hearing Aid Characteristics,” dated June 5, 2020, is incorporated by reference into this section with the approval of the Director of the Office of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. This material is available for inspection at the Food and Drug Administration and at the National Archives and Records Administration (NARA). Contact the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500. For information on the availability of this material at NARA, email: fr.inspection@nara.gov, or go to: www.archives.gov/federal-register/cfr/ibr-locations.html. The material may be obtained from the Acoustical Society of America (ASA), 1305 Walt Whitman Road, Suite 300, Melville, NY 11747; phone: (631) 390-0215; fax: (631) 923-2875; email: asastds@acousticalsociety.org.

[87 FR 50755, Aug. 17, 2022]

§ 801.430 User labeling for menstrual tampons.

(a) This section applies to scented or scented deodorized menstrual tampons as identified in § 884.5460 and unscented menstrual tampons as identified in § 884.5470 of this chapter.

(b) Data show that toxic shock syndrome (TSS), a rare but serious and sometimes fatal disease, is associated with the use of menstrual tampons. To protect the public and to minimize the serious adverse effects of TSS, menstrual tampons shall be labeled as set forth in paragraphs (c), (d), and (e) of this section and tested for absorbency as set forth in paragraph (f) of this section.

(c) If the information specified in paragraph (d) of this section is to be included as a package insert, the following alert statement shall appear prominently and legibly on the package label:

Attention: Tampons are associated with Toxic Shock Syndrome (TSS). TSS is a rare but serious disease that may cause death. Read and save the enclosed information.

(d) The labeling of menstrual tampons shall contain the following consumer information prominently and legibly, in such terms as to render the information likely to be read and understood by the ordinary individual under customary conditions of purchase and use:

(1)(i) Warning signs of TSS, e.g., sudden fever (usually 102° or more) and vomiting, diarrhea, fainting or near fainting when standing up, dizziness, or a rash that looks like a sunburn;

(ii) What to do if these or other signs of TSS appear, including the need to remove the tampon at once and seek medical attention immediately;

(2) The risk of TSS to all women using tampons during their menstrual period, especially the reported higher risks to women under 30 years of age and teenage girls, the estimated incidence of TSS of 1 to 17 per 100,000 menstruating women and girls per year, and the risk of death from contracting TSS;

(3) The advisability of using tampons with the minimum absorbency needed to control menstrual flow in order to reduce the risk of contracting TSS;

(4) Avoiding the risk of getting tampon-associated TSS by not using tampons, and reducing the risk of getting TSS by alternating tampon use with sanitary napkin use during menstrual periods; and

(5) The need to seek medical attention before again using tampons if TSS warning signs have occurred in the past, or if women have any questions about TSS or tampon use.

(e) The statements required by paragraph (e) of this section shall be prominently and legibly placed on the package label of menstrual tampons in conformance with section 502(c) of the Federal Food, Drug, and Cosmetic Act (the act) (unless the menstrual tampons are exempt under paragraph (g) of this section).

(1) Menstrual tampon package labels shall bear one of the following absorbency terms representing the absorbency of the production run, lot, or batch as measured by the test described in paragraph (f)(2) of this section;

Ranges of absorbency in grams 1 | Corresponding term of absorbency

6 and under | Light absorbency

6 to 9 | Regular absorbency

9 to 12 | Super absorbency

12 to 15 | Super plus absorbency

15 to 18 | Ultra absorbency

Above 18 | No term

1These ranges are defined, respectively, as follows: Less than or equal to 6 grams (g); greater than 6 g up to and including 9 g; greater than 9 g up to and including 12 g; greater than 12 g up to and including 15 g; greater than 15 g up to and including 18 g; and greater than 18 g.

(2) The package label shall include an explanation of the ranges of absorbency and a description of how consumers can use a range of absorbency, and its corresponding absorbency term, to make comparisons of absorbency of tampons to allow selection of the tampons with the minimum absorbency needed to control menstrual flow in order to reduce the risk of contracting TSS.

(f) A manufacturer shall measure the absorbency of individual tampons using the test method specified in paragraph (f)(2) of this section and calculate the mean absorbency of a production run, lot, or batch by rounding to the nearest 0.1 gram.

(1) A manufacturer shall design and implement a sampling plan that includes collection of probability samples of adequate size to yield consistent tolerance intervals such that the probability is 90 percent that at least 90 percent of the absorbencies of individual tampons within a brand and type are within the range of absorbency stated on the package label.

(2) In the absorbency test, an unlubricated condom, with tensile strength between 17 Mega Pascals (MPa) and 30 MPa, as measured according to the procedure in the American Society for Testing and Materials (ASTM) D 3492-97, “Standard Specification for Rubber Contraceptives (Male Condoms)” 1 for determining tensile strength, which is incorporated by reference in accordance with 5 U.S.C. 552(a), is attached to the large end of a glass chamber (or a chamber made from hard transparent plastic) with a rubber band (see figure 1) and pushed through the small end of the chamber using a smooth, finished rod. The condom is pulled through until all slack is removed. The tip of the condom is cut off and the remaining end of the condom is stretched over the end of the tube and secured with a rubber band. A preweighed (to the nearest 0.01 gram) tampon is placed within the condom membrane so that the center of gravity of the tampon is at the center of the chamber. An infusion needle (14 gauge) is inserted through the septum created by the condom tip until it contacts the end of the tampon. The outer chamber is filled with water pumped from a temperature-controlled waterbath to maintain the average temperature at 27±1 °C. The water returns to the waterbath as shown in figure 2. Syngyna fluid (10 grams sodium chloride, 0.5 gram Certified Reagent Acid Fushsin, 1,000 milliliters distilled water) is then pumped through the infusion needle at a rate of 50 milliliters per hour. The test shall be terminated when the tampon is saturated and the first drop of fluid exits the apparatus. (The test result shall be discarded if fluid is detected in the folds of the condom before the tampon is saturated). The water is then drained and the tampon is removed and immediately weighed to the nearest 0.01 gram. The absorbency of the tampon is determined by subtracting its dry weight from this value. The condom shall be replaced after 10 tests or at the end of the day during which the condom is used in testing, whichever occurs first.

1The Director of the Federal Register approves this incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the American Society for Testing and Materials International, 100 Barr Harbor Dr., P.O. Box C700, West Conshohocken, PA 19428-2959, 610-832-9578, www.astm.org. You may inspect a copy at the FDA Main Library, 10903 New Hampshire Ave., Bldg. 2, 3d floor, Silver Spring, MD 20993-0002, 301-796-2039, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-2139, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

(3) The Food and Drug Administration may permit the use of an absorbency test method different from the test method specified in this section if each of the following conditions is met:

(i) The manufacturer presents evidence, in the form of a citizen petition submitted in accordance with the requirements of § 10.30 of this chapter, demonstrating that the alternative test method will yield results that are equivalent to the results yielded by the test method specified in this section; and

(ii) FDA approves the method and has published notice of its approval of the alternative test method in the Federal Register.

(g) Any menstrual tampon intended to be dispensed by a vending machine is exempt from the requirements of this section.

(h) Any menstrual tampon that is not labeled as required by paragraphs (c), (d), and (e) of this section and that is initially introduced or initially delivered for introduction into commerce after March 1, 1990, is misbranded under sections 201(n), 502 (a) and (f) of the act.

(Information collection requirements contained in paragraphs (e) and (f) were approved by the Office of Management and Budget under control number 0910-0257)

[47 FR 26989, June 22, 1982, as amended at 54 FR 43771, Oct. 26, 1989; 55 FR 17600, Apr. 26, 1990; 65 FR 3586, Jan. 24, 2000; 65 FR 44436, July 18, 2000; 65 FR 62284, Oct. 18, 2000; 69 FR 18803, Apr. 9, 2004; 69 FR 52171, Aug. 25, 2004; 75 FR 20914, Apr. 22, 2010]

§ 801.433 Warning statements for prescription and restricted device products containing or manufactured with chlorofluorocarbons or other ozone-depleting substances.

(a)(1) All prescription and restricted device products containing or manufactured with chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or any other class I substance designated by the Environmental Protection Agency (EPA) shall, except as provided in paragraph (b) of this section, bear the following warning statement:

Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a substance which harms public health and environment by destroying ozone in the upper atmosphere.

(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.

(b)(1) For prescription and restricted device products, the following alternative warning statement may be used:

Note:

The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:

This product contains [or is manufactured with, if applicable] [insert name of substance], a substance which harms the environment by destroying ozone in the upper atmosphere.

Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.

(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.

(3) If the warning statement in paragraph (b)(1) of this section is used, the following warning statement must be placed on the package labeling intended to be read by the physician (physician package insert) after the “How supplied” section, which describes special handling and storage conditions on the physician labeling:

Note:

The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:

Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a substance which harms public health and environment by destroying ozone in the upper atmosphere.

A notice similar to the above WARNING has been placed in the information for the patient [or patient information leaflet, if applicable] of this product under Environmental Protection Agency (EPA) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.

(c) This section does not replace or relieve a person from any requirements imposed under 40 CFR part 82.

[61 FR 20101, May 3, 1996]

§ 801.435 User labeling for latex condoms.

(a) This section applies to the subset of condoms as identified in § 884.5300 of this chapter, and condoms with spermicidal lubricant as identified in § 884.5310 of this chapter, which products are formed from latex films.

(b) Data show that the material integrity of latex condoms degrade over time. To protect the public health and minimize the risk of device failure, latex condoms must bear an expiration date which is supported by testing as described in paragraphs (d) and (h) of this section.

(c) The expiration date, as demonstrated by testing procedures required by paragraphs (d) and (h) of this section, must be displayed prominently and legibly on the primary packaging (i.e., individual package), and higher levels of packaging (e.g., boxes of condoms), in order to ensure visibility of the expiration date by consumers.

(d) Except as provided under paragraph (f) of this section, the expiration date must be supported by data demonstrating physical and mechanical integrity of the product after three discrete and representative lots of the product have been subjected to each of the following conditions:

(1) Storage of unpackaged bulk product for the maximum amount of time the manufacturer allows the product to remain unpackaged, followed by storage of the packaged product at 70 °C (plus or minus 2 °C) for 7 days;

(2) Storage of unpackaged bulk product for the maximum amount of time the manufacturer allows the product to remain unpackaged, followed by storage of the packaged product at a selected temperature between 40 and 50 °C (plus or minus 2 °C) for 90 days; and

(3) Storage of unpackaged bulk product for the maximum amount of time the manufacturer allows the product to remain unpackaged, followed by storage of the packaged product at a monitored or controlled temperature between 15 and 30 °C for the lifetime of the product (real time storage).

(e) If a product fails the physical and mechanical integrity tests commonly used by industry after the completion of the accelerated storage tests described in paragraphs (d)(1) and (d)(2) of this section, the product expiration date must be demonstrated by real time storage conditions described in paragraph (d)(3) of this section. If all of the products tested after storage at temperatures as described in paragraphs (d)(1) and (d)(2) of this section pass the manufacturer's physical and mechanical integrity tests, the manufacturer may label the product with an expiration date of up to 5 years from the date of product packaging. If the extrapolated expiration date under paragraphs (d)(1) and (d)(2) of this section is used, the labeled expiration date must be confirmed by physical and mechanical integrity tests performed at the end of the stated expiration period as described in paragraph (d)(3) of this section. If the data from tests following real time storage described in paragraph (d)(3) of this section fails to confirm the extrapolated expiration date, the manufacturer must, at that time, relabel the product to reflect the actual shelf life.

(f) Products that already have established shelf life data based upon real time storage and testing and have such storage and testing data available for inspection are not required to confirm such data using accelerated and intermediate aging data described in paragraphs (d)(1) and (d)(2) of this section. If, however, such real time expiration dates were based upon testing of products that were not first left unpackaged for the maximum amount of time as described in paragraph (d)(3) of this section, the real time testing must be confirmed by testing products consistent with the requirements of paragraph (d)(3) of this section. This testing shall be initiated no later than the effective date of this regulation. Until the confirmation testing in accordance with paragraph (d)(3) of this section is completed, the product may remain on the market labeled with the expiration date based upon previous real time testing.

(g) If a manufacturer uses testing data from one product to support expiration dating on any variation of that product, the manufacturer must document and provide, upon request, an appropriate justification for the application of the testing data to the variation of the tested product.

(h) If a latex condom contains a spermicide, and the expiration date based on spermicidal stability testing is different from the expiration date based upon latex integrity testing, the product shall bear only the earlier expiration date.

(i) The time period upon which the expiration date is based shall start with the date of packaging.

(j) As provided in part 820 of this chapter, all testing data must be retained in each company's files, and shall be made available upon request for inspection by the Food and Drug Administration.

(k) Any latex condom not labeled with an expiration date as required by paragraph (c) of this section, and initially delivered for introduction into interstate commerce after the effective date of this regulation is misbranded under sections 201(n) and 502(a) and (f) of Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(n) and 352(a) and (f)).

[62 FR 50501, Sept. 26, 1997]

§ 801.437 User labeling for devices that contain natural rubber.

(a) Data in the Medical Device Reporting System and the scientific literature indicate that some individuals are at risk of severe anaphylactic reactions to natural latex proteins. This labeling regulation is intended to minimize the risk to individuals sensitive to natural latex proteins and protect the public health.

(b) This section applies to all devices composed of or containing, or having packaging or components that are composed of, or contain, natural rubber that contacts humans. The term “natural rubber” includes natural rubber latex, dry natural rubber, and synthetic latex or synthetic rubber that contains natural rubber in its formulation.

(1) The term “natural rubber latex” means rubber that is produced by the natural rubber latex process that involves the use of natural latex in a concentrated colloidal suspension. Products are formed from natural rubber latex by dipping, extruding, or coating.

(2) The term “dry natural rubber” means rubber that is produced by the dry natural rubber process that involves the use of coagulated natural latex in the form of dried or milled sheets. Products are formed from dry natural rubber by compression molding, extrusion, or by converting the sheets into a solution for dipping.

(3) The term “contacts humans” means that the natural rubber contained in a device is intended to contact or is likely to contact the user or patient. This includes contact when the device that contains natural rubber is connected to the patient by a liquid path or an enclosed gas path; or the device containing the natural rubber is fully or partially coated with a powder, and such powder may carry natural rubber proteins that may contaminate the environment of the user or patient.

(c) Devices containing natural rubber shall be labeled as set forth in paragraphs (d) through (h) of this section. Each required labeling statement shall be prominently and legibly displayed in conformance with section 502(c) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(c)).

(d) Devices containing natural rubber latex that contacts humans, as described in paragraph (b) of this section, shall bear the following statement in bold print on the device labeling:

“Caution: This Product Contains Natural Rubber Latex Which May Cause Allergic Reactions.”

This statement shall appear on all device labels, and other labeling, and shall appear on the principal display panel of the device packaging, the outside package, container or wrapper, and the immediate device package, container, or wrapper.

(e) Devices containing dry natural rubber that contacts humans, as described in paragraph (b) of this section, that are not already subject to paragraph (d) of this section, shall bear the following statement in bold print on the device labeling:

“This Product Contains Dry Natural Rubber.”

This statement shall appear on all device labels, and other labeling, and shall appear on the principal display panel of the device packaging, the outside package, container or wrapper, and the immediate device package, container, or wrapper.

(f) Devices that have packaging containing natural rubber latex that contacts humans, as described in paragraph (b) of this section, shall bear the following statement in bold print on the device labeling:

“Caution: The Packaging of This Product Contains Natural Rubber Latex Which May Cause Allergic Reactions.”

This statement shall appear on the packaging that contains the natural rubber, and the outside package, container, or wrapper.

(g) Devices that have packaging containing dry natural rubber that contacts humans, as described in paragraph (b) of this section, shall bear the following statement in bold print on the device labeling:

“The Packaging of This Product Contains Dry Natural Rubber.”

This statement shall appear on the packaging that contains the natural rubber, and the outside package, container, or wrapper.

(h) Devices that contain natural rubber that contacts humans, as described in paragraph (b) of this section, shall not contain the term “hypoallergenic” on their labeling.

(i) Any affected person may request an exemption or variance from the requirements of this section by submitting a citizen petition in accordance with § 10.30 of this chapter.

(j) Any device subject to this section that is not labeled in accordance with paragraphs (d) through (h) of this section and that is initially introduced or initially delivered for introduction into interstate commerce after the effective date of this regulation is misbranded under sections 201(n) and 502(a), (c), and (f) of the act (21 U.S.C. 321(n) and 352(a), (c), and (f)).

Note to § 801.437:

Paragraphs (f) and (g) are stayed until June 27, 1999, as those regulations relate to device packaging that uses “cold seal” adhesives.

[62 FR 51029, Sept. 30, 1997, as amended at 63 FR 46175, Aug. 31, 1998]

§ 803.1 What does this part cover?

(a) This part establishes the requirements for medical device reporting for device user facilities, manufacturers, importers, and distributors. If you are a device user facility, you must report deaths and serious injuries that a device has or may have caused or contributed to, establish and maintain adverse event files, and submit summary annual reports. If you are a manufacturer or importer, you must report deaths and serious injuries that your device has or may have caused or contributed to, you must report certain device malfunctions, and you must establish and maintain adverse event files. If you are a manufacturer, you must also submit specified followup. These reports help us to protect the public health by helping to ensure that devices are not adulterated or misbranded and are safe and effective for their intended use. If you are a medical device distributor, you must maintain records (files) of incidents, but you are not required to report these incidents.

(b) This part supplements and does not supersede other provisions of this chapter, including the provisions of part 820 of this chapter.

(c) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

§ 803.3 How does FDA define the terms used in this part?

Some of the terms we use in this part are specific to medical device reporting and reflect the language used in the statute (law). Other terms are more general and reflect our interpretation of the law. This section defines the following terms as used in this part:

(a) Ambulatory surgical facility (ASF) means a distinct entity that operates for the primary purpose of furnishing same day outpatient surgical services to patients. An ASF may be either an independent entity (i.e., not a part of a provider of services or any other facility) or operated by another medical entity (e.g., under the common ownership, licensure, or control of an entity). An ASF is subject to this regulation regardless of whether it is licensed by a Federal, State, municipal, or local government or regardless of whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the ASF must report that event regardless of the nature or location of the medical service provided by the ASF.

(b) Become aware means that an employee of the entity required to report has acquired information that reasonably suggests a reportable adverse event has occurred.

(1) If you are a device user facility, you are considered to have “become aware” when medical personnel, as defined in this section, who are employed by or otherwise formally affiliated with your facility, obtain information about a reportable event.

(2) If you are a manufacturer, you are considered to have become aware of an event when any of your employees becomes aware of a reportable event that is required to be reported within 30 calendar days or that is required to be reported within 5 work days because we had requested reports in accordance with § 803.53(b). You are also considered to have become aware of an event when any of your employees with management or supervisory responsibilities over persons with regulatory, scientific, or technical responsibilities, or whose duties relate to the collection and reporting of adverse events, becomes aware, from any information, including any trend analysis, that a reportable MDR event or events necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health.

(3) If you are an importer, you are considered to have become aware of an event when any of your employees becomes aware of a reportable event that is required to be reported by you within 30 days.

(c) Caused or contributed means that a death or serious injury was or may have been attributed to a medical device, or that a medical device was or may have been a factor in a death or serious injury, including events occurring as a result of:

(1) Failure,

(2) Malfunction,

(3) Improper or inadequate design,

(4) Manufacture,

(5) Labeling, or

(6) User error.

(d) Device user facility means a hospital, ambulatory surgical facility, nursing home, outpatient diagnostic facility, or outpatient treatment facility as defined in this section, which is not a physician's office, as defined in this section. School nurse offices and employee health units are not device user facilities.

(e) Distributor means any person (other than the manufacturer or importer) who furthers the marketing of a device from the original place of manufacture to the person who makes final delivery or sale to the ultimate user, but who does not repackage or otherwise change the container, wrapper, or labeling of the device or device package. If you repackage or otherwise change the container, wrapper, or labeling, you are considered a manufacturer as defined in this section.

(f) Expected life of a device means the time that a device is expected to remain functional after it is placed into use. Certain implanted devices have specified “end of life” (EOL) dates. Other devices are not labeled as to their respective EOL, but are expected to remain operational through activities such as maintenance, repairs, or upgrades, for an estimated period of time.

(g) FDA, we, us, or Agency means the Food and Drug Administration.

(h) Five-day report means a medical device report that must be submitted by a manufacturer to us under § 803.53 within 5 work days.

(i) Hospital means a distinct entity that operates for the primary purpose of providing diagnostic, therapeutic (such as medical, occupational, speech, physical), surgical, and other patient services for specific and general medical conditions. Hospitals include general, chronic disease, rehabilitative, psychiatric, and other special-purpose facilities. A hospital may be either independent (e.g., not a part of a provider of services or any other facility) or may be operated by another medical entity (e.g., under the common ownership, licensure, or control of another entity). A hospital is covered by this regulation regardless of whether it is licensed by a Federal, State, municipal or local government or whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the hospital must report that event regardless of the nature or location of the medical service provided by the hospital.

(j) Importer means any person who imports a device into the United States and who furthers the marketing of a device from the original place of manufacture to the person who makes final delivery or sale to the ultimate user, but who does not repackage or otherwise change the container, wrapper, or labeling of the device or device package. If you repackage or otherwise change the container, wrapper, or labeling, you are considered a manufacturer as defined in this section.

(k) Malfunction means the failure of a device to meet its performance specifications or otherwise perform as intended. Performance specifications include all claims made in the labeling for the device. The intended performance of a device refers to the intended use for which the device is labeled or marketed, as defined in § 801.4 of this chapter.

(l) Manufacturer means any person who manufactures, prepares, propagates, compounds, assembles, or processes a device by chemical, physical, biological, or other procedure. The term includes any person who either:

(1) Repackages or otherwise changes the container, wrapper, or labeling of a device in furtherance of the distribution of the device from the original place of manufacture;

(2) Initiates specifications for devices that are manufactured by a second party for subsequent distribution by the person initiating the specifications;

(3) Manufactures components or accessories that are devices that are ready to be used and are intended to be commercially distributed and intended to be used as is, or are processed by a licensed practitioner or other qualified person to meet the needs of a particular patient; or

(4) Is the U.S. agent of a foreign manufacturer.

(m) Manufacturer or importer report number. This number uniquely identifies each individual adverse event report submitted by a manufacturer or importer. This number consists of the following three parts:

(1) The FDA registration number for the manufacturing site of the reported device, or the registration number for the importer. If the manufacturing site or the importer does not have an establishment registration number, we will assign a temporary MDR reporting number until the site is registered in accordance with part 807 of this chapter. We will inform the manufacturer or importer of the temporary MDR reporting number;

(2) The four-digit calendar year in which the report is submitted; and

(3) The five-digit sequence number of the reports submitted during the year, starting with 00001. (For example, the complete number will appear as follows: 1234567-2011-00001.)

(n) MDR means medical device report.

(o) MDR reportable event (or reportable event) means:

(1) An event that user facilities become aware of that reasonably suggests that a device has or may have caused or contributed to a death or serious injury or

(2) An event that manufacturers or importers become aware of that reasonably suggests that one of their marketed devices:

(i) May have caused or contributed to a death or serious injury, or

(ii) Has malfunctioned and that the device or a similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

(p) Medical personnel means an individual who:

(1) Is licensed, registered, or certified by a State, territory, or other governing body, to administer health care;

(2) Has received a diploma or a degree in a professional or scientific discipline;

(3) Is an employee responsible for receiving medical complaints or adverse event reports; or

(4) Is a supervisor of these persons.

(q) Nursing home means:

(1) An independent entity (i.e., not a part of a provider of services or any other facility) or one operated by another medical entity (e.g., under the common ownership, licensure, or control of an entity) that operates for the primary purpose of providing:

(i) Skilled nursing care and related services for persons who require medical or nursing care;

(ii) Hospice care to the terminally ill; or

(iii) Services for the rehabilitation of the injured, disabled, or sick.

(2) A nursing home is subject to this regulation regardless of whether it is licensed by a Federal, State, municipal, or local government or whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the nursing home must report that event regardless of the nature or location of the medical service provided by the nursing home.

(r) Outpatient diagnostic facility means:

(1) A distinct entity that:

(i) Operates for the primary purpose of conducting medical diagnostic tests on patients,

(ii) Does not assume ongoing responsibility for patient care, and

(iii) Provides its services for use by other medical personnel.

(2) Outpatient diagnostic facilities include outpatient facilities providing radiography, mammography, ultrasonography, electrocardiography, magnetic resonance imaging, computerized axial tomography, and in vitro testing. An outpatient diagnostic facility may be either independent (i.e., not a part of a provider of services or any other facility) or operated by another medical entity (e.g., under the common ownership, licensure, or control of an entity). An outpatient diagnostic facility is covered by this regulation regardless of whether it is licensed by a Federal, State, municipal, or local government or whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the outpatient diagnostic facility must report that event regardless of the nature or location of the medical service provided by the outpatient diagnostic facility.

(s) Outpatient treatment facility means a distinct entity that operates for the primary purpose of providing nonsurgical therapeutic (medical, occupational, or physical) care on an outpatient basis or in a home health care setting. Outpatient treatment facilities include ambulance providers, rescue services, and home health care groups. Examples of services provided by outpatient treatment facilities include the following: Cardiac defibrillation, chemotherapy, radiotherapy, pain control, dialysis, speech or physical therapy, and treatment for substance abuse. An outpatient treatment facility may be either independent (i.e., not a part of a provider of services or any other facility) or operated by another medical entity (e.g., under the common ownership, licensure, or control of an entity). An outpatient treatment facility is covered by this regulation regardless of whether it is licensed by a Federal, State, municipal, or local government or whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the outpatient treatment facility must report that event regardless of the nature or location of the medical service provided by the outpatient treatment facility.

(t) Patient of the facility means any individual who is being diagnosed or treated and/or receiving medical care at or under the control or authority of the facility. This includes employees of the facility or individuals affiliated with the facility who, in the course of their duties, suffer a device-related death or serious injury that has or may have been caused or contributed to by a device used at the facility.

(u) Physician's office means a facility that operates as the office of a physician or other health care professional for the primary purpose of examination, evaluation, and treatment or referral of patients. Examples of physician offices include: Dentist offices, chiropractor offices, optometrist offices, nurse practitioner offices, school nurse offices, school clinics, employee health clinics, or freestanding care units. A physician's office may be independent, a group practice, or part of a Health Maintenance Organization.

(v) Remedial action means any action other than routine maintenance or servicing of a device where such action is necessary to prevent recurrence of a reportable event.

(w) Serious injury means an injury or illness that:

(1) Is life-threatening,

(2) Results in permanent impairment of a body function or permanent damage to a body structure, or

(3) Necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure. Permanent means irreversible impairment or damage to a body structure or function, excluding trivial impairment or damage.

(x) User facility report number means the number that uniquely identifies each report submitted by a user facility to manufacturers and to us. This number consists of the following three parts:

(1) The user facility's 10-digit Centers for Medicare and Medicaid Services (CMS) number (if the CMS number has fewer than 10 digits, fill the remaining spaces with zeros);

(2) The four-digit calendar year in which the report is submitted; and

(3) The four-digit sequence number of the reports submitted for the year, starting with 0001. (For example, a complete user facility report number will appear as follows: 1234560000-2011-0001. If a user facility has more than one CMS number, it must select one that will be used for all of its MDR reports. If a user facility has no CMS number, it should use all zeros in the appropriate space in its initial report (e.g., 0000000000-2011-0001). We will assign a number for future use and send that number to the user facility. This number is used in our record of the initial report, in subsequent reports, and in any correspondence with the user facility. If a facility has multiple sites, the primary site may submit reports for all sites and use one reporting number for all sites if the primary site provides the name, address, and CMS number for each respective site.)

(y) Work day means Monday through Friday, except Federal holidays.

(z) [Reserved]

(aa) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(bb) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015]

§ 803.9 What information from the reports do we disclose to the public?

(a) We may disclose to the public any report, including any FDA record of a telephone report, submitted under this part. Our disclosures are governed by part 20 of this chapter.

(b) Before we disclose a report to the public, we will delete the following:

(1) Any information that constitutes trade secret or confidential commercial or financial information under § 20.61 of this chapter;

(2) Any personal, medical, and similar information, including the serial number of implanted devices, which would constitute an invasion of personal privacy under § 20.63 of this chapter. However, if a patient requests a report, we will disclose to that patient all the information in the report concerning that patient, as provided in § 20.61 of this chapter; and

(3) Any names and other identifying information of a third party that voluntarily submitted an adverse event report.

(c) We may not disclose the identity of a device user facility that makes a report under this part except in connection with:

(1) An action brought to enforce section 301(q) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331(q)), including the failure or refusal to furnish material or information required by section 519 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360i));

(2) A communication to a manufacturer of a device that is the subject of a report required to be submitted by a user facility under § 803.30; or

(3) A disclosure to employees of the Department of Health and Human Services, to the Department of Justice, or to the duly authorized committees and subcommittees of the Congress.

§ 803.10 Generally, what are the reporting requirements that apply to me?

(a) If you are a device user facility, you must submit reports (described in subpart C of this part), as follows:

(1) Submit reports of individual adverse events no later than 10 work days after the day that you become aware of a reportable event:

(i) Submit reports of device-related deaths to us and to the manufacturer, if known, or

(ii) Submit reports of device-related serious injuries to the manufacturers or, if the manufacturer is unknown, submit reports to us.

(2) Submit annual reports (described in § 803.33) to us.

(b) If you are an importer, you must submit reports (described in subpart D of this part), as follows:

(1) Submit reports of individual adverse events no later than 30 calendar days after the day that you become aware of a reportable event:

(i) Submit reports of device-related deaths or serious injuries to us and to the manufacturer or

(ii) Submit reports of device-related malfunctions to the manufacturer.

(2) [Reserved]

(c) If you are a manufacturer, you must submit reports (described in subpart E of this part) to us, as follows:

(1) Submit reports of individual adverse events no later than 30 calendar days after the day that you become aware of a reportable death, serious injury, or malfunction.

(2) Submit reports of individual adverse events no later than 5 work days after the day that you become aware of:

(i) A reportable event that requires remedial action to prevent an unreasonable risk of substantial harm to the public health or

(ii) A reportable event for which we made a written request.

(3) Submit supplemental reports if you obtain information that you did not submit in an initial report.

§ 803.11 What form should I use to submit reports of individual adverse events and where do I obtain these forms?

(a) If you are a manufacturer or importer, you must submit reports of individual adverse events to FDA in an electronic format in accordance with § 803.12(a) and § 803.20, unless granted an exemption under § 803.19.

(b) Importer reports submitted to device manufacturers may be in paper format or an electronic format that includes all required data fields to ensure that the manufacturer has all required information.

(c) If you are a user facility, you must submit reports of individual adverse events in accordance with § 803.12(b) and § 803.20.

(d) Form FDA 3500A is available on the internet at https://www.accessdata.fda.gov/scripts/medwatch/index.cfm.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015; 85 FR 18441, Apr. 2, 2020]

§ 803.12 How do I submit initial and supplemental or followup reports?

(a) Manufacturers and importers must submit initial and supplemental or followup reports to FDA in an electronic format that FDA can process, review, and archive.

(b) User facilities that submit their reports and additional information to FDA electronically must use an electronic format that FDA can process, review, and archive. User facilities that submit their reports to FDA on paper must submit any written report or additional information required under this part to FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville, MD 20847-3002, using Form FDA 3500A. Each report must be identified (e.g., “User Facility Report” or “Annual Report”).

(c) If you are confronted with a public health emergency, this can be brought to FDA's attention by contacting FDA's Office of Crisis Management, Emergency Operations Center by telephone, 24-hours a day, at 301-796-8240 or toll free at 866-300-4374, followed by the submission of an email to: emergency.operations@fda.hhs.gov.

Note:

This action does not satisfy your obligation to report under part 803.

(d) You may submit a voluntary telephone report to the MedWatch office at 800-FDA-1088. You may also obtain information regarding voluntary reporting from the MedWatch office at 800-FDA-1088. You may also find the voluntary Form FDA 3500 and instructions to complete it at: http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.

§ 803.13 Do I need to submit reports in English?

Yes. You must submit all reports required by this part in English.

§ 803.15 How will I know if you require more information about my medical device report?

(a) We will notify you in writing if we require additional information and will tell you what information we need. We will require additional information if we determine that protection of the public health requires additional or clarifying information for medical device reports submitted to us and in cases when the additional information is beyond the scope of FDA reporting forms or is not readily accessible to us.

(b) In any request under this section, we will state the reason or purpose for the information request, specify the due date for submitting the information, and clearly identify the reported event(s) related to our request. If we verbally request additional information, we will confirm the request in writing.

§ 803.16 When I submit a report, does the information in my report constitute an admission that the device caused or contributed to the reportable event?

No. A report or other information submitted by you, and our release of that report or information, is not necessarily an admission that the device, or you or your employees, caused or contributed to the reportable event. You do not have to admit and may deny that the report or information submitted under this part constitutes an admission that the device, you, or your employees, caused or contributed to a reportable event.

§ 803.17 What are the requirements for developing, maintaining, and implementing written MDR procedures that apply to me?

If you are a user facility, importer, or manufacturer, you must develop, maintain, and implement written MDR procedures for the following:

(a) Internal systems that provide for:

(1) Timely and effective identification, communication, and evaluation of events that may be subject to MDR requirements;

(2) A standardized review process or procedure for determining when an event meets the criteria for reporting under this part; and

(3) Timely transmission of complete medical device reports to manufacturers or to us, or to both if required.

(b) Documentation and recordkeeping requirements for:

(1) Information that was evaluated to determine if an event was reportable;

(2) All medical device reports and information submitted to manufacturers and/or us;

(3) Any information that was evaluated for the purpose of preparing the submission of annual reports; and

(4) Systems that ensure access to information that facilitates timely followup and inspection by us.

§ 803.18 What are the requirements for establishing and maintaining MDR files or records that apply to me?

(a) If you are a user facility, importer, or manufacturer, you must establish and maintain MDR event files. You must clearly identify all MDR event files and maintain them to facilitate timely access.

(b)(1) For purposes of this part, “MDR event files” are written or electronic files maintained by user facilities, importers, and manufacturers. MDR event files may incorporate references to other information (e.g., medical records, patient files, engineering reports), in lieu of copying and maintaining duplicates in this file. Your MDR event files must contain:

(i) Information in your possession or references to information related to the adverse event, including all documentation of your deliberations and decision making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable under this part;

(ii) Copies of all reports submitted under this part (whether paper or electronic), and of all other information related to the event that you submitted to us or other entities such as an importer, distributor, or manufacturer; and

(iii) Copies of all electronic acknowledgments FDA sends you in response to electronic MDR submissions.

(2) If you are a user facility, importer, or manufacturer, you must permit any authorized FDA employee, at all reasonable times, to access, to copy, and to verify the records required by this part.

(c) If you are a user facility, you must retain an MDR event file relating to an adverse event for a period of 2 years from the date of the event. If you are a manufacturer or importer, you must retain an MDR event file relating to an adverse event for a period of 2 years from the date of the event or a period of time equivalent to the expected life of the device, whichever is greater. If the device is no longer distributed, you still must maintain MDR event files for the time periods described in this paragraph (c).

(d)(1) If you are a device distributor, you must establish and maintain device complaint records (files). Your records must contain any incident information, including any written, electronic, or oral communication, either received or generated by you, that alleges deficiencies related to the identity (e.g., labeling), quality, durability, reliability, safety, effectiveness, or performance of a device. You must also maintain information about your evaluation of the allegations, if any, in the incident record. You must clearly identify the records as device incident records and file these records by device name. You may maintain these records in written or electronic format. You must back up any file maintained in electronic format.

(2) You must retain copies of the required device incident records for a period of 2 years from the date of inclusion of the record in the file or for a period of time equivalent to the expected life of the device, whichever is greater. You must maintain copies of these records for this period even if you no longer distribute the device.

(3) You must maintain the device complaint files established under this section at your principal business establishment. If you are also a manufacturer, you may maintain the file at the same location as you maintain your complaint file under part 820 of this chapter. You must permit any authorized FDA employee, at all reasonable times, to access, to copy, and to verify the records required by this part.

(e) If you are a manufacturer, you may maintain MDR event files as part of your complaint file, under part 820 of this chapter, if you prominently identify these records as MDR reportable events. We will not consider your submitted MDR report to comply with this part unless you evaluate an event in accordance with the quality management system requirements described in part 820 of this chapter. You must document and maintain in your MDR event files an explanation of why you did not submit or could not obtain any information required by this part, as well as the results of your evaluation of each event.

[79 FR 8846, Feb. 14, 2014, as amended at 90 FR 55979, Dec. 4, 2025]

§ 803.19 Are there exemptions, variances, or alternative forms of adverse event reporting requirements?

(a) We exempt the following persons from the adverse event reporting requirements in this part:

(1) A licensed practitioner who prescribes or administers devices intended for use in humans and manufactures or imports devices solely for use in diagnosing and treating persons with whom the practitioner has a “physician-patient” relationship;

(2) An individual who manufactures devices intended for use in humans solely for this person's use in research or teaching and not for sale. This includes any person who is subject to alternative reporting requirements under the investigational device exemption regulations (described in part 812 of this chapter), which require reporting of all adverse device effects; and

(3) Dental laboratories or optical laboratories.

(b) If you are a manufacturer, importer, or user facility, you may request an exemption or variance from any or all of the reporting requirements in this part, including the requirements of § 803.12. You must submit the request to the Center for Devices and Radiological Health (CDRH) in writing at MDRPolicy@fda.hhs.gov. Your request must include information necessary to identify you and the device; a complete statement of the request for exemption, variance, or alternative reporting; and an explanation why your request is justified. If you are requesting an exemption from the requirement to submit reports to FDA in electronic format under § 803.12(a), your request should indicate for how long you will require this exemption.

(c) If you are a manufacturer, importer, or user facility, we may grant in writing an exemption or variance from, or alternative to, any or all of the reporting requirements in this part, and may change the frequency of reporting to quarterly, semiannually, annually or other appropriate time period. We may grant these modifications in response to your request, as described in paragraph (b) of this section, or at our discretion. When we grant modifications to the reporting requirements, we may impose other reporting requirements to ensure the protection of public health.

(d) We may revoke or modify in writing an exemption, variance, or alternative reporting requirement if we determine that revocation or modification is necessary to protect the public health.

(e) If we grant your request for a reporting modification, you must submit any reports or information required in our approval of the modification. The conditions of the approval will replace and supersede the regular reporting requirement specified in this part until such time that we revoke or modify the alternative reporting requirements in accordance with paragraph (d) of this section or until the date specified in our response granting your variance, at which time the provisions of this part will again apply.

[79 FR 8846, Feb. 14, 2014, as amended at 85 FR 18441, Apr. 2, 2020; 88 FR 16879, Mar. 21, 2023]

§ 803.20 How do I complete and submit an individual adverse event report?

(a) What form must I complete and submit?

(1) If you are a health professional or consumer or other entity, you may submit voluntary reports to FDA regarding devices or other FDA-regulated products using the Form FDA 3500.

(2) To submit a mandatory report in written form, a user facility must use Form FDA 3500A.

(3) An electronic submission of a mandatory report from a user facility, importer, or manufacturer must contain the information from the applicable blocks of Form FDA 3500A. All electronic submissions must include information about the patient, the event, the device, and the “initial reporter.” An electronic submission from a user facility or importer must include the information from block F. An electronic submission from a manufacturer must include the information from blocks G and H. If you are a manufacturer and you receive a report from a user facility or importer, you must incorporate that information in your electronic submission and include any corrected or missing information.

(b) To whom must I submit reports and when?

(1) If you are a user facility, you must submit MDR reports to:

(i) The manufacturer and to us no later than 10 work days after the day that you become aware of information that reasonably suggests that a device has or may have caused or contributed to a death or

(ii) The manufacturer no later than 10 work days after the day that you become aware of information that reasonably suggests that a device has or may have caused or contributed to a serious injury. If the manufacturer is not known, you must submit this report to us.

(2) If you are an importer, you must submit MDR reports to:

(i) The manufacturer and to us, no later than 30 calendar days after the day that you become aware of information that reasonably suggests that a device has or may have caused or contributed to a death or serious injury or

(ii) The manufacturer, no later than 30 calendar days after receiving information that a device you market has malfunctioned and that this device or a similar device that you market would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

(3) If you are a manufacturer, you must submit MDR reports to us:

(i) No later than 30 calendar days after the day that you become aware of information that reasonably suggests that a device may have caused or contributed to a death or serious injury or

(ii) No later than 30 calendar days after the day that you become aware of information that reasonably suggests a device has malfunctioned and that this device or a similar device that you market would be likely to cause or contribute to a death or serious injury if the malfunction were to recur; or

(iii) Within 5 work days if required by § 803.53.

(c) What kind of information reasonably suggests that a reportable event has occurred?

(1) Any information, including professional, scientific, or medical facts, observations, or opinions, may reasonably suggest that a device has caused or may have caused or contributed to an MDR reportable event. An MDR reportable event is a death, a serious injury, or, if you are a manufacturer or importer, a malfunction that would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

(2) If you are a user facility, importer, or manufacturer, you do not have to report an adverse event if you have information that would lead a person who is qualified to make a medical judgment reasonably to conclude that a device did not cause or contribute to a death or serious injury, or that a malfunction would not be likely to cause or contribute to a death or serious injury if it were to recur. Persons qualified to make a medical judgment include physicians, nurses, risk managers, and biomedical engineers. You must keep in your MDR event files (described in § 803.18) the information that the qualified person used to determine whether or not a device-related event was reportable.

§ 803.21 Where can I find the reporting codes for adverse events that I use with medical device reports?

(a) The MedWatch Medical Device Reporting Code Instruction Manual contains adverse event codes for use with Form FDA 3500A. You may obtain the coding manual from FDA's website at: https://www.fda.gov/medical-devices/mandatory-reporting-requirements-manufacturers-importers-and-device-user-facilities/mdr-adverse-event-codes.

(b) We may sometimes use additional coding of information on the reporting forms or modify the existing codes. If we do make modifications, we will ensure that we make the new coding information available to all reporters.

[79 FR 8846, Feb. 14, 2014, as amended at 85 FR 18441, Apr. 2, 2020]

§ 803.22 What are the circumstances in which I am not required to file a report?

(a) If you become aware of information from multiple sources regarding the same patient and same reportable event, you may submit one medical device report.

(b) You are not required to submit a medical device report if:

(1) You are a user facility, importer, or manufacturer, and you determine that the information received is erroneous in that a device-related adverse event did not occur. You must retain documentation of these reports in your MDR files for the time periods specified in § 803.18.

(2) You are a manufacturer or importer and you did not manufacture or import the device about which you have adverse event information. When you receive reportable event information in error, you must forward this information to us with a cover letter explaining that you did not manufacture or import the device in question.

§ 803.23 Where can I find information on how to prepare and submit an MDR in electronic format?

(a) You may obtain information on how to prepare and submit reports in an electronic format that FDA can process, review, and archive at: http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm107903.htm.

(b) We may sometimes update information on how to prepare and submit reports electronically. If we do make modifications, we will ensure that we alert reporters by updating the eMDR Web page.

§ 803.30 If I am a user facility, what reporting requirements apply to me?

(a) You must submit reports to the manufacturer or to us, or both, as specified in paragraphs (a)(1) and (a)(2) of this section as follows:

(1) Reports of death. You must submit a report to us as soon as practicable but no more than 10 work days after the day that you become aware of information, from any source, that reasonably suggests that a device has or may have caused or contributed to the death of a patient of your facility. You must also submit the report to the device manufacturer, if known. You must submit the information required by § 803.32. Reports sent to the Agency must be submitted in accordance with the requirements of § 803.12(b).

(2) Reports of serious injury. You must submit a report to the manufacturer of the device no later than 10 work days after the day that you become aware of information, from any source, that reasonably suggests that a device has or may have caused or contributed to a serious injury to a patient of your facility. If the manufacturer is not known, you must submit the report to us. You must report information required by § 803.32. Reports sent to the Agency must be submitted in accordance with the requirements of § 803.12 (b).

(b) What information does FDA consider “reasonably known” to me? You must submit all information required in this subpart C that is reasonably known to you. This information includes information found in documents that you possess and any information that becomes available as a result of reasonable followup within your facility. You are not required to evaluate or investigate the event by obtaining or evaluating information that you do not reasonably know.

§ 803.32 If I am a user facility, what information must I submit in my individual adverse event reports?

You must include the following information in your report, if reasonably known to you, as described in § 803.30(b). These types of information correspond generally to the elements of Form FDA 3500A:

(a) Patient information (Form FDA 3500A, Block A). You must submit the following:

(1) Patient name or other identifier;

(2) Patient age at the time of event, or date of birth;

(3) Patient gender; and

(4) Patient weight.

(b) Adverse event or product problem (Form FDA 3500A, Block B). You must submit the following:

(1) Identification of adverse event or product problem;

(2) Outcomes attributed to the adverse event (e.g., death or serious injury). An outcome is considered a serious injury if it is:

(i) A life-threatening injury or illness;

(ii) A disability resulting in permanent impairment of a body function or permanent damage to a body structure; or

(iii) An injury or illness that requires intervention to prevent permanent impairment of a body structure or function;

(3) Date of event;

(4) Date of this report;

(5) Description of event or problem, including a discussion of how the device was involved, nature of the problem, patient followup or required treatment, and any environmental conditions that may have influenced the event;

(6) Description of relevant tests, including dates and laboratory data; and

(7) Description of other relevant history, including preexisting medical conditions.

(c) Device information (Form FDA 3500A, Block D). You must submit the following:

(1) Brand name;

(2) Product Code, if known, and Common Device Name;

(3) Manufacturer name, city, and state;

(4) Model number, catalog number, serial number, lot number, or other identifying number; expiration date; and unique device identifier (UDI) that appears on the device label or on the device package;

(5) Operator of the device (health professional, lay user/patient, other);

(6) Date of device implantation (month, day, year), if applicable;

(7) Date of device explantation (month, day, year), if applicable;

(8) Whether the device is a single-use device that was reprocessed and reused on a patient (Yes, No)?

(9) If the device is a single-use device that was reprocessed and reused on a patient (yes to paragraph (c)(8) of this section), the name and address of the reprocessor;

(10) Whether the device was available for evaluation and whether the device was returned to the manufacturer; if so, the date it was returned to the manufacturer; and

(11) Concomitant medical products and therapy dates. (Do not report products that were used to treat the event.)

(d) Initial reporter information (Form FDA 3500A, Block E). You must submit the following:

(1) Name, address, and telephone number of the reporter who initially provided information to you, or to the manufacturer or distributor;

(2) Whether the initial reporter is a health professional;

(3) Occupation; and

(4) Whether the initial reporter also sent a copy of the report to us, if known.

(e) User facility information (Form FDA 3500A, Block F). You must submit the following:

(1) An indication that this is a user facility report (by marking the user facility box on the form);

(2) Your user facility number;

(3) Your address;

(4) Your contact person;

(5) Your contact person's telephone number;

(6) Date that you became aware of the event (month, day, year);

(7) Type of report (initial or followup); if it is a followup, you must include the report number of the initial report;

(8) Date of your report (month, day, year);

(9) Approximate age of device;

(10) Event problem codes—patient code and device code (refer to the “MedWatch Medical Device Reporting Code Instructions”);

(11) Whether a report was sent to us and the date it was sent (month, day, year);

(12) Location where the event occurred;

(13) Whether the report was sent to the manufacturer and the date it was sent (month, day, year); and

(14) Manufacturer name and address, if available.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015]

§ 803.33 If I am a user facility, what must I include when I submit an annual report?

(a) You must submit to us an annual report on Form FDA 3419. You must submit an annual report by January 1, of each year. You may obtain this form on the internet at: https://www.fda.gov/media/72292/download.

(b) You must clearly identify your annual report as such. You must submit your annual report to FDA, CDRH, Medical Device Reporting, P.O. Box 3002, Rockville, MD 20847-3002. Your annual report must include:

(1) Your CMS provider number used for medical device reports, or the number assigned by us for reporting purposes in accordance with § 803.3;

(2) Reporting year;

(3) Your name and complete address;

(4) Total number of reports attached or summarized;

(5) Date of the annual report and report numbers identifying the range of medical device reports that you submitted during the report period (e.g., 1234567890-2011-0001 through 1000);

(6) Name, position title, and complete address of the individual designated as your contact person responsible for reporting to us and whether that person is a new contact for you; and

(7) Information for each reportable event that occurred during the annual reporting period including:

(i) Report number;

(ii) Name and address of the device manufacturer;

(iii) Device brand name and common name;

(iv) Product model, catalog, serial, and lot number and unique device identifier (UDI) that appears on the device label or on the device package;

(v) A brief description of the event reported to the manufacturer and/or us; and

(vi) Where the report was submitted, i.e., to the manufacturer, importer, or us.

(c) In lieu of submitting the information in paragraph (b)(7) of this section, you may submit a copy of each medical device report that you submitted to the manufacturers and/or to us during the reporting period.

(d) If you did not submit any medical device reports to manufacturers or us during the time period, you do not need to submit an annual report.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015; 85 FR 18442, Apr. 2, 2020]

§ 803.40 If I am an importer, what reporting requirements apply to me?

(a) Reports of deaths or serious injuries. You must submit a report to us, and a copy of this report to the manufacturer, as soon as practicable, but no later than 30 calendar days after the day that you receive or otherwise become aware of information from any source, including user facilities, individuals, or medical or scientific literature, whether published or unpublished, that reasonably suggests that one of your marketed devices may have caused or contributed to a death or serious injury. You must submit the information required by § 803.42. Reports sent to the Agency must be submitted in accordance with the requirements of § 803.12(a).

(b) Reports of malfunctions. You must submit a report to the manufacturer as soon as practicable but no later than 30 calendar days after the day that you receive or otherwise become aware of information from any source, including user facilities, individuals, or through your own research, testing, evaluation, servicing, or maintenance of one of your devices, that reasonably suggests that one of your devices has malfunctioned and that this device or a similar device that you market would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. You must submit the information required by § 803.42. Reports to manufacturers may be made in accordance with § 803.11(b).

§ 803.42 If I am an importer, what information must I submit in my individual adverse event reports?

You must include the following information in your report, if the information is known or should be known to you, as described in § 803.40. These types of information correspond generally to the format of Form FDA 3500A:

(a) Patient information (Form FDA 3500A, Block A). You must submit the following:

(1) Patient name or other identifier;

(2) Patient age at the time of event, or date of birth;

(3) Patient gender; and

(4) Patient weight.

(b) Adverse event or product problem (Form FDA 3500A, Block B). You must submit the following:

(1) Identification of adverse event or product problem;

(2) Outcomes attributed to the adverse event (e.g., death or serious injury). An outcome is considered a serious injury if it is:

(i) A life-threatening injury or illness;

(ii) A disability resulting in permanent impairment of a body function or permanent damage to a body structure; or

(iii) An injury or illness that requires intervention to prevent permanent impairment of a body structure or function;

(3) Date of event;

(4) Date of this report;

(5) Description of the event or problem, including a discussion of how the device was involved, nature of the problem, patient followup or required treatment, and any environmental conditions that may have influenced the event;

(6) Description of relevant tests, including dates and laboratory data; and

(7) Description of other relevant patient history, including preexisting medical conditions.

(c) Device information (Form FDA 3500A, Block D). You must submit the following:

(1) Brand name;

(2) Product Code, if known, and Common Device Name;

(3) Manufacturer name, city, and state;

(4) Model number, catalog number, serial number, lot number, or other identifying number; expiration date; and unique device identifier (UDI) that appears on the device label or on the device package;

(5) Operator of the device (health professional, lay user/patient, other);

(6) Date of device implantation (month, day, year), if applicable;

(7) Date of device explanation (month, day, year), if applicable;

(8) Whether the device is a single-use device that was reprocessed and reused on a patient (Yes, No)?

(9) If the device is a single-use device that was reprocessed and reused on a patient (yes to paragraph (c)(8) of this section), the name and address of the reprocessor;

(10) Whether the device was available for evaluation, and whether the device was returned to the manufacturer, and if so, the date it was returned to the manufacturer; and

(11) Concomitant medical products and therapy dates. (Do not report products that were used to treat the event.)

(d) Initial reporter information (Form FDA 3500A, Block E). You must submit the following:

(1) Name, address, and telephone number of the reporter who initially provided information to the manufacturer, user facility, or distributor;

(2) Whether the initial reporter is a health professional;

(3) Occupation; and

(4) Whether the initial reporter also sent a copy of the report to us, if known.

(e) Importer information (Form FDA 3500A, Block F). You must submit the following:

(1) An indication that this is an importer report (by marking the importer box on the form);

(2) Your importer report number;

(3) Your address;

(4) Your contact person;

(5) Your contact person's telephone number;

(6) Date that you became aware of the event (month, day, year);

(7) Type of report (initial or followup). If it is a followup report, you must include the report number of your initial report;

(8) Date of your report (month, day, year);

(9) Approximate age of device;

(10) Event problem codes—patient code and device code (refer to FDA MedWatch Medical Device Reporting Code Instructions);

(11) Whether a report was sent to us and the date it was sent (month, day, year);

(12) Location where event occurred;

(13) Whether a report was sent to the manufacturer and the date it was sent (month, day, year); and

(14) Manufacturer name and address, if available.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015]

§ 803.50 If I am a manufacturer, what reporting requirements apply to me?

(a) If you are a manufacturer, you must report to us the information required by § 803.52 in accordance with the requirements of § 803.12(a), no later than 30 calendar days after the day that you receive or otherwise become aware of information, from any source, that reasonably suggests that a device that you market:

(1) May have caused or contributed to a death or serious injury or

(2) Has malfunctioned and this device or a similar device that you market would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur.

(b) What information does FDA consider “reasonably known” to me?

(1) You must submit all information required in this subpart E that is reasonably known to you. We consider the following information to be reasonably known to you:

(i) Any information that you can obtain by contacting a user facility, importer, or other initial reporter;

(ii) Any information in your possession; or

(iii) Any information that you can obtain by analysis, testing, or other evaluation of the device.

(2) You are responsible for obtaining and submitting to us information that is incomplete or missing from reports submitted by user facilities, importers, and other initial reporters.

(3) You are also responsible for conducting an investigation of each event and evaluating the cause of the event. If you cannot submit complete information on a report, you must provide a statement explaining why this information was incomplete and the steps you took to obtain the information. If you later obtain any required information that was not available at the time you filed your initial report, you must submit this information in a supplemental report under § 803.56 in accordance with the requirements of § 803.12(a).

§ 803.52 If I am a manufacturer, what information must I submit in my individual adverse event reports?

You must include the following information in your reports, if known or reasonably known to you, as described in § 803.50(b). These types of information correspond generally to the format of Form FDA 3500A:

(a) Patient information (Form FDA 3500A, Block A). You must submit the following:

(1) Patient name or other identifier;

(2) Patient age at the time of event, or date of birth;

(3) Patient gender; and

(4) Patient weight.

(b) Adverse event or product problem (Form FDA 3500A, Block B). You must submit the following:

(1) Identification of adverse event or product problem;

(2) Outcomes attributed to the adverse event (e.g., death or serious injury). An outcome is considered a serious injury if it is:

(i) A life-threatening injury or illness;

(ii) A disability resulting in permanent impairment of a body function or permanent damage to a body structure; or

(iii) An injury or illness that requires intervention to prevent permanent impairment of a body structure or function;

(3) Date of event;

(4) Date of this report;

(5) Description of the event or problem, including a discussion of how the device was involved, nature of the problem, patient followup or required treatment, and any environmental conditions that may have influenced the event;

(6) Description of relevant tests, including dates and laboratory data; and

(7) Other relevant patient history including preexisting medical conditions.

(c) Device information (Form FDA 3500A, Block D). You must submit the following:

(1) Brand name;

(2) Product Code, if known, and Common Device Name;

(3) Manufacturer name, city, and state;

(4) Model number, catalog number, serial number, lot number, or other identifying number; expiration date; and unique device identifier (UDI) that appears on the device label or on the device package;

(5) Operator of the device (health professional, lay user/patient, other);

(6) Date of device implantation (month, day, year), if applicable;

(7) Date of device explantation (month, day, year), if applicable;

(8) Whether the device is a single-use device that was reprocessed and reused on a patient (Yes, No)?

(9) If the device is a single-use device that was reprocessed and reused on a patient (yes to paragraph (c)(8) of this section), the name and address of the reprocessor;

(10) Whether the device was available for evaluation, and whether the device was returned to the manufacturer, and if so, the date it was returned to the manufacturer; and

(11) Concomitant medical products and therapy dates. (Do not report products that were used to treat the event.)

(d) Initial reporter information (Form FDA 3500A, Block E). You must submit the following:

(1) Name, address, and telephone number of the reporter who initially provided information to you, or to the user facility or importer;

(2) Whether the initial reporter is a health professional;

(3) Occupation; and

(4) Whether the initial reporter also sent a copy of the report to us, if known.

(e) Reporting information for all manufacturers (Form FDA 3500A, Block G). You must submit the following:

(1) Your reporting office's contact name and address and device manufacturing site;

(2) Your contact person's telephone number;

(3) Your report sources;

(4) Date received by you (month, day, year);

(5) PMA/510k Number and whether or not the product is a combination product;

(6) Type of report being submitted (e.g., 5-day, initial, followup); and

(7) Your report number.

(f) Device manufacturer information (Form FDA 3500A, Block H). You must submit the following:

(1) Type of reportable event (death, serious injury, malfunction, etc.);

(2) Type of followup report, if applicable (e.g., correction, response to FDA request, etc);

(3) If the device was returned to you and evaluated by you, you must include a summary of the evaluation. If you did not perform an evaluation, you must explain why you did not perform an evaluation;

(4) Device manufacture date (month, day, year);

(5) Whether the device was labeled for single use;

(6) Evaluation codes (including event codes, method of evaluation, result, and conclusion codes) (refer to FDA MedWatch Medical Device Reporting Code Instructions);

(7) Whether remedial action was taken and the type of action;

(8) Whether the use of the device was initial, reuse, or unknown;

(9) Whether remedial action was reported as a removal or correction under section 519(f) of the Federal Food, Drug, and Cosmetic Act, and if it was, provide the correction/removal report number; and

(10) Your additional narrative; and/or

(11) Corrected data, including:

(i) Any information missing on the user facility report or importer report, including any event codes that were not reported, or information corrected on these forms after your verification;

(ii) For each event code provided by the user facility under § 803.32(e)(10) or the importer under § 803.42(e)(10), you must include a statement of whether the type of the event represented by the code is addressed in the device labeling; and

(iii) If your report omits any required information, you must explain why this information was not provided and the steps taken to obtain this information.

[79 FR 8846, Feb. 14, 2014, as amended at 80 FR 10587, Feb. 27, 2015]

§ 803.53 If I am a manufacturer, in which circumstances must I submit a 5-day report?

You must submit a 5-day report to us with the information required by § 803.52 in accordance with the requirements of § 803.12(a) no later than 5 work days after the day that you become aware that:

(a) An MDR reportable event necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health. You may become aware of the need for remedial action from any information, including any trend analysis or

(b) We have made a written request for the submission of a 5-day report. If you receive such a written request from us, you must submit, without further requests, a 5-day report for all subsequent events of the same nature that involve substantially similar devices for the time period specified in the written request. We may extend the time period stated in the original written request if we determine it is in the interest of the public health.

§ 803.56 If I am a manufacturer, in what circumstances must I submit a supplemental or followup report and what are the requirements for such reports?

If you are a manufacturer, when you obtain information required under this part that you did not provide because it was not known or was not available when you submitted the initial report, you must submit the supplemental information to us within 30 calendar days of the day that you receive this information. You must submit the supplemental or followup report in accordance with the requirements of § 803.12(a). On a supplemental or followup report, you must:

(a) Indicate that the report being submitted is a supplemental or followup report;

(b) Submit the appropriate identification numbers of the report that you are updating with the supplemental information (e.g., your original manufacturer report number and the user facility or importer report number of any report on which your report was based), if applicable; and

(c) Include only the new, changed, or corrected information.

§ 803.58 Foreign manufacturers.

(a) Every foreign manufacturer whose devices are distributed in the United States shall designate a U.S. agent to be responsible for reporting in accordance with § 807.40 of this chapter. The U.S. designated agent accepts responsibility for the duties that such designation entails. Upon the effective date of this regulation, foreign manufacturers shall inform FDA, by letter, of the name and address of the U.S. agent designated under this section and § 807.40 of this chapter, and shall update this information as necessary. Such updated information shall be submitted to FDA, within 5 days of a change in the designated agent information.

(b) U.S.-designated agents of foreign manufacturers are required to:

(1) Report to FDA in accordance with §§ 803.50, 803.52, 803.53, and 803.56;

(2) Conduct, or obtain from the foreign manufacturer the necessary information regarding, the investigation and evaluation of the event to comport with the requirements of § 803.50;

(3) Forward MDR complaints to the foreign manufacturer and maintain documentation of this requirement;

(4) Maintain complaint files in accordance with § 803.18; and

(5) Register, list, and submit premarket notifications in accordance with part 807 of this chapter.

Effective Date Note:At 79 FR 8846, Feb. 14, 2014, part 803 was revised. At 79 FR 8855, Feb. 14, 2014, § 803.58 was stayed indefinitely.

§ 806.1 Scope.

(a) This part implements the provisions of section 519(g) of the Federal Food, Drug, and Cosmetic Act (the act) requiring device manufacturers and importers to report promptly to the Food and Drug Administration (FDA) certain actions concerning device corrections and removals, and to maintain records of all corrections and removals regardless of whether such corrections and removals are required to be reported to FDA.

(b) The following actions are exempt from the reporting requirements of this part:

(1) Actions taken by device manufacturers or importers to improve the performance or quality of a device but that do not reduce a risk to health posed by the device or remedy a violation of the act caused by the device.

(2) Market withdrawal as defined in § 806.2(i)

(3) Routine servicing as defined in § 806.2(l).

(4) Stock recovery as defined in § 806.2(m).

[62 FR 27191, May 19, 1997, as amended at 63 FR 42232, Aug. 7, 1998; 84 FR 12083, Apr. 1, 2019]

§ 806.2 Definitions.

As used in this part:

(a) Act means the Federal Food, Drug, and Cosmetic Act.

(b) Agency or FDA means the Food and Drug Administration.

(c) Consignee means any person or firm that has received, purchased, or used a device subject to correction or removal.

(d) Correction means the repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device without its physical removal from its point of use to some other location.

(e) Correction or removal report number means the number that uniquely identifies each report submitted.

(f) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(g) Importer means, for the purposes of this part, any person who imports a device into the United States.

(h) Manufacturer means any person who manufactures, prepares, propagates, compounds, assembles, or processes a device by chemical, physical, biological, or other procedures. The term includes any person who:

(1) Repackages or otherwise changes the container, wrapper, or labeling of a device in furtherance of the distribution of the device from the original place of manufacture to the person who makes final delivery or sale to the ultimate user or consumer;

(2) Initiates specifications for devices that are manufactured by a second party for subsequent distribution by the person initiating the specifications; or

(3) Manufactures components or accessories which are devices that are ready to be used and are intended to be commercially distributed and are intended to be used as is, or are processed by a licensed practitioner or other qualified person to meet the needs of a particular patient.

(i) Market withdrawal means a correction or removal of a distributed device that involves a minor violation of the act that would not be subject to legal action by FDA or that involves no violation of the act, e.g., normal stock rotation practices.

(j) Removal means the physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.

(k) Risk to health means

(1) A reasonable probability that use of, or exposure to, the product will cause serious adverse health consequences or death; or

(2) That use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences, or an outcome where the probability of serious adverse health consequences is remote.

(l) Routine servicing means any regularly scheduled maintenance of a device, including the replacement of parts at the end of their normal life expectancy, e.g., calibration, replacement of batteries, and responses to normal wear and tear. Repairs of an unexpected nature, replacement of parts earlier than their normal life expectancy, or identical repairs or replacements of multiple units of a device are not routine servicing.

(m) Stock recovery means the correction or removal of a device that has not been marketed or that has not left the direct control of the manufacturer, i.e., the device is located on the premises owned, or under the control of, the manufacturer, and no portion of the lot, model, code, or other relevant unit involved in the corrective or removal action has been released for sale or use.

(n) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A UDI is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

[62 FR 27191, May 19, 1997, as amended at 63 FR 42232, Aug. 7, 1998; 78 FR 58821, Sept. 24, 2013]

§ 806.10 Reports of corrections and removals.

(a) Each device manufacturer or importer shall submit a written report to FDA of any correction or removal of a device initiated by such manufacturer or importer if the correction or removal was initiated:

(1) To reduce a risk to health posed by the device; or

(2) To remedy a violation of the act caused by the device which may present a risk to health unless the information has already been provided as set forth in paragraph (f) of this section or the corrective or removal action is exempt from the reporting requirements under § 806.1(b).

(b) The manufacturer or importer shall submit any report required by paragraph (a) of this section within 10-working days of initiating such correction or removal.

(c) The manufacturer or importer shall include the following information in the report:

(1) The seven digit registration number of the entity responsible for submission of the report of corrective or removal action (if applicable), the month, day, and year that the report is made, and a sequence number (i.e., 001 for the first report, 002 for the second report, 003 etc.), and the report type designation “C” or “R”. For example, the complete number for the first correction report submitted on June 1, 1997, will appear as follows for a firm with the registration number 1234567: 1234567-6/1/97-001-C. The second correction report number submitted by the same firm on July 1, 1997, would be 1234567-7/1/97-002-C etc. For removals, the number will appear as follows: 1234567-6/1/97-001-R and 1234567-7/1/97-002-R, etc. Firms that do not have a seven digit registration number may use seven zeros followed by the month, date, year, and sequence number (i.e. 0000000-6/1/97-001-C for corrections and 0000000-7/1/97-001-R for removals). Reports received without a seven digit registration number will be assigned a seven digit central file number by the district office reviewing the reports.

(2) The name, address, and telephone number of the manufacturer or importer, and the name, title, address, and telephone number of the manufacturer or importer representative responsible for conducting the device correction or removal.

(3) The brand name and the common name, classification name, or usual name of the device and the intended use of the device.

(4) Marketing status of the device, i.e., any applicable premarket notification number, premarket approval number, or indication that the device is a preamendments device, and the device listing number. A manufacturer or importer that does not have an FDA establishment registration number shall indicate in the report whether it has ever registered with FDA.

(5) The unique device identifier (UDI) that appears on the device label or on the device package, or the device identifier, universal product code (UPC), model, catalog, or code number of the device and the manufacturing lot or serial number of the device or other identification number.

(6) The manufacturer's name, address, telephone number, and contact person if different from that of the person submitting the report.

(7) A description of the event(s) giving rise to the information reported and the corrective or removal actions that have been, and are expected to be taken.

(8) Any illness or injuries that have occurred with use of the device. If applicable, include the medical device report numbers.

(9) The total number of devices manufactured or distributed subject to the correction or removal and the number in the same batch, lot, or equivalent unit of production subject to the correction or removal.

(10) The date of manufacture or distribution and the device's expiration date or expected life.

(11) The names, addresses, and telephone numbers of all domestic and foreign consignees of the device and the dates and number of devices distributed to each such consignee.

(12) A copy of all communications regarding the correction or removal and the names and addresses of all recipients of the communications not provided in accordance with paragraph (c)(11) of this section.

(13) If any required information is not immediately available, a statement as to why it is not available and when it will be submitted.

(d) If, after submitting a report under this part, a manufacturer or importer determines that the same correction or removal should be extended to additional lots or batches of the same device, the manufacturer or importer shall within 10-working days of initiating the extension of the correction or removal, amend the report by submitting an amendment citing the original report number assigned according to paragraph (c)(1) of this section, all of the information required by paragraph (c)(2), and any information required by paragraphs (c)(3) through (c)(12) of this section that is different from the information submitted in the original report. The manufacturer or importer shall also provide a statement in accordance with paragraph (c)(13) of this section for any required information that is not readily available.

(e) A report submitted by a manufacturer or importer under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, importer, or FDA that the report or information constitutes an admission that the device caused or contributed to a death or serious injury. A manufacturer or importer need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the device caused or contributed to a death or serious injury.

(f) No report of correction or removal is required under this part, if a report of the correction or removal is required and has been submitted under parts 803 or 1004 of this chapter.

[62 FR 27191, May 19, 1997, as amended at 63 FR 42232, Aug. 7, 1998; 69 FR 11311, Mar. 10, 2004; 78 FR 58821, Sept. 24, 2013]

§ 806.20 Records of corrections and removals not required to be reported.

(a) Each device manufacturer or importer who initiates a correction or removal of a device that is not required to be reported to FDA under § 806.10 shall keep a record of such correction or removal.

(b) Records of corrections and removals not required to be reported to FDA under § 806.10 shall contain the following information:

(1) The brand name, common or usual name, classification, name and product code if known, and the intended use of the device.

(2) The unique device identifier (UDI) of the device, or the device identifier, universal product code (UPC), model, catalog, or code number of the device and the manufacturing lot or serial number of the device or other identification number.

(3) A description of the event(s) giving rise to the information reported and the corrective or removal action that has been, and is expected to be taken.

(4) Justification for not reporting the correction or removal action to FDA, which shall contain conclusions and any followups, and be reviewed and evaluated by a designated person.

(5) A copy of all communications regarding the correction or removal.

(c) The manufacturer or importer shall retain records required under this section for a period of 2 years beyond the expected life of the device, even if the manufacturer or importer has ceased to manufacture or import the device. Records required to be maintained under paragraph (b) of this section must be transferred to the new manufacturer or importer of the device and maintained for the required period of time.

[62 FR 27191, May 19, 1997, as amended at 63 FR 42233, Aug. 7, 1998; 78 FR 58821, Sept. 24, 2013]

§ 806.30 FDA access to records.

Each device manufacturer or importer required under this part to maintain records and every person who is in charge or custody of such records shall, upon request of an officer or employee designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable times to have access to, and to copy and verify, such records and reports.

[63 FR 42233, Aug. 7, 1998]

§ 806.40 Public availability of reports.

(a) Any report submitted under this part is available for public disclosure in accordance with part 20 of this chapter.

(b) Before public disclosure of a report, FDA will delete from the report:

(1) Any information that constitutes trade secret or confidential commercial or financial information under § 20.61 of this chapter; and

(2) Any personnel, medical, or similar information, including the serial numbers of implanted devices, which would constitute a clearly unwarranted invasion of personal privacy under § 20.63 of this chapter or 5 U.S.C. 552(b)(6); provided, that except for the information under § 20.61 of this chapter or 5 U.S.C. 552(b)(4), FDA will disclose to a patient who requests a report all the information in the report concerning that patient.

§ 807.3 Definitions.

(a) Act means the Federal Food, Drug, and Cosmetic Act.

(b) Commercial distribution means any distribution of a device intended for human use which is held or offered for sale but does not include the following:

(1) Internal or interplant transfer of a device between establishments within the same parent, subsidiary, and/or affiliate company;

(2) Any distribution of a device intended for human use which has in effect an approved exemption for investigational use under section 520(g) of the act and part 812 of this chapter;

(3) Any distribution of a device, before the effective date of part 812 of this chapter, that was not introduced or delivered for introduction into interstate commerce for commercial distribution before May 28, 1976, and that is classified into class III under section 513(f) of the act: Provided, That the device is intended solely for investigational use, and under section 501(f)(2)(A) of the act the device is not required to have an approved premarket approval application as provided in section 515 of the act; or

(4) For foreign establishments, the distribution of any device that is neither imported nor offered for import into the United States.

(c) Establishment means a place of business under one management at one general physical location at which a device is manufactured, assembled, or otherwise processed.

(d) Manufacture, preparation, propagation, compounding, assembly, or processing of a device means the making by chemical, physical, biological, or other procedures of any article that meets the definition of device in section 201(h) of the act. These terms include the following activities:

(1) Repackaging or otherwise changing the container, wrapper, or labeling of any device package in furtherance of the distribution of the device from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer;

(2) Initial importation of devices manufactured in foreign establishments; or

(3) Initiation of specifications for devices that are manufactured by a second party for subsequent commercial distribution by the person initiating specifications.

(e) Official correspondent means the person designated by the owner or operator of an establishment as responsible for the following:

(1) The annual registration of the establishment;

(2) Contact with the Food and Drug Administration for device listing;

(3) Maintenance and submission of a current list of officers and directors to the Food and Drug Administration upon the request of the Commissioner; and

(4) The receipt of pertinent correspondence from the Food and Drug Administration directed to and involving the owner or operator and/or any of the firm's establishments.

(f) Owner or operator means the corporation, subsidiary, affiliated company, partnership, or proprietor directly responsible for the activities of the registering establishment.

(g) Initial importer means any importer who furthers the marketing of a device from a foreign manufacturer to the person who makes the final delivery or sale of the device to the ultimate consumer or user, but does not repackage, or otherwise change the container, wrapper, or labeling of the device or device package.

(h) Any term defined in section 201 of the act shall have that meaning.

(i) Restricted device means a device for which a requirement restricting sale, distribution, or use has been established by a regulation issued under section 520(e) of the act, by order as a condition of premarket approval under section 515(d)(1)(B)(ii) of the act, or by a performance standard issued in accordance with sections 514(a)(2)(B)(v) and 514(b) of the act.

(j) Classification name means the term used by the Food and Drug Administration and its classification panels to describe a device or class of devices for purposes of classifying devices under section 513 of the act.

(k) Product code means the code used by FDA to identify the generic category of a device.

(l) Representative sampling of advertisements means typical advertising material that gives the promotional claims made for the device.

(m) Representative sampling of any other labeling means typical labeling material (excluding labels and package inserts) that gives the promotional claims made for the device.

(n) Material change includes any change or modification in the labeling or advertisements that affects the identity or safety and effectiveness of the device. These changes may include, but are not limited to, changes in the common or usual or proprietary name, declared ingredients or components, intended use, contraindications, warnings, or instructions for use. Changes that are not material may include graphic layouts, grammar, or correction of typographical errors which do not change the content of the labeling, changes in lot number, and, for devices where the biological activity or known composition differs with each lot produced, the labeling containing the actual values for each lot.

(o) 510(k) summary (summary of any information respecting safety and effectiveness) means a summary, submitted under section 513(i) of the act, of the safety and effectiveness information contained in a premarket notification submission upon which a determination of substantial equivalence can be based. Safety and effectiveness information refers to safety and effectiveness data and information supporting a finding of substantial equivalence, including all adverse safety and effectiveness information.

(p) 510(k) statement means a statement, made under section 513(i) of the act, asserting that all information in a premarket notification submission regarding safety and effectiveness will be made available within 30 days of request by any person if the device described in the premarket notification submission is determined to be substantially equivalent. The information to be made available will be a duplicate of the premarket notification submission, including any adverse safety and effectiveness information, but excluding all patient identifiers, and trade secret or confidential commercial information, as defined in § 20.61 of this chapter.

(q) Class III certification means a certification that the submitter of the 510(k) has conducted a reasonable search of all known information about the class III device and other similar, legally marketed devices.

(r) Class III summary means a summary of the types of safety and effectiveness problems associated with the type of device being compared and a citation to the information upon which the summary is based. The summary must be comprehensive and describe the problems to which the type of device is susceptible and the causes of such problems.

(s) United States agent means a person residing or maintaining a place of business in the United States whom a foreign establishment designates as its agent. This definition excludes mailboxes, answering machines or services, or other places where an individual acting as the foreign establishment's agent is not physically present.

(t) Wholesale distributor means any person (other than the manufacturer or the initial importer) who distributes a device from the original place of manufacture to the person who makes the final delivery or sale of the device to the ultimate consumer or user.

(u) Fiscal year means the FDA fiscal year, which runs from October 1 through September 30.

(v) FURLS means the Food and Drug Administration's Unified

Registration and Listing System,

(w) FDA premarket submission number means the number assigned by FDA to a premarket device submission, such as a Premarket Approval Application (PMA); Humanitarian Device Exemption (HDE); New Drug Application (NDA); Biologics License Application (BLA); de novo classification petition; or Premarket Notification (510(k)).

(x) Importer means, for purposes of this part, a company or individual in the United States that is an owner, consignee, or recipient, even if not the initial owner, consignee, or recipient, of the foreign establishment's device that is imported into the United States. An importer does not include the consumer or patient who ultimately purchases, receives, or uses the device, unless the foreign establishment ships the device directly to the consumer or patient.

(y) Person who imports or offers for import means, for purposes of this part, an agent, broker, or other entity, other than a carrier, that the foreign establishment uses to facilitate the import of its device into the United States.

[42 FR 42526, Aug. 23, 1977, as amended at 43 FR 37997, Aug. 25, 1978; 57 FR 18066, Apr. 28, 1992; 58 FR 46522, Sept. 1, 1993; 59 FR 64295, Dec. 14, 1994; 60 FR 63606, Dec. 11, 1995; 63 FR 51826, Sept. 29, 1998; 66 FR 59159, Nov. 27, 2001; 77 FR 45940, Aug. 2, 2012]

§ 807.20 Who must register and submit a device list?

(a) An owner or operator of an establishment not exempt under section 510(g) of the Federal Food, Drug, and Cosmetic Act or subpart D of this part who is engaged in the manufacture, preparation, propagation, compounding, assembly, or processing of a device intended for human use shall register and submit listing information for those devices in commercial distribution, except that registration and listing information may be submitted by the parent, subsidiary, or affiliate company for all the domestic or foreign establishments under the control of one of these organizations when operations are conducted at more than one establishment and there exists joint ownership and control among all the establishments. The term “device” includes all in vitro diagnostic products and in vitro diagnostic biological products not subject to licensing under section 351 of the Public Health Service Act. An owner or operator of an establishment located in any State as defined in section 201(a)(1) of the Federal Food, Drug, and Cosmetic Act shall register its name, places of business, and all establishments and list the devices whether or not the output of the establishments or any particular device so listed enters interstate commerce. The registration and listing requirements shall pertain to any person who is engaged in the manufacture, preparation, propagation, compounding, assembly, or processing of a device intended for human use, including any person who:

(1) Initiates or develops specifications for a device that is to be manufactured by a second party;

(2) Sterilizes or otherwise makes a device for or on behalf of a specifications developer or any other person;

(3) Repackages or relabels a device;

(4) Reprocesses a single use device that has previously been used on a patient;

(5) Acts as an initial importer as defined in § 807.3(g), except that initial importers may fulfill their listing obligation for any device for which they did not initiate or develop the specifications for the device or repackage or relabel the device by submitting the name and address of the manufacturer. Initial importers shall also be prepared to submit, when requested by FDA, the proprietary name, if any, and the common or usual name of each device for which they are the initial importer;

(6) Manufactures components or accessories that are ready to be used for any intended health-related purpose and are packaged or labeled for commercial distribution for such health-related purpose, e.g. blood filters, hemodialysis tubing, or devices which of necessity must be further processed by a licensed practitioner or other qualified person to meet the needs of a particular patient, e.g., a manufacturer of ophthalmic lens blanks.

(b) Registration or listing does not constitute an admission or agreement or determination that a product is a device within the meaning of section 201(h) of the Federal Food, Drug, and Cosmetic Act.

(c) Registration and listing requirements shall not pertain to any person who acts as a wholesale distributor, as defined in § 807.3(t), and who does not manufacture, repackage, process, or relabel a device.

(d) Owners and operators of establishments or persons engaged in the recovery, screening, testing, processing, storage, or distribution of human cells, tissues, and cellular and tissue-based products, as defined in § 1271.3(d) of this chapter, that are regulated under the Federal Food, Drug, and Cosmetic Act must register and list those human cells, tissues, and cellular and tissue-based products with the Center for Biologics Evaluation and Research on Form FDA 3356 following the procedures set out in subpart B of part 1271 of this chapter, instead of the procedures for registration and listing contained in this part, except that the additional listing information requirements of § 807.26 remain applicable.

(e) Owners and operators of establishments that manufacture devices licensed under section 351 of the Public Health Service Act as well as licensed biological products used in the manufacture of a licensed device must register and list following the procedures set out in part 607 of this chapter, instead of the procedures for registration and listing contained in this part.

[77 FR 45941, Aug. 2, 2012]

§ 807.21 How to register establishments and list devices.

(a) Owners or operators of establishments that are subject to the registration and listing requirements of this part must provide the following information to us using our electronic device registration and listing system, except as provided in paragraphs (b), (c), and (d) of this section:

(1) Initial establishment registration information as required by §§ 807.22(a) and 807.25;

(2) Updates to registration information as required by §§ 807.22(b) and 807.25;

(3) Initial device listing information as required by §§ 807.22(a), 807.25, and 807.28;

(4) Updates to device listing information as required by §§ 807.22(b), 807.25, and 807.28, including updates to reflect the discontinuance or resumption of the commercial distribution of a previously-listed device as specified at paragraphs (d) and (e) of § 807.28.

(b) If the information under § 807.21(a) cannot be submitted electronically, a waiver may be requested. Waivers will be granted only if use of electronic means is not reasonable for the person requesting the waiver. To request a waiver, applicants must send a letter to the Imports and Registration and Listing Team, Division of Regulatory Programs 2, Office of Regulatory Programs, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm.1432, Silver Spring, MD 20993-0002, that includes the following information:

(1) The name and address of the device establishment(s) to be registered, a contact person for the owner or operator of the establishment, and the telephone number at which that person can be reached. If the establishment has already registered in the past, the letter should also include the owner or operator number, registration number, and any listing numbers previously assigned by FDA for devices manufactured at that establishment.

(2) Information about whether the company is an initial importer as defined in § 807.3(g) and, if so, whether it also conducts any other activities or operations relating to devices.

(3) A statement that use of the Internet is not reasonable for the person requesting the waiver, and an explanation of why such use is not reasonable. The statement must be signed by the owner or operator of the establishment, or by a person employed by the owner or operator who is authorized to make the declaration on behalf of the owner or operator.

(c) Those owners or operators who have obtained a waiver from filing registration and listing information electronically should refer to § 807.34 for information on how to submit such information by postal mail.

(d) When additional device listing information (e.g., copies of labeling or advertisements) is requested by FDA as described at § 807.26(e), such information may be submitted by postal mail or electronically by email, but will not be submitted using the FDA electronic device registration and listing system.

[77 FR 45941, Aug. 2, 2012, as amended at 85 FR 18442, Apr. 2, 2020]

§ 807.22 Times for establishment registration and device listing.

(a) Initial registration and listing. An owner or operator of an establishment who has not previously entered into an operation described in § 807.20(a) shall register within 30 days after entering into such an operation and submit device listing information at that time.

(b) Registration and listing updates. Owners or operators shall review and update all of their establishment registration and device listing information that is on file at FDA, documenting any changes that were not previously reported as follows:

(1) Annual registration for each fiscal year is required for all establishments. Annual registration shall take place during the period beginning on October 1 and ending on December 31 of each fiscal year;

(2) Updates to the registration information as described in § 807.25(b) shall be made within 30 days of any change to such information;

(3) Every fiscal year, during the period beginning on October 1 and ending on December 31, owners or operators shall review and update all of their device listing information that is on file at FDA, reporting any changes or deletions to listings and any new listings that were not previously reported. The accuracy of all information on file must be confirmed each year regardless of whether any changes were made to the owner or operator's list of devices; and

(4) Changes to listing information may also be made at other times, such as when a device is introduced into commercial distribution, when a change is made to a previously-listed device, or when a previously-listed device is removed from commercial distribution.

(c) Failure to submit required information. Failure to submit any of the required information on time, as specified in paragraphs (a) and (b) of this section, will put the establishment in a “failed to register” or “failed to list” status as applicable. The establishment will not be considered active and the establishment registration and device listing information may not appear on the FDA Web site until such time as the owner or operator submits and FDA processes the required information.

[77 FR 45942, Aug. 2, 2012]

§ 807.25 Information required for device establishment registration and device listing.

(a) All owners or operators that are subject to the registration and listing requirements of this part shall provide such information to us by using the FDA electronic device registration and listing system, unless granted a waiver from electronic submission in accordance with § 807.21(b). Electronic submissions of registration and listing information must comply with part 11 of this chapter, except for the requirements in § 11.10(b), (c), and (e), and the corresponding requirements in § 11.30 of this chapter. Those owners or operators granted a waiver from electronic submission should refer to paragraphs (c) and (g) of this section and § 807.34 for instructions on how to submit device registration and listing information.

(b) Registration information required to be submitted includes: The name and mailing address of the device establishment; the Web site address of the device establishment, if any; the name, address, phone number, fax number, and email address of the owner or operator; the name, address, phone number, fax number, and email address of the establishment's official correspondent; and all trade names used by the establishment.

(c) Owners or operators who have been granted a waiver from electronic filing must submit the establishment registration information described in paragraph (b) of this section, except for the Web site and email address information, in paper form using the procedures set forth in § 807.34.

(d) Each owner or operator is required to maintain a listing of all officers, directors, and partners for each establishment registered by the owner or operator and to furnish this information to FDA upon request.

(e) For each establishment, an official correspondent must be designated by the owner or operator to serve as a point of contact with FDA on matters relating to the registration of device establishments and the listing of device products. Each owner or operator shall also provide FDA with the name of a contact person at the owner or operator's offices who will be responsible for identifying the official correspondent for each establishment. The owner or operator contact person will be the official correspondent in the event no one else has been properly designated. The official correspondent is responsible for:

(1) Providing FDA with all required registration and listing information electronically unless a waiver from electronic submission has been granted in accordance with § 807.21(b);

(2) Receiving all correspondence from FDA concerning registration and listing;

(3) Supplying, when requested by FDA, the names of all officers, directors, and partners; and

(4) Receiving communications from FDA by email, or by postal mail if the owner or operator has been granted a waiver from the requirement to file registration and listing information electronically.

(f) The designation of an official correspondent does not in any manner affect the liability of the owner or operator of the establishment or any other individual under section 301(p) or any other provision of the Federal Food, Drug, and Cosmetic Act.

(g) Device listing information must be submitted to FDA electronically unless a waiver from electronic submission has been granted in accordance with § 807.21(b). Owners or operators who have been granted a waiver must submit the required device listing information, including information required by this paragraph, § 807.28, and any listing information requested by FDA under § 807.26(e), in paper form using the procedures set forth in § 807.34. The information required for each device listed includes:

(1) The current registration number and name of each establishment under the ownership and control of the owner or operator where the device is manufactured, repackaged, relabeled, or otherwise processed, or where specifications are developed.

(2) The product code for each device that is exempt from premarket notification and approval or which was in commercial distribution prior to May 28, 1976.

(3) The proprietary or brand name(s) under which each device is marketed.

(4) The FDA-assigned premarket submission number of the approved application, cleared premarket notification, granted de novo classification petition, or approved humanitarian device exemption for each device listed that is subject to sections 505, 510(k), 513(f)(2), 515, or 520(m) of the Federal Food, Drug, and Cosmetic Act, which includes devices that are not exempt from premarket notification and approval.

(5) Each activity or process that is conducted on or done to the device at each establishment, such as manufacturing, repacking, relabeling, developing specifications, remanufacturing, single-use device reprocessing, contract manufacturing, contract sterilizing, or manufacturing for export only.

[77 FR 45942, Aug. 2, 2012]

§ 807.26 Additional listing information.

(a) Each owner or operator shall maintain a historical file containing the labeling and advertisements in use on the date of initial listing, and in use after October 10, 1978, but before the date of initial listing, as follows:

(1) For each device subject to section 514 or 515 of the act that is not a restricted device, a copy of all labeling for the device;

(2) For each restricted device, a copy of all labeling and advertisements for the device;

(3) For each device that is neither restricted nor subject to section 514 or 515 of the act, a copy of all labels, package inserts, and a representative sampling of any other labeling.

(b) In addition to the requirements set forth in paragraph (a) of this section, each owner or operator shall maintain in the historical file any labeling or advertisements in which a material change has been made anytime after initial listing.

(c) Each owner or operator may discard labeling and advertisements from the historical file 3 years after the date of the last shipment of a discontinued device by an owner or operator.

(d) Location of the file:

(1) Currently existing systems for maintenance of labeling and advertising may be used for the purpose of maintaining the historical file as long as the information included in the systems fulfills the requirements of this section, but only if the labeling and advertisements are retrievable in a timely manner.

(2) The contents of the historical file may be physically located in more than one place in the establishment or in more than one establishment provided there exists joint ownership and control among all the establishments maintaining the historical file. If no joint ownership and control exists, the registered establishment must provide the Food and Drug Administration with a letter authorizing the establishment outside its control to maintain the historical file.

(3) A copy of the certification and disclosure statements as required by part 54 of this chapter shall be retained and physically located at the establishment maintaining the historical file.

(e) Each owner or operator shall be prepared to submit to the Food and Drug Administration, only upon specific request, the following information:

(1) For a device subject to section 514 or 515 of the act that is not a restricted device, a copy of all labeling for the device.

(2) For a device that is a restricted device, a copy of all labeling for the device, a representative sampling of advertisements for the device, and for good cause, a copy of all advertisements for a particular device. A request for all advertisements will, where feasible, be accompanied by an explanation of the basis for such request.

(3) For a device that is neither a restricted device, nor subject to section 514 of 515 of the act, the label and package insert for the device and a representative sampling of any other labeling for the device.

(4) For a particular device, a statement of the basis upon which the registrant has determined that the device is not subject to section 514 or 515 of the act.

(5) For a particular device, a statement of the basis upon which the registrant has determined the device is not a restricted device.

(6) For a particular device, a statement of the basis for determining that the product is a device rather than a drug.

(7) For a device that the owner or operator has manufactured for distribution under a label other than its own, the names of all distributors for whom it has been manufactured.

(f) Labeling, advertisements, and other information to be submitted upon request in accordance with paragraph (e) of this section may be submitted by postal mail or electronically by email, but will not be submitted using the FDA electronic device registration and listing system. Electronic submissions of such information must comply with part 11 of this chapter, except for the requirements in § 11.10 (a), (c) through (h), and (k), and the corresponding requirements in § 11.30 of this chapter. The information provided in electronic format must be in a form that we can process, review, and archive.

[43 FR 37999, Aug. 25, 1978, as amended at 51 FR 33033, Sept. 18, 1986; 63 FR 5253, Feb. 2, 1998. Redesignated and amended at 77 FR 45943, Aug. 2, 2012]

§ 807.28 Updating device listing information.

(a) Updating of device listing information is required if an additional establishment begins to engage in any of the activities described in § 807.3(d) with respect to a listed device, such as manufacturing, developing specifications, repackaging, relabeling, or otherwise processing the device. Updating of the listing is also required if an establishment begins performing another activity on or to the device, or ceases to perform an activity on or to the device that had previously been identified on the device listing.

(b) An owner or operator shall create a new device listing using the FDA electronic device registration and listing system:

(1) If introducing into commercial distribution an exempt device identified with a product code that is not currently listed by the owner or operator; or

(2) If introducing into commercial distribution a non-exempt device with an FDA premarket submission number that is not currently listed by the owner or operator.

(c) All device listings for foreign establishments must be submitted before the device may be imported or offered for import into the United States.

(d) An owner or operator who discontinues commercial distribution of a device shall discontinue the device listing using the FDA electronic device registration and listing system. A device listing is considered discontinued if:

(1) All devices under an exempt product code have been discontinued or

(2) All devices associated with an FDA premarket submission number have been discontinued.

(e) If commercial distribution of a discontinued device is resumed, the owner or operator must reactivate the previously-discontinued listing using the electronic device registration and listing system. Any changes to the listing information for the product that is the subject of the listing such as a new establishment, new activity, or new proprietary name must be made using the electronic device registration and listing system at the time the listing is reactivated.

(f) FDA will assign one listing number for all devices exempt from premarket notification requirements under a single product code. For products not exempt from premarket notification requirements, a single listing number will be assigned by FDA for each FDA premarket submission number.

[77 FR 45943, Aug. 2, 2012]

§ 807.34 Summary of requirements for owners or operators granted a waiver from submitting required information electronically.

(a) For initial registration and listing, owners or operators who have been granted a waiver from electronic filing using the procedures set forth in § 807.21(b) must send a letter containing all of the registration and listing information described in §§ 807.22, 807.25 (and § 807.26 when such information is requested by FDA), at the times described in § 807.22, to: The Imports and Registration and Listing Team, Division of Regulatory Programs 2, Office of Regulatory Programs, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 1432, Silver Spring, MD 20993-0002.

(b) As specified in § 807.22(b)(1) and (b)(3), all owners or operators shall update their establishment registration and device listings annually during the period beginning on October 1 and ending on December 31 of each fiscal year.

(c) Failure to submit any of the required information on time, as specified in § 807.22(a) and (b), will put the establishment in a “failed to register” or “failed to list” status as applicable.

The establishment will not be considered active and the establishment registration and device listing information may not appear on the FDA Web site until the required information is submitted to and processed by FDA.

[77 FR 45943, Aug. 2, 2012, as amended at 85 FR 18442, Apr. 2, 2020]

§ 807.35 Notification of registrant.

(a) The Food and Drug Administration will assign each device establishment a registration number after verifying the initial establishment registration information that has been submitted. The owner or operator of the establishment will also be assigned an identifying number. Both numbers will be sent to the official correspondent by email, or by postal mail if the owner or operator has been granted a waiver from the requirement to file registration and listing information electronically.

(b) Owners or operators of device establishments who also manufacture or process biological products (including devices licensed under section 351 of the Public Health Service Act) or drug products at the same establishment must also register and list those products under part 607 or part 207 of this chapter, as appropriate. Registration and listing for human blood and blood products, devices licensed under section 351 of the Public Health Service Act, and licensed biological products used in the manufacture of a device licensed under section 351 of the Public Health Service Act, are subject to part 607 of this chapter; registration and listing for all other drug products (including other biological products that are also regulated as drug products) are subject to part 207 of this chapter.

(c) Although establishment registration and device listing are required to engage in the device activities described in § 807.20, validation of registration and the assignment of a device listing number in itself does not establish that the holder of the registration is legally qualified to deal in such devices and does not represent a determination by the Food and Drug Administration as to the status of any device.

[69 FR 11312, Mar. 10, 2004, as amended at 77 FR 45943, Aug. 2, 2012]

§ 807.37 Public availability of establishment registration and device listing information.

(a) Establishment registration and device listing information is available for public inspection in accordance with section 510(f) of the Federal Food, Drug, and Cosmetic Act and will be posted on the FDA website, with the exception of the information identified in paragraph (b) of this section. Requests for information by persons who do not have access to the internet should be directed to the Imports and Registration and Listing Team, Division of Regulatory Programs 2, Office of Regulatory Programs, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm.1432, Silver Spring, MD 20993-0002. In addition, there will be available for inspection at each of the Food and Drug Administration district offices the same information for firms within the geographical area of such district offices. Upon request, verification of a registration number or location of a registered establishment will be provided.

(b) The following listing information will not be available for public inspection or posted on the FDA Web site:

(1) For contract manufacturers, contract sterilizers, and private label manufacturers, the proprietary or brand name(s) under which a device is marketed and the FDA-assigned premarket submission number, if this information would reveal a confidential business relationship;

(2) FDA-assigned listing numbers.

[77 FR 45943, Aug. 2, 2012, as amended at 85 FR 18442, Apr. 2, 2020]

§ 807.39 Misbranding by reference to establishment registration or to registration number.

Registration of a device establishment or assignment of a registration number does not in any way denote approval of the establishment or its products. Any representation that creates an impression of official approval because of registration or possession of a registration number is misleading and constitutes misbranding.

§ 807.40 Establishment registration and device listing for foreign establishments importing or offering for import devices into the United States.

(a) Any establishment within any foreign country engaged in the manufacture, preparation, propagation, compounding, or processing of a device that is imported or offered for import into the United States shall register such establishment and list such devices using the FDA electronic device registration and listing system in conformance with the procedures in this section, § 807.41, and subpart B of this part. The official correspondent for the foreign establishment shall facilitate communication between the foreign establishment's management and representatives of FDA for matters relating to the registration of device establishments and the listing of device products.

(b) Each foreign establishment required to register under paragraph (a) of this section shall submit the name, address, and phone number of its United States agent as part of its initial and updated registration information in accordance with subpart B of this part. Each foreign establishment shall designate only one United States agent and may designate the United States agent to act as its official correspondent.

(1) The United States agent shall reside or maintain a place of business in the United States.

(2) Upon request from FDA, the United States agent shall assist FDA in communications with the foreign establishment, respond to questions concerning the foreign establishment's products that are imported or offered for import into the United States, and assist FDA in scheduling inspections of the foreign establishment. If the agency is unable to contact the foreign establishment directly or expeditiously, FDA may provide information or documents to the United States agent, and such an action shall be considered to be equivalent to providing the same information or documents to the foreign establishment.

(3) The foreign establishment or the United States agent shall report changes in the United States agent's name, address, or phone number to FDA within 10-business days of the change.

(c) No device may be imported or offered for import into the United States unless it is the subject of a device listing as required under subpart B of this part and is manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment; however, this restriction does not apply to devices imported or offered for import under the investigational use provisions of part 812 of this chapter.

(d) The device establishment registration and device listing information shall be in the English language.

[66 FR 59160, Nov. 27, 2001, as amended at 77 FR 45944, Aug. 2, 2012]

§ 807.41 Identification of importers and persons who import or offer for import.

(a) Upon initial registration, annually, and at the time of any changes, each foreign establishment required to register and list as provided in § 807.40(a) must, using the FDA electronic device registration and listing system, submit the name, address, telephone and fax numbers, email address, and registration number, if any has been assigned, of any importer (defined in § 807.3(x)) of the establishment's devices that is known to the foreign establishment. The foreign establishment must also specify which of the establishment's listed products each importer receives from the foreign establishment.

(b) Upon initial registration, annually, and at the time of any changes, each foreign establishment required to register and list as provided in § 807.40(a) must, using the FDA electronic device registration and listing system, submit the name, address, telephone and fax numbers, email address, and registration number, if any has been assigned, of each person who imports or offers for import the establishment's devices into the United States. The term “person who imports or offers for import,” which is defined in § 807.3(y), includes agents, brokers, or other parties used by the foreign establishment to facilitate the import of its device into the United States.

(c) For each individual or organization identified by the foreign establishment under paragraphs (a) and (b) of this section, the foreign establishment must submit to FDA electronically the current FDA premarket submission number and any other identifying information that is known to the establishment for each device being imported or offered for import by the named individuals or organizations.

[77 FR 45944, Aug. 2, 2012]

§ 807.65 Exemptions for device establishments.

The following classes of persons are exempt from registration in accordance with § 807.20 under the provisions of section 510(g)(1), (g)(2), and (g)(3) of the act, or because the Commissioner of Food and Drugs has found, under section 510(g)(5) of the act, that such registration is not necessary for the protection of the public health. The exemptions in paragraphs (d), (e), (f), and (i) of this section are limited to those classes of persons located in any State as defined in section 201(a)(1) of the act.

(a) A manufacturer of raw materials or components to be used in the manufacture or assembly of a device who would otherwise not be required to register under the provisions of this part.

(b) A manufacturer of devices to be used solely for veterinary purposes.

(c) A manufacturer of general purpose articles such as chemical reagents or laboratory equipment whose uses are generally known by persons trained in their use and which are not labeled or promoted for medical uses.

(d) Licensed practitioners, including physicians, dentists, and optometrists, who manufacture or otherwise alter devices solely for use in their practice.

(e) Pharmacies, surgical supply outlets, or other similar retail establishments making final delivery or sale to the ultimate user. This exemption also applies to a pharmacy or other similar retail establishment that purchases a device for subsequent distribution under its own name, e.g., a properly labeled health aid such as an elastic bandage or crutch, indicating “distributed by” or “manufactured for” followed by the name of the pharmacy.

(f) Persons who manufacture, prepare, propagate, compound, or process devices solely for use in research, teaching, or analysis and do not introduce such devices into commercial distribution.

(g) [Reserved]

(h) Carriers by reason of their receipt, carriage, holding or delivery of devices in the usual course of business as carriers.

(i) Persons who dispense devices to the ultimate consumer or whose major responsibility is to render a service necessary to provide the consumer (i.e., patient, physician, layman, etc.) with a device or the benefits to be derived from the use of a device; for example, a hearing aid dispenser, optician, clinical laboratory, assembler of diagnostic x-ray systems, and personnel from a hospital, clinic, dental laboratory, orthotic or prosthetic retail facility, whose primary responsibility to the ultimate consumer is to dispense or provide a service through the use of a previously manufactured device.

[42 FR 42526, Aug. 23, 1977, as amended at 58 FR 46523, Sept. 1, 1993; 61 FR 44615, Aug. 28, 1996; 65 FR 17136, Mar. 31, 2000; 66 FR 59160, Nov. 27, 2001]

§ 807.81 When a premarket notification submission is required.

(a) Except as provided in paragraph (b) of this section, each person who is required to register his establishment pursuant to § 807.20 must submit a premarket notification submission to the Food and Drug Administration at least 90 days before he proposes to begin the introduction or delivery for introduction into interstate commerce for commercial distribution of a device intended for human use which meets any of the following criteria:

(1) The device is being introduced into commercial distribution for the first time; that is, the device is not of the same type as, or is not substantially equivalent to, (i) a device in commercial distribution before May 28, 1976, or (ii) a device introduced for commercial distribution after May 28, 1976, that has subsequently been reclassified into class I or II.

(2) The device is being introduced into commercial distribution for the first time by a person required to register, whether or not the device meets the criteria in paragraph (a)(1) of this section.

(3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification:

(i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.

(ii) A major change or modification in the intended use of the device.

(b)(1) A premarket notification under this subpart is not required for a device for which:

(i) A premarket approval application under section 515 of the act, or for which a petition to reclassify under section 513(f)(2) of the act, is pending before the Food and Drug Administration, or

(ii) There is a predetermined change control plan (PCCP) cleared under section 515C of the act, provided that the change is consistent with the PCCP.

(2) The appropriate FDA Center Director may determine that the submission and grant of a written request for an exception or alternative under § 801.128 or § 809.11 of this chapter satisfies the requirement in paragraph (a)(3) of this section.

(c) In addition to complying with the requirements of this part, owners or operators of device establishments that manufacture radiation-emitting electronic products, as defined in § 1000.3 of this chapter, shall comply with the reporting requirements of part 1002 of this chapter.

[42 FR 42526, Aug. 23, 1977, as amended at 72 FR 73601, Dec. 28, 2007; 89 FR 18792, Mar. 15, 2024]

§ 807.85 Exemption from premarket notification.

(a) A custom device is exempt from premarket notification requirements of this subpart if the device is within the meaning of section 520(b) of the Federal Food, Drug, and Cosmetic Act.

(1) It is intended for use by a patient named in the order of the physician or dentist (or other specially qualified person); or

(2) It is intended solely for use by a physician or dentist (or other specially qualified person) and is not generally available to, or generally used by, other physicians or dentists (or other specially qualified persons).

(b) A distributor who places a device into commercial distribution for the first time under his own name and a repackager who places his own name on a device and does not change any other labeling or otherwise affect the device shall be exempted from the premarket notification requirements of this subpart if:

(1) The device was in commercial distribution before May 28, 1976; or

(2) A premarket notification submission was filed by another person.

[42 FR 42526, Aug. 23, 1977, as amended at 81 FR 70340, Oct. 12, 2016]

§ 807.87 Information required in a premarket notification submission.

Each premarket notification submission shall contain the following information:

(a) The device name, including both the trade or proprietary name and the common or usual name or classification name of the device.

(b) The establishment registration number, if applicable, of the owner or operator submitting the premarket notification submission.

(c) The class in which the device has been put under section 513 of the act and, if known, its appropriate panel; or, if the owner or operator determines that the device has not been classified under such section, a statement of that determination and the basis for the person's determination that the device is not so classified.

(d) Action taken by the person required to register to comply with the requirements of the act under section 514 for performance standards.

(e) Proposed labels, labeling, and advertisements sufficient to describe the device, its intended use, and the directions for its use. Where applicable, photographs or engineering drawings should be supplied.

(f) A statement indicating the device is similar to and/or different from other products of comparable type in commercial distribution, accompanied by data to support the statement. This information may include an identification of similar products, materials, design considerations, energy expected to be used or delivered by the device, and a description of the operational principles of the device.

(g) Where a person required to register intends to introduce into commercial distribution a device that has undergone a significant change or modification that could significantly affect the safety or effectiveness of the device, or the device is to be marketed for a new or different indication for use, the premarket notification submission must include appropriate supporting data to show that the manufacturer has considered what consequences and effects the change or modification or new use might have on the safety and effectiveness of the device.

(h) A 510(k) summary as described in § 807.92 or a 510(k) statement as described in § 807.93.

(i) A financial certification or disclosure statement or both, as required by part 54 of this chapter.

(j) For a submission supported by clinical data:

(1) If the data are from clinical investigations conducted in the United States, a statement that each investigation was conducted in compliance with applicable requirements in the protection of human subjects regulations in part 50 of this chapter, the institutional review boards regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105, and the investigational device exemptions regulations in part 812 of this chapter, or if the investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.

(2) If the data are from clinical investigations conducted outside the United States, the requirements under § 812.28 of this chapter apply. If any such investigation was not conducted in accordance with good clinical practice (GCP) as described in § 812.28(a) of this chapter, include either a waiver request in accordance with § 812.28(c) of the chapter or a brief statement of the reason for not conducting the investigation in accordance with GCP and a description of steps taken to ensure that the data and results are credible and accurate and that the rights, safety, and well-being of subjects have been adequately protected.

(k) For submissions claiming substantial equivalence to a device which has been classified into class III under section 513(b) of the act:

(1) Which was introduced or delivered for introduction into interstate commerce for commercial distribution before December 1, 1990; and

(2) For which no final regulation requiring premarket approval has been issued under section 515(b) of the act, a summary of the types of safety and effectiveness problems associated with the type of devices being compared and a citation to the information upon which the summary is based (class III summary). The 510(k) submitter shall also certify that a reasonable search of all information known or otherwise available about the class III device and other similar legally marketed devices has been conducted (class III certification), as described in § 807.94. This information does not refer to information that already has been submitted to the Food and Drug Administration (FDA) under section 519 of the act. FDA may require the submission of the adverse safety and effectiveness data described in the class III summary or citation.

(l) A statement that the submitter believes, to the best of his or her knowledge, that all data and information submitted in the premarket notification are truthful and accurate and that no material fact has been omitted.

(m) Any additional information regarding the device requested by the Commissioner that is necessary for the Commissioner to make a finding as to whether or not the device is substantially equivalent to a device in commercial distribution. A request for additional information will advise the owner or operator that there is insufficient information contained in the original premarket notification submission for the Commissioner to make this determination and that the owner or operator may either submit the requested data or a new premarket notification containing the requested information at least 90 days before the owner or operator intends to market the device, or submit a premarket approval application in accordance with section 515 of the act. If the additional information is not submitted within 30 days following the date of the request, the Commissioner will consider the premarket notification to be withdrawn.

[42 FR 42526, Aug. 23, 1977, as amended at 57 FR 18066, Apr. 28, 1992; 59 FR 64295, Dec. 14, 1994; 63 FR 5253, Feb. 2, 1998; 83 FR 7385, Feb. 21, 2018; 89 FR 18793, Mar. 15, 2024]

§ 807.90 Format of a premarket notification submission.

Each premarket notification submission pursuant to this part shall be submitted in accordance with this section. Each submission shall:

(a)(1) For devices regulated by the Center for Devices and Radiological Health, be addressed to the current address displayed on the website https://www.fda.gov/cdrhsubmissionaddress.

(2) For devices regulated by the Center for Biologics Evaluation and Research, be addressed to the current address displayed on the website https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm; or for devices regulated by the Center for Drug Evaluation and Research, be addressed to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Information about devices regulated by the Center for Biologics Evaluation and Research is available at https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/default.htm.

(3) All inquiries regarding a premarket notification submission should be sent to the address in this section or one of the current addresses displayed on the Food and Drug Administration's website.

(b) [Reserved]

(c) Be submitted as a single version in electronic format.

(d) Be submitted separately for each product the manufacturer intends to market.

(e) Designated “510(k) Notification” in the cover letter.

[42 FR 42526, Aug. 23, 1977, as amended at 53 FR 11252, Apr. 6, 1988; 55 FR 11169, Mar. 27, 1990; 65 FR 17137, Mar. 31, 2000; 70 FR 14986, Mar. 24, 2005; 75 FR 20915, Apr. 22, 2010; 80 FR 18094, Apr. 3, 2015; 84 FR 68339, Dec. 16, 2019]

§ 807.92 Content and format of a 510(k) summary.

(a) A 510(k) summary shall be in sufficient detail to provide an understanding of the basis for a determination of substantial equivalence. FDA will accept summaries as well as amendments thereto until such time as FDA issues a determination of substantial equivalence. All 510(k) summaries shall contain the following information:

(1) The submitter's name, address, telephone number, a contact person, and the date the summary was prepared;

(2) The name of the device, including the trade or proprietary name if applicable, the common or usual name, and the classification name, if known;

(3) An identification of the legally marketed device to which the submitter claims equivalence. A legally marketed device to which a new device may be compared for a determination regarding substantial equivalence is a device that was legally marketed prior to May 28, 1976, or a device which has been reclassified from class III to class II or I (the predicate), or a device which has been found to be substantially equivalent through the 510(k) premarket notification process;

(4) A description of the device that is the subject of the premarket notification submission, such as might be found in the labeling or promotional material for the device, including an explanation of how the device functions, the scientific concepts that form the basis for the device, and the significant physical and performance characteristics of the device, such as device design, material used, and physical properties;

(5) A statement of the intended use of the device that is the subject of the premarket notification submission, including a general description of the diseases or conditions that the device will diagnose, treat, prevent, cure, or mitigate, including a description, where appropriate, of the patient population for which the device is intended. If the indication statements are different from those of the legally marketed device identified in paragraph (a)(3) of this section, the 510(k) summary shall contain an explanation as to why the differences are not critical to the intended therapeutic, diagnostic, prosthetic, or surgical use of the device, and why the differences do not affect the safety and effectiveness of the device when used as labeled; and

(6) If the device has the same technological characteristics (i.e., design, material, chemical composition, energy source) as the predicate device identified in paragraph (a)(3) of this section, a summary of the technological characteristics of the new device in comparison to those of the predicate device. If the device has different technological characteristics from the predicate device, a summary of how the technological characteristics of the device compare to a legally marketed device identified in paragraph (a)(3) of this section.

(b) 510(k) summaries for those premarket submissions in which a determination of substantial equivalence is also based on an assessment of performance data shall contain the following information:

(1) A brief discussion of the nonclinical tests submitted, referenced, or relied on in the premarket notification submission for a determination of substantial equivalence;

(2) A brief discussion of the clinical tests submitted, referenced, or relied on in the premarket notification submission for a determination of substantial equivalence. This discussion shall include, where applicable, a description of the subjects upon whom the device was tested, a discussion of the safety or effectiveness data obtained from the testing, with specific reference to adverse effects and complications, and any other information from the clinical testing relevant to a determination of substantial equivalence; and

(3) The conclusions drawn from the nonclinical and clinical tests that demonstrate that the device is as safe, as effective, and performs as well as or better than the legally marketed device identified in paragraph (a)(3) of this section.

(c) The summary should be in a separate section of the submission, beginning on a new page and ending on a page not shared with any other section of the premarket notification submission, and should be clearly identified as a “510(k) summary.”

(d) Any other information reasonably deemed necessary by the agency.

[57 FR 18066, Apr. 28, 1992, as amended at 59 FR 64295, Dec. 14, 1994]

§ 807.93 Content and format of a 510(k) statement.

(a)(1) A 510(k) statement submitted as part of a premarket notification shall state as follows:

I certify that, in my capacity as (the position held in company by person required to submit the premarket notification, preferably the official correspondent in the firm), of (company name), I will make available all information included in this premarket notification on safety and effectiveness within 30 days of request by any person if the device described in the premarket notification submission is determined to be substantially equivalent. The information I agree to make available will be a duplicate of the premarket notification submission, including any adverse safety and effectiveness information, but excluding all patient identifiers, and trade secret and confidential commercial information, as defined in 21 CFR 20.61.

(2) The statement in paragraph (a)(1) of this section should be signed by the certifier, made on a separate page of the premarket notification submission, and clearly identified as “510(k) statement.”

(b) All requests for information included in paragraph (a) of this section shall be made in writing to the certifier, whose name will be published by FDA on the list of premarket notification submissions for which substantial equivalence determinations have been made.

(c) The information provided to requestors will be a duplicate of the premarket notification submission, including any adverse information, but excluding all patient identifiers, and trade secret and confidential commercial information as defined in § 20.61 of this chapter.

[59 FR 64295, Dec. 14, 1994]

§ 807.94 Format of a class III certification.

(a) A class III certification submitted as part of a premarket notification shall state as follows:

I certify, in my capacity as (position held in company), of (company name), that I have conducted a reasonable search of all information known or otherwise available about the types and causes of safety or effectiveness problems that have been reported for the (type of device). I further certify that I am aware of the types of problems to which the (type of device) is susceptible and that, to the best of my knowledge, the following summary of the types and causes of safety or effectiveness problems about the (type of device) is complete and accurate.

(b) The statement in paragraph (a) of this section should be signed by the certifier, clearly identified as “class III certification,” and included at the beginning of the section of the premarket notification submission that sets forth the class III summary.

[59 FR 64296, Dec. 14, 1994]

§ 807.95 Confidentiality of information.

(a) The Food and Drug Administration will disclose publicly whether there exists a premarket notification submission under this part:

(1) Where the device is on the market, i.e., introduced or delivered for introduction into interstate commerce for commercial distribution;

(2) Where the person submitting the premarket notification submission has disclosed, through advertising or any other manner, his intent to market the device to scientists, market analysts, exporters, or other individuals who are not employees of, or paid consultants to, the establishment and who are not in an advertising or law firm pursuant to commercial arrangements with appropriate safeguards for secrecy; or

(3) Where the device is not on the market and the intent to market the device has not been so disclosed, except where the submission is subject to an exception under paragraph (b) or (c) of this section.

(b) The Food and Drug Administration will not disclose publicly the existence of a premarket notification submission for a device that is not on the market and where the intent to market the device has not been disclosed for 90 days from the date of receipt of the submission, if:

(1) The person submitting the premarket notification submission requests in the submission that the Food and Drug Administration hold as confidential commercial information the intent to market the device and submits a certification to the Commissioner:

(i) That the person considers his intent to market the device to be confidential commercial information;

(ii) That neither the person nor, to the best of his knowledge, anyone else, has disclosed through advertising or any other manner, his intent to market the device to scientists, market analysts, exporters, or other individuals, except employees of, or paid consultants to, the establishment or individuals in an advertising or law firm pursuant to commercial arrangements with appropriate safeguards for secrecy;

(iii) That the person will immediately notify the Food and Drug Administration if he discloses the intent to market the device to anyone, except employees of, or paid consultants to, the establishment or individuals in an advertising or law firm pursuant to commercial arrangements with appropriate safeguards for secrecy;

(iv) That the person has taken precautions to protect the confidentiality of the intent to market the device; and

(v) That the person understands that the submission to the government of false information is prohibited by 18 U.S.C. 1001 and 21 U.S.C. 331(q); and

(2) The Commissioner agrees that the intent to market the device is confidential commercial information.

(c) Where the Commissioner determines that the person has complied with the procedures described in paragraph (b) of this section with respect to a device that is not on the market and where the intent to market the device has not been disclosed, and the Commissioner agrees that the intent to market the device is confidential commercial information, the Commissioner will not disclose the existence of the submission for 90 days from the date of its receipt by the agency. In addition, the Commissioner will continue not to disclose the existence of such a submission for the device for an additional time when any of the following occurs:

(1) The Commissioner requests in writing additional information regarding the device pursuant to § 807.87(h), in which case the Commissioner will not disclose the existence of the submission until 90 days after the Food and Drug Administration's receipt of a complete premarket notification submission;

(2) The Commissioner determines that the device intended to be introduced is a class III device and cannot be marketed without premarket approval or reclassification, in which case the Commissioner will not disclose the existence of the submission unless a petition for reclassification is submitted under section 513(f)(2) of the act and its existence can be disclosed under § 860.5(d) of this chapter; or

(d) FDA will make a 510(k) summary of the safety and effectiveness data available to the public within 30 days of the issuance of a determination that the device is substantially equivalent to another device. Accordingly, even when a 510(k) submitter has complied with the conditions set forth in paragraphs (b) and (c) of this section, confidentiality for a premarket notification submission cannot be granted beyond 30 days after FDA issues a determination of equivalency.

(e) Data or information submitted with, or incorporated by reference in, a premarket notification submission (other than safety and effectiveness data that have not been disclosed to the public) shall be available for disclosure by the Food and Drug Administration when the intent to market the device is no longer confidential in accordance with this section, unless exempt from public disclosure in accordance with part 20 of this chapter. Upon final classification, data and information relating to safety and effectiveness of a device classified in class I (general controls) or class II (performance standards) shall be available for public disclosure. Data and information relating to safety and effectiveness of a device classified in class III (premarket approval) that have not been released to the public shall be retained as confidential unless such data and information become available for release to the public under § 860.5(d) or other provisions of this chapter.

[42 FR 42526, Aug. 23, 1977, as amended at 53 FR 11252, Apr. 6, 1988; 57 FR 18067, Apr. 28, 1992; 59 FR 64296, Dec. 14, 1994; 84 FR 68339, Dec. 16, 2019]

§ 807.97 Misbranding by reference to premarket notification.

Submission of a premarket notification in accordance with this subpart, and a subsequent determination by the Commissioner that the device intended for introduction into commercial distribution is substantially equivalent to a device in commercial distribution before May 28, 1976, or is substantially equivalent to a device introduced into commercial distribution after May 28, 1976, that has subsequently been reclassified into class I or II, does not in any way denote official approval of the device. Any representation that creates an impression of official approval of a device because of complying with the premarket notification regulations is misleading and constitutes misbranding.

§ 807.100 FDA action on a premarket notification.

(a) After review of a premarket notification, FDA will:

(1) Issue an order declaring the device to be substantially equivalent to a legally marketed predicate device;

(2) Issue an order declaring the device to be not substantially equivalent to any legally marketed predicate device;

(3) Request additional information; or

(4) Withhold the decision until a certification or disclosure statement is submitted to FDA under part 54 of this chapter.

(5) Advise the applicant that the premarket notification is not required. Until the applicant receives an order declaring a device substantially equivalent, the applicant may not proceed to market the device.

(b) FDA will determine that a device is substantially equivalent to a predicate device using the following criteria:

(1) The device has the same intended use as the predicate device; and

(2) The device:

(i) Has the same technological characteristics as the predicate device; or

(ii)(A) Has different technological characteristics, such as a significant change in the materials, design, energy source, or other features of the device from those of the predicate device;

(B) The data submitted establishes that the device is substantially equivalent to the predicate device and contains information, including clinical data if deemed necessary by the Commissioner, that demonstrates that the device is as safe and as effective as a legally marketed device; and

(C) Does not raise different questions of safety and effectiveness than the predicate device.

(3) The predicate device has not been removed from the market at the initiative of the Commissioner of Food and Drugs or has not been determined to be misbranded or adulterated by a judicial order.

[57 FR 58403, Dec. 10, 1992, as amended at 63 FR 5253, Feb. 2, 1998]

§ 808.1 Scope.

(a) Introduction. This part prescribes procedures for the submission, review, and approval of applications for exemption from Federal preemption of State and local requirements applicable to medical devices under section 521 of the Federal Food, Drug, and Cosmetic Act.

(b) General rule for State and local requirements respecting devices. Section 521(a) of the Federal Food, Drug, and Cosmetic Act contains special provisions governing the regulation of devices by States and localities. That section prescribes a general rule that after May 28, 1976, no State or political subdivision of a State may establish or continue in effect any requirement with respect to a medical device intended for human use having the force and effect of law (whether established by statute, ordinance, regulation, or court decision), which is different from, or in addition to, any requirement applicable to such device under any provision of the Federal Food, Drug, and Cosmetic Act and which relates to the safety or effectiveness of the device or to any other matter included in a requirement applicable to the device under the Federal Food, Drug, and Cosmetic Act.

(c) Exempting from preemption certain State or local requirements respecting devices. Section 521(b) of the Federal Food, Drug, and Cosmetic Act contains a provision whereby the Commissioner of Food and Drugs may, upon application by a State or political subdivision, allow imposition of a requirement which is different from, or in addition to, any requirement applicable under the Federal Food, Drug, and Cosmetic Act to the device (and which is thereby preempted) by promulgating a regulation in accordance with this part exempting the State or local requirement from preemption. The granting of an exemption does not affect the applicability to the device of any requirements under the Federal Food, Drug, and Cosmetic Act. The Commissioner may promulgate an exemption regulation for the preempted requirement if he makes either of the following findings:

(1) That the requirement is more stringent than a requirement under the Federal Food, Drug, and Cosmetic Act applicable to the device; or

(2) That the requirement is required by compelling local conditions and compliance with the requirement would not cause the device to be in violation of any applicable requirement under the Federal Food, Drug, and Cosmetic Act.

(d) Meaning of “requirements applicable to a device.” State or local requirements are preempted only when the Food and Drug Administration has established specific counterpart regulations or there are other specific requirements applicable to a particular device under the Federal Food, Drug, and Cosmetic Act, thereby making any existing divergent State or local requirements applicable to the device different from, or in addition to, the specific Food and Drug Administration requirements. There are other State or local requirements that affect devices that are not preempted by section 521(a) of the Federal Food, Drug, and Cosmetic Act because they are not “requirements applicable to a device” within the meaning of section 521(a) of the Federal Food, Drug, and Cosmetic Act. The following are examples of State or local requirements that are not regarded as preempted by section 521 of the Federal Food, Drug, and Cosmetic Act:

(1) Section 521(a) does not preempt State or local requirements of general applicability where the purpose of the requirement relates either to other products in addition to devices (e.g., requirements such as general electrical codes, and the Uniform Commercial Code (warranty of fitness)), or to unfair trade practices in which the requirements are not limited to devices.

(2) Section 521(a) does not preempt State or local requirements that are equal to, or substantially identical to, requirements imposed by or under the Federal Food, Drug, and Cosmetic Act.

(3) Section 521(a) does not preempt State or local permits, licensing, registration, certification, or other requirements relating to the approval or sanction of the practice of medicine, dentistry, optometry, pharmacy, nursing, podiatry, or any other of the healing arts or allied medical sciences or related professions or occupations that administer, dispense, or sell devices. However, regulations issued under section 520(e) or (g) of the Federal Food, Drug, and Cosmetic Act may impose restrictions on the sale, distribution, or use of a device beyond those prescribed in State or local requirements. If there is a conflict between such restrictions and State or local requirements, the Federal regulations shall prevail.

(4) Section 521(a) does not preempt specifications in contracts entered into by States or localities for procurement of devices.

(5) Section 521(a) does not preempt criteria for payment of State or local obligations under Medicaid and similar Federal, State or local health-care programs.

(6)(i) Section 521(a) does not preempt State or local requirements respecting general enforcement, e.g., requirements that State inspection be permitted of factory records concerning all devices, registration, and licensing requirements for manufacturers and others, and prohibition of manufacture of devices in unlicensed establishments. However, Federal regulations issued under sections 519 and 520(f) of the Federal Food, Drug, and Cosmetic Act may impose requirements for records and reports and good manufacturing practices beyond those prescribed in State or local requirements. If there is a conflict between such regulations and State or local requirements, the Federal regulations shall prevail.

(ii) Generally, section 521(a) does not preempt a State or local requirement prohibiting the manufacture of adulterated or misbranded devices. Where, however, such a prohibition has the effect of establishing a substantive requirement for a specific device, e.g., a specific labeling requirement, then the prohibition will be preempted if the requirement is different from, or in addition to, a Federal requirement established under the Federal Food, Drug, and Cosmetic Act. In determining whether such a requirement is preempted, the determinative factor is how the requirement is interpreted and enforced by the State or local government and not the literal language of the statute, which may be identical to a provision in the Federal Food, Drug, and Cosmetic Act.

(7) Section 521(a) does not preempt State or local provisions respecting delegations of authority and related administrative matters relating to devices.

(8) Section 521(a) does not preempt a State or local requirement whose sole purpose is raising revenue or charging fees for services, registration, or regulatory programs.

(9) Section 521(a) does not preempt State or local requirements of the types that have been developed under the Atomic Energy Act of 1954 (42 U.S.C. 2011 note), as amended, Subchapter C—Electronic Product Radiation Control of the Federal Food, Drug, and Cosmetic Act (formerly the Radiation Control for Health and Safety Act of 1968), and other Federal statutes, until such time as the Food and Drug Administration issues specific requirements under the Federal Food, Drug, and Cosmetic Act applicable to these types of devices.

(10) Part 820 of this chapter (21 CFR part 820) (CGMP requirements) does not preempt remedies created by States or Territories of the United States, the District of Columbia, or the Commonwealth of Puerto Rico.

(e) Determination of equivalence or difference of requirements applicable to a device. It is the responsibility of the Food and Drug Administration, subject to review by Federal courts, to determine whether a State or local requirement is equal to, or substantially identical to, requirements imposed by or under the Federal Food, Drug, and Cosmetic Act, or is different from, or in addition to, such requirements, in accordance with the procedures provided by this part. However, it is the responsibility of States and political subdivisions to determine initially whether to seek exemptions from preemption. Any State or political subdivision whose requirements relating to devices are preempted by section 521(a) may petition the Commissioner of Food and Drugs for exemption from preemption, in accordance with the procedures provided by this part.

(f) Applicability of Federal requirements respecting devices. The Federal requirement with respect to a device applies whether or not a corresponding State or local requirement is preempted or exempted from preemption. As a result, if a State or local requirement that the Food and Drug Administration has exempted from preemption is not as broad in its application as the Federal requirement, the Federal requirement applies to all circumstances not covered by the State or local requirement.

(g) Exemptions not applicable to certain State or local government requirements specifically related to hearing products. An exemption under this part shall not apply to any State or local government law, regulation, order, or other requirement specifically related to hearing products, including any requirement for the supervision, prescription, or other order, involvement, or intervention of a licensed person for consumers to access over-the-counter hearing aids, that:

(1) Would restrict or interfere with the servicing, marketing, sale, dispensing, use, customer support, or distribution of over-the-counter hearing aids, as defined under section 520(q) of the Federal Food, Drug, and Cosmetic Act, through in-person transactions, by mail, or online; and

(2) Is different from, in addition to, or otherwise not identical to, the regulations issued under section 709(b) of the FDA Reauthorization Act of 2017.

[43 FR 18665, May 2, 1978, as amended at 45 FR 67336, Oct. 10, 1980; 61 FR 52654, Oct. 7, 1996; 73 FR 34859, June 19, 2008; 87 FR 50761, Aug. 17, 2022]

§ 808.3 Definitions.

Compelling local conditions includes any factors, considerations, or circumstances prevailing in, or characteristic of, the geographic area or population of the State or political subdivision that justify exemption from preemption.

More stringent refers to a requirement of greater restrictiveness or one that is expected to afford to those who may be exposed to a risk of injury from a device a higher degree of protection than is afforded by a requirement applicable to the device under the Federal Food, Drug, and Cosmetic Act.

Political subdivision or locality means any lawfully established local governmental unit within a State which unit has the authority to establish or continue in effect any requirement having the force and effect of law with respect to a device intended for human use.

State means any State or Territory of the United States, including but not limited to, the District of Columbia and the Commonwealth of Puerto Rico.

Substantially identical to refers to the fact that a State or local requirement does not significantly differ in effect from a Federal requirement.

[87 FR 50762, Aug. 17, 2022]

§ 808.5 Advisory opinions.

(a) Any State, political subdivision, or other interested person may request an advisory opinion from the Commissioner with respect to any general matter concerning preemption of State or local device requirements or with respect to whether the Food and Drug Administration regards particular State or local requirements, or proposed requirements, as preempted.

(1) Such an advisory opinion may be requested and may be granted in accordance with § 10.85 of this chapter.

(2) The Food and Drug Administration, in its discretion and after consultation with the State or political subdivision, may treat a request by a State or political subdivision for an advisory opinion as an application for exemption from preemption under § 808.20.

(b) The Commissioner may issue an advisory opinion relating to a State or local requirement on his own initiative when he makes one of the following determinations:

(1) A requirement with respect to a device for which an application for exemption from preemption has been submitted under § 808.20 is not preempted by section 521(a) of the Federal Food, Drug, and Cosmetic Act because it is: (i) Equal to or substantially identical to a requirement under the Federal Food, Drug, and Cosmetic Act applicable to the device, or (ii) is not a requirement within the meaning of section 521 of the Federal Food, Drug, and Cosmetic Act and therefore is not preempted;

(2) A proposed State or local requirement with respect to a device is not eligible for exemption from preemption because the State or local requirement has not been issued in final form. In such a case, the advisory opinion may indicate whether the proposed requirement would be preempted and, if it would be preempted, whether the Food and Drug Administration would propose to grant an exemption from preemption;

(3) Issuance of such an advisory opinion is in the public interest.

[43 FR 18665, May 2, 1978, as amended at 87 FR 50761, Aug. 17, 2022]

§ 808.20 Application.

(a) Any State or political subdivision may apply to the Food and Drug Administration for an exemption from preemption for any requirement that it has enacted and that is preempted. An exemption may only be granted for a requirement that has been enacted, promulgated, or issued in final form by the authorized body or official of the State or political subdivision so as to have the force and effect of law. However, an application for exemption may be submitted before the effective date of the requirement.

(b) An application for exemption shall be in the form of a letter to the Commissioner of Food and Drugs and shall be signed by an individual who is authorized to request the exemption on behalf of the State or political subdivision. An original and two copies of the letter and any accompanying material, as well as any subsequent reports or correspondence concerning an application, shall be submitted to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. The outside wrapper of any application, report, or correspondence should indicate that it concerns an application for exemption from preemption of device requirements.

(c) For each requirement for which an exemption is sought, the application shall include the following information to the fullest extent possible, or an explanation of why such information has not been included:

(1) Identification and a current copy of any statute, rule, regulation, or ordinance of the State or political subdivision considered by the State or political subdivision to be a requirement which is preempted, with a reference to the date of enactment, promulgation, or issuance in final form. The application shall also include, where available, copies of any legislative history or background materials pertinent to enactment, promulgation, or issuance of the requirement, including hearing reports or studies concerning development or consideration of the requirement. If the requirement has been subject to any judicial or administrative interpretations, the State or political subdivision shall furnish copies of such judicial or administrative interpretations.

(2) A comparison of the requirement of the State or political subdivision and any applicable Federal requirements to show similarities and differences.

(3) Information on the nature of the problem addressed by the requirement of the State or political subdivision.

(4) Identification of which (or both) of the following bases is relied upon for seeking an exemption from preemption:

(i) The requirement is more stringent than a requirement applicable to a device under the Federal Food, Drug, and Cosmetic Act. If the State or political subdivision relies upon this basis for exemption from preemption, the application shall include information, data, or material showing how and why the requirement of the State or political subdivision is more stringent than requirements under the Federal Food, Drug, and Cosmetic Act.

(ii) The requirement is required by compelling local conditions, and compliance with the requirement would not cause the device to be in violation of any applicable requirement under the Federal Food, Drug, and Cosmetic Act. If the State or political subdivision relies upon this basis for exemption from preemption, the application shall include information, data, or material showing why compliance with the requirement of the State or political subdivision would not cause a device to be in violation of any applicable requirement under the Federal Food, Drug, and Cosmetic Act and why the requirement is required by compelling local conditions. The application shall also explain in detail the compelling local conditions that justify the requirement.

(5) The title of the chief administrative or legal officers of that State or local agency that has primary responsibility for administration of the requirement.

(6) When requested by the Food and Drug Administration, any records concerning administration of any requirement which is the subject of an exemption or an application for an exemption from preemption.

(7) Information on how the public health may be benefitted and how interstate commerce may be affected, if an exemption is granted.

(8) Any other pertinent information respecting the requirement voluntarily submitted by the applicant.

(d) If litigation regarding applicability of the requirement is pending, the State or political subdivision may so indicate in its application and request expedited action on such application.

[43 FR 18665, May 2, 1978; 43 FR 22010, May 23, 1978, as amended at 49 FR 3646, Jan. 30, 1984; 59 FR 14365, Mar. 28, 1994; 87 FR 50761, Aug. 17, 2022; 88 FR 45067, July 14, 2023]

§ 808.25 Procedures for processing an application.

(a) Upon receipt of an application for an exemption from preemption submitted in accordance with § 808.20, the Commissioner shall notify the State or political subdivision of the date of such receipt.

(b) If the Commissioner finds that an application does not meet the requirements of § 808.20, he shall notify the State or political subdivision of the deficiencies in the application and of the opportunity to correct such deficiencies. A deficient application may be corrected at any time.

(c) After receipt of an application meeting the requirements of § 808.20, the Commissioner shall review such application and determine whether to grant or deny an exemption from preemption for each requirement which is the subject of the application. The Commissioner shall then issue in the Federal Register a proposed regulation either to grant or to deny an exemption from preemption. The Commissioner shall also issue in the Federal Register a notice of opportunity to request an oral hearing before the Commissioner or the Commissioner's designee.

(d) A request for an oral hearing may be made by the State or political subdivision or any other interested person. Such request shall be submitted to the Dockets Management Staff within the period of time prescribed in the notice and shall include an explanation of why an oral hearing, rather than submission of written comments only, is essential to the presentation of views on the application for exemption from preemption and the proposed regulation.

(e) If a timely request for an oral hearing is made, the Commissioner shall review such a request and may grant a legislative-type informal oral hearing pursuant to part 15 of this chapter by publishing in the Federal Register a notice of the hearing in accordance with § 15.20 of this chapter. The scope of the oral hearing shall be limited to matters relevant to the application for exemption from preemption and the proposed regulation. Oral or written presentations at the oral hearing which are not relevant to the application shall be excluded from the administrative record of the hearing.

(f) If a request for hearing is not timely made or a notice of appearance is not filed pursuant to § 15.21 of this chapter, the Commissioner shall consider all written comments submitted and publish a final rule in accordance with paragraph (g) of this section.

(g)(1) The Commissioner shall review all written comments submitted on the proposed rule and the administrative record of the oral hearing, if an oral hearing has been granted, and shall publish in the Federal Register a final rule in subpart C of this part identifying any requirement in the application for which exemption from preemption is granted, or conditionally granted, and any requirement in the application for which exemption from preemption is not granted.

(2) The Commissioner may issue a regulation granting or conditionally granting an application for an exemption from preemption for any requirement if the Commissioner makes either of the following findings:

(i) The requirement is more stringent than a requirement applicable to the device under the Federal Food, Drug, and Cosmetic Act;

(ii) The requirement is required by compelling local conditions, and compliance with the requirement would not cause the device to be in violation of any requirement applicable to the device under the Federal Food, Drug, and Cosmetic Act.

(3) The Commissioner may not grant an application for an exemption from preemption for any requirement with respect to a device if the Commissioner determines that the granting of an exemption would not be in the best interest of public health, taking into account the potential burden on interstate commerce.

(h) An advisory opinion pursuant to § 808.5 or a regulation pursuant to paragraph (g) of this section constitutes final agency action.

[43 FR 18665, May 2, 1978, as amended at 87 FR 50761, Aug. 17, 2022; 88 FR 45067, July 14, 2023]

§ 808.35 Revocation of an exemption.

(a) An exemption from preemption pursuant to a regulation under this part shall remain effective until the Commissioner revokes such exemption.

(b) The Commissioner may by regulation, in accordance with § 808.25, revoke an exemption from preemption for any of the following reasons:

(1) An exemption may be revoked upon the effective date of a newly established requirement under the Federal Food, Drug, and Cosmetic Act which, in the Commissioner's view, addresses the objectives of an exempt requirement and which is described, when issued, as preempting a previously exempt State or local requirement.

(2) An exemption may be revoked upon a finding that there has occurred a change in the bases listed in § 808.20(c)(4) upon which the exemption was granted.

(3) An exemption may be revoked if it is determined that a condition placed on the exemption by the regulation under which the exemption was granted has not been met or is no longer being met.

(4) An exemption may be revoked if a State or local jurisdiction fails to submit records as provided in § 808.20(c)(6).

(5) An exemption may be revoked if a State or local jurisdiction to whom the exemption was originally granted requests revocation.

(6) An exemption may be revoked if it is determined that it is no longer in the best interests of the public health to continue the exemption.

(c) An exemption that has been revoked may be reinstated, upon request from the State or political subdivision, if the Commissioner, in accordance with the procedures in § 808.25, determines that the grounds for revocation are no longer applicable except that the Commissioner may permit abbreviated submissions of the documents and materials normally required for an application for exemption under § 808.20.

[43 FR 18665, May 2, 1978, as amended at 87 FR 50761, Aug. 17, 2022]

§ 808.53 [Reserved]

§ 808.55 California.

The following California medical device requirements are preempted under section 521(a) of the Federal Food, Drug, and Cosmetic Act, and FDA has denied them exemption from preemption:

(a) Medical devices; general provisions. Sherman Food, Drug, and Cosmetic Law, Division 21 of the California Health and Safety Code, sections 26207, 26607, 26614, 26615, 26618, 26631, 26640, and 26441, to the extent that they apply to devices; and

(b) Ophthalmic devices; quality standards. California Business and Professions Code, section 2541.3 to the extent that it requires adoption of the American National Standards Institute standards Z-80.1 and Z-80.2.

[87 FR 50762, Aug. 17, 2022]

§§ 808.57--808.101 [Reserved]

§ 809.3 Definitions.

(a) In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act.

(b) A product class is all those products intended for use for a particular determination or for a related group of determinations or products with common or related characteristics or those intended for common or related uses. A class may be further divided into subclasses when appropriate.

(c) [Reserved]

(d) Act means the Federal Food, Drug, and Cosmetic Act.

[41 FR 6903, Feb. 13, 1976, as amended at 45 FR 7484, Feb. 1, 1980; 89 FR 37445, May 6, 2024; 90 FR 45136, Sept. 19, 2025]

§ 809.4 Confidentiality of submitted information.

Data and information submitted under § 809.10(c) that are shown to fall within the exemption established in § 20.61 of this chapter shall be treated as confidential by the Food and Drug Administration and any person to whom the data and information are referred. The Food and Drug Administration will determine whether information submitted will be treated as confidential in accordance with the provisions of part 20 of this chapter.

[45 FR 7484, Feb. 1, 1980]

§ 809.10 Labeling for in vitro diagnostic products.

(a) The label for an in vitro diagnostic product shall state the following information, except where such information is not applicable, or as otherwise specified in a standard for a particular product class or as provided in paragraph (e) of this section. Section 201(k) of the act provides that “a requirement made by or under authority of this act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper.”

(1) The proprietary name and established name (common or usual name), if any.

(2) The intended use or uses of the product.

(3) For a reagent, a declaration of the established name (common or usual name), if any, and quantity, proportion or concentration of each reactive ingredient; and for a reagent derived from biological material, the source and a measure of its activity. The quantity, proportion, concentration, or activity shall be stated in the system generally used and recognized by the intended user, e.g., metric, international units, etc.

(4) A statement of warnings or precautions for users as established in the regulations contained in 16 CFR part 1500 and any other warnings appropriate to the hazard presented by the product; and a statement “For In Vitro Diagnostic Use” and any other limiting statements appropriate to the intended use of the product. The limiting statement appropriate to the intended use of a prescription in vitro diagnostic product shall bear the symbol statement “Rx only” or “℞ only” or the statement “Caution: Federal law restricts this device to sale by or on the order of a ___”, the blank to be filled with the word “physician”, “dentist”, “veterinarian”, or with the descriptive designation of any other practitioner licensed by the law of the State in which the practitioner practices to use or order the use of the device.

(5) For a reagent, appropriate storage instructions adequate to protect the stability of the product. When applicable, these instructions shall include such information as conditions of temperature, light, humidity, and other pertinent factors. For products requiring manipulation, such as reconstitution and/or mixing before use, appropriate storage instructions shall be provided for the reconstituted or mixed product which is to be stored in the original container. The basis for such instructions shall be determined by reliable, meaningful, and specific test methods such as those described in § 211.166 of this chapter.

(6) For a reagent, a means by which the user may be assured that the product meets appropriate standards of identity, strength, quality and purity at the time of use. This shall be provided, both for the product as provided and for any resultant reconstituted or mixed product, by including on the label one or more of the following:

(i) An expiration date based upon the stated storage instructions.

(ii) A statement of an observable indication of an alteration of the product, e.g., turbidity, color change, precipitate, beyond its appropriate standards.

(iii) Instructions for a simple method by which the user can reasonably determine that the product meets its appropriate standards.

(7) For a reagent, a declaration of the net quantity of contents, expressed in terms of weight or volume, numerical count, or any combination of these or other terms which accurately reflect the contents of the package. The use of metric designations is encouraged, wherever appropriate. If more than a single determination may be performed using the product, any statement of the number of tests shall be consistent with instructions for use and amount of material provided.

(8) Name and place of business of manufacturer, packer, or distributor.

(9) A lot or control number, identified as such, from which it is possible to determine the complete manufacturing history of the product.

(i) If it is a multiple unit product, the lot or control number shall permit tracing the identity of the individual units.

(ii) For an instrument, the lot or control number shall permit tracing the identity of all functional subassemblies.

(iii) For multiple unit products which require the use of included units together as a system, all units should bear the same lot or control number, if appropriate, or other suitable uniform identification should be used.

(10) Except that for items in paragraphs (a) (1) through (9) of this section: (i) In the case of immediate containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information and which are packaged within an outer container from which they are removed for use, the information required by paragraphs (a) (2), (3), (4), (5), (6) (ii), (iii) and (7) of this section may appear in the outer container labeling only.

(ii) In any case in which the presence of this information on the immediate container will interfere with the test, the information may appear on the outside container or wrapper rather than on the immediate container label.

(b) Labeling accompanying each product, e.g., a package insert, shall state in one place the following information in the format and order specified below, except where such information is not applicable, or as specified in a standard for a particular product class. The labeling for a multiple-purpose instrument used for diagnostic purposes, and not committed to specific diagnostic procedures or systems, may bear only the information indicated in paragraphs (b) (1), (2), (6), (14), and (15) of this section. The labeling for a reagent intended for use as a replacement in a diagnostic system may be limited to that information necessary to identify the reagent adequately and to describe its proper use in the system.

(1) The proprietary name and established name, i.e., common or usual name, if any.

(2) The intended use or uses of the product and the type of procedure, e.g., qualitative or quantitative.

(3) Summary and explanation of the test. Include a short history of the methodology, with pertinent references and a balanced statement of the special merits and limitations of this method or product. If the product labeling refers to any other procedure, appropriate literature citations shall be included and the labeling shall explain the nature of any differences from the original and their effect on the results.

(4) The chemical, physical, physiological, or biological principles of the procedure. Explain concisely, with chemical reactions and techniques involved, if applicable.

(5) Reagents:

(i) A declaration of the established name (common or usual name), if any, and quantity, proportion or concentration or each reactive ingredient; and for biological material, the source and a measure of its activity. The quantity, proportion, concentration or activity shall be stated in the system generally used and recognized by the intended user, e.g., metric, international units, etc. A statement indicating the presence of and characterizing any catalytic or nonreactive ingredients, e.g., buffers, preservatives, stabilizers.

(ii) A statement of warnings or precautions for users as established in the regulations contained in 16 CFR part 1500 and any other warnings appropriate to the hazard presented by the product; and a statement “For In Vitro Diagnostic Use” and any other limiting statements appropriate to the intended use of the product. The limiting statement appropriate to the intended use of a prescription in vitro diagnostic product shall bear the symbol statement “Rx only” or “℞ only” or the statement “Caution: Federal law restricts this device to sale by or on the order of a ___”, the blank to be filled with the word “physician”, “dentist”, “veterinarian”, or with the descriptive designation of any other practitioner licensed by the law of the State in which the practitioner practices to use or order the use of the device.

(iii) Adequate instructions for reconstitution, mixing, dilution, etc.

(iv) Appropriate storage instructions adequate to protect the stability of the product. When applicable, these instructions shall include such information as conditions of temperature, light, humidity, and other pertinent factors. For products requiring manipulation, such as reconstitution and/or mixing before use, appropriate storage instructions shall be provided for the reconstituted or mixed product. The basis for such instructions shall be determined by reliable, meaningful, and specific test methods such as those described in § 211.166 of this chapter.

(v) A statement of any purification or treatment required for use.

(vi) Physical, biological, or chemical indications of instability or deterioration.

(6) Instruments:

(i) Use or function.

(ii) Installation procedures and special requirements.

(iii) Principles of operation.

(iv) Performance characteristics and specifications.

(v) Operating instructions.

(vi) Calibration procedures including materials and/or equipment to be used.

(vii) Operational precautions and limitations.

(viii) Hazards.

(ix) Service and maintenance information.

(7) Specimen collection and preparation for analysis, including a description of:

(i) Special precautions regarding specimen collection including special preparation of the patient as it bears on the validity of the test.

(ii) Additives, preservatives, etc., necessary to maintain the integrity of the specimen.

(iii) Known interfering substances.

(iv) Recommended storage, handling or shipping instructions for the protection and maintenance of stability of the specimen.

(8) Procedure: A step-by-step outline of recommended procedures from reception of the specimen to obtaining results. List any points that may be useful in improving precision and accuracy.

(i) A list of all materials provided, e.g., reagents, instruments and equipment, with instructions for their use.

(ii) A list of all materials required but not provided. Include such details as sizes, numbers, types, and quality.

(iii) A description of the amounts of reagents necessary, times required for specific steps, proper temperatures, wavelengths, etc.

(iv) A statement describing the stability of the final reaction material to be measured and the time within which it shall be measured to assure accurate results.

(v) Details of calibration: Identify reference material. Describe preparation of reference sample(s), use of blanks, preparation of the standard curve, etc. The description of the range of calibration should include the highest and the lowest values measurable by the procedure.

(vi) Details of kinds of quality control procedures and materials required. If there is need for both positive and negative controls, this should be stated. State what are considered satisfactory limits of performance.

(9) Results: Explain the procedure for calculating the value of the unknown. Give an explanation for each component of the formula used for the calculation of the unknown. Include a sample calculation, step-by-step, explaining the answer. The values shall be expressed to the appropriate number of significant figures. If the test provides other than quantitative results, provide an adequate description of expected results.

(10) Limitation of the procedure: Include a statement of limitations of the procedure. State known extrinsic factors or interfering substances affecting results. If further testing, either more specific or more sensitive, is indicated in all cases where certain results are obtained, the need for the additional test shall be stated.

(11) Expected values: State the range(s) of expected values as obtained with the product from studies of various populations. Indicate how the range(s) was established and identify the population(s) on which it was established.

(12) Specific performance characteristics: Include, as appropriate, information describing such things as accuracy, precision, specificity, and sensitivity. These shall be related to a generally accepted method using biological specimens from normal and abnormal populations. Include a statement summarizing the data upon which the specific performance characteristics are based.

(13) Bibliography: Include pertinent references keyed to the text.

(14) Name and place of business of manufacturer, packer, or distributor.

(15) Date of issuance of the last revision of the labeling identified as such.

(c) A shipment or other delivery of an in vitro diagnostic product shall be exempt from the requirements of paragraphs (a) and (b) of this section and from a standard promulgated under part 861 provided that the following conditions are met:

(1) In the case of a shipment or delivery for an investigation subject to part 812, if there has been compliance with part 812; or

(2) In the case of a shipment or delivery for an investigation that is not subject to part 812 (see § 812.2(c)), if the following conditions are met:

(i) For a product in the laboratory research phase of development, and not represented as an effective in vitro diagnostic product, all labeling bears the statement, prominently placed: “For Research Use Only. Not for use in diagnostic procedures.”

(ii) For a product being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful), all labeling bears the statement, prominently placed: “For Investigational Use Only. The performance characteristics of this product have not been established.”

(d) The labeling of general purpose laboratory reagents (e.g., hydrochloric acid) and equipment (e.g., test tubes and pipettes) whose uses are generally known by persons trained in their use need not bear the directions for use required by § 809.10(a) and (b), if their labeling meets the requirements of this paragraph.

(1) The label of a reagent shall bear the following information:

(i) The proprietary name and established name (common or usual name), if any, of the reagent.

(ii) A declaration of the established name (common or usual name), if any, and quantity, proportion or concentration of the reagent ingredient (e.g., hydrochloric acid: Formula weight 36.46, assay 37.9 percent, specific gravity 1.192 at 60 °F); and for a reagent derived from biological material, the source and where applicable a measure of its activity. The quantity, proportion, concentration or activity shall be stated in the system generally used and recognized by the intended user, e.g., metric, international units, etc.

(iii) A statement of the purity and quality of the reagent, including a quantitative declaration of any impurities present. The requirement for this information may be met by a statement of conformity with a generally recognized and generally available standard which contains the same information, e.g., those established by the American Chemical Society, U.S. Pharmacopeia, National Formulary, National Research Council.

(iv) A statement of warnings or precautions for users as established in the regulations contained in 16 CFR part 1500 and any other warnings appropriate to the hazard presented by the product; and a statement “For Laboratory Use.”

(v) Appropriate storage instructions adequate to protect the stability of the product. When applicable, these instructions shall include such information as conditions of temperature, light, humidity, and other pertinent factors. The basis for such information shall be determined by reliable, meaningful, and specific test methods such as those described in § 211.166 of this chapter.

(vi) A declaration of the net quantity of contents, expressed in terms of weight or volume, numerical count, or any combination of these or other terms which accurately reflect the contents of the package. The use of metric designations is encouraged, wherever appropriate.

(vii) Name and place of business of manufacturer, packer, or distributor.

(viii) A lot or control number, identified as such, from which it is possible to determine the complete manufacturing history of the product.

(ix) In the case of immediate containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, and which are packaged within an outer container from which they are removed for use, the information required by paragraphs (d)(1)(ii), (iii), (iv), (v), and (vi) of this section may appear in the outer container labeling only.

(2) The label of general purpose laboratory equipment, e.g., a beaker or a pipette, shall bear a statement adequately describing the product, its composition, and physical characteristics if necessary for its proper use.

(e)(1) The labeling for analyte specific reagents (e.g., monoclonal antibodies, deoxyribonucleic acid (DNA) probes, viral antigens, ligands) shall bear the following information:

(i) The proprietary name and established name (common or usual name), if any, of the reagent;

(ii) A declaration of the established name (common or usual name), if any;

(iii) The quantity, proportion, or concentration of the reagent ingredient; and for a reagent derived from biological material, the source and where applicable, a measure of its activity. The quantity, proportion, concentration, or activity shall be stated in the system generally used and recognized by the intended user, e.g., metric, international units, etc.;

(iv) A statement of the purity and quality of the reagent, including a quantitative declaration of any impurities present and method of analysis or characterization. The requirement for this information may be met by a statement of conformity with a generally recognized and generally available standard that contains the same information, e.g., those established by the American Chemical Society, U.S. Pharmacopeia, National Formulary, and National Research Council. The labeling may also include information concerning chemical/molecular composition, nucleic acid sequence, binding affinity, cross-reactivities, and interaction with substances of known clinical significance;

(v) A statement of warnings or precautions for users as established in the regulations contained in 16 CFR part 1500 and any other warnings appropriate to the hazard presented by the product;

(vi) The date of manufacture and appropriate storage instructions adequate to protect the stability of the product. When applicable, these instructions shall include such information as conditions of temperature, light, humidity, date of expiration, and other pertinent factors. The basis for such instructions shall be determined by reliable, meaningful, and specific test methods, such as those described in § 211.166 of this chapter;

(vii) A declaration of the net quantity of contents, expressed in terms of weight or volume, numerical count, or any combination of these or other terms that accurately reflect the contents of the package. The use of metric designations is encouraged, wherever appropriate;

(viii) The name and place of business of manufacturer, packer, or distributor;

(ix) A lot or control number, identified as such, from which it is possible to determine the complete manufacturing history of the product;

(x) For class I exempt ASR's, the statement: “Analyte Specific Reagent. Analytical and performance characteristics are not established”; and

(xi) For class II and III ASR's, the statement: “Analyte Specific Reagent. Except as a component of the approved/cleared test (Name of approved/cleared test), analytical and performance characteristics of this ASR are not established.”

(2) In the case of immediate containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, and which are packaged within an outer container from which they are removed for use, the information required by paragraphs (e)(1) through (e)(6) of this section may appear in the outer container labeling only.

(f) The labeling for over-the-counter (OTC) test sample collection systems for drugs of abuse testing shall bear the following information in language appropriate for the intended users:

(1) Adequate instructions for specimen collection and handling, and for preparation and mailing of the specimen to the laboratory for testing.

(2) An identification system to ensure that specimens are not mixed up or otherwise misidentified at the laboratory, and that user anonymity is maintained.

(3) The intended use or uses of the product, including what drugs are to be identified in the specimen, a quantitative description of the performance characteristics for those drugs (e.g., sensitivity and specificity) in terms understandable to lay users, and the detection period.

(4) A statement that confirmatory testing will be conducted on all samples that initially test positive.

(5) A statement of warnings or precautions for users as established in the regulations contained in 16 CFR part 1500 and any other warnings appropriate to the hazard presented by the product.

(6) Adequate instructions on how to obtain test results from a person who can explain their meaning, including the probability of false positive and false negative results, as well as how to contact a trained health professional if additional information on interpretation of test results from the laboratory or followup counseling is desired.

(7) Name and place of business of the manufacturer, packer, or distributor.

(g)(1) The applicant may provide the labeling information referenced in this section in the form of:

(i) A symbol accompanied by explanatory text adjacent to the symbol;

(ii) A symbol not accompanied by adjacent explanatory text that:

(A) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the act;

(B) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and

(C) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used;

(iii) A symbol not accompanied by adjacent explanatory text that:

(A) Is established in a standard developed by a standards development organization (SDO);

(B) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition;

(C) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the act;

(D) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and

(E) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or

(iv) The symbol statement “Rx only” or “℞ only” used as provided under paragraphs (a)(4) and (b)(5)(ii) of this section.

(2) The use of symbols in device labeling which do not meet the requirements of paragraph (g)(1) of this section renders a device misbranded under section 502(c) of the act.

(3) For purposes of paragraph (g)(1) of this section:

(i) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(ii) The term “symbols glossary” means a compiled listing of:

(A) Each SDO-established symbol used in the labeling for the device;

(B) The title and designation number of the SDO-developed standard containing the symbol;

(C) The title of the symbol and its reference number, if any, in the standard; and

(D) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard.

[41 FR 6903, Feb. 13, 1976, as amended at 45 FR 3750, Jan. 18, 1980; 45 FR 7484, Feb. 1, 1980; 47 FR 41107, Sept. 17, 1982; 47 FR 51109, Nov. 12, 1982; 48 FR 34470, July 29, 1983; 62 FR 62259, Nov. 21, 1997; 65 FR 18234, Apr. 7, 2000; 81 FR 38391, June 15, 2016]

§ 809.11 Exceptions or alternatives to labeling requirements for in vitro diagnostic products for human use held by the Strategic National Stockpile.

(a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of an in vitro diagnostic product for human use, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such products that are or will be included in the Strategic National Stockpile.

(b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores an in vitro diagnostic product for human use that is or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director.

(ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative.

(2) A written request for an exception or alternative described in paragraph (a) of this section must:

(i) Identify the specified lots, batches, or other units of an in vitro diagnostic product for human use that would be subject to the exception or alternative;

(ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request;

(iii) Explain why compliance with such labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of the in vitro diagnostic product for human use that are or will be held in the Strategic National Stockpile;

(iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the product includes appropriate information necessary for the safe and effective use of the product, given the anticipated circumstances of use of the product;

(v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the in vitro diagnostic products for human use subject to the exception or alternative; and

(vi) Provide any other information requested by the Center Director in support of the request.

(c) The Center Director must respond in writing to all requests under this section. The Center Director may impose appropriate conditions or safeguards when granting such an exception or alternative under this section.

(d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director to ensure that the labeling of the product subject to the exception or alternative includes the information necessary for the safe and effective use of the product, given the anticipated circumstances of use.

(e) If the Center Director grants a request for an exception or alternative to the labeling requirements under this section:

(1) The Center Director may determine that the submission and grant of a written request under this section satisfies the provisions relating to premarket notification submissions under § 807.81(a)(3) of this chapter.

(2)(i) For a Premarket Approval Application (PMA)-approved in vitro diagnostic product for human use, the submission and grant of a written request under this section satisfies the provisions relating to submission of PMA supplements under § 814.39 of this chapter; however,

(ii) The grant of the request must be identified in a periodic report under § 814.84 of this chapter.

(f) The Center Director may grant an exception or alternative under this section to the following provisions of this part, to the extent that the requirements in these provisions are not explicitly required by statute:

(1) § 809.10(a)(1) through (a)(6) and (a)(9);

(2) § 809.10(b);

(3) § 809.10(c)(2);

(4) § 809.10(d)(1)(i) through (d)(1)(v), (d)(1)(viii), and (d)(2); and

(5) § 809.10(e)(1)(i) through (e)(1)(vi) and (e)(1)(ix) through (e)(1)(xi).

[72 FR 73601, Dec. 28, 2007]

§ 809.20 General requirements for manufacturers and producers of in vitro diagnostic products.

(a) [Reserved]

(b) Compliance with good manufacturing practices. In vitro diagnostic products shall be manufactured in accordance with the good manufacturing practices requirements found in part 820 of this chapter and, if applicable, with § 610.44 of this chapter.

[41 FR 6903, Feb. 13, 1976, as amended at 42 FR 42530, Aug. 23, 1977; 43 FR 31527, July 21, 1978; 66 FR 31165, June 11, 2001]

§ 809.30 Restrictions on the sale, distribution and use of analyte specific reagents.

(a) Analyte specific reagents (ASR's) (§ 864.4020 of this chapter) are restricted devices under section 520(e) of the Federal Food, Drugs, and Cosmetic Act (the act) subject to the restrictions set forth in this section.

(b) ASR's may only be sold to:

(1) In vitro diagnostic manufacturers;

(2) Clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), as qualified to perform high complexity testing under 42 CFR part 493 or clinical laboratories regulated under VHA Directive 1106 (available from Department of Veterans Affairs, Veterans Health Administration, Washington, DC 20420); and

(3) Organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners, e.g., forensic, academic, research, and other nonclinical laboratories.

(c) ASR's must be labeled in accordance with § 809.10(e).

(d) Advertising and promotional materials for ASR's:

(1) Shall include the identity and purity (including source and method of acquisition) of the analyte specific reagent and the identity of the analyte;

(2) Shall include the statement for class I exempt ASR's: “Analyte Specific Reagent. Analytical and performance characteristics are not established”;

(3) Shall include the statement for class II or III ASR's: “Analyte Specific Reagent. Except as a component of the approved/cleared test (name of approved/cleared test), analytical and performance characteristics are not established”; and

(4) Shall not make any statement regarding analytical or clinical performance.

(e) The laboratory that develops an in-house test using the ASR shall inform the ordering person of the test result by appending to the test report the statement: “This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration.” This statement would not be applicable or required when test results are generated using the test that was cleared or approved in conjunction with review of the class II or III ASR.

(f) Ordering in-house tests that are developed using analyte specific reagents is limited under section 520(e) of the act to physicians and other persons authorized by applicable State law to order such tests.

(g) The restrictions in paragraphs (c) through (f) of this section do not apply when reagents that otherwise meet the analyte specific reagent definition are sold to:

(1) In vitro diagnostic manufacturers; or

(2) Organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners, e.g., forensic, academic, research, and other nonclinical laboratories.

[62 FR 62259, Nov. 21, 1997]

§ 809.40 Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing.

(a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (§ 864.3260 of this chapter) are restricted devices under section 520(e) of the Act subject to the restrictions set forth in this section.

(b) Sample testing shall be performed in a laboratory using screening tests that have been approved, cleared, or otherwise recognized by the Food and Drug Administration as accurate and reliable for the testing of such specimens for identifying drugs of abuse or their metabolites.

(c) The laboratory performing the test(s) shall have, and shall be recognized as having, adequate capability to reliably perform the necessary screening and confirmatory tests, including adequate capability to perform integrity checks of the biological specimens for possible adulteration.

(d) All OTC test sample collection systems for drugs of abuse testing shall be labeled in accordance with § 809.10(f) and shall provide an adequate system to communicate the proper interpretation of test results from the laboratory to the lay purchaser.

[65 FR 18234, Apr. 7, 2000]

§ 810.1 Scope.

Part 810 describes the procedures that the Food and Drug Administration will follow in exercising its medical device recall authority under section 518(e) of the Federal Food, Drug, and Cosmetic Act.

§ 810.2 Definitions.

As used in this part:

(a) Act means the Federal Food, Drug, and Cosmetic Act.

(b) Agency or FDA means the Food and Drug Administration.

(c) Cease distribution and notification strategy or mandatory recall strategy means a planned, specific course of action to be taken by the person named in a cease distribution and notification order or in a mandatory recall order, which addresses the extent of the notification or recall, the need for public warnings, and the extent of effectiveness checks to be conducted.

(d) Consignee means any person or firm that has received, purchased, or used a device that is subject to a cease distribution and notification order or a mandatory recall order. Consignee does not mean lay individuals or patients, i.e., nonhealth professionals.

(e) Correction means repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device, without its physical removal from its point of use to some other location.

(f) Device user facility means a hospital, ambulatory surgical facility, nursing home, or outpatient treatment or diagnostic facility that is not a physician's office.

(g) Health professionals means practitioners, including physicians, nurses, pharmacists, dentists, respiratory therapists, physical therapists, technologists, or any other practitioners or allied health professionals that have a role in using a device for human use.

(h) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(i) Reasonable probability means that it is more likely than not that an event will occur.

(j) Serious, adverse health consequence means any significant adverse experience, including those that may be either life-threatening or involve permanent or long-term injuries, but excluding injuries that are nonlife-threatening and that are temporary and reasonably reversible.

(k) Recall means the correction or removal of a device for human use where FDA finds that there is a reasonable probability that the device would cause serious, adverse health consequences or death.

(l) Removal means the physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.

(m) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

[61 FR 59018, Nov. 20, 1996, as amended at 78 FR 58821, Sept. 24, 2013]

§ 810.3 Computation of time.

In computing any period of time prescribed or allowed by this part, the day of the act or event from which the designated period of time begins to run shall not be included. The computation of time is based only on working days.

§ 810.4 Service of orders.

Orders issued under this part will be served in person by a designated employee of FDA, or by certified or registered mail or similar mail delivery service with a return receipt record reflecting receipt, to the named person or designated agent at the named person's or designated agent's last known address in FDA's records.

§ 810.10 Cease distribution and notification order.

(a) If, after providing the appropriate person with an opportunity to consult with the agency, FDA finds that there is a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death, the agency may issue a cease distribution and notification order requiring the person named in the order to immediately:

(1) Cease distribution of the device;

(2) Notify health professionals and device user facilities of the order; and

(3) Instruct these professionals and device user facilities to cease use of the device.

(b) FDA will include the following information in the order:

(1) The requirements of the order relating to cessation of distribution and notification of health professionals and device user facilities;

(2) Pertinent descriptive information to enable accurate and immediate identification of the device subject to the order, including, where known:

(i) The brand name of the device;

(ii) The common name, classification name, or usual name of the device;

(iii) The model, catalog, or product code numbers of the device;

(iv) The manufacturing lot numbers or serial numbers of the device or other identification numbers; and

(v) The unique device identifier (UDI) that appears on the device label or on the device package; and

(3) A statement of the grounds for FDA's finding that there is a reasonable probability that the device would cause serious, adverse health consequences or death.

(c) FDA may also include in the order a model letter for notifying health professionals and device user facilities of the order and a requirement that notification of health professionals and device user facilities be completed within a specified timeframe. The model letter will include the key elements of information that the agency in its discretion has determined, based on the circumstances surrounding the issuance of each order, are necessary to inform health professionals and device user facilities about the order.

(d) FDA may also require that the person named in the cease distribution and notification order submit any or all of the following information to the agency by a time specified in the order:

(1) The total number of units of the device produced and the timespan of the production;

(2) The total number of units of the device estimated to be in distribution channels;

(3) The total number of units of the device estimated to be distributed to health professionals and device user facilities;

(4) The total number of units of the device estimated to be in the hands of home users;

(5) Distribution information, including the names and addresses of all consignees;

(6) A copy of any written communication used by the person named in the order to notify health professionals and device user facilities;

(7) A proposed strategy for complying with the cease distribution and notification order;

(8) Progress reports to be made at specified intervals, showing the names and addresses of health professionals and device user facilities that have been notified, names of specific individuals contacted within device user facilities, and the dates of such contacts; and

(9) The name, address, and telephone number of the person who should be contacted concerning implementation of the order.

(e) FDA will provide the person named in a cease distribution and notification order with an opportunity for a regulatory hearing on the actions required by the cease distribution and notification order and on whether the order should be modified, or vacated, or amended to require a mandatory recall of the device.

(f) FDA will also provide the person named in the cease distribution and notification order with an opportunity, in lieu of a regulatory hearing, to submit a written request to FDA asking that the order be modified, or vacated, or amended.

(g) FDA will include in the cease distribution and notification order the name, address, and telephone number of an agency employee to whom any request for a regulatory hearing or agency review is to be addressed.

[61 FR 59018, Nov. 20, 1996, as amended at 78 FR 58821, Sept. 24, 2013]

§ 810.11 Regulatory hearing.

(a) Any request for a regulatory hearing shall be submitted in writing to the agency employee identified in the order within the timeframe specified by FDA. Under § 16.22(b) of this chapter, this timeframe ordinarily will not be fewer than 3 working days after receipt of the cease distribution and notification order. However, as provided in § 16.60(h) of this chapter, the Commissioner of Food and Drugs or presiding officer may waive, suspend, or modify any provision of part 16 under § 10.19 of this chapter, including those pertaining to the timing of the hearing. As provided in § 16.26(a), the Commissioner or presiding officer may deny a request for a hearing, in whole or in part, if he or she determines that no genuine and substantial issue of fact is raised by the material submitted in the request.

(b) If a request for a regulatory hearing is granted, the regulatory hearing shall be limited to:

(1) Reviewing the actions required by the cease distribution and notification order, determining if FDA should affirm, modify, or vacate the order, and addressing an appropriate cease distribution and notification strategy; and

(2) Determining whether FDA should amend the cease distribution and notification order to require a recall of the device that was the subject of the order. The hearing may also address the actions that might be required by a recall order, including an appropriate recall strategy, if FDA later orders a recall.

(c) If a request by the person named in a cease distribution and notification order for a regulatory hearing is granted, the regulatory hearing will be conducted in accordance with the procedures set out in section 201(x) of the act (21 U.S.C. 321(x)) and part 16 of this chapter, except that the order issued under § 810.10, rather than a notice under § 16.22(a) of this chapter, provides the notice of opportunity for a hearing and is part of the administrative record of the regulatory hearing under § 16.80(a) of this chapter. As provided in § 16.60(h) of this chapter, the Commissioner of Food and Drugs or presiding officer may waive, suspend, or modify any provision of part 16 under § 10.19 of this chapter. As provided in § 16.26(b), after the hearing commences, the presiding officer may issue a summary decision on any issue if the presiding officer determines that there is no genuine and substantial issue of fact respecting that issue.

(d) If the person named in the cease distribution and notification order does not request a regulatory hearing within the timeframe specified by FDA in the cease distribution and notification order, that person will be deemed to have waived his or her right to request a hearing.

(e) The presiding officer will ordinarily hold any regulatory hearing requested under paragraph (a) of this section no fewer than 2 working days after receipt of the request for a hearing, under § 16.24(e) of this chapter, and no later than 10 working days after the date of issuance of the cease distribution and notification order. However, FDA and the person named in the order may agree to a later date or the presiding officer may determine that the hearing should be held in fewer than 2 days. Moreover, as provided for in § 16.60(h) of this chapter, the Commissioner of Food and Drugs or presiding officer may waive, suspend, or modify any provision of part 16 under § 10.19 of this chapter, including those pertaining to the timing of the hearing. After the presiding officer prepares a written report of the hearing and the agency issues a final decision based on the report, the presiding officer shall provide the requestor written notification of the final decision to affirm, modify, or vacate the order or to amend the order to require a recall of the device within 15 working days of conducting a regulatory hearing.

§ 810.12 Written request for review of cease distribution and notification order.

(a) In lieu of requesting a regulatory hearing under § 810.11, the person named in a cease distribution and notification order may submit a written request to FDA asking that the order be modified or vacated. Such person shall address the written request to the agency employee identified in the order and shall submit the request within the timeframe specified in the order, unless FDA and the person named in the order agree to a later date.

(b) A written request for review of a cease distribution and notification order shall identify each ground upon which the requestor relies in asking that the order be modified or vacated, as well as addressing an appropriate cease distribution and notification strategy, and shall address whether the order should be amended to require a recall of the device that was the subject of the order and the actions required by such a recall order, including an appropriate recall strategy.

(c) The agency official who issued the cease distribution and notification order shall provide the requestor written notification of the agency's decision to affirm, modify, or vacate the order or amend the order to require a recall of the device within 15 working days of receipt of the written request. The agency official shall include in this written notification:

(1) A statement of the grounds for the decision to affirm, modify, vacate, or amend the order; and

(2) The requirements of any modified or amended order.

§ 810.13 Mandatory recall order.

(a) If the person named in a cease distribution and notification order does not request a regulatory hearing or submit a request for agency review of the order, or, if the Commissioner of Food and Drugs or the presiding officer denies a request for a hearing, or, if after conducting a regulatory hearing under § 810.11 or completing agency review of a cease distribution and notification order under § 810.12, FDA determines that the order should be amended to require a recall of the device with respect to which the order was issued, FDA shall amend the order to require such a recall. FDA shall amend the order to require such a recall within 15 working days of issuance of a cease distribution and notification order if a regulatory hearing or agency review of the order is not requested, or within 15 working days of denying a request for a hearing, or within 15 working days of completing a regulatory hearing under § 810.11, or within 15 working days of receipt of a written request for review of a cease distribution and notification order under § 810.12.

(b) In a mandatory recall order, FDA may:

(1) Specify that the recall is to extend to the wholesale, retail, or user level;

(2) Specify a timetable in accordance with which the recall is to begin and be completed;

(3) Require the person named in the order to submit to the agency a proposed recall strategy, as described in § 810.14, and periodic reports describing the progress of the mandatory recall, as described in § 810.16; and

(4) Provide the person named in the order with a model recall notification letter that includes the key elements of information that FDA has determined are necessary to inform health professionals and device user facilities.

(c) FDA will not include in a mandatory recall order a requirement for:

(1) Recall of a device from individuals; or

(2) Recall of a device from device user facilities, if FDA determines that the risk of recalling the device from the facilities presents a greater health risk than the health risk of not recalling the device from use, unless the device can be replaced immediately with an equivalent device.

(d) FDA will include in a mandatory recall order provisions for notification to individuals subject to the risks associated with use of the device. If a significant number of such individuals cannot be identified, FDA may notify such individuals under section 705(b) of the act.

§ 810.14 Cease distribution and notification or mandatory recall strategy.

(a) General. The person named in a cease distribution and notification order issued under § 810.10 shall comply with the order, which FDA will fashion as appropriate for the individual circumstances of the case. The person named in a cease distribution and notification order modified under § 810.11(e) or § 810.12(c) or a mandatory recall order issued under § 810.13 shall develop a strategy for complying with the order that is appropriate for the individual circumstances and that takes into account the following factors:

(1) The nature of the serious, adverse health consequences related to the device;

(2) The ease of identifying the device;

(3) The extent to which the risk presented by the device is obvious to a health professional or device user facility; and

(4) The extent to which the device is used by health professionals and device user facilities.

(b) Submission and review. (1) The person named in the cease distribution and notification order modified under § 810.11(e) or § 810.12(c) or mandatory recall order shall submit a copy of the proposed strategy to the agency within the timeframe specified in the order.

(2) The agency will review the proposed strategy and make any changes to the strategy that it deems necessary within 7 working days of receipt of the proposed strategy. The person named in the order shall act in accordance with a strategy determined by FDA to be appropriate.

(c) Elements of the strategy. A proposed strategy shall meet all of the following requirements:

(1)(i) The person named in the order shall specify the level in the chain of distribution to which the cease distribution and notification order or mandatory recall order is to extend as follows:

(A) Consumer or user level, e.g., health professionals, consignee, or device user facility level, including any intermediate wholesale or retail level; or

(B) Retail level, to the level immediately preceding the consumer or user level, and including any intermediate level; or

(C) Wholesale level.

(ii) The person named in the order shall not recall a device from individuals; and

(iii) The person named in the order shall not recall a device from device user facilities if FDA notifies the person not to do so because of a risk determination under § 810.13(c)(2).

(2) The person named in a recall order shall ensure that the strategy provides for notice to individuals subject to the risks associated with use of the recalled device. The notice may be provided through the individuals' health professionals if FDA determines that such consultation is appropriate and would be the most effective method of notifying patients.

(3) Effectiveness checks by the person named in the order are required to verify that all health professionals, device user facilities, consignees, and individuals, as appropriate, have been notified of the cease distribution and notification order or mandatory recall order and of the need to take appropriate action. The person named in the cease distribution and notification order or the mandatory recall order shall specify in the strategy the method(s) to be used in addition to written communications as required by § 810.15, i.e., personal visits, telephone calls, or a combination thereof to contact all health professionals, device user facilities, consignees, and individuals, as appropriate. The agency may conduct additional audit checks where appropriate.

§ 810.15 Communications concerning a cease distribution and notification or mandatory recall order.

(a) General. The person named in a cease distribution and notification order issued under § 810.10 or a mandatory recall order issued under § 810.13 is responsible for promptly notifying each health professional, device user facility, consignee, or individual, as appropriate, of the order. In accordance with § 810.10(c) or § 810.13(b)(4), FDA may provide the person named in the cease distribution and notification or mandatory recall order with a model letter for notifying each health professional, device user facility, consignee, or individual, as appropriate, of the order. However, if FDA does not provide the person named in the cease distribution and notification or mandatory recall order with a model letter, the person named in a cease distribution and notification order issued under § 810.10, or a mandatory recall order issued under § 810.13, is responsible for providing such notification. The purpose of the communication is to convey:

(1) That FDA has found that there is a reasonable probability that use of the device would cause a serious, adverse health consequence or death;

(2) That the person named in the order has ceased distribution of the device;

(3) That health professionals and device user facilities should cease use of the device immediately;

(4) Where appropriate, that the device is subject to a mandatory recall order; and

(5) Specific instructions on what should be done with the device.

(b) Implementation. The person named in a cease distribution and notification order, or a mandatory recall order, shall notify the appropriate person(s) of the order by verified written communication, e.g., telegram, mailgram, or fax. The written communication and any envelope in which it is sent or enclosed shall be conspicuously marked, preferably in bold red ink: “URGENT—[DEVICE CEASE DISTRIBUTION AND NOTIFICATION ORDER] or [MANDATORY DEVICE RECALL ORDER].” Telephone calls or other personal contacts may be made in addition to, but not as a substitute for, the verified written communication, and shall be documented in an appropriate manner.

(c) Contents. The person named in the order shall ensure that the notice of a cease distribution and notification order or mandatory recall order:

(1) Is brief and to the point;

(2) Identifies clearly the device, size, lot number(s), code(s), or serial number(s), and any other pertinent descriptive information to facilitate accurate and immediate identification of the device;

(3) Explains concisely the serious, adverse health consequences that may occur if use of the device were continued;

(4) Provides specific instructions on what should be done with the device;

(5) Provides a ready means for the recipient of the communication to confirm receipt of the communication and to notify the person named in the order of the actions taken in response to the communication. Such means may include, but are not limited to, the return of a postage-paid, self-addressed post card or a toll-free call to the person named in the order; and

(6) Does not contain irrelevant qualifications, promotional materials, or any other statement that may detract from the message.

(d) Followup communications. The person named in the cease distribution and notification order or mandatory recall order shall ensure that followup communications are sent to all who fail to respond to the initial communication.

(e) Responsibility of the recipient. Health professionals, device user facilities, and consignees who receive a communication concerning a cease distribution and notification order or a mandatory recall order should immediately follow the instructions set forth in the communication. Where appropriate, these recipients should immediately notify their consignees of the order in accordance with paragraphs (b) and (c) of this section.

§ 810.16 Cease distribution and notification or mandatory recall order status reports.

(a) The person named in a cease distribution and notification order issued under § 810.10 or a mandatory recall order issued under § 810.13 shall submit periodic status reports to FDA to enable the agency to assess the person's progress in complying with the order. The frequency of such reports and the agency official to whom such reports shall be submitted will be specified in the order.

(b) Unless otherwise specified in the order, each status report shall contain the following information:

(1) The number and type of health professionals, device user facilities, consignees, or individuals notified about the order and the date and method of notification;

(2) The number and type of health professionals, device user facilities, consignees, or individuals who have responded to the communication and the quantity of the device on hand at these locations at the time they received the communication;

(3) The number and type of health professionals, device user facilities, consignees, or individuals who have not responded to the communication;

(4) The number of devices returned or corrected by each health professional, device user facility, consignee, or individual contacted, and the quantity of products accounted for;

(5) The number and results of effectiveness checks that have been made; and

(6) Estimated timeframes for completion of the requirements of the cease distribution and notification order or mandatory recall order.

(c) The person named in the cease distribution and notification order or recall order may discontinue the submission of status reports when the agency terminates the order in accordance with § 810.17.

§ 810.17 Termination of a cease distribution and notification or mandatory recall order.

(a) The person named in a cease distribution and notification order issued under § 810.10 or a mandatory recall order issued under § 810.13 may request termination of the order by submitting a written request to FDA. The person submitting a request shall certify that he or she has complied in full with all of the requirements of the order and shall include a copy of the most current status report submitted to the agency under § 810.16. A request for termination of a recall order shall include a description of the disposition of the recalled device.

(b) FDA may terminate a cease distribution and notification order issued under § 810.10 or a mandatory recall order issued under § 810.13 when the agency determines that the person named in the order:

(1) Has taken all reasonable efforts to ensure and to verify that all health professionals, device user facilities, consignees, and, where appropriate, individuals have been notified of the cease distribution and notification order, and to verify that they have been instructed to cease use of the device and to take other appropriate action; or

(2) Has removed the device from the market or has corrected the device so that use of the device would not cause serious, adverse health consequences or death.

(c) FDA will provide written notification to the person named in the order when a request for termination of a cease distribution and notification order or a mandatory recall order has been granted or denied. FDA will respond to a written request for termination of a cease distribution and notification or recall order within 30 working days of its receipt.

§ 810.18 Public notice.

The agency will make available to the public in the weekly FDA Enforcement Report a descriptive listing of each new mandatory recall issued under § 810.13. The agency will delay public notification of orders when the agency determines that such notification may cause unnecessary and harmful anxiety in individuals and that initial consultation between individuals and their health professionals is essential.

§ 812.1 Scope.

(a) The purpose of this part is to encourage, to the extent consistent with the protection of public health and safety and with ethical standards, the discovery and development of useful devices intended for human use, and to that end to maintain optimum freedom for scientific investigators in their pursuit of this purpose. This part provides procedures for the conduct of clinical investigations of devices. An approved investigational device exemption (IDE) permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device. An IDE approved under § 812.30 or considered approved under § 812.2(b) exempts a device from the requirements of the following sections of the Federal Food, Drug, and Cosmetic Act (the act) and the regulations in this chapter issued thereunder: Misbranding under section 502 of the act, registration, listing, and premarket notification under section 510, performance standards under section 514, premarket approval under section 515, a banned device regulation under section 516, records and reports under section 519, restricted device requirements under section 520(e), good manufacturing practice requirements under section 520(f) except for the requirements found in § 820.10(c), if applicable (unless the sponsor states an intention to comply with these requirements under § 812.20(b)(3) or § 812.140(b)(4)(v)) and color additive requirements under section 721.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

[45 FR 3751, Jan. 18, 1980, as amended at 59 FR 14366, Mar. 28, 1994; 61 FR 52654, Oct. 7, 1996; 90 FR 55979, Dec. 4, 2025]

§ 812.2 Applicability.

(a) General. This part applies to all clinical investigations of devices to determine safety and effectiveness, except as provided in paragraph (c) of this section.

(b) Abbreviated requirements. The following categories of investigations are considered to have approved applications for IDE's, unless FDA has notified a sponsor under § 812.20(a) that approval of an application is required:

(1) An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor:

(i) Labels the device in accordance with § 812.5;

(ii) Obtains IRB approval of the investigation after presenting the reviewing IRB with a brief explanation of why the device is not a significant risk device, and maintains such approval;

(iii) Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator's care, informed consent in accordance with part 50 of this chapter.

(iv) Complies with the requirements of § 812.46 with respect to monitoring investigations;

(v) Maintains the records required under § 812.140(b) (4) and (5) and makes the reports required under § 812.150(b) (1) through (3) and (5) through (10);

(vi) Ensures that participating investigators maintain the records required by § 812.140(a)(3)(i) and make the reports required under § 812.150(a) (1), (2), (5), and (7); and

(vii) Complies with the prohibitions in § 812.7 against promotion and other practices.

(2) An investigation of a device other than one subject to paragraph (e) of this section, if the investigation was begun on or before July 16, 1980, and to be completed, and is completed, on or before January 19, 1981.

(c) Exempted investigations. This part, with the exception of § 812.119, does not apply to investigations of the following categories of devices:

(1) A device, other than a transitional device, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the indications in labeling in effect at that time.

(2) A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence.

(3) A diagnostic device, if the sponsor complies with applicable requirements in § 809.10(c) and if the testing:

(i) Is noninvasive,

(ii) Does not require an invasive sampling procedure that presents significant risk,

(iii) Does not by design or intention introduce energy into a subject, and

(iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

(4) A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.

(5) A device intended solely for veterinary use.

(6) A device shipped solely for research on or with laboratory animals and labeled in accordance with § 812.5(c).

(7) A custom device as defined in § 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.

(d) Limit on certain exemptions. In the case of class II or class III device described in paragraph (c)(1) or (2) of this section, this part applies beginning on the date stipulated in an FDA regulation or order that calls for the submission of premarket approval applications for an unapproved class III device, or establishes a performance standard for a class II device.

(e) Investigations subject to IND's. A sponsor that, on July 16, 1980, has an effective investigational new drug application (IND) for an investigation of a device shall continue to comply with the requirements of part 312 until 90 days after that date. To continue the investigation after that date, a sponsor shall comply with paragraph (b)(1) of this section, if the device is not a significant risk device, or shall have obtained FDA approval under § 812.30 of an IDE application for the investigation of the device.

[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; 53 FR 11252, Apr. 6, 1988; 62 FR 4165, Jan. 29, 1997; 62 FR 12096, Mar. 14, 1997; 88 FR 88249, Dec. 21, 2023]

§ 812.3 Definitions.

(a) Act means the Federal Food, Drug, and Cosmetic Act (sections 201-901, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

(b) A custom device means a device within the meaning of section 520(b) of the Federal Food, Drug, and Cosmetic Act.

(c) FDA means the Food and Drug Administration.

(d) Implant means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. FDA may, in order to protect public health, determine that devices placed in subjects for shorter periods are also “implants” for purposes of this part.

(e) Institution means a person, other than an individual, who engages in the conduct of research on subjects or in the delivery of medical services to individuals as a primary activity or as an adjunct to providing residential or custodial care to humans. The term includes, for example, a hospital, retirement home, confinement facility, academic establishment, and device manufacturer. The term has the same meaning as “facility” in section 520(g) of the act.

(f) Institutional review board (IRB) means any board, committee, or other group formally designated by an institution to review biomedical research involving subjects and established, operated, and functioning in conformance with part 56. The term has the same meaning as “institutional review committee” in section 520(g) of the act.

(g) Investigational device means a device, including a transitional device, that is the object of an investigation.

(h) Investigation means a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device.

(i) Investigator means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.

(j) Monitor, when used as a noun, means an individual designated by a sponsor or contract research organization to oversee the progress of an investigation. The monitor may be an employee of a sponsor or a consultant to the sponsor, or an employee of or consultant to a contract research organization. Monitor, when used as a verb, means to oversee an investigation.

(k) Noninvasive, when applied to a diagnostic device or procedure, means one that does not by design or intention: (1) Penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra, or (2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os. For purposes of this part, blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for noninvestigational purposes is also considered noninvasive.

(l) Person includes any individual, partnership, corporation, association, scientific or academic establishment, Government agency or organizational unit of a Government agency, and any other legal entity.

(m) Significant risk device means an investigational device that:

(1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

(2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;

(3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or

(4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

(n) Sponsor means a person who initiates, but who does not actually conduct, the investigation, that is, the investigational device is administered, dispensed, or used under the immediate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

(o) Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, an investigation, that is, under whose immediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator under this part include those of an investigator and those of a sponsor.

(p) Subject means a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease.

(q) Termination means a discontinuance, by sponsor or by withdrawal of IRB or FDA approval, of an investigation before completion.

(r) Transitional device means a device subject to section 520(l) of the act, that is, a device that FDA considered to be a new drug or an antibiotic drug before May 28, 1976.

(s) Unanticipated adverse device effect means any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

(t) Independent ethics committee (IEC) means an independent review panel that is responsible for ensuring the protection of the rights, safety, and well-being of subjects involved in a clinical investigation and is adequately constituted to ensure that protection. An institutional review board (IRB), as defined in paragraph (f) of this section and subject to the requirements of part 56 of this chapter, is one type of IEC.

[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 48 FR 15622, Apr. 12, 1983; 81 FR 70340, Oct. 12, 2016; 83 FR 7385, Feb. 21, 2018; 83 FR 7385, Feb. 21, 2018]

§ 812.5 Labeling of investigational devices.

(a) Contents. An investigational device or its immediate package shall bear a label with the following information: the name and place of business of the manufacturer, packer, or distributor (in accordance with § 801.1), the quantity of contents, if appropriate, and the following statement: “CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use.” The label or other labeling shall describe all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions.

(b) Prohibitions. The labeling of an investigational device shall not bear any statement that is false or misleading in any particular and shall not represent that the device is safe or effective for the purposes for which it is being investigated.

(c) Animal research. An investigational device shipped solely for research on or with laboratory animals shall bear on its label the following statement: “CAUTION—Device for investigational use in laboratory animals or other tests that do not involve human subjects.”

(d) The appropriate FDA Center Director, according to the procedures set forth in § 801.128 or § 809.11 of this chapter, may grant an exception or alternative to the provisions in paragraphs (a) and (c) of this section, to the extent that these provisions are not explicitly required by statute, for specified lots, batches, or other units of a device that are or will be included in the Strategic National Stockpile.

[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980; 72 FR 73602, Dec. 28, 2007]

§ 812.7 Prohibition of promotion and other practices.

A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator shall not:

(a) Promote or test market an investigational device, until after FDA has approved the device for commercial distribution.

(b) Commercialize an investigational device by charging the subjects or investigators for a device a price larger than that necessary to recover costs of manufacture, research, development, and handling.

(c) Unduly prolong an investigation. If data developed by the investigation indicate in the case of a class III device that premarket approval cannot be justified or in the case of a class II device that it will not comply with an applicable performance standard or an amendment to that standard, the sponsor shall promptly terminate the investigation.

(d) Represent that an investigational device is safe or effective for the purposes for which it is being investigated.

§ 812.10 Waivers.

(a) Request. A sponsor may request FDA to waive any requirement of this part. A waiver request, with supporting documentation, may be submitted separately or as part of an application to the address in § 812.19.

(b) FDA action. FDA may by letter grant a waiver of any requirement that FDA finds is not required by the act and is unnecessary to protect the rights, safety, or welfare of human subjects.

(c) Effect of request. Any requirement shall continue to apply unless and until FDA waives it.

§ 812.18 Import and export requirements.

(a) Imports. In addition to complying with other requirements of this part, a person who imports or offers for importation an investigational device subject to this part shall be the agent of the foreign exporter with respect to investigations of the device and shall act as the sponsor of the clinical investigation, or ensure that another person acts as the agent of the foreign exporter and the sponsor of the investigation.

(b) Exports. A person exporting an investigational device subject to this part shall obtain FDA's prior approval, as required by section 801(e) of the act or comply with section 802 of the act.

[45 FR 3751, Jan. 18, 1980, as amended at 62 FR 26229, May 13, 1997]

§ 812.19 Address for IDE correspondence.

(a) If you are sending an application, supplemental application, report, request for waiver, request for import or export approval, or other correspondence relating to matters covered by this part, you must send the submission to the appropriate address as follows:

(1) For devices regulated by the Center for Devices and Radiological Health, send it to the current address displayed on the website https://www.fda.gov/cdrhsubmissionaddress.

(2) For devices regulated by the Center for Biologics Evaluation and Research, send it to the current address displayed on the website https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm.

(3) For devices regulated by the Center for Drug Evaluation and Research, send it to Central Document Control Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

(b) You must state on the outside wrapper of each submission what the submission is, for example, an “IDE application,” a “supplemental IDE application,” or a “correspondence concerning an IDE (or an IDE application).”

[71 FR 42048, July 25, 2006, as amended at 75 FR 20915, Apr. 22, 2010; 80 FR 18094, Apr. 3, 2015; 84 FR 68339, Dec. 16, 2019]

§ 812.20 Application.

(a) Submission. (1) A sponsor shall submit an application to FDA if the sponsor intends to use a significant risk device in an investigation, intends to conduct an investigation that involves an exception from informed consent under § 50.24 of this chapter, or if FDA notifies the sponsor that an application is required for an investigation.

(2) A sponsor shall not begin an investigation for which FDA's approval of an application is required until FDA has approved the application.

(3) A sponsor shall submit a signed “Application for an Investigational Device Exemption” (IDE application), together with accompanying materials in electronic format, to one of the addresses in § 812.19, and if eCopy by registered mail or by hand. Subsequent correspondence concerning an application or a supplemental application shall be submitted in electronic format and if eCopy by registered mail or by hand.

(4)(i) A sponsor shall submit a separate IDE for any clinical investigation involving an exception from informed consent under § 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization of FDA. FDA shall provide a written determination 30 days after FDA receives the IDE or earlier.

(ii) If the investigation involves an exception from informed consent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in § 50.24 of this chapter.

(b) Contents. An IDE application shall include, in the following order:

(1) The name and address of the sponsor.

(2) A complete report of prior investigations of the device and an accurate summary of those sections of the investigational plan described in § 812.25(a) through (e) or, in lieu of the summary, the complete plan. The sponsor shall submit to FDA a complete investigational plan and a complete report of prior investigations of the device if no IRB has reviewed them, if FDA has found an IRB's review inadequate, or if FDA requests them.

(3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device.

(4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement.

(5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement.

(6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB.

(7) The name and address of any institution at which a part of the investigation may be conducted that has not been identified in accordance with paragraph (b)(6) of this section.

(8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device.

(9) A claim for categorical exclusion under § 25.30 or § 25.34 or an environmental assessment under § 25.40.

(10) Copies of all labeling for the device.

(11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent.

(12) Any other relevant information FDA requests for review of the application.

(c) Additional information. FDA may request additional information concerning an investigation or revision in the investigational plan. The sponsor may treat such a request as a disapproval of the application for purposes of requesting a hearing under part 16.

(d) Information previously submitted. Information previously submitted to the Center for Devices and Radiological Health, the Center for Biologics Evaluation and Research, or the Center for Drug Evaluation and Research, as applicable, in accordance with this chapter ordinarily need not be resubmitted, but may be incorporated by reference.

[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 50 FR 16669, Apr. 26, 1985; 53 FR 11252, Apr. 6, 1988; 61 FR 51530, Oct. 2, 1996; 62 FR 40600, July 29, 1997; 64 FR 10942, Mar. 8, 1999; 73 FR 49942, Aug. 25, 2008; 84 FR 68339, Dec. 16, 2019]

§ 812.25 Investigational plan.

The investigational plan shall include, in the following order:

(a) Purpose. The name and intended use of the device and the objectives and duration of the investigation.

(b) Protocol. A written protocol describing the methodology to be used and an analysis of the protocol demonstrating that the investigation is scientifically sound.

(c) Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the investigation; the manner in which these risks will be minimized; a justification for the investigation; and a description of the patient population, including the number, age, sex, and condition.

(d) Description of device. A description of each important component, ingredient, property, and principle of operation of the device and of each anticipated change in the device during the course of the investigation.

(e) Monitoring procedures. The sponsor's written procedures for monitoring the investigation and the name and address of any monitor.

(f) Labeling. Copies of all labeling for the device.

(g) Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain informed consent.

(h) IRB information. A list of the names, locations, and chairpersons of all IRB's that have been or will be asked to review the investigation, and a certification of any action taken by any of those IRB's with respect to the investigation.

(i) Other institutions. The name and address of each institution at which a part of the investigation may be conducted that has not been identified in paragraph (h) of this section.

(j) Additional records and reports. A description of records and reports that will be maintained on the investigation in addition to those prescribed in subpart G.

§ 812.27 Report of prior investigations.

(a) General. The report of prior investigations shall include reports of all prior clinical, animal, and laboratory testing of the device and shall be comprehensive and adequate to justify the proposed investigation.

(b) Specific contents. The report also shall include:

(1) A bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device, copies of all published and unpublished adverse information, and, if requested by an IRB or FDA, copies of other significant publications.

(2) A summary of all other unpublished information (whether adverse or supportive) in the possession of, or reasonably obtainable by, the sponsor that is relevant to an evaluation of the safety or effectiveness of the device.

(3) If information on nonclinical laboratory studies is provided, a statement that all such studies have been conducted in compliance with applicable requirements in the good laboratory practice regulations in part 58, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study.

(4)(i) If data from clinical investigations conducted in the United States are provided, a statement that each investigation was conducted in compliance with applicable requirements in the protection of human subjects regulations in part 50 of this chapter, the institutional review boards regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105, and the investigational device exemptions regulations in this part, or if any such investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation.

(ii) If data from clinical investigations conducted outside the United States are provided to support the IDE, the requirements under § 812.28 apply. If any such investigation was not conducted in accordance with good clinical practice (GCP) as described in § 812.28(a), the report of prior investigations shall include either a waiver request in accordance with § 812.28(c) or a brief statement of the reason for not conducting the investigation in accordance with GCP and a description of steps taken to ensure that the data and results are credible and accurate and that the rights, safety, and well-being of subjects have been adequately protected. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation.

[45 FR 3751, Jan. 18, 1980, as amended at 50 FR 7518, Feb. 22, 1985; 83 FR 7385, Feb. 21, 2018]

§ 812.28 Acceptance of data from clinical investigations conducted outside the United States.

(a) Acceptance of data from clinical investigations conducted outside the United States to support an IDE or a device marketing application or submission (an application under section 515 or 520(m) of the Federal Food, Drug, and Cosmetic Act, a premarket notification submission under section 510(k) of the Federal Food, Drug, and Cosmetic Act, or a request for De Novo classification under section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act). FDA will accept information on a clinical investigation conducted outside the United States to support an IDE or a device marketing application or submission if the investigation is well-designed and well-conducted and the following conditions are met:

(1) A statement is provided that the investigation was conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical investigations in a way that provides assurance that the data and results are credible and accurate and that the rights, safety, and well-being of subjects are protected. GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) before initiating an investigation, continuing review of an ongoing investigation by an IEC, and obtaining and documenting the freely given informed consent of the subject (or a subject's legally authorized representative, if the subject is unable to provide informed consent) before initiating an investigation. GCP does not require informed consent in life-threatening situations when the IEC reviewing the investigation finds, before initiation of the investigation, that informed consent is not feasible and either that the conditions present are consistent with those described in § 50.23 or § 50.24(a) of this chapter, or that the measures described in the protocol or elsewhere will protect the rights, safety, and well-being of subjects.

(2) In addition to the information required elsewhere in parts 807, 812, and 814 of this chapter, as applicable, the information in paragraph (b) of this section is submitted, as follows:

(i) For an investigation of a significant risk device, as defined in § 812.3(m), the supporting information as described in paragraph (b) of this section is submitted.

(ii) For an investigation of a device, other than a significant risk device, the supporting information as described in paragraphs (b)(1), (4), (5), (7) through (9), and (11) of this section is submitted, and the supporting information as described in paragraph (b)(10) of this section and the rationale for determining the investigation is of a device other than a significant risk device are made available for agency review upon request by FDA.

(iii) For a device investigation that meets the exemption criteria in § 812.2(c), the supporting information as described in paragraphs (b)(1), (4), (5), (7) through (11) of this section and the rationale for determining the investigation meets the exemption criteria in § 812.2(c) are made available for agency review upon request by FDA.

(3) FDA is able to validate the data from the investigation through an onsite inspection, or through other appropriate means, if the agency deems it necessary.

(b) Supporting information. A sponsor or applicant who submits data from a clinical investigation conducted outside the United States to support an IDE or a device marketing application or submission, in addition to information required elsewhere in parts 807, 812, and 814 of this chapter, as applicable, shall provide a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP as described in paragraph (a)(1) of this section. The description is not required to duplicate information already submitted in the application or submission. Instead, the description must provide either the following information, as specified in paragraph (a)(2) of this section, or a cross-reference to another section of the application or submission where the information is located:

(1) The names of the investigators and the names and addresses of the research facilities and sites where records relating to the investigation are maintained;

(2) The investigator's qualifications;

(3) A description of the research facility(ies);

(4) A detailed summary of the protocol and results of the investigation and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records;

(5) Either a statement that the device used in the investigation conducted outside the United States is identical to the device that is the subject of the submission or application, or a detailed description of the device and each important component (including all materials and specifications), ingredient, property, and principle of operation of the device used in the investigation conducted outside the United States and a comparison to the device that is the subject of the submission or application that indicates how the device used in the investigation is similar to and/or different from the device that is the subject of the submission or application;

(6) If the investigation is intended to support the safety and effectiveness of a device, a discussion demonstrating that the data and information constitute valid scientific evidence within the meaning of § 860.7 of this chapter;

(7) The name and address of the IEC that reviewed the investigation and a statement that the IEC meets the definition in § 812.3(t). The sponsor or applicant must maintain records supporting such statement, including records describing the qualifications of IEC members, and make these records available for agency review upon request;

(8) A summary of the IEC's decision to approve or modify and approve the investigation, or to provide a favorable opinion;

(9) A description of how informed consent was obtained;

(10) A description of what incentives, if any, were provided to subjects to participate in the investigation;

(11) A description of how the sponsor(s) monitored the investigation and ensured that the investigation was carried out consistently with the protocol; and

(12) A description of how investigators were trained to comply with GCP (as described in paragraph (a)(1) of this section) and to conduct the investigation in accordance with the protocol, and a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained. Any signed written commitments by investigators must be maintained by the sponsor or applicant and made available for agency review upon request.

(c) Waivers. (1) A sponsor or applicant may ask FDA to waive any applicable requirements under paragraphs (a)(1) and (b) of this section. A waiver request may be submitted in an IDE or in an amendment or supplement to an IDE, in a device marketing application or submission (an application under section 515 or 520(m) of the Federal Food, Drug, and Cosmetic Act, a premarket notification submission under section 510(k) of the Federal Food, Drug, and Cosmetic Act, or a request for De Novo classification under section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act) or in an amendment or supplement to a device marketing application or submission, or in a pre-submission. A waiver request is required to contain at least one of the following:

(i) An explanation why the sponsor's or applicant's compliance with the requirement is unnecessary or cannot be achieved;

(ii) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or

(iii) Other information justifying a waiver.

(2) FDA may grant a waiver if it finds that doing so would be in the interest of the public health.

(d) Records. A sponsor or applicant must retain the records required by this section for a clinical investigation conducted outside the United States as follows:

(1) If the investigation is submitted in support of an IDE, for 2 years after the termination or completion of the IDE; and

(2) If the investigation is submitted in support of a premarket approval application, a notice of completion of a product development protocol, a humanitarian device exemption application, a premarket notification submission, or a request for De Novo classification, for 2 years after an agency decision on that submission or application.

(e) Clinical investigations conducted outside of the United States that do not meet conditions. For clinical investigations conducted outside the United States that do not meet the conditions under paragraph (a) of this section, FDA may accept the information from such clinical investigations to support an IDE or a device marketing application or submission if FDA believes that the data and results from such clinical investigation are credible and accurate and that the rights, safety, and well-being of subjects have been adequately protected.

[83 FR 7386, Feb. 21, 2018]

§ 812.30 FDA action on applications.

(a) Approval or disapproval. FDA will notify the sponsor in writing of the date it receives an application. FDA may approve an investigation as proposed, approve it with modifications, or disapprove it. An investigation may not begin until:

(1) Thirty days after FDA receives the application at the address in § 812.19 for the investigation of a device other than a banned device, unless FDA notifies the sponsor that the investigation may not begin; or

(2) FDA approves, by order, an IDE for the investigation.

(b) Grounds for disapproval or withdrawal. FDA may disapprove or withdraw approval of an application if FDA finds that:

(1) There has been a failure to comply with any requirement of this part or the act, any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA.

(2) The application or a report contains an untrue statement of a material fact, or omits material information required by this part.

(3) The sponsor fails to respond to a request for additional information within the time prescribed by FDA.

(4) There is reason to believe that the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or informed consent is inadequate, or the investigation is scientifically unsound, or there is reason to believe that the device as used is ineffective.

(5) It is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of:

(i) The report of prior investigations or the investigational plan;

(ii) The methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or

(iii) Monitoring and review of the investigation.

(c) Notice of disapproval or withdrawal. If FDA disapproves an application or proposes to withdraw approval of an application, FDA will notify the sponsor in writing.

(1) A disapproval order will contain a complete statement of the reasons for disapproval and a statement that the sponsor has an opportunity to request a hearing under part 16.

(2) A notice of a proposed withdrawal of approval will contain a complete statement of the reasons for withdrawal and a statement that the sponsor has an opportunity to request a hearing under part 16. FDA will provide the opportunity for hearing before withdrawal of approval, unless FDA determines in the notice that continuation of testing under the exemption will result in an unreasonble risk to the public health and orders withdrawal of approval before any hearing.

[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980]

§ 812.35 Supplemental applications.

(a) Changes in investigational plan—(1) Changes requiring prior approval. Except as described in paragraphs (a)(2) through (a)(4) of this section, a sponsor must obtain approval of a supplemental application under § 812.30(a), and IRB approval when appropriate (see §§ 56.110 and 56.111 of this chapter), prior to implementing a change to an investigational plan. If a sponsor intends to conduct an investigation that involves an exception to informed consent under § 50.24 of this chapter, the sponsor shall submit a separate investigational device exemption (IDE) application in accordance with § 812.20(a).

(2) Changes effected for emergency use. The requirements of paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such deviation shall be reported to FDA within 5-working days after the sponsor learns of it (see § 812.150(a)(4)).

(3) Changes effected with notice to FDA within 5 days. A sponsor may make certain changes without prior approval of a supplemental application under paragraph (a)(1) of this section if the sponsor determines that these changes meet the criteria described in paragraphs (a)(3)(i) and (a)(3)(ii) of this section, on the basis of credible information defined in paragraph (a)(3)(iii) of this section, and the sponsor provides notice to FDA within 5-working days of making these changes.

(i) Developmental changes. The requirements in paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply to developmental changes in the device (including manufacturing changes) that do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of an investigation.

(ii) Changes to clinical protocol. The requirements in paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply to changes to clinical protocols that do not affect:

(A) The validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol;

(B) The scientific soundness of the investigational plan; or

(C) The rights, safety, or welfare of the human subjects involved in the investigation.

(iii) Definition of credible information. (A) Credible information to support developmental changes in the device (including manufacturing changes) includes data generated under the design and development activities of § 820.10(c) of this chapter, preclinical/animal testing, peer reviewed published literature, or other reliable information such as clinical information gathered during a trial or marketing.

(B) Credible information to support changes to clinical protocols is defined as the sponsor's documentation supporting the conclusion that a change does not have a significant impact on the study design or planned statistical analysis, and that the change does not affect the rights, safety, or welfare of the subjects. Documentation shall include information such as peer reviewed published literature, the recommendation of the clinical investigator(s), and/or the data gathered during the clinical trial or marketing.

(iv) Notice of IDE change. Changes meeting the criteria in paragraphs (a)(3)(i) and (a)(3)(ii) of this section that are supported by credible information as defined in paragraph (a)(3)(iii) of this section may be made without prior FDA approval if the sponsor submits a notice of the change to the IDE not later than 5-working days after making the change. Changes to devices are deemed to occur on the date the device, manufactured incorporating the design or manufacturing change, is distributed to the investigator(s). Changes to a clinical protocol are deemed to occur when a clinical investigator is notified by the sponsor that the change should be implemented in the protocol or, for sponsor-investigator studies, when a sponsor-investigator incorporates the change in the protocol. Such notices shall be identified as a “notice of IDE change.”

(A) For a developmental or manufacturing change to the device, the notice shall include a summary of the relevant information gathered during the course of the investigation upon which the change was based; a description of the change to the device or manufacturing process (cross-referenced to the appropriate sections of the original device description or manufacturing process); and, if the design and development activities of § 820.10(c) of this chapter were used to assess the change, a statement that no new risks were identified by appropriate risk analysis and that the verification and validation testing, as appropriate, demonstrated that the design outputs met the design input requirements. If another method of assessment was used, the notice shall include a summary of the information which served as the credible information supporting the change.

(B) For a protocol change, the notice shall include a description of the change (cross-referenced to the appropriate sections of the original protocol); an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and a summary of the information that served as the credible information supporting the sponsor's determination that the change does not affect the rights, safety, or welfare of the subjects.

(4) Changes submitted in annual report. The requirements of paragraph (a)(1) of this section do not apply to minor changes to the purpose of the study, risk analysis, monitoring procedures, labeling, informed consent materials, and IRB information that do not affect:

(i) The validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol;

(ii) The scientific soundness of the investigational plan; or

(iii) The rights, safety, or welfare of the human subjects involved in the investigation. Such changes shall be reported in the annual progress report for the IDE, under § 812.150(b)(5).

(b) IRB approval for new facilities. A sponsor shall submit to FDA a certification of any IRB approval of an investigation or a part of an investigation not included in the IDE application. If the investigation is otherwise unchanged, the supplemental application shall consist of an updating of the information required by § 812.20(b) and (c) and a description of any modifications in the investigational plan required by the IRB as a condition of approval. A certification of IRB approval need not be included in the initial submission of the supplemental application, and such certification is not a precondition for agency consideration of the application. Nevertheless, a sponsor may not begin a part of an investigation at a facility until the IRB has approved the investigation, FDA has received the certification of IRB approval, and FDA, under § 812.30(a), has approved the supplemental application relating to that part of the investigation (see § 56.103(a)).

[50 FR 25909, June 24, 1985; 50 FR 28932, July 17, 1985, as amended at 61 FR 51531, Oct. 2, 1996; 63 FR 64625, Nov. 23, 1998; 90 FR 55980, Dec. 4, 2025]

§ 812.36 Treatment use of an investigational device.

(a) General. A device that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease or condition in patients for whom no comparable or satisfactory alternative device or other therapy is available. During the clinical trial or prior to final action on the marketing application, it may be appropriate to use the device in the treatment of patients not in the trial under the provisions of a treatment investigational device exemption (IDE). The purpose of this section is to facilitate the availability of promising new devices to desperately ill patients as early in the device development process as possible, before general marketing begins, and to obtain additional data on the device's safety and effectiveness. In the case of a serious disease, a device ordinarily may be made available for treatment use under this section after all clinical trials have been completed. In the case of an immediately life-threatening disease, a device may be made available for treatment use under this section prior to the completion of all clinical trials. For the purpose of this section, an “immediately life-threatening” disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. For purposes of this section, “treatment use”of a device includes the use of a device for diagnostic purposes.

(b) Criteria. FDA shall consider the use of an investigational device under a treatment IDE if:

(1) The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition;

(2) There is no comparable or satisfactory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population;

(3) The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed; and

(4) The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.

(c) Applications for treatment use. (1) A treatment IDE application shall include, in the following order:

(i) The name, address, and telephone number of the sponsor of the treatment IDE;

(ii) The intended use of the device, the criteria for patient selection, and a written protocol describing the treatment use;

(iii) An explanation of the rationale for use of the device, including, as appropriate, either a list of the available regimens that ordinarily should be tried before using the investigational device or an explanation of why the use of the investigational device is preferable to the use of available marketed treatments;

(iv) A description of clinical procedures, laboratory tests, or other measures that will be used to evaluate the effects of the device and to minimize risk;

(v) Written procedures for monitoring the treatment use and the name and address of the monitor;

(vi) Instructions for use for the device and all other labeling as required under § 812.5(a) and (b);

(vii) Information that is relevant to the safety and effectiveness of the device for the intended treatment use. Information from other IDE's may be incorporated by reference to support the treatment use;

(viii) A statement of the sponsor's commitment to meet all applicable responsibilities under this part and part 56 of this chapter and to ensure compliance of all participating investigators with the informed consent requirements of part 50 of this chapter;

(ix) An example of the agreement to be signed by all investigators participating in the treatment IDE and certification that no investigator will be added to the treatment IDE before the agreement is signed; and

(x) If the device is to be sold, the price to be charged and a statement indicating that the price is based on manufacturing and handling costs only.

(2) A licensed practitioner who receives an investigational device for treatment use under a treatment IDE is an “investigator” under the IDE and is responsible for meeting all applicable investigator responsibilities under this part and parts 50 and 56 of this chapter.

(d) FDA action on treatment IDE applications—(1) Approval of treatment IDE's. Treatment use may begin 30 days after FDA receives the treatment IDE submission at the address specified in § 812.19, unless FDA notifies the sponsor in writing earlier than the 30 days that the treatment use may or may not begin. FDA may approve the treatment use as proposed or approve it with modifications.

(2) Disapproval or withdrawal of approval of treatment IDE's. FDA may disapprove or withdraw approval of a treatment IDE if:

(i) The criteria specified in § 812.36(b) are not met or the treatment IDE does not contain the information required in § 812.36(c);

(ii) FDA determines that any of the grounds for disapproval or withdrawal of approval listed in § 812.30(b)(1) through (b)(5) apply;

(iii) The device is intended for a serious disease or condition and there is insufficient evidence of safety and effectiveness to support such use;

(iv) The device is intended for an immediately life-threatening disease or condition and the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the device:

(A) May be effective for its intended use in its intended population; or

(B) Would not expose the patients to whom the device is to be administered to an unreasonable and significant additional risk of illness or injury;

(v) There is reasonable evidence that the treatment use is impeding enrollment in, or otherwise interfering with the conduct or completion of, a controlled investigation of the same or another investigational device;

(vi) The device has received marketing approval/clearance or a comparable device or therapy becomes available to treat or diagnose the same indication in the same patient population for which the investigational device is being used;

(vii) The sponsor of the controlled clinical trial is not pursuing marketing approval/clearance with due diligence;

(viii) Approval of the IDE for the controlled clinical investigation of the device has been withdrawn; or

(ix) The clinical investigator(s) named in the treatment IDE are not qualified by reason of their scientific training and/or experience to use the investigational device for the intended treatment use.

(3) Notice of disapproval or withdrawal. If FDA disapproves or proposes to withdraw approval of a treatment IDE, FDA will follow the procedures set forth in § 812.30(c).

(e) Safeguards. Treatment use of an investigational device is conditioned upon the sponsor and investigators complying with the safeguards of the IDE process and the regulations governing informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter).

(f) Reporting requirements. The sponsor of a treatment IDE shall submit progress reports on a semi-annual basis to all reviewing IRB's and FDA until the filing of a marketing application. These reports shall be based on the period of time since initial approval of the treatment IDE and shall include the number of patients treated with the device under the treatment IDE, the names of the investigators participating in the treatment IDE, and a brief description of the sponsor's efforts to pursue marketing approval/clearance of the device. Upon filing of a marketing application, progress reports shall be submitted annually in accordance with § 812.150(b)(5). The sponsor of a treatment IDE is responsible for submitting all other reports required under § 812.150.

[62 FR 48947, Sept. 18, 1997]

§ 812.38 Confidentiality of data and information.

(a) Existence of IDE. FDA will not disclose the existence of an IDE unless its existence has previously been publicly disclosed or acknowledged, until FDA approves an application for premarket approval of the device subject to the IDE; or a notice of completion of a product development protocol for the device has become effective.

(b) Availability of summaries or data. (1) FDA will make publicly available, upon request, a detailed summary of information concerning the safety and effectiveness of the device that was the basis for an order approving, disapproving, or withdrawing approval of an application for an IDE for a banned device. The summary shall include information on any adverse effect on health caused by the device.

(2) If a device is a banned device or if the existence of an IDE has been publicly disclosed or acknowledged, data or information contained in the file is not available for public disclosure before approval of an application for premarket approval or the effective date of a notice of completion of a product development protocol except as provided in this section. FDA may, in its discretion, disclose a summary of selected portions of the safety and effectiveness data, that is, clinical, animal, or laboratory studies and tests of the device, for public consideration of a specific pending issue.

(3) If the existence of an IDE file has not been publicly disclosed or acknowledged, no data or information in the file are available for public disclosure except as provided in paragraphs (b)(1) and (c) of this section.

(4) Notwithstanding paragraph (b)(2) of this section, FDA will make available to the public, upon request, the information in the IDE that was required to be filed in Docket Number FDA-1995-S-0036 in the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

(c) Reports of adverse effects. Upon request or on its own initiative, FDA shall disclose to an individual on whom an investigational device has been used a copy of a report of adverse device effects relating to that use.

(d) Other rules. Except as otherwise provided in this section, the availability for public disclosure of data and information in an IDE file shall be handled in accordance with § 814.9.

[45 FR 3751, Jan. 18, 1980, as amended at 53 FR 11253, Apr. 6, 1988; 61 FR 51531, Oct. 2, 1996; 88 FR 16880, Mar. 21, 2023]

§ 812.40 General responsibilities of sponsors.

Sponsors are responsible for selecting qualified investigators and providing them with the information they need to conduct the investigation properly, ensuring proper monitoring of the investigation, ensuring that IRB review and approval are obtained, submitting an IDE application to FDA, and ensuring that any reviewing IRB and FDA are promptly informed of significant new information about an investigation. Additional responsibilities of sponsors are described in subparts B and G.

§ 812.42 FDA and IRB approval.

A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both approved the application or supplemental application relating to the investigation or part of an investigation.

[46 FR 8957, Jan. 27, 1981]

§ 812.43 Selecting investigators and monitors.

(a) Selecting investigators. A sponsor shall select investigators qualified by training and experience to investigate the device.

(b) Control of device. A sponsor shall ship investigational devices only to qualified investigators participating in the investigation.

(c) Obtaining agreements. A sponsor shall obtain from each participating investigator a signed agreement that includes:

(1) The investigator's curriculum vitae.

(2) Where applicable, a statement of the investigator's relevant experience, including the dates, location, extent, and type of experience.

(3) If the investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to termination.

(4) A statement of the investigator's commitment to:

(i) Conduct the investigation in accordance with the agreement, the investigational plan, this part and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB or FDA;

(ii) Supervise all testing of the device involving human subjects; and

(iii) Ensure that the requirements for obtaining informed consent are met.

(5) Sufficient accurate financial disclosure information to allow the sponsor to submit a complete and accurate certification or disclosure statement as required under part 54 of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. This information shall not be submitted in an investigational device exemption application, but shall be submitted in any marketing application involving the device.

(d) Selecting monitors. A sponsor shall select monitors qualified by training and experience to monitor the investigational study in accordance with this part and other applicable FDA regulations.

[45 FR 3751, Jan. 18, 1980, as amended at 63 FR 5253, Feb. 2, 1998]

§ 812.45 Informing investigators.

A sponsor shall supply all investigators participating in the investigation with copies of the investigational plan and the report of prior investigations of the device.

§ 812.46 Monitoring investigations.

(a) Securing compliance. A sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, the requirements of this part or other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA shall promptly either secure compliance, or discontinue shipments of the device to the investigator and terminate the investigator's participation in the investigation. A sponsor shall also require such an investigator to dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a subject.

(b) Unanticipated adverse device effects. (1) A sponsor shall immediately conduct an evaluation of any unanticipated adverse device effect.

(2) A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to subjects shall terminate all investigations or parts of investigations presenting that risk as soon as possible. Termination shall occur not later than 5 working days after the sponsor makes this determination and not later than 15 working days after the sponsor first received notice of the effect.

(c) Resumption of terminated studies. If the device is a significant risk device, a sponsor may not resume a terminated investigation without IRB and FDA approval. If the device is not a significant risk device, a sponsor may not resume a terminated investigation without IRB approval and, if the investigation was terminated under paragraph (b)(2) of this section, FDA approval.

§ 812.47 Emergency research under § 50.24 of this chapter.

(a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under § 50.24 of this chapter. When the sponsor receives from the IRB information concerning the public disclosures under § 50.24(a)(7)(ii) and (iii) of this chapter, the sponsor shall promptly submit to the IDE file and to Docket Number FDA-1995-S-0036 in the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, copies of the information that was disclosed, identified by the IDE number.

(b) The sponsor also shall monitor such investigations to determine when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this information in writing to FDA, investigators who are asked to participate in this or a substantially equivalent clinical investigation, and other IRB's that are asked to review this or a substantially equivalent investigation.

[61 FR 51531, Oct. 2, 1996, as amended at 64 FR 10943, Mar. 8, 1999; 88 FR 16880, Mar. 21, 2023]

§ 812.60 IRB composition, duties, and functions.

An IRB reviewing and approving investigations under this part shall comply with the requirements of part 56 in all respects, including its composition, duties, and functions.

[46 FR 8957, Jan. 27, 1981]

§ 812.62 IRB approval.

(a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all investigations covered by this part.

(b) If no IRB exists or if FDA finds that an IRB's review is inadequate, a sponsor may submit an application to FDA.

[46 FR 8957, Jan. 27, 1981]

§ 812.64 IRB's continuing review.

The IRB shall conduct its continuing review of an investigation in accordance with part 56.

[46 FR 8957, Jan. 27, 1981]

§ 812.65 [Reserved]

§ 812.66 Significant risk device determinations.

If an IRB determines that an investigation, presented for approval under § 812.2(b)(1)(ii), involves a significant risk device, it shall so notify the investigator and, where appropriate, the sponsor. A sponsor may not begin the investigation except as provided in § 812.30(a).

[46 FR 8957, Jan. 27, 1981]

§ 812.100 General responsibilities of investigators.

An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this chapter. Additional responsibilities of investigators are described in subpart G.

[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8957, Jan. 27, 1981]

§ 812.110 Specific responsibilities of investigators.

(a) Awaiting approval. An investigator may determine whether potential subjects would be interested in participating in an investigation, but shall not request the written informed consent of any subject to participate, and shall not allow any subject to participate before obtaining IRB and FDA approval.

(b) Compliance. An investigator shall conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.

(c) Supervising device use. An investigator shall permit an investigational device to be used only with subjects under the investigator's supervision. An investigator shall not supply an investigational device to any person not authorized under this part to receive it.

(d) Financial disclosure. A clinical investigator shall disclose to the sponsor sufficient accurate financial information to allow the applicant to submit complete and accurate certification or disclosure statements required under part 54 of this chapter. The investigator shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study.

(e) Disposing of device. Upon completion or termination of a clinical investigation or the investigator's part of an investigation, or at the sponsor's request, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.

[45 FR 3751, Jan. 18, 1980, as amended at 63 FR 5253, Feb. 2, 1998]

§ 812.119 Disqualification of a clinical investigator.

(a) If FDA has information indicating that an investigator (including a sponsor-investigator) has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Center for Devices and Radiological Health, the Center for Biologics Evaluation and Research, or the Center for Drug Evaluation and Research will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered and accepted by the applicable Center, the Center will discontinue the disqualification proceeding. If an explanation is offered but not accepted by the applicable Center, the investigator will be given an opportunity for a regulatory hearing under part 16 of this chapter on the question of whether the investigator is eligible to receive test articles under this part and eligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA.

(b) After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Commissioner will notify the investigator, the sponsor of any investigation in which the investigator has been named as a participant, and the reviewing investigational review boards (IRBs) that the investigator is not eligible to receive test articles under this part. The notification to the investigator, sponsor and IRBs will provide a statement of the basis for such determination. The notification also will explain that an investigator determined to be ineligible to receive test articles under this part will be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, including drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products.

(c) Each application or submission to FDA under the provisions of this chapter containing data reported by an investigator who has been determined to be ineligible to receive FDA-regulated test articles is subject to examination to determine whether the investigator has submitted unreliable data that are essential to the continuation of an investigation or essential to the clearance or approval of a marketing application, or essential to the continued marketing of an FDA-regulated product.

(d) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor, who shall have an opportunity for a regulatory hearing under part 16 of this chapter. If a danger to the public health exists, however, the Commissioner shall terminate the investigational device exemption (IDE) immediately and notify the sponsor and the reviewing IRBs of the termination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under part 16 of this chapter on the question of whether the IDE should be reinstated. The determination that an investigation may not be considered in support of a research or marketing application or a notification or petition submission does not, however, relieve the sponsor of any obligation under any other applicable regulation to submit to FDA the results of the investigation.

(e) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued clearance or approval of the product for which the data were submitted cannot be justified, the Commissioner will proceed to rescind clearance or withdraw approval of the product in accordance with the applicable provisions of the relevant statutes.

(f) An investigator who has been determined to be ineligible under paragraph (b) of this section may be reinstated as eligible when the Commissioner determines that the investigator has presented adequate assurances that the investigator will employ all test articles, and will conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, solely in compliance with the applicable provisions of this chapter.

[77 FR 25360, Apr. 30, 2012]

§ 812.140 Records.

(a) Investigator records. A participating investigator shall maintain the following accurate, complete, and current records relating to the investigator's participation in an investigation:

(1) All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports.

(2) Records of receipt, use or disposition of a device that relate to:

(i) The type and quantity of the device, the dates of its receipt, and the batch number or code mark.

(ii) The names of all persons who received, used, or disposed of each device.

(iii) Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.

(3) Records of each subject's case history and exposure to the device. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. Such records shall include:

(i) Documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the failure to obtain informed consent. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

(ii) All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests.

(iii) A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy.

(4) The protocol, with documents showing the dates of and reasons for each deviation from the protocol.

(5) Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.

(b) Sponsor records. A sponsor shall maintain the following accurate, complete, and current records relating to an investigation:

(1) All correspondence with another sponsor, a monitor, an investigator, an IRB, or FDA, including required reports.

(2) Records of shipment and disposition. Records of shipment shall include the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal.

(3) Signed investigator agreements including the financial disclosure information required to be collected under § 812.43(c)(5) in accordance with part 54 of this chapter.

(4) For each investigation subject to § 812.2(b)(1) of a device other than a significant risk device, the records described in paragraph (b)(5) of this section and the following records, consolidated in one location and available for FDA inspection and copying:

(i) The name and intended use of the device and the objectives of the investigation;

(ii) A brief explanation of why the device is not a significant risk device:

(iii) The name and address of each investigator:

(iv) The name and address of each IRB that has reviewed the investigation:

(v) A statement of the extent to which the good manufacturing practice regulation in part 820 will be followed in manufacturing the device; and

(vi) Any other information required by FDA.

(5) Records concerning adverse device effects (whether anticipated or unanticipated) and complaints and

(6) Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigation or a particular investigation.

(c) IRB records. An IRB shall maintain records in accordance with part 56 of this chapter.

(d) Retention period. An investigator or sponsor shall maintain the records required by this subpart during the investigation and for a period of 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application, a notice of completion of a product development protocol, a humanitarian device exemption application, a premarket notification submission, or a request for De Novo classification.

(e) Records custody. An investigator or sponsor may withdraw from the responsibility to maintain records for the period required in paragraph (d) of this section and transfer custody of the records to any other person who will accept responsibility for them under this part, including the requirements of § 812.145. Notice of a transfer shall be given to FDA not later than 10 working days after transfer occurs.

[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58843, Sept. 5, 1980; 46 FR 8957, Jan. 27, 1981; 61 FR 57280, Nov. 5, 1996; 63 FR 5253, Feb. 2, 1998; 83 FR 7387, Feb. 21, 2018; 83 FR 7387, Feb. 21, 2018]

§ 812.145 Inspections.

(a) Entry and inspection. A sponsor or an investigator who has authority to grant access shall permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any establishment where devices are held (including any establishment where devices are manufactured, processed, packed, installed, used, or implanted or where records of results from use of devices are kept).

(b) Records inspection. A sponsor, IRB, or investigator, or any other person acting on behalf of such a person with respect to an investigation, shall permit authorized FDA employees, at reasonable times and in a reasonable manner, to inspect and copy all records relating to an investigation.

(c) Records identifying subjects. An investigator shall permit authorized FDA employees to inspect and copy records that identify subjects, upon notice that FDA has reason to suspect that adequate informed consent was not obtained, or that reports required to be submitted by the investigator to the sponsor or IRB have not been submitted or are incomplete, inaccurate, false, or misleading.

§ 812.150 Reports.

(a) Investigator reports. An investigator shall prepare and submit the following complete, accurate, and timely reports:

(1) Unanticipated adverse device effects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.

(2) Withdrawal of IRB approval. An investigator shall report to the sponsor, within 5 working days, a withdrawal of approval by the reviewing IRB of the investigator's part of an investigation.

(3) Progress. An investigator shall submit progress reports on the investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but in no event less often than yearly.

(4) Deviations from the investigational plan. An investigator shall notify the sponsor and the reviewing IRB (see § 56.108(a) (3) and (4)) of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 working days after the emergency occurred. Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB in accordance with § 812.35(a) also is required.

(5) Informed consent. If an investigator uses a device without obtaining informed consent, the investigator shall report such use to the sponsor and the reviewing IRB within 5 working days after the use occurs.

(6) Final report. An investigator shall, within 3 months after termination or completion of the investigation or the investigator's part of the investigation, submit a final report to the sponsor and the reviewing IRB.

(7) Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and current information about any aspect of the investigation.

(b) Sponsor reports. A sponsor shall prepare and submit the following complete, accurate, and timely reports:

(1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of an unanticipated adverse device effect under § 812.46(b) shall report the results of such evaluation to FDA and to all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.

(2) Withdrawal of IRB approval. A sponsor shall notify FDA and all reviewing IRB's and participating investigators of any withdrawal of approval of an investigation or a part of an investigation by a reviewing IRB within 5 working days after receipt of the withdrawal of approval.

(3) Withdrawal of FDA approval. A sponsor shall notify all reviewing IRB's and participating investigators of any withdrawal of FDA approval of the investigation, and shall do so within 5 working days after receipt of notice of the withdrawal of approval.

(4) Current investigator list. A sponsor shall submit to FDA, at 6-month intervals, a current list of the names and addresses of all investigators participating in the investigation. The sponsor shall submit the first such list 6 months after FDA approval.

(5) Progress reports. At regular intervals, and at least yearly, a sponsor shall submit progress reports to all reviewing IRB's. In the case of a significant risk device, a sponsor shall also submit progress reports to FDA. A sponsor of a treatment IDE shall submit semi-annual progress reports to all reviewing IRB's and FDA in accordance with § 812.36(f) and annual reports in accordance with this section.

(6) Recall and device disposition. A sponsor shall notify FDA and all reviewing IRB's of any request that an investigator return, repair, or otherwise dispose of any units of a device. Such notice shall occur within 30 working days after the request is made and shall state why the request was made.

(7) Final report. In the case of a significant risk device, the sponsor shall notify FDA within 30 working days of the completion or termination of the investigation and shall submit a final report to FDA and all reviewing the IRB's and participating investigators within 6 months after completion or termination. In the case of a device that is not a significant risk device, the sponsor shall submit a final report to all reviewing IRB's within 6 months after termination or completion.

(8) Informed consent. A sponsor shall submit to FDA a copy of any report by an investigator under paragraph (a)(5) of this section of use of a device without obtaining informed consent, within 5 working days of receipt of notice of such use.

(9) Significant risk device determinations. If an IRB determines that a device is a significant risk device, and the sponsor had proposed that the IRB consider the device not to be a significant risk device, the sponsor shall submit to FDA a report of the IRB's determination within 5 working days after the sponsor first learns of the IRB's determination.

(10) Other. A sponsor shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and current information about any aspect of the investigation.

[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58843, Sept. 5, 1980; 48 FR 15622, Apr. 12, 1983; 62 FR 48948, Sept. 18, 1997]

§ 814.1 Scope.

(a) This section implements sections 515 and 515A of the act by providing procedures for the premarket approval of medical devices intended for human use.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

(c) This part applies to any class III medical device, unless exempt under section 520(g) of the act, that:

(1) Was not on the market (introduced or delivered for introduction into commerce for commercial distribution) before May 28, 1976, and is not substantially equivalent to a device on the market before May 28, 1976, or to a device first marketed on, or after that date, which has been classified into class I or class II; or

(2) Is required to have an approved premarket approval application (PMA) or a declared completed product development protocol under a regulation issued under section 515(b) of the act; or

(3) Was regulated by FDA as a new drug or antibiotic drug before May 28, 1976, and therefore is governed by section 520(1) of the act.

(d) This part amends the conditions to approval for any PMA approved before the effective date of this part. Any condition to approval for an approved PMA that is inconsistent with this part is revoked. Any condition to approval for an approved PMA that is consistent with this part remains in effect.

[51 FR 26364, July 22, 1986, as amended at 79 FR 1740, Jan. 10, 2014]

§ 814.2 Purpose.

The purpose of this part is to establish an efficient and thorough device review process—

(a) To facilitate the approval of PMA's for devices that have been shown to be safe and effective and that otherwise meet the statutory criteria for approval; and

(b) To ensure the disapproval of PMA's for devices that have not been shown to be safe and effective or that do not otherwise meet the statutory criteria for approval. This part shall be construed in light of these objectives.

§ 814.3 Definitions.

For the purposes of this part:

(a) Act means the Federal Food, Drug, and Cosmetic Act (sections 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321-392)).

(b) FDA means the Food and Drug Administration.

(c) IDE means an approved or considered approved investigational device exemption under section 520(g) of the act and parts 812 and 813.

(d) Master file means a reference source that a person submits to FDA. A master file may contain detailed information on a specific manufacturing facility, process, methodology, or component used in the manufacture, processing, or packaging of a medical device.

(e) PMA means any premarket approval application for a class III medical device, including all information submitted with or incorporated by reference therein. “PMA” includes a new drug application for a device under section 520(1) of the act.

(f) PMA amendment means information an applicant submits to FDA to modify a pending PMA or a pending PMA supplement.

(g) PMA supplement means a supplemental application to an approved PMA for approval of a change or modification in a class III medical device, including all information submitted with or incorporated by reference therein.

(h) Person includes any individual, partnership, corporation, association, scientific or academic establishment, Government agency, or organizational unit thereof, or any other legal entity.

(i) Statement of material fact means a representation that tends to show that the safety or effectiveness of a device is more probable than it would be in the absence of such a representation. A false affirmation or silence or an omission that would lead a reasonable person to draw a particular conclusion as to the safety or effectiveness of a device also may be a false statement of material fact, even if the statement was not intended by the person making it to be misleading or to have any probative effect.

(j) 30-day PMA supplement means a supplemental application to an approved PMA in accordance with § 814.39(e).

(k) Reasonable probability means that it is more likely than not that an event will occur.

(l) Serious, adverse health consequences means any significant adverse experience, including those which may be either life-threatening or involve permanent or long term injuries, but excluding injuries that are nonlife-threatening and that are temporary and reasonably reversible.

(m) HDE means a premarket approval application submitted pursuant to this subpart seeking a humanitarian device exemption from the effectiveness requirements of sections 514 and 515 of the act as authorized by section 520(m)(2) of the act.

(n) HUD (humanitarian use device) means a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year.

(o) Newly acquired information means data, analyses, or other information not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.

(p) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(q) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

(r) Universal product code (UPC) means the product identifier used to identify an item sold at retail in the United States.

(s) Pediatric patients means patients who are 21 years of age or younger (that is, from birth through the twenty-first year of life, up to but not including the twenty-second birthday) at the time of the diagnosis or treatment.

(t) Readily available means available in the public domain through commonly used public resources for conducting biomedical, regulatory, and medical product research.

[51 FR 26364, July 22, 1986, as amended at 61 FR 15190, Apr. 5, 1996; 61 FR 33244, June 26, 1996; 73 FR 49610, Aug. 22, 2008; 78 FR 58821, Sept. 24, 2013; 79 FR 1740, Jan. 10, 2014; 82 FR 26349, June 7, 2017]

§ 814.9 Confidentiality of data and information in a premarket approval application (PMA) file.

(a) A “PMA file” includes all data and information submitted with or incorporated by reference in the PMA, any IDE incorporated into the PMA, any PMA supplement, any report under § 814.82, any master file, or any other related submission. Any record in the PMA file will be available for public disclosure in accordance with the provisions of this section and part 20. The confidentiality of information in a color additive petition submitted as part of a PMA is governed by § 71.15.

(b) The existence of a PMA file may not be disclosed by FDA before an approval order is issued to the applicant unless it previously has been publicly disclosed or acknowledged.

(c) If the existence of a PMA file has not been publicly disclosed or acknowledged, data or information in the PMA file are not available for public disclosure.

(d)(1) If the existence of a PMA file has been publicly disclosed or acknowledged before an order approving, or an order denying approval of the PMA is issued, data or information contained in the file are not available for public disclosure before such order issues. FDA may, however, disclose a summary of portions of the safety and effectiveness data before an approval order or an order denying approval of the PMA issues if disclosure is relevant to public consideration of a specific pending issue.

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IDE that was required to be filed in Docket Number 95S-0158 in the Dockets Management Staff (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

(e) Upon issuance of an order approving, or an order denying approval of any PMA, FDA will make available to the public the fact of the existence of the PMA and a detailed summary of information submitted to FDA respecting the safety and effectiveness of the device that is the subject of the PMA and that is the basis for the order.

(f) After FDA issues an order approving, or an order denying approval of any PMA, the following data and information in the PMA file are immediately available for public disclosure:

(1) All safety and effectiveness data and information previously disclosed to the public, as such disclosure is defined in § 20.81.

(2) Any protocol for a test or study unless the protocol is shown to constitute trade secret or confidential commercial or financial information under § 20.61.

(3) Any adverse reaction report, product experience report, consumer complaint, and other similar data and information, after deletion of:

(i) Any information that constitutes trade secret or confidential commercial or financial information under § 20.61; and

(ii) Any personnel, medical, and similar information disclosure of which would constitute a clearly unwarranted invasion of personal privacy under § 20.63; provided, however, that except for the information that constitutes trade secret or confidential commercial or financial information under § 20.61, FDA will disclose to a patient who requests a report all the information in the report concerning that patient.

(4) A list of components previously disclosed to the public, as such disclosure is defined in § 20.81.

(5) An assay method or other analytical method, unless it does not serve any regulatory purpose and is shown to fall within the exemption in § 20.61 for trade secret or confidential commercial or financial information.

(6) All correspondence and written summaries of oral discussions relating to the PMA file, in accordance with the provisions of §§ 20.103 and 20.104.

(g) All safety and effectiveness data and other information not previously disclosed to the public are available for public disclosure if any one of the following events occurs and the data and information do not constitute trade secret or confidential commercial or financial information under § 20.61:

(1) The PMA has been abandoned. FDA will consider a PMA abandoned if:

(i)(A) The applicant fails to respond to a request for additional information within 180 days after the date FDA issues the request or

(B) Other circumstances indicate that further work is not being undertaken with respect to it, and

(ii) The applicant fails to communicate with FDA within 7 days after the date on which FDA notifies the applicant that the PMA appears to have been abandoned.

(2) An order denying approval of the PMA has issued, and all legal appeals have been exhausted.

(3) An order withdrawing approval of the PMA has issued, and all legal appeals have been exhausted.

(4) The device has been reclassified.

(5) The device has been found to be substantially equivalent to a class I or class II device.

(6) The PMA is considered voluntarily withdrawn under § 814.44(g).

(h) The following data and information in a PMA file are not available for public disclosure unless they have been previously disclosed to the public, as such disclosure is defined in § 20.81, or they relate to a device for which a PMA has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61:

(1) Manufacturing methods or processes, including quality control procedures.

(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which are not available for public disclosure under this provision is available for public disclosure.

(3) Quantitative or semiquantitative formulas.

[51 FR 26364, July 22, 1986, as amended at 61 FR 51531, Oct. 2, 1996; 88 FR 45067, July 14, 2023]

§ 814.15 Research conducted outside the United States.

(a) Data to support PMA. If data from clinical investigations conducted outside the United States are submitted to support a PMA, the applicant shall comply with the provisions in § 812.28 of this chapter, as applicable.

(b) As sole basis for marketing approval. A PMA based solely on foreign clinical data and otherwise meeting the criteria for approval under this part may be approved if:

(1) The foreign data are applicable to the U.S. population and U.S. medical practice;

(2) The studies have been performed by clinical investigators of recognized competence; and

(3) The data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA can validate the data through an on-site inspection or other appropriate means.

(c) Consultation between FDA and applicants. Applicants are encouraged to meet with FDA officials in a “presubmission” meeting when approval based solely on foreign data will be sought.

[51 FR 26364, July 22, 1986; 51 FR 40415, Nov. 7, 1986, as amended at 51 FR 43344, Dec. 2, 1986; 83 FR 7387, Feb. 21, 2018]

§ 814.17 Service of orders.

Orders issued under this part will be served in person by a designated officer or employee of FDA on, or by registered mail to, the applicant or the designated agent at the applicant's or designated agent's last known address in FDA's records.

§ 814.19 Product development protocol (PDP).

A class III device for which a product development protocol has been declared completed by FDA under this chapter will be considered to have an approved PMA.

§ 814.20 Application.

(a) The applicant or an authorized representative shall sign the PMA. If the applicant does not reside or have a place of business within the United States, the PMA shall be countersigned by an authorized representative residing or maintaining a place of business in the United States and shall identify the representative's name and address.

(b) Unless the applicant justifies an omission in accordance with paragraph (d) of this section, a PMA shall include in electronic format:

(1) The name and address of the applicant.

(2) A table of contents that specifies the volume and page number for each item referred to in the table. A PMA shall include separate sections on nonclinical laboratory studies and on clinical investigations involving human subjects. A PMA shall be submitted as a single version. The applicant shall include information that it believes to be trade secret or confidential commercial or financial information in the PMA and identify the information that it believes to be trade secret or confidential commercial or financial information.

(3) A summary in sufficient detail that the reader may gain a general understanding of the data and information in the application. The summary shall contain the following information:

(i) Indications for use. A general description of the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended.

(ii) Device description. An explanation of how the device functions, the basic scientific concepts that form the basis for the device, and the significant physical and performance characteristics of the device. A brief description of the manufacturing process should be included if it will significantly enhance the reader's understanding of the device. The generic name of the device as well as any proprietary name or trade name should be included.

(iii) Alternative practices and procedures. A description of existing alternative practices or procedures for diagnosing, treating, preventing, curing, or mitigating the disease or condition for which the device is intended.

(iv) Marketing history. A brief description of the foreign and U.S. marketing history, if any, of the device, including a list of all countries in which the device has been marketed and a list of all countries in which the device has been withdrawn from marketing for any reason related to the safety or effectiveness of the device. The description shall include the history of the marketing of the device by the applicant and, if known, the history of the marketing of the device by any other person.

(v) Summary of studies. An abstract of any information or report described in the PMA under paragraph (b)(8)(ii) of this section and a summary of the results of technical data submitted under paragraph (b)(6) of this section. Such summary shall include a description of the objective of the study, a description of the experimental design of the study, a brief description of how the data were collected and analyzed, and a brief description of the results, whether positive, negative, or inconclusive. This section shall include the following:

(A) A summary of the nonclinical laboratory studies submitted in the application;

(B) A summary of the clinical investigations involving human subjects submitted in the application including a discussion of subject selection and exclusion criteria, study population, study period, safety and effectiveness data, adverse reactions and complications, patient discontinuation, patient complaints, device failures and replacements, results of statistical analyses of the clinical investigations, contraindications and precautions for use of the device, and other information from the clinical investigations as appropriate (any investigation conducted under an IDE shall be identified as such).

(vi) Conclusions drawn from the studies. A discussion demonstrating that the data and information in the application constitute valid scientific evidence within the meaning of § 860.7 and provide reasonable assurance that the device is safe and effective for its intended use. A concluding discussion shall present benefit and risk considerations related to the device including a discussion of any adverse effects of the device on health and any proposed additional studies or surveillance the applicant intends to conduct following approval of the PMA.

(4) A complete description of:

(i) The device, including pictorial representations;

(ii) Each of the functional components or ingredients of the device if the device consists of more than one physical component or ingredient;

(iii) The properties of the device relevant to the diagnosis, treatment, prevention, cure, or mitigation of a disease or condition;

(iv) The principles of operation of the device; and

(v) The methods used in, and the facilities and controls used for, the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with current good manufacturing practice can make a knowledgeable judgment about the quality control used in the manufacture of the device.

(5) Reference to any performance standard under section 514 of the Federal Food, Drug, and Cosmetic Act or under section 534 of Subchapter C—Electronic Product Radiation Control of the Federal Food, Drug, and Cosmetic Act (formerly the Radiation Control for Health and Safety Act of 1968) in effect or proposed at the time of the submission and to any voluntary standard that is relevant to any aspect of the safety or effectiveness of the device and that is known to or that should reasonably be known to the applicant. The applicant shall—

(i) Provide adequate information to demonstrate how the device meets, or justify any deviation from, any performance standard established under section 514 of the Federal Food, Drug, and Cosmetic Act or under section 534 of Subchapter C—Electronic Product Radiation Control of the Federal Food, Drug, and Cosmetic Act (formerly the Radiation Control for Health and Safety Act of 1968); and

(ii) Explain any deviation from a voluntary standard.

(6) The following technical sections which shall contain data and information in sufficient detail to permit FDA to determine whether to approve or deny approval of the application:

(i) A section containing results of the nonclinical laboratory studies with the device including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests as appropriate. Information on nonclinical laboratory studies shall include a statement that each such study was conducted in compliance with part 58, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

(ii) A section containing results of the clinical investigations involving human subjects with the device including clinical protocols, number of investigators and subjects per investigator, subject selection and exclusion criteria, study population, study period, safety and effectiveness data, adverse reactions and complications, patient discontinuation, patient complaints, device failures and replacements, tabulations of data from all individual subject report forms and copies of such forms for each subject who died during a clinical investigation or who did not complete the investigation, results of statistical analyses of the clinical investigations, device failures and replacements, contraindications and precautions for use of the device, and any other appropriate information from the clinical investigations. Any investigation conducted under an IDE shall be identified as such. Information on clinical investigations involving human subjects shall include the following:

(A) For clinical investigations conducted in the United States, a statement with respect to each investigation that it either was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter; or if the investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation.

(B) For clinical investigations conducted in the United States, a statement that each investigation was conducted in compliance with part 812 of this chapter concerning sponsors of clinical investigations and clinical investigators, or if the investigation was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation.

(C) For clinical investigations conducted outside the United States that are intended to support the PMA, the requirements under § 812.28 of this chapter apply. If any such investigation was not conducted in accordance with good clinical practice (GCP) as described in § 812.28(a), include either a waiver request in accordance with § 812.28(c) or a brief statement of the reason for not conducting the investigation in accordance with GCP and a description of steps taken to ensure that the data and results are credible and accurate and that the rights, safety, and well-being of subjects have been adequately protected. Failure or inability to comply with these requirements does not justify failure to provide information on a relevant clinical investigation.

(7) For a PMA supported solely by data from one investigation, a justification showing that data and other information from a single investigator are sufficient to demonstrate the safety and effectiveness of the device and to ensure reproducibility of test results.

(8)(i) A bibliography of all published reports not submitted under paragraph (b)(6) of this section, whether adverse or supportive, known to or that should reasonably be known to the applicant and that concern the safety or effectiveness of the device.

(ii) An identification, discussion, and analysis of any other data, information, or report relevant to an evaluation of the safety and effectiveness of the device known to or that should reasonably be known to the applicant from any source, foreign or domestic, including information derived from investigations other than those proposed in the application and from commercial marketing experience.

(iii) Copies of such published reports or unpublished information in the possession of or reasonably obtainable by the applicant if an FDA advisory committee or FDA requests.

(9) One or more samples of the device and its components, if requested by FDA. If it is impractical to submit a requested sample of the device, the applicant shall name the location at which FDA may examine and test one or more devices.

(10) Copies of all proposed labeling for the device. Such labeling may include, e.g., instructions for installation and any information, literature, or advertising that constitutes labeling under section 201(m) of the Federal Food, Drug, and Cosmetic Act.

(11) An environmental assessment under § 25.20(n) prepared in the applicable format in § 25.40, unless the action qualifies for exclusion under § 25.30 or § 25.34. If the applicant believes that the action qualifies for exclusion, the PMA shall under § 25.15(a) and (d) provide information that establishes to FDA's satisfaction that the action requested is included within the excluded category and meets the criteria for the applicable exclusion.

(12) A financial certification or disclosure statement or both as required by part 54 of this chapter.

(13) Information concerning uses in pediatric patients. The application must include the following information, if readily available:

(i) A description of any pediatric subpopulations (neonates, infants, children, adolescents) that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and

(ii) The number of affected pediatric patients.

(14) Such other information as FDA may request. If necessary, FDA will obtain the concurrence of the appropriate FDA advisory committee before requesting additional information.

(c) Pertinent information in FDA files specifically referred to by an applicant may be incorporated into a PMA by reference. Information in a master file or other information submitted to FDA by a person other than the applicant will not be considered part of a PMA unless such reference is authorized in a record submitted to FDA by the person who submitted the information or the master file. If a master file is not referenced within 5 years after the date that it is submitted to FDA, FDA will return the master file to the person who submitted it.

(d) If the applicant believes that certain information required under paragraph (b) of this section to be in a PMA is not applicable to the device that is the subject of the PMA, and omits any such information from its PMA, the applicant shall submit a statement that identifies the omitted information and justifies the omission. The statement shall be submitted as a separate section in the PMA and identified in the table of contents. If the justification for the omission is not accepted by the agency, FDA will so notify the applicant.

(e) The applicant shall periodically update its pending application with new safety and effectiveness information learned about the device from ongoing or completed studies that may reasonably affect an evaluation of the safety or effectiveness of the device or that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling. The update report shall be consistent with the data reporting provisions of the protocol. The applicant shall submit any update report in electronic format and shall include in the report the number assigned by FDA to the PMA. These updates are considered to be amendments to the PMA. The time frame for review of a PMA will not be extended due to the submission of an update report unless the update is a major amendment under § 814.37(c)(1). The applicant shall submit these reports—

(1) 3 months after the filing date;

(2) Following receipt of an approvable letter; and

(3) At any other time as requested by FDA.

(f) If a color additive subject to section 721 of the Federal Food, Drug, and Cosmetic Act is used in or on the device and has not previously been listed for such use, then, in lieu of submitting a color additive petition under part 71 of this chapter, at the option of the applicant, the information required to be submitted under part 71 may be submitted as part of the PMA. When submitted as part of the PMA, the information shall be submitted in electronic format. A PMA for a device that contains a color additive that is subject to section 721 of the Federal Food, Drug, and Cosmetic Act will not be approved until the color additive is listed for use in or on the device.

(g) Additional information on FDA policies and procedures, as well as links to PMA guidance documents, is available on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/default.htm.

(h) If you are sending a PMA, PMA amendment, PMA supplement, or correspondence with respect to a PMA, you must send the submission to the appropriate address as follows:

(1) For devices regulated by the Center for Devices and Radiological Health, send it to the current address displayed on the website https://www.fda.gov/cdrhsubmissionaddress.

(2) For devices regulated by the Center for Biologics Evaluation and Research, send it to the current address displayed on the website https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm.

(3) For devices regulated by the Center for Drug Evaluation and Research, send it to: Central Document Control Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

[51 FR 26364, July 22, 1986; 51 FR 40415, Nov. 7, 1986, as amended at 51 FR 43344, Dec. 2, 1986; 55 FR 11169, Mar. 27, 1990; 62 FR 40600, July 29, 1997; 63 FR 5253, Feb. 2, 1998; 65 FR 17137, Mar. 31, 2000; 65 FR 56480, Sept. 19, 2000; 67 FR 9587, Mar. 4, 2002; 71 FR 42048, July 25, 2006; 72 FR 17399, Apr. 9, 2007; 73 FR 34859, June 19, 2008; 74 FR 14478, Mar. 31, 2009; 75 FR 20915, Apr. 22, 2010; 78 FR 18233, Mar. 26, 2013; 79 FR 1740, Jan. 10, 2014; 80 FR 18094, Apr. 3, 2015; 83 FR 7387, Feb. 21, 2018; 84 FR 68339, Dec. 16, 2019]

§ 814.37 PMA amendments and resubmitted PMAs.

(a) An applicant may amend a pending PMA or PMA supplement to revise existing information or provide additional information.

(b)(1) FDA may request the applicant to amend a PMA or PMA supplement with any information regarding the device that is necessary for FDA or the appropriate advisory committee to complete the review of the PMA or PMA supplement.

(2) FDA may request the applicant to amend a PMA or PMA supplement with information concerning pediatric uses as required under §§ 814.20(b)(13) and 814.39(c)(2).

(c) A PMA amendment submitted to FDA shall include the PMA or PMA supplement number assigned to the original submission and, if submitted on the applicant's own initiative, the reason for submitting the amendment. FDA may extend the time required for its review of the PMA, or PMA supplement, as follows:

(1) If the applicant on its own initiative or at FDA's request submits a major PMA amendment (e.g., an amendment that contains significant new data from a previously unreported study, significant updated data from a previously reported study, detailed new analyses of previously submitted data, or significant required information previously omitted), the review period may be extended up to 180 days.

(2) If an applicant declines to submit a major amendment requested by FDA, the review period may be extended for the number of days that elapse between the date of such request and the date that FDA receives the written response declining to submit the requested amendment.

(d) An applicant may on its own initiative withdraw a PMA or PMA supplement. If FDA requests an applicant to submit a PMA amendment and a written response to FDA's request is not received within 180 days of the date of the request, FDA will consider the pending PMA or PMA supplement to be withdrawn voluntarily by the applicant.

(e) An applicant may resubmit a PMA or PMA supplement after withdrawing it or after it is considered withdrawn under paragraph (d) of this section, or after FDA has refused to accept it for filing, or has denied approval of the PMA or PMA supplement. A resubmitted PMA or PMA supplement shall comply with the requirements of § 814.20 or § 814.39, respectively, and shall include the PMA number assigned to the original submission and the applicant's reasons for resubmission of the PMA or PMA supplement.

[51 FR 26364, July 22, 1986, as amended at 79 FR 1740, Jan. 10, 2014]

§ 814.39 PMA supplements.

(a) After FDA's approval of a PMA, an applicant shall submit a PMA supplement for review and approval by FDA before making a change affecting the safety or effectiveness of the device for which the applicant has an approved PMA, unless the change is of a type for which FDA, under paragraph (e) of this section, has advised that an alternate submission is permitted or is of a type which, under section 515(d)(6)(A) of the act and paragraph (f) of this section, does not require a PMA supplement under this paragraph. While the burden for determining whether a supplement is required is primarily on the PMA holder, changes for which an applicant shall submit a PMA supplement include, but are not limited to, the following types of changes if they affect the safety or effectiveness of the device:

(1) New indications for use of the device.

(2) Labeling changes.

(3) The use of a different facility or establishment to manufacture, process, or package the device.

(4) Changes in sterilization procedures.

(5) Changes in packaging.

(6) Changes in the performance or design specifications, circuits, components, ingredients, principle of operation, or physical layout of the device.

(7) Extension of the expiration date of the device based on data obtained under a new or revised stability or sterility testing protocol that has not been approved by FDA. If the protocol has been approved, the change shall be reported to FDA under paragraph (b) of this section.

(b) An applicant may make a change in a device after FDA's approval of a PMA for the device without submitting a PMA supplement if the change does not affect the device's safety or effectiveness and the change is reported to FDA in post approval periodic reports required as a condition to approval of the device, e.g., an editorial change in labeling which does not affect the safety or effectiveness of the device, or if the change is consistent with a predetermined change control plan (PCCP) approved under section 515C of the act.

(c)(1) All procedures and actions that apply to an application under § 814.20 also apply to PMA supplements except that the information required in a supplement is limited to that needed to support the change. A summary under § 814.20(b)(3) is required for only a supplement submitted for new indications for use of the device, significant changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device, or when otherwise required by FDA. The applicant shall submit a PMA supplement in electronic format and shall include information relevant to the proposed changes in the device. A PMA supplement shall include a separate section that identifies each change for which approval is being requested and explains the reason for each such change. The applicant shall submit additional information, if requested by FDA, in electronic format. The time frames for review of, and FDA action on, a PMA supplement are the same as those provided in § 814.40 for a PMA.

(2) The supplement must include the following information:

(i) Information concerning pediatric uses as required under § 814.20(b)(13).

(ii) If information concerning the device that is the subject of the supplement was previously submitted under § 814.20(b)(13) or under this section in a previous supplement, that information may be included by referencing a previous application or submission that contains the information. However, if additional information required under § 814.20(b)(13) has become readily available to the applicant since the previous submission, the applicant must submit that information as part of the supplement.

(d)(1) After FDA approves a PMA, any change described in paragraph (d)(2) of this section to reflect newly acquired information that enhances the safety of the device or the safety in the use of the device may be placed into effect by the applicant prior to the receipt under § 814.17 of a written FDA order approving the PMA supplement provided that:

(i) The PMA supplement and its mailing cover are plainly marked “Special PMA Supplement—Changes Being Effected”;

(ii) The PMA supplement provides a full explanation of the basis for the changes;

(iii) The applicant has received acknowledgement from FDA of receipt of the supplement; and

(iv) The PMA supplement specifically identifies the date that such changes are being effected.

(2) The following changes are permitted by paragraph (d)(1) of this section:

(i) Labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction for which there is reasonable evidence of a causal association.

(ii) Labeling changes that add or strengthen an instruction that is intended to enhance the safe use of the device.

(iii) Labeling changes that delete misleading, false, or unsupported indications.

(iv) Changes in quality controls or manufacturing process that add a new specification or test method, or otherwise provide additional assurance of purity, identity, strength, or reliability of the device.

(e)(1) FDA will identify a change to a device for which an applicant has an approved PMA and for which a PMA supplement under paragraph (a) is not required. FDA will identify such a change in an advisory opinion under § 10.85, if the change applies to a generic type of device, or in correspondence to the applicant, if the change applies only to the applicant's device. FDA will require that a change for which a PMA supplement under paragraph (a) is not required be reported to FDA in:

(i) A periodic report under § 814.84 or

(ii) A 30-day PMA supplement under this paragraph.

(2) FDA will identify, in the advisory opinion or correspondence, the type of information that is to be included in the report or 30-day PMA supplement. If the change is required to be reported to FDA in a periodic report, the change may be made before it is reported to FDA. If the change is required to be reported in a 30-day PMA supplement, the change may be made 30 days after FDA files the 30-day PMA supplement unless FDA requires the PMA holder to provide additional information, informs the PMA holder that the supplement is not approvable, or disapproves the supplement. The 30-day PMA supplement shall follow the instructions in the correspondence or advisory opinion. Any 30-day PMA supplement that does not meet the requirements of the correspondence or advisory opinion will not be filed and, therefore, will not be deemed approved 30 days after receipt.

(f) Under section 515(d) of the act, modifications to manufacturing procedures or methods of manufacture that affect the safety and effectiveness of a device subject to an approved PMA do not require submission of a PMA supplement under paragraph (a) of this section and are eligible to be the subject of a 30-day notice. A 30-day notice shall describe in detail the change, summarize the data or information supporting the change, and state that the change has been made in accordance with the requirements of part 820 of this chapter. The manufacturer may distribute the device 30 days after the date on which FDA receives the 30-day notice, unless FDA notifies the applicant within 30 days from receipt of the notice that the notice is not adequate. If the notice is not adequate, FDA shall inform the applicant in writing that a 135-day PMA supplement is needed and shall describe what further information or action is required for acceptance of such change. The number of days under review as a 30-day notice shall be deducted from the 135-day PMA supplement review period if the notice meets appropriate content requirements for a PMA supplement.

(g) The submission and grant of a written request for an exception or alternative under § 801.128 or § 809.11 of this chapter satisfies the requirement in paragraph (a) of this section.

[51 FR 26364, July 22, 1986, as amended at 51 FR 43344, Dec. 2, 1986; 63 FR 54044, Oct. 8, 1998; 67 FR 9587, Mar. 4, 2002; 69 FR 11313, Mar. 10, 2004; 72 FR 73602, Dec. 28, 2007; 73 FR 49610, Aug. 22, 2008; 79 FR 1740, Jan. 10, 2014; 84 FR 68340, Dec. 16, 2019; 89 FR 18793, Mar. 15, 2024]

§ 814.40 Time frames for reviewing a PMA.

Within 180 days after receipt of an application that is accepted for filing and to which the applicant does not submit a major amendment, FDA will review the PMA and, after receiving the report and recommendation of the appropriate FDA advisory committee, send the applicant an approval order under § 814.44(d), an approvable letter under § 814.44(e), a not approvable letter under § 814.44(f), or an order denying approval under § 814.45. The approvable letter and the not approvable letter will provide an opportunity for the applicant to amend or withdraw the application, or to consider the letter to be a denial of approval of the PMA under § 814.45 and to request administrative review under section 515 (d)(4) and (g) of the act.

[51 FR 26364, July 22, 1986, as amended at 87 FR 2045, Jan. 13, 2022]

§ 814.42 Filing a PMA.

(a) The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to permit a substantive review. Within 45 days after a PMA is received by FDA, the agency will notify the applicant whether the application has been filed.

(b) If FDA does not find that any of the reasons in paragraph (e) of this section for refusing to file the PMA applies, the agency will file the PMA and will notify the applicant in writing of the filing. The notice will include the PMA reference number and the date FDA filed the PMA. The date of filing is the date that a PMA accepted for filing was received by the agency. The 180-day period for review of a PMA starts on the date of filing.

(c) If FDA refuses to file a PMA, the agency will notify the applicant of the reasons for the refusal. This notice will identify the deficiencies in the application that prevent filing and will include the PMA reference number.

(d) If FDA refuses to file the PMA, the applicant may:

(1) Resubmit the PMA with additional information necessary to comply with the requirements of section 515(c)(1) (A)-(G) of the act and § 814.20. A resubmitted PMA shall include the PMA reference number of the original submission. If the resubmitted PMA is accepted for filing, the date of filing is the date FDA receives the resubmission;

(2) Request in writing within 10 working days of the date of receipt of the notice refusing to file the PMA, an informal conference with the Director of the associated Office of Health Technology to review FDA's decision not to file the PMA. FDA will hold the informal conference within 10 working days of its receipt of the request and will render its decision on filing within 5 working days after the informal conference. If, after the informal conference, FDA accepts the PMA for filing, the date of filing will be the date of the decision to accept the PMA for filing. If FDA does not reverse its decision not to file the PMA, the applicant may request reconsideration of the decision from the Director of the Office of Product Evaluation and Quality, the Director of the Center for Biologics Evaluation and Research, or the Director of the Center for Drug Evaluation and Research, as applicable. The Director's decision will constitute final administrative action for the purpose of judicial review.

(e) FDA may refuse to file a PMA if any of the following applies:

(1) The application is incomplete because it does not on its face contain all the information required under section 515(c)(1) (A)-(G) of the act;

(2) The PMA does not contain each of the items required under § 814.20 and justification for omission of any item is inadequate;

(3) The applicant has a pending premarket notification under section 510(k) of the act with respect to the same device, and FDA has not determined whether the device falls within the scope of § 814.1(c).

(4) The PMA contains a false statement of material fact.

(5) The PMA is not accompanied by a statement of either certification or disclosure as required by part 54 of this chapter.

[51 FR 26364, July 22, 1986, as amended at 63 FR 5254, Feb. 2, 1998; 73 FR 49942, Aug. 25, 2008; 85 FR 18442, Apr. 2, 2020]

§ 814.44 Procedures for review of a PMA.

(a) FDA will begin substantive review of a PMA after the PMA is accepted for filing under § 814.42. FDA may refer the PMA to a panel on its own initiative, and will do so upon request of an applicant, unless FDA determines that the application substantially duplicates information previously reviewed by a panel. If FDA refers an application to a panel, FDA will forward the PMA, or relevant portions thereof, to each member of the appropriate FDA panel for review. During the review process, FDA may communicate with the applicant as set forth under § 814.37(b), or with a panel to respond to questions that may be posed by panel members or to provide additional information to the panel. FDA will maintain a record of all communications with the applicant and with the panel.

(b) The advisory committee shall submit a report to FDA which includes the committee's recommendation and the basis for such recommendation on the PMA. Before submission of this report, the committee shall hold a public meeting to review the PMA in accordance with part 14. This meeting may be held by a telephone conference under § 14.22(g). The advisory committee report and recommendation may be in the form of a meeting transcript signed by the chairperson of the committee.

(c) FDA will complete its review of the PMA and the advisory committee report and recommendation and, within the later of 180 days from the date of filing of the PMA under § 814.42 or the number of days after the date of filing as determined under § 814.37(c), issue an approval order under paragraph (d) of this section, an approvable letter under paragraph (e) of this section, a not approvable letter under paragraph (f) of this section, or an order denying approval of the application under § 814.45(a).

(d)(1) FDA will issue to the applicant an order approving a PMA if none of the reasons in § 814.45 for denying approval of the application applies. FDA will approve an application on the basis of draft final labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft final labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed and upon the applicant submitting to FDA a copy of the final printed labeling before marketing. FDA will also give the public notice of the order, including notice of and opportunity for any interested persons to request review under section 515(d)(4) of the act. The notice of approval will be placed on FDA's home page on the Internet (http://www.fda.gov), and it will state that a detailed summary of information respecting the safety and effectiveness of the device, which was the basis for the order approving the PMA, including information about any adverse effects of the device on health, is available on the Internet and has been placed on public display, and that copies are available upon request. When a notice of approval is published, data and information in the PMA file will be available for public disclosure in accordance with § 814.9.

(2) A request for copies of the current PMA approvals and denials document and for copies of summaries of safety and effectiveness shall be sent in writing to the Freedom of Information Staff's address listed on the Agency's website at https://www.fda.gov.

(e) FDA will send the applicant an approvable letter if the application substantially meets the requirements of this part and the agency believes it can approve the application if specific additional information is submitted or specific conditions are agreed to by the applicant.

(1) The approvable letter will describe the information FDA requires to be provided by the applicant or the conditions the applicant is required to meet to obtain approval. For example, FDA may require, as a condition to approval:

(i) The submission of certain information identified in the approvable letter, e.g., final labeling;

(ii) The submission of additional information concerning pediatric uses required by § 814.20(b)(13);

(iii) An FDA inspection that finds the manufacturing facilities, methods, and controls in compliance with part 820 and, if applicable, that verifies records pertinent to the PMA;

(iv) Restrictions imposed on the device under section 515(d)(1)(B)(ii) or 520(e) of the act;

(v) Postapproval requirements as described in subpart E of this part.

(2) In response to an approvable letter the applicant may:

(i) Amend the PMA as requested in the approvable letter; or

(ii) Consider the approvable letter to be a denial of approval of the PMA under § 814.45 and request administrative review under section 515(d)(4) of the act by filing a petition in the form of a petition for reconsideration under § 10.33; or

(iii) Withdraw the PMA.

(f) FDA will send the applicant a not approvable letter if the agency believes that the application may not be approved for one or more of the reasons given in § 814.45(a). The not approvable letter will describe the deficiencies in the application, including each applicable ground for denial under section 515(d)(2) (A)-(E) of the act, and, where practical, will identify measures required to place the PMA in approvable form. In response to a not approvable letter, the applicant may:

(1) Amend the PMA as requested in the not approvable letter (such an amendment will be considered a major amendment under § 814.37(c)(1)); or

(2) Consider the not approvable letter to be a denial of approval of the PMA under § 814.45 and request administrative review under section 515(d)(4) of the act by filing a petition in the form of a petition for reconsideration under § 10.33; or

(3) Withdraw the PMA.

(g) FDA will consider a PMA to have been withdrawn voluntarily if:

(1) The applicant fails to respond in writing to a written request for an amendment within 180 days after the date FDA issues such request;

(2) The applicant fails to respond in writing to an approvable or not approvable letter within 180 days after the date FDA issues such letter; or

(3) The applicant submits a written notice to FDA that the PMA has been withdrawn.

[51 FR 26364, July 22, 1986, as amended at 57 FR 58403, Dec. 10, 1992; 63 FR 4572, Jan. 30, 1998; 79 FR 1740, Jan. 10, 2014; 87 FR 2045, Jan. 13, 2022]

§ 814.45 Denial of approval of a PMA.

(a) FDA may issue an order denying approval of a PMA if the applicant fails to follow the requirements of this part or if, upon the basis of the information submitted in the PMA or any other information before the agency, FDA determines that any of the grounds for denying approval of a PMA specified in section 515(d)(2) (A)-(E) of the act applies. In addition, FDA may deny approval of a PMA for any of the following reasons:

(1) The PMA contains a false statement of material fact;

(2) The device's proposed labeling does not comply with the requirements in part 801 or part 809;

(3) The applicant does not permit an authorized FDA employee an opportunity to inspect at a reasonable time and in a reasonable manner the facilities, controls, and to have access to and to copy and verify all records pertinent to the application;

(4) A nonclinical laboratory study that is described in the PMA and that is essential to show that the device is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations in part 58 and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study; or

(5) Any clinical investigation involving human subjects described in the PMA, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter or GCP referenced in § 814.15(a) and described in § 812.28(a) of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected or the supporting data were determined to be otherwise unreliable.

(b) FDA will issue any order denying approval of the PMA in accordance with § 814.17. The order will inform the applicant of the deficiencies in the PMA, including each applicable ground for denial under section 515(d)(2) of the act and the regulations under this part, and, where practical, will identify measures required to place the PMA in approvable form. The order will include a notice of an opportunity to request review under section 515(d)(4) of the act.

(c) FDA will use the criteria specified in § 860.7 to determine the safety and effectiveness of a device in deciding whether to approve or deny approval of a PMA. FDA may use information other than that submitted by the applicant in making such determination.

(d)(1) FDA will give the public notice of an order denying approval of the PMA. The notice will be placed on the FDA's home page on the Internet (http://www.fda.gov), and it will state that a detailed summary of information respecting the safety and effectiveness of the device, including information about any adverse effects of the device on health, is available on the Internet and has been placed on public display and that copies are available upon request. When a notice of denial of approval is made publicly available, data and information in the PMA file will be available for public disclosure in accordance with § 814.9.

(2) A request for copies of the current PMA approvals and denials document and copies of summaries of safety and effectiveness shall be sent in writing to the Freedom of Information Staff's address listed on the Agency's Web site at http://www.fda.gov.

(e) FDA will issue an order denying approval of a PMA after an approvable or not approvable letter has been sent and the applicant:

(1) Submits a requested amendment but any ground for denying approval of the application under section 515(d)(2) of the act still applies; or

(2) Notifies FDA in writing that the requested amendment will not be submitted; or

(3) Petitions for review under section 515(d)(4) of the act by filing a petition in the form of a petition for reconsideration under § 10.33.

[51 FR 26364, July 22, 1986, as amended at 63 FR 4572, Jan. 30, 1998; 73 FR 34859, June 19, 2008; 76 FR 31470, June 1, 2011; 79 FR 68115, Nov. 14, 2014; 83 FR 7387, Feb. 21, 2018; 87 FR 2045, Jan. 13, 2022]

§ 814.46 Withdrawal of approval of a PMA.

(a) FDA may issue an order withdrawing approval of a PMA if, from any information available to the agency, FDA determines that:

(1) Any of the grounds under section 515(e)(1) (A)-(G) of the act applies.

(2) Any postapproval requirement imposed by the PMA approval order or by regulation has not been met.

(3) A nonclinical laboratory study that is described in the PMA and that is essential to show that the device is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations in part 58 and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.

(4) Any clinical investigation involving human subjects described in the PMA, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter or GCP referenced in § 814.15(a) and described in § 812.28(a) of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected or the supporting data were determined to be otherwise unreliable.

(b)(1) FDA may seek advice on scientific matters from any appropriate FDA advisory committee in deciding whether to withdraw approval of a PMA.

(2) FDA may use information other than that submitted by the applicant in deciding whether to withdraw approval of a PMA.

(c) Before issuing an order withdrawing approval of a PMA, FDA will issue the holder of the approved application a notice of opportunity for an informal hearing under part 16.

(d) If the applicant does not request a hearing or if after the part 16 hearing is held the agency decides to proceed with the withdrawal, FDA will issue to the holder of the approved application an order withdrawing approval of the application. The order will be issued under § 814.17, will state each ground for withdrawing approval, and will include a notice of an opportunity for administrative review under section 515(e)(2) of the act.

(e) FDA will give the public notice of an order withdrawing approval of a PMA. The notice will be published in the Federal Register and will state that a detailed summary of information respecting the safety and effectiveness of the device, including information about any adverse effects of the device on health, has been placed on public display and that copies are available upon request. When a notice of withdrawal of approval is published, data and information in the PMA file will be available for public disclosure in accordance with § 814.9.

[51 FR 26364, July 22, 1986, as amended at 83 FR 7387, Feb. 21, 2018]

§ 814.47 Temporary suspension of approval of a PMA.

(a) Scope. (1) This section describes the procedures that FDA will follow in exercising its authority under section 515(e)(3) of the act (21 U.S.C. 360e(e)(3)). This authority applies to the original PMA, as well as any PMA supplement(s), for a medical device.

(2) FDA will issue an order temporarily suspending approval of a PMA if FDA determines that there is a reasonable probability that continued distribution of the device would cause serious, adverse health consequences or death.

(b) Regulatory hearing. (1) If FDA believes that there is a reasonable probability that the continued distribution of a device subject to an approved PMA would cause serious, adverse health consequences or death, FDA may initiate and conduct a regulatory hearing to determine whether to issue an order temporarily suspending approval of the PMA.

(2) Any regulatory hearing to determine whether to issue an order temporarily suspending approval of a PMA shall be initiated and conducted by FDA pursuant to part 16 of this chapter. If FDA believes that immediate action to remove a dangerous device from the market is necessary to protect the public health, the agency may, in accordance with § 16.60(h) of this chapter, waive, suspend, or modify any part 16 procedure pursuant to § 10.19 of this chapter.

(3) FDA shall deem the PMA holder's failure to request a hearing within the timeframe specified by FDA in the notice of opportunity for hearing to be a waiver.

(c) Temporary suspension order. If the PMA holder does not request a regulatory hearing or if, after the hearing, and after consideration of the administrative record of the hearing, FDA determines that there is a reasonable probability that the continued distribution of a device under an approved PMA would cause serious, adverse health consequences or death, the agency shall, under the authority of section 515(e)(3) of the act, issue an order to the PMA holder temporarily suspending approval of the PMA.

(d) Permanent withdrawal of approval of the PMA. If FDA issues an order temporarily suspending approval of a PMA, the agency shall proceed expeditiously, but within 60 days, to hold a hearing on whether to permanently withdraw approval of the PMA in accordance with section 515(e)(1) of the act and the procedures set out in § 814.46.

[61 FR 15190, Apr. 5, 1996]

§ 814.80 General.

A device may not be manufactured, packaged, stored, labeled, distributed, or advertised in a manner that is inconsistent with any conditions to approval specified in the PMA approval order for the device.

§ 814.82 Postapproval requirements.

(a) FDA may impose postapproval requirements in a PMA approval order or by regulation at the time of approval of the PMA or by regulation subsequent to approval. Postapproval requirements may include as a condition to approval of the device:

(1) Restriction of the sale, distribution, or use of the device as provided by section 515(d)(1)(B)(ii) or 520(e) of the act.

(2) Continuing evaluation and periodic reporting on the safety, effectiveness, and reliability of the device for its intended use. FDA will state in the PMA approval order the reason or purpose for such requirement and the number of patients to be evaluated and the reports required to be submitted.

(3) Prominent display in the labeling of a device and in the advertising of any restricted device of warnings, hazards, or precautions important for the device's safe and effective use, including patient information, e.g., information provided to the patient on alternative modes of therapy and on risks and benefits associated with the use of the device.

(4) Inclusion of identification codes on the device or its labeling, or in the case of an implant, on cards given to patients if necessary to protect the public health.

(5) Maintenance of records that will enable the applicant to submit to FDA information needed to trace patients if such information is necessary to protect the public health. Under section 519(a)(4) of the act, FDA will require that the identity of any patient be disclosed in records maintained under this paragraph only to the extent required for the medical welfare of the individual, to determine the safety or effectiveness of the device, or to verify a record, report, or information submitted to the agency.

(6) Maintenance of records for specified periods of time and organization and indexing of records into identifiable files to enable FDA to determine whether there is reasonable assurance of the continued safety and effectiveness of the device.

(7) Submission to FDA at intervals specified in the approval order of periodic reports containing the information required by § 814.84(b).

(8) Batch testing of the device.

(9) Such other requirements as FDA determines are necessary to provide reasonable assurance, or continued reasonable assurance, of the safety and effectiveness of the device.

(b) An applicant shall grant to FDA access to any records and reports required under the provisions of this part, and shall permit authorized FDA employees to copy and verify such records and reports and to inspect at a reasonable time and in a reasonable manner all manufacturing facilities to verify that the device is being manufactured, stored, labeled, and shipped under approved conditions.

(c) Failure to comply with any postapproval requirement constitutes a ground for withdrawal of approval of a PMA.

(Approved by the Office of Management and Budget under control number 0910-0231)

[51 FR 26364, July 22, 1986, as amended at 51 FR 43344, Dec. 2, 1986]

§ 814.84 Reports.

(a) The holder of an approved PMA shall comply with the requirements of part 803 and with any other requirements applicable to the device by other regulations in this subchapter or by order approving the device.

(b) Unless FDA specifies otherwise, any periodic report shall:

(1) Identify changes described in § 814.39(a) and changes required to be reported to FDA under § 814.39(b).

(2) Contain a summary and bibliography of the following information not previously submitted as part of the PMA:

(i) Unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related devices and known to or that reasonably should be known to the applicant.

(ii) Reports in the scientific literature concerning the device and known to or that reasonably should be known to the applicant. If, after reviewing the summary and bibliography, FDA concludes that the agency needs a copy of the unpublished or published reports, FDA will notify the applicant that copies of such reports shall be submitted.

(3) Identify changes made pursuant to an exception or alternative granted under § 801.128 or § 809.11 of this chapter.

(4) Identify each device identifier currently in use for the device, and each device identifier for the device that has been discontinued since the previous periodic report. It is not necessary to identify any device identifier discontinued prior to December 23, 2013.

[51 FR 26364, July 22, 1986, as amended at 51 FR 43344, Dec. 2, 1986; 67 FR 9587, Mar. 4, 2002; 72 FR 73602, Dec. 28, 2007; 78 FR 58822, Sept. 24, 2013]

§ 814.100 Purpose and scope.

(a) This subpart H implements sections 515A and 520(m) of the act.

(b) The purpose of section 520(m) is, to the extent consistent with the protection of the public health and safety and with ethical standards, to encourage the discovery and use of devices intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in not more than 8,000 individuals in the United States per year. This subpart provides procedures for obtaining:

(1) HUD designation of a medical device; and

(2) Marketing approval for the HUD notwithstanding the absence of reasonable assurance of effectiveness that would otherwise be required under sections 514 and 515 of the act.

(c) Section 515A of the act is intended to ensure the submission of readily available information concerning:

(1) Any pediatric subpopulations (neonates, infants, children, adolescents) that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and

(2) The number of affected pediatric patients.

(d) Although a HUD may also have uses that differ from the humanitarian use, applicants seeking approval of any non-HUD use shall submit a PMA as required under § 814.20, or a premarket notification as required under part 807 of this chapter.

(e) Obtaining marketing approval for a HUD involves two steps:

(1) Obtaining designation of the device as a HUD from FDA's Office of Orphan Products Development, and

(2) Submitting an HDE to the Office of Product Evaluation and Quality (OPEQ), Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), or the Center for Drug Evaluation and Research (CDER), as applicable.

(f) A person granted an exemption under section 520(m) of the act shall submit periodic reports as described in § 814.126(b).

(g) FDA may suspend or withdraw approval of an HDE after providing notice and an opportunity for an informal hearing.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59220, Nov. 3, 1998; 73 FR 49942, Aug. 25, 2008; 79 FR 1740, Jan. 10, 2014; 82 FR 26349, June 7, 2017; 85 FR 18442, Apr. 2, 2020]

§ 814.102 Designation of HUD status.

(a) Request for designation. Prior to submitting an HDE application, the applicant shall submit a request for HUD designation to FDA's Office of Orphan Products Development. The request shall contain the following:

(1) A statement that the applicant requests HUD designation for a rare disease or condition or a valid subset of a disease or condition which shall be identified with specificity;

(2) The name and address of the applicant, the name of the applicant's primary contact person and/or resident agent, including title, address, and telephone number;

(3) A description of the rare disease or condition for which the device is to be used, the proposed indication or indications for use of the device, and the reasons why such therapy is needed. If the device is proposed for an indication that represents a subset of a common disease or condition, a demonstration that the subset is medically plausible should be included;

(4) A description of the device and a discussion of the scientific rationale for the use of the device for the rare disease or condition; and

(5) Documentation, with appended authoritative references, to demonstrate that the device is designed to treat or diagnose a disease or condition that affects or is manifested in not more than 8,000 people in the United States per year. If the device is for diagnostic purposes, the documentation must demonstrate that not more than 8,000 patients per year would be subjected to diagnosis by the device in the United States. Authoritative references include literature citations in specialized medical journals, textbooks, specialized medical society proceedings, or governmental statistics publications. When no such studies or literature citations exist, the applicant may be able to demonstrate the prevalence of the disease or condition in the United States by providing credible conclusions from appropriate research or surveys.

(b) FDA action. Within 45 days of receipt of a request for HUD designation, FDA will take one of the following actions:

(1) Approve the request and notify the applicant that the device has been designated as a HUD based on the information submitted;

(2) Return the request to the applicant pending further review upon submission of additional information. This action will ensue if the request is incomplete because it does not on its face contain all of the information required under § 814.102(a). Upon receipt of this additional information, the review period may be extended up to 45 days; or

(3) Disapprove the request for HUD designation based on a substantive review of the information submitted. FDA may disapprove a request for HUD designation if:

(i) There is insufficient evidence to support the estimate that the disease or condition for which the device is designed to treat or diagnose affects or is manifested in not more than 8,000 people in the United States per year;

(ii) FDA determines that, for a diagnostic device, more than 8,000 patients in the United States would be subjected to diagnosis using the device per year; or

(iii) FDA determines that the patient population defined in the request is not a medically plausible subset of a larger population.

(c) Revocation of designation. FDA may revoke a HUD designation if the agency finds that:

(1) The request for designation contained an untrue statement of material fact or omitted material information; or

(2) Based on the evidence available, the device is not eligible for HUD designation.

(d) Submission. The applicant shall submit two copies of a completed, dated, and signed request for HUD designation to: Office of Orphan Products Development (HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

[61 FR 33244, June 26, 1996, as amended at 82 FR 26349, June 7, 2017]

§ 814.104 Original applications.

(a) United States applicant or representative. The applicant or an authorized representative shall sign the HDE. If the applicant does not reside or have a place of business within the United States, the HDE shall be countersigned by an authorized representative residing or maintaining a place of business in the United States and shall identify the representative's name and address.

(b) Contents. Unless the applicant justifies an omission in accordance with paragraph (d) of this section, an HDE shall include:

(1) A copy of or reference to the determination made by FDA's Office of Orphan Products Development (in accordance with § 814.102) that the device qualifies as a HUD;

(2) An explanation of why the device would not be available unless an HDE were granted and a statement that no comparable device (other than another HUD approved under this subpart or a device under an approved IDE) is available to treat or diagnose the disease or condition. The application also shall contain a discussion of the risks and benefits of currently available devices or alternative forms of treatment in the United States;

(3) An explanation of why the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Such explanation shall include a description, explanation, or theory of the underlying disease process or condition, and known or postulated mechanism(s) of action of the device in relation to the disease process or condition;

(4) All of the information required to be submitted under § 814.20(b), except that:

(i) In lieu of the summaries, conclusions, and results from clinical investigations required under § 814.20(b)(3)(v)(B), (b)(3)(vi), and the introductory text of (b)(6)(ii), the applicant shall include the summaries, conclusions, and results of all clinical experience or investigations (whether adverse or supportive) reasonably obtainable by the applicant that are relevant to an assessment of the risks and probable benefits of the device and to the extent the applicant includes data from clinical investigations, the applicant shall include the statements described in § 814.20(b)(6)(ii)(A) and (B) with respect to clinical investigations conducted in the United States and the information described in § 814.20(b)(6)(ii)(C) with respect to clinical investigations conducted outside the United States; and

(ii) In addition to the proposed labeling requirement set forth in § 814.20(b)(10), the labeling shall bear the following statement: Humanitarian Device. Authorized by Federal law for use in the [treatment or diagnosis] of [specify disease or condition]. The effectiveness of this device for this use has not been demonstrated;

(5) The amount to be charged for the device and, if the amount is more than $250, a report by an independent certified public accountant, made in accordance with the Statement on Standards for Attestation established by the American Institute of Certified Public Accountants, or in lieu of such a report, an attestation by a responsible individual of the organization, verifying that the amount charged does not exceed the costs of the device's research, development, fabrication, and distribution. If the amount charged is $250 or less, the requirement for a report by an independent certified public accountant or an attestation by a responsible individual of the organization is waived; and

(6) Information concerning pediatric uses of the device, as required by § 814.20(b)(13).

(c) Omission of information. If the applicant believes that certain information required under paragraph (b) of this section is not applicable to the device that is the subject of the HDE, and omits any such information from its HDE, the applicant shall submit a statement that identifies and justifies the omission. The statement shall be submitted as a separate section in the HDE and identified in the table of contents. If the justification for the omission is not accepted by the agency, FDA will so notify the applicant.

(d) Address for submissions and correspondence. All original HDEs, amendments and supplements, as well as any correspondence relating to an HDE, must be provided in electronic format. These materials must be sent or delivered to one of the following:

(1) For devices regulated by the Center for Devices and Radiological Health, send it to the current address found on the website https://www.fda.gov/cdrhsubmissionaddress.

(2) For devices regulated by the Center for Biologics Evaluation and Research, send it to the current address displayed on the website https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm.

(3) For devices regulated by the Center for Drug Evaluation and Research, send this information to the Central Document Control Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59220, Nov. 3, 1998; 73 FR 49942, Aug. 25, 2008; 75 FR 20915, Apr. 22, 2010; 79 FR 1740, Jan. 10, 2014; 80 FR 18094, Apr. 3, 2015; 83 FR 7388, Feb. 21, 2018; 84 FR 68340, Dec. 16, 2019]

§ 814.106 HDE amendments and resubmitted HDE's.

An HDE or HDE supplement may be amended or resubmitted upon an applicant's own initiative, or at the request of FDA, for the same reasons and in the same manner as prescribed for PMA's in § 814.37, except that the timeframes set forth in § 814.37(c)(1) and (d) do not apply. If FDA requests an HDE applicant to submit an HDE amendment, and a written response to FDA's request is not received within 75 days of the date of the request, FDA will consider the pending HDE or HDE supplement to be withdrawn voluntarily by the applicant. Furthermore, if the HDE applicant, on its own initiative or at FDA's request, submits a major amendment as described in § 814.37(c)(1), the review period may be extended up to 75 days.

[63 FR 59220, Nov. 3, 1998]

§ 814.108 Supplemental applications.

After FDA approval of an original HDE, an applicant shall submit supplements in accordance with the requirements for PMA's under § 814.39, except that a request for a new indication for use of a HUD shall comply with requirements set forth in § 814.110. The timeframes for review of, and FDA action on, an HDE supplement are the same as those provided in § 814.114 for an HDE.

[63 FR 59220, Nov. 3, 1998]

§ 814.110 New indications for use.

(a) An applicant seeking a new indication for use of a HUD approved under this subpart H shall obtain a new designation of HUD status in accordance with § 814.102 and shall submit an original HDE in accordance with § 814.104.

(b) An application for a new indication for use made under § 814.104 may incorporate by reference any information or data previously submitted to the agency under an HDE.

§ 814.112 Filing an HDE.

(a) The filing of an HDE means that FDA has made a threshold determination that the application is sufficiently complete to permit substantive review. Within 30 days from the date an HDE is received by FDA, the agency will notify the applicant whether the application has been filed. FDA may refuse to file an HDE if any of the following applies:

(1) The application is incomplete because it does not on its face contain all the information required under § 814.104(b);

(2) FDA determines that there is a comparable device available (other than another HUD approved under this subpart or a device under an approved IDE) to treat or diagnose the disease or condition for which approval of the HUD is being sought; or

(3) The application contains an untrue statement of material fact or omits material information.

(4) The HDE is not accompanied by a statement of either certification or disclosure, or both, as required by part 54 of this chapter.

(b) The provisions contained in § 814.42(b), (c), and (d) regarding notification of filing decisions, filing dates, the start of the 75-day review period, and applicant's options in response to FDA refuse to file decisions shall apply to HDE's.

[61 FR 33244, June 26, 1996, as amended at 63 FR 5254, Feb. 2, 1998; 63 FR 59221, Nov. 3, 1998]

§ 814.114 Timeframes for reviewing an HDE.

Within 75 days after receipt of an HDE that is accepted for filing and to which the applicant does not submit a major amendment, FDA shall send the applicant an approval order, an approvable letter, a not approvable letter (under § 814.116), or an order denying approval (under § 814.118).

[63 FR 59221, Nov. 3, 1998]

§ 814.116 Procedures for review of an HDE.

(a) Substantive review. FDA will begin substantive review of an HDE after the HDE is accepted for filing under § 814.112. FDA may refer an original HDE application to a panel on its own initiative, and shall do so upon the request of an applicant, unless FDA determines that the application substantially duplicates information previously reviewed by a panel. If the HDE is referred to a panel, the agency shall follow the procedures set forth under § 814.44, with the exception that FDA will complete its review of the HDE and the advisory committee report and recommendations within 75 days from receipt of an HDE that is accepted for filing under § 814.112 or the date of filing as determined under § 814.106, whichever is later. Within the later of these two timeframes, FDA will issue an approval order under paragraph (b) of this section, an approvable letter under paragraph (c) of this section, a not approvable letter under paragraph (d) of this section, or an order denying approval of the application under § 814.118(a).

(b) Approval order. FDA will issue to the applicant an order approving an HDE if none of the reasons in § 814.118 for denying approval of the application applies. FDA will approve an application on the basis of draft final labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft final labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed and upon the applicant submitting to FDA a copy of the final printed labeling before marketing. The notice of approval of an HDE will be placed on the FDA's home page on the internet (https://www.fda.gov) in accordance with the rules and policies applicable to PMAs submitted under § 814.20. Following the issuance of an approval order, data and information in the HDE file will be available for public disclosure in accordance with § 814.9(b) through (h), as applicable.

(c) Approvable letter. FDA will send the applicant an approvable letter if the application substantially meets the requirements of this subpart and the agency believes it can approve the application if specific additional information is submitted or specific conditions are agreed to by the applicant. The approvable letter will describe the information FDA requires to be provided by the applicant or the conditions the applicant is required to meet to obtain approval. For example, FDA may require as a condition to approval:

(1) The submission of certain information identified in the approvable letter, e.g., final labeling;

(2) The submission of additional information concerning pediatric uses of the device, as required by § 814.20(b)(13);

(3) Restrictions imposed on the device under section 520(e) of the act;

(4) Postapproval requirements as described in subpart E of this part; and

(5) An FDA inspection that finds the manufacturing facilities, methods, and controls in compliance with part 820 of this chapter and, if applicable, that verifies records pertinent to the HDE.

(d) Not approvable letter. FDA will send the applicant a not approvable letter if the agency believes that the application may not be approved for one or more of the reasons given in § 814.118. The not approvable letter will describe the deficiencies in the application and, where practical, will identify measures required to place the HDE in approvable form. The applicant may respond to the not approvable letter in the same manner as permitted for not approvable letters for PMA's under § 814.44(f), with the exception that if a major HDE amendment is submitted, the review period may be extended up to 75 days.

(e) FDA will consider an HDE to have been withdrawn voluntarily if:

(1) The applicant fails to respond in writing to a written request for an amendment within 75 days after the date FDA issues such request;

(2) The applicant fails to respond in writing to an approvable or not approvable letter within 75 days after the date FDA issues such letter; or

(3) The applicant submits a written notice to FDA that the HDE has been withdrawn.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59221, Nov. 3, 1998; 79 FR 1741, Jan. 10, 2014; 87 FR 2045, Jan. 13, 2022]

§ 814.118 Denial of approval or withdrawal of approval of an HDE.

(a) FDA may deny approval or withdraw approval of an application if the applicant fails to meet the requirements of section 520(m) of the act or of this part, or of any condition of approval imposed by an IRB or by FDA, or any postapproval requirements imposed under § 814.126. In addition, FDA may deny approval or withdraw approval of an application if, upon the basis of the information submitted in the HDE or any other information before the agency, FDA determines that:

(1) There is a lack of a showing of reasonable assurance that the device is safe under the conditions of use prescribed, recommended, or suggested in the labeling thereof;

(2) The device is ineffective under the conditions of use prescribed, recommended, or suggested in the labeling thereof;

(3) The applicant has not demonstrated that there is a reasonable basis from which to conclude that the probable benefit to health from the use of the device outweighs the risk of injury or illness, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment;

(4) The application or a report submitted by or on behalf of the applicant contains an untrue statement of material fact, or omits material information;

(5) The device's labeling does not comply with the requirements in part 801 or part 809 of this chapter;

(6) A nonclinical laboratory study that is described in the HDE and that is essential to show that the device is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study;

(7) Any clinical investigation involving human subjects described in the HDE, subject to the institutional review board regulations in part 56 of this chapter or the informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected;

(8) The applicant does not permit an authorized FDA employee an opportunity to inspect at a reasonable time and in a reasonable manner the facilities and controls, and to have access to and to copy and verify all records pertinent to the application; or

(9) The device's HUD designation should be revoked in accordance with § 814.102(c).

(b) If FDA issues an order denying approval of an application, the agency will comply with the same notice and disclosure provisions required for PMA's under § 814.45(b) and (d), as applicable.

(c) FDA will issue an order denying approval of an HDE after an approvable or not approvable letter has been sent and the applicant:

(1) Submits a requested amendment but any ground for denying approval of the application under § 814.118(a) still applies;

(2) Notifies FDA in writing that the requested amendment will not be submitted; or

(3) Petitions for review under section 515(d)(4) of the act by filing a petition in the form of a petition for reconsideration under § 10.33 of this chapter.

(d) Before issuing an order withdrawing approval of an HDE, FDA will provide the applicant with notice and an opportunity for a hearing as required for PMA's under § 814.46(c) and (d), and will provide the public with notice in accordance with § 814.46(e), as applicable.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59221, Nov. 3, 1998; 87 FR 2045, Jan. 13, 2022]

§ 814.120 Temporary suspension of approval of an HDE.

An HDE or HDE supplement may be temporarily suspended for the same reasons and in the same manner as prescribed for PMA's in § 814.47.

[63 FR 59221, Nov. 3, 1998]

§ 814.122 Confidentiality of data and information.

(a) Requirement for disclosure. The “HDE file” includes all data and information submitted with or referenced in the HDE, any IDE incorporated into the HDE, any HDE amendment or supplement, any report submitted under § 814.126, any master file, or any other related submission. Any record in the HDE file will be available for public disclosure in accordance with the provisions of this section and part 20 of this chapter.

(b) Extent of disclosure. Disclosure by FDA of the existence and contents of an HDE file shall be subject to the same rules that pertain to PMA's under § 814.9(b) through (h), as applicable.

§ 814.124 Institutional Review Board requirements.

(a) IRB approval. The HDE holder is responsible for ensuring that a HUD approved under this subpart is administered only in facilities having oversight by an Institutional Review Board (IRB) constituted and acting pursuant to part 56 of this chapter, including continuing review of use of the device. In addition, a HUD may be administered only if such use has been approved by an IRB. If, however, a physician in an emergency situation determines that approval from an IRB cannot be obtained in time to prevent serious harm or death to a patient, a HUD may be administered without prior approval by an IRB. In such an emergency situation, the physician shall, within 5 days after the use of the device, provide written notification to the chairman of the IRB of such use. Such written notification shall include the identification of the patient involved, the date on which the device was used, and the reason for the use.

(b) Withdrawal of IRB approval. A holder of an approved HDE shall notify FDA of any withdrawal of approval for the use of a HUD by a reviewing IRB within 5 working days after being notified of the withdrawal of approval.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59221, Nov. 3, 1998; 82 FR 26349, June 7, 2017]

§ 814.126 Postapproval requirements and reports.

(a) An HDE approved under this subpart H shall be subject to the postapproval requirements and reports set forth under subpart E of this part, as applicable, with the exception of § 814.82(a)(7). In addition, medical device reports submitted to FDA in compliance with the requirements of part 803 of this chapter shall also be submitted to the IRB of record.

(b) In addition to the reports identified in paragraph (a) of this section, the holder of an approved HDE shall prepare and submit the following complete, accurate, and timely reports:

(1) Periodic reports. An HDE applicant is required to submit reports in accordance with the approval order. Unless FDA specifies otherwise, any periodic report shall include:

(i) An update of the information required under § 814.102(a) in a separately bound volume;

(ii) An update of the information required under § 814.104(b)(2), (b)(3), and (b)(5);

(iii) The number of devices that have been shipped or sold since initial marketing approval under this subpart H and, if the number shipped or sold exceeds 8,000, an explanation and estimate of the number of devices used per patient. If a single device is used on multiple patients, the applicant shall submit an estimate of the number of patients treated or diagnosed using the device together with an explanation of the basis for the estimate;

(iv) Information describing the applicant's clinical experience with the device since the HDE was initially approved. This information shall include safety information that is known or reasonably should be known to the applicant, medical device reports made under part 803 of this chapter, any data generated from the postmarketing studies, and information (whether published or unpublished) that is known or reasonably expected to be known by the applicant that may affect an evaluation of the safety of the device or that may affect the statement of contraindications, warnings, precautions, and adverse reactions in the device's labeling; and

(v) A summary of any changes made to the device in accordance with supplements submitted under § 814.108. If information provided in the periodic reports, or any other information in the possession of FDA, gives the agency reason to believe that a device raises public health concerns or that the criteria for exemption are no longer met, the agency may require the HDE holder to submit additional information to demonstrate continued compliance with the HDE requirements.

(2) Other. An HDE holder shall maintain records of the names and addresses of the facilities to which the HUD has been shipped, correspondence with reviewing IRB's, as well as any other information requested by a reviewing IRB or FDA. Such records shall be maintained in accordance with the HDE approval order.

[61 FR 33244, June 26, 1996, as amended at 63 FR 59221, Nov. 3, 1998; 71 FR 16228, Mar. 31, 2006; 82 FR 26349, June 7, 2017]

§ 820.1 Scope.

(a) Applicability. Current good manufacturing practice (CGMP) requirements are set forth in this quality management system regulation (QMSR). The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The requirements in this part are intended to assure that finished devices will be safe and effective and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act and that the use of other terminology, such as “safety and performance,” in this part does not change this statutory standard or the requirements of this part. Any manufacturers engaged in the design, manufacture, packaging, labeling, storage, installation, or servicing of a finished device must establish and maintain a quality management system that is appropriate for its specific device(s). Manufacturers subject to this part include, but are not limited to, manufacturers that perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, as well as initial distributors of foreign entities that perform these functions. If a manufacturer engages in only some operations subject to the requirements in this part, and not in others, that manufacturer need only comply with those requirements applicable to the operations in which it is engaged.

(1) Finished devices. The provisions of this part shall apply to any finished device, as defined in this part, intended for human use, that is manufactured in any State or Territory of the United States, the District of Columbia, or the Commonwealth of Puerto Rico, or that is imported or offered for import into the United States.

(2) Components or parts. The provisions of this part do not apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to consider provisions of this regulation as appropriate.

(3) Blood and blood components. The provisions of this part do not apply to manufacturers of blood and blood components used for transfusion or for further manufacturing. Such manufacturers are subject to subchapter F of this chapter.

(4) HCT/Ps. The provisions of this part apply to manufacturers of human cells, tissues, and cellular and tissue-based products (HCT/Ps), as defined in § 1271.3(d) of this chapter, that are devices (subject to premarket review or notification, or exempt from notification, under an application submitted under the device provisions of the Federal Food, Drug, and Cosmetic Act or under a biological product license application under section 351 of the Public Health Service Act). HCT/Ps regulated as devices are also subject to the donor-eligibility requirements set forth in part 1271, subpart C of this chapter and applicable current good tissue practice requirements in part 1271, subpart D of this chapter. In the event of a conflict between applicable regulations in part 1271 and in other parts of this chapter, the regulation specifically applicable to the device in question shall supersede the more general regulation.

(b) Conflicts with other requirements under the Federal Food, Drug, and Cosmetic Act. The QMSR for devices in this part supplements regulations in other parts of this chapter except where explicitly stated otherwise. To the extent that any applicable requirements in this part conflict with requirements in other parts of this chapter, the requirements specifically applicable to the device in question shall supersede the more generally applicable requirements. Moreover, to the extent that any clauses of ISO 13485 (incorporated by reference, see § 820.7) conflict with any provisions of the Federal Food, Drug, and Cosmetic Act and/or its other implementing regulations, the Federal Food, Drug, and Cosmetic Act and/or its other implementing regulations will control.

(c) Foreign manufacturers. A device that is imported or offered for import into the United States is subject to refusal of admission to the United States under section 801(a) of the Federal Food, Drug, and Cosmetic Act if, among other things, it appears to be adulterated as set forth in the Federal Food, Drug, and Cosmetic Act and its implementing regulations.

(d) Exemptions or variances. (1) A manufacturer subject to any requirement under section 520(f)(1) of the Federal Food, Drug, and Cosmetic Act, including any requirements under this part, may petition for an exemption or variance from such requirement in accordance with section 520(f)(2) of the Federal Food, Drug, and Cosmetic Act. Petitions for an exemption or variance shall be submitted in accordance with the procedures set forth in § 10.30 of this chapter.

(2) FDA may initiate and grant a variance from any requirement(s) in this part when the Agency determines that such variance is in the best interest of the public health, including that there is a public health need for the device and the device would not likely be made sufficiently available without the variance. Such variance will remain in effect only so long as there remains a public health need for the device and the device would not likely be made sufficiently available without the variance.

§ 820.3 Definitions.

The definitions in ISO 13485 and in Clause 3 of ISO 9000 (incorporated by reference, see § 820.7) apply to this part, except as specified in paragraph (b) of this section, and do not affect the meaning of similar terms defined in this title.

(a) The following terms, which are either not used or not defined in ISO 13485 or in Clause 3 of ISO 9000, also apply for the purposes of this part:

Batch or lot means one or more components or finished devices that consist of a single type, model, class, size, composition, or software version that are manufactured under essentially the same conditions and that are intended to have uniform characteristics and quality within specified limits.

Component means any raw material, substance, piece, part, software, firmware, labeling, or assembly that is intended to be included as part of the finished, packaged, and labeled device.

Federal Food, Drug, and Cosmetic Act means the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 321 et seq., as amended.

Finished device means any device or accessory to any device that is suitable for use or capable of functioning, whether or not it is packaged, labeled, or sterilized.

Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) of this chapter and that is also regulated as a device.

Remanufacturer means any person who processes, conditions, renovates, repackages, restores, or does any other act to a finished device that significantly changes the finished device's performance or safety specifications, or intended use.

(b) All definitions in section 201 of the Federal Food, Drug, and Cosmetic Act shall apply to the regulation of quality management systems under this part and shall supersede the correlating terms and definitions in ISO 13485 (e.g., the definitions of device and labeling in section 201(h) and (m) of the Federal Food, Drug, and Cosmetic Act apply to this part and supersede the definitions for the correlating terms in ISO 13485 (labelling and medical device)). In addition, the following terms and definitions apply to this part and supersede the definitions for the correlating terms in ISO 13485 or ISO 9000:

Implantable medical device shall have the meaning of “implant” as defined in section 860.3 of this chapter.

Manufacturer means any person who designs, manufactures, fabricates, assembles, or processes a finished device. Manufacturer includes, but is not limited to, those who perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions.

Organization shall have the meaning of “manufacturer” as defined in this part.

Rework means action taken on a nonconforming product so that it will fulfill the specified requirements in the medical device file (MDF) before it is released for distribution.

Safety and Performance shall have the meaning of “safety and effectiveness” in Clause 0.1 of ISO 13485. The phrase “safety and performance” does not relieve a manufacturer from any obligation to implement controls or other measures that provide reasonable assurance of safety and effectiveness.

[89 FR 7523, Feb. 2, 2024; 89 FR 82945, Oct. 15, 2024]

§ 820.5 [Reserved]

§ 820.7 Incorporation by reference.

Certain material is incorporated by reference into this part with the approval of the Director of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. All approved incorporation by reference (IBR) material is available for inspection at the Food and Drug Administration, and at the National Archives and Records Administration (NARA). Contact FDA at: Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852; 240-402-7500; https://www.regulations.gov/document/FDA-2013-S-0610-0003. For information on the availability of this material at NARA, visit www.archives.gov/federal-register/cfr/ibr-locations or email fr.inspection@nara.gov. This material may be obtained from the International Organization for Standardization (ISO), BIBC II, Chemin de Blandonnet 8, CP 401, 1214 Vernier, Geneva, Switzerland; +41-22-749-01-11; customerservice@iso.org, https://www.iso.org/store.html.

(a) ISO 9000:2015(E) (“ISO 9000”), Quality Management systems—Fundamentals and vocabulary, Clause 3—Terms and definitions, Fourth edition, September 15, 2015. IBR approved for § 820.3.

(b) ISO 13485:2016(E) (“ISO 13485”), Medical devices—Quality management systems—Requirements for regulatory purposes, Third edition, March 1, 2016; IBR approved for §§ 820.1, 820.3, 820.10, 820.35, and 820.45.

§ 820.10 Requirements for a quality management system.

A manufacturer subject to this part as described by § 820.1(a) must:

(a) Document. Document a quality management system that complies with the applicable requirements of ISO 13485 (incorporated by reference, see § 820.7) and other applicable requirements of this part; and

(b) Applicable regulatory requirements. Comply, as appropriate, with the other applicable regulatory requirements in this title, including, but not limited to the following, to fully comply with the listed ISO 13485 Clause:

(1) For Clause 7.5.8 in ISO 13485, Identification, the manufacturer must document a system to assign unique device identification to the medical device in accordance with the requirements of part 830 of this chapter.

(2) For Clause 7.5.9.1 in ISO 13485, Traceability—General, the manufacturer must document procedures for traceability in accordance with the requirements of part 821 of this chapter, if applicable.

(3) For Clause 8.2.3 in ISO 13485, Reporting to regulatory authorities, the manufacturer must notify FDA of complaints that meet the reporting criteria of part 803 of this chapter.

(4) For Clauses 7.2.3, 8.2.3, and 8.3.3, advisory notices shall be handled in accordance with the requirements of part 806 of this chapter.

(c) Design and development. Manufacturers of class II, class III, and those class I devices listed in paragraph (c)(1) of this section and table 1 to paragraph (c)(2) of this section must comply with the requirements in Design and Development, Clause 7.3 and its Subclauses in ISO 13485. The class I devices are as follows:

(1) Devices automated with computer software; and

(2) The devices listed in the following table:

Table 1 to Paragraph (c)(2)

Section | Device

868.6810 | Catheter, Tracheobronchial Suction.

878.4460 | Glove, Non-powdered Surgeon's.

880.6760 | Restraint, Protective.

892.5650 | System, Applicator, Radionuclide, Manual.

892.5740 | Source, Radionuclide Teletherapy.

(d) Devices that support or sustain life. Manufacturers of devices that support or sustain life, the failure of which to perform when properly used in accordance with instructions for use provided in the labeling can be reasonably expected to result in a significant injury, must comply with the requirements in Traceability for Implantable Devices, Clause 7.5.9.2 in ISO 13485, in addition to all other applicable requirements in this part, as appropriate.

(e) Enforcement. The failure to comply with any applicable requirement in this part renders a device adulterated under section 501(h) of the Federal Food, Drug, and Cosmetic Act. Such a device, as well as any person responsible for the failure to comply, is subject to regulatory action.

§§ 820.20--820.30 [Reserved]

§ 820.35 Control of records.

In addition to the requirements of Clause 4.2.5 in ISO 13485 (incorporated by reference, see § 820.7), Control of Records, the manufacturer must include the following information in certain records:

(a) Records of complaints. In addition to Clause 8.2.2 in ISO 13485, Complaint Handling, the manufacturer shall maintain records of the review, evaluation, and investigation for any complaints involving the possible failure of a device, labeling, or packaging to meet any of its specifications. If an investigation has already been performed for a similar complaint, another investigation is not necessary, and the manufacturer shall maintain records documenting justification for not performing such investigation. For complaints that must be reported to FDA under part 803 of this chapter, complaints that a manufacturer determines must be investigated, and complaints that the manufacturer investigated regardless of those requirements, the manufacturer must record the following information:

(1) The name of the device;

(2) The date the complaint was received;

(3) Any unique device identifier (UDI) or universal product code (UPC), and any other device identification(s);

(4) The name, address, and phone number of the complainant;

(5) The nature and details of the complaint;

(6) Any correction or corrective action taken; and

(7) Any reply to the complainant.

(b) Records of servicing activities. In adhering to Clause 7.5.4 in ISO 13485, Servicing Activities, the manufacturer must record the following information, at a minimum, for servicing activities:

(1) The name of the device serviced;

(2) Any UDI or UPC, and any other device identification(s);

(3) The date of service;

(4) The individual(s) who serviced the device;

(5) The service performed; and

(6) Any test and inspection data.

(c) Unique Device Identification. In addition to the requirements of Clauses 7.5.1, 7.5.8, and 7.5.9 in ISO 13485, the UDI must be recorded for each medical device or batch of medical devices.

(d) Confidentiality. Records deemed confidential by the manufacturer may be marked to aid FDA in determining whether information may be disclosed under the public information regulation in part 20 of this chapter.

§ 820.40 [Reserved]

§ 820.45 Device labeling and packaging controls.

In addition to the requirements of Clause 7.5.1 of ISO 13485 (incorporated by reference, see § 820.7), Control of production and service provision, each manufacturer must document and maintain procedures that provide a detailed description of the activities to ensure the integrity, inspection, storage, and operations for labeling and packaging, during the customary conditions of processing, storage, handling, distribution, and, as appropriate, use of the device.

(a) The manufacturer must ensure labeling and packaging has been examined for accuracy prior to release or storage where applicable, to include the following:

(1) The correct unique device identifier (UDI) or universal product code (UPC), or any other device identification(s);

(2) Expiration date;

(3) Storage instructions;

(4) Handling instructions; and

(5) Any additional processing instructions.

(b) The release of the labeling for use must be documented in accordance with Clause 4.2.5 of ISO 13485.

(c) The manufacturer must ensure labeling and packaging operations have been established and maintained to prevent mixups, including, but not limited to, inspection of the labeling and packaging before use to assure that all devices have correct labeling and packaging, as specified in the medical device file. Results of such labeling inspection must be documented in accordance with Clause 4.2.5 of ISO 13485.

§ 821.1 Scope.

(a) The regulations in this part implement section 519(e) of the Federal Food, Drug, and Cosmetic Act (the act), which provides that the Food and Drug Administration may require a manufacturer to adopt a method of tracking a class II or class III device, if the device meets one of the following three criteria and FDA issues an order to the manufacturer: the failure of the device would be reasonably likely to have serious adverse health consequences; or the device is intended to be implanted in the human body for more than 1 year; or the device is a life-sustaining or life-supporting device used outside a device user facility. A device that meets one of these criteria and is the subject of an FDA order must comply with this part and is referred to, in this part, as a “tracked device.”

(b) These regulations are intended to ensure that tracked devices can be traced from the device manufacturing facility to the person for whom the device is indicated, that is, the patient. Effective tracking of devices from the manufacturing facility, through the distributor network (including distributors, retailers, rental firms and other commercial enterprises, device user facilities, and licensed practitioners) and, ultimately, to the patient is necessary for the effectiveness of remedies prescribed by the act, such as patient notification (section 518(a) of the act) or device recall (section 518(e) of the act). Although these regulations do not preclude a manufacturer from involving outside organizations in that manufacturer's device tracking effort, the legal responsibility for complying with this part rests with manufacturers who are subject to tracking orders, and that responsibility cannot be altered, modified, or in any way abrogated by contracts or other agreements.

(c) The primary burden for ensuring that the tracking system works rests upon the manufacturer. A manufacturer or any other person, including a distributor, final distributor, or multiple distributor, who distributes a device subject to tracking, who fails to comply with any applicable requirement of section 519(e) of the act or of this part, or any person who causes such failure, misbrands the device within the meaning of section 502(t)(2) of the act and commits a prohibited act within the meaning of sections 301(e) and 301(q)(1)(B) of the act.

(d) Any person subject to this part who permanently discontinues doing business is required to notify FDA at the time the person notifies any government agency, court, or supplier, and provide FDA with a complete set of its tracking records and information. However, if a person ceases distribution of a tracked device but continues to do other business, that person continues to be responsible for compliance with this part unless another person, affirmatively and in writing, assumes responsibility for continuing the tracking of devices previously distributed under this part. Further, if a person subject to this part goes out of business completely, but other persons acquire the right to manufacture or distribute tracked devices, those other persons are deemed to be responsible for continuing the tracking responsibility of the previous person under this part.

[58 FR 43447, Aug. 16, 1993, as amended at 67 FR 5951, Feb. 8, 2002; 73 FR 34860, June 19, 2008]

§ 821.2 Exemptions and variances.

(a) A manufacturer, importer, or distributor may seek an exemption or variance from one or more requirements of this part.

(b) A request for an exemption or variance shall be submitted in the form of a petition under § 10.30 of this chapter and shall comply with the requirements set out therein, except that a response shall be issued in 90 days. The Director or Deputy Directors, CDRH, or the Director or Principal Deputy Director of the Office of Product Evaluation and Quality, CDRH, shall issue responses to requests under this section. The petition shall also contain the following:

(1) The name of the device and device class and representative labeling showing the intended use(s) of the device;

(2) The reasons that compliance with the tracking requirements of this part is unnecessary;

(3) A complete description of alternative steps that are available, or that the petitioner has already taken, to ensure that an effective tracking system is in place; and

(4) Other information justifying the exemption or variance.

(c) An exemption or variance is not effective until the Director or Deputy Directors, CDRH, or the Director or Principal Deputy Director of the Office of Product Evaluation and Quality, CDRH, approves the request under § 10.30(e)(2)(i) of this chapter.

[58 FR 43447, Aug. 16, 1993, as amended at 59 FR 31138, June 17, 1994; 67 FR 5951, Feb. 8, 2002; 72 FR 17399, Apr. 9, 2007; 85 FR 18443, Apr. 2, 2020; 86 FR 17065, Apr. 1, 2021]

§ 821.3 Definitions.

The following definitions and terms apply to this part:

(a) Act means the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 321 et seq., as amended.

(b) Importer means the initial distributor of an imported device who is subject to a tracking order. “Importer” does not include anyone who only furthers the marketing, e.g., brokers, jobbers, or warehousers.

(c) Manufacturer means any person, including any importer, repacker and/or relabeler, who manufactures, prepares, propagates, compounds, assembles, or processes a device or engages in any of the activities described in § 807.3(d) of this chapter.

(d) Device failure means the failure of a device to perform or function as intended, including any deviations from the device's performance specifications or intended use.

(e) Serious adverse health consequences means any significant adverse experience related to a device, including device-related events which are life-threatening or which involve permanent or long-term injuries or illnesses.

(f) Device intended to be implanted in the human body for more than 1 year means a device that is intended to be placed into a surgically or naturally formed cavity of the human body for more than 1 year to continuously assist, restore, or replace the function of an organ system or structure of the human body throughout the useful life of the device. The term does not include a device that is intended and used only for temporary purposes or that is intended for explantation in 1 year or less.

(g) Life-supporting or life-sustaining device used outside a device user facility means a device which is essential, or yields information that is essential, to the restoration or continuation of a bodily function important to the continuation of human life that is intended for use outside a hospital, nursing home, ambulatory surgical facility, or diagnostic or outpatient treatment facility. Physicians' offices are not device user facilities and, therefore, devices used therein are subject to tracking if they otherwise satisfy the statutory and regulatory criteria.

(h) Distributor means any person who furthers the distribution of a device from the original place of manufacture to the person who makes delivery or sale to the ultimate user, i.e., the final or multiple distributor, but who does not repackage or otherwise change the container, wrapper, or labeling of the device or device package.

(i) Final distributor means any person who distributes a tracked device intended for use by a single patient over the useful life of the device to the patient. This term includes, but is not limited to, licensed practitioners, retail pharmacies, hospitals, and other types of device user facilities.

(j) Distributes means any distribution of a tracked device, including the charitable distribution of a tracked device. This term does not include the distribution of a device under an effective investigational device exemption in accordance with section 520(g) of the act and part 812 of this chapter or the distribution of a device for teaching, law enforcement, research, or analysis as specified in § 801.125 of this chapter.

(k) Multiple distributor means any device user facility, rental company, or any other entity that distributes a life-sustaining or life-supporting device intended for use by more than one patient over the useful life of the device.

(l) Licensed practitioner means a physician, dentist, or other health care practitioner licensed by the law of the State in which he or she practices to use or order the use of the tracked device.

(m) Any term defined in section 201 of the act shall have the same definition in this part.

(n) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(o) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

[58 FR 43447, Aug. 16, 1993, as amended at 67 FR 5951, Feb. 8, 2002; 78 FR 58822, Sept. 24, 2013]

§ 821.4 Imported devices.

For purposes of this part, the importer of a tracked device shall be considered the manufacturer and shall be required to comply with all requirements of this part applicable to manufacturers. Importers must keep all information required under this part in the United States.

§ 821.20 Devices subject to tracking.

(a) A manufacturer of any class II or class III device that fits within one of the three criteria within § 821.1(a) must track that device in accordance with this part, if FDA issues a tracking order to that manufacturer.

(b) When responding to premarket notification submissions and premarket approval applications, FDA will notify the sponsor by issuing an order that states that FDA believes the device meets the criteria of section 519(e)(1) of the act and, by virtue of the order, the sponsor must track the device.

[67 FR 5951, Feb. 8, 2002]

§ 821.25 Device tracking system and content requirements: manufacturer requirements.

(a) A manufacturer of a tracked device shall adopt a method of tracking for each such type of device that it distributes that enables a manufacturer to provide FDA with the following information in writing for each tracked device distributed:

(1) Except as required by order under section 518(e) of the act, within 3 working days of a request from FDA, prior to the distribution of a tracked device to a patient, the name, address, and telephone number of the distributor, multiple distributor, or final distributor holding the device for distribution and the location of the device;

(2) Within 10 working days of a request from FDA for tracked devices that are intended for use by a single patient over the life of the device, after distribution to or implantation in a patient:

(i) The unique device identifier (UDI), lot number, batch number, model number, or serial number of the device or other identifier necessary to provide for effective tracking of the devices;

(ii) The date the device was shipped by the manufacturer;

(iii) The name, address, telephone number, and social security number (if available) of the patient receiving the device, unless not released by the patient under § 821.55(a);

(iv) The date the device was provided to the patient;

(v) The name, mailing address, and telephone number of the prescribing physician;

(vi) The name, mailing address, and telephone number of the physician regularly following the patient if different than the prescribing physician; and

(vii) If applicable, the date the device was explanted and the name, mailing address, and telephone number of the explanting physician; the date of the patient's death; or the date the device was returned to the manufacturer, permanently retired from use, or otherwise permanently disposed of.

(3) Except as required by order under section 518(e) of the act, within 10 working days of a request from FDA for tracked devices that are intended for use by more than one patient, after the distribution of the device to the multiple distributor:

(i) The unique device identifier (UDI), lot number, batch number, model number, or serial number of the device or other identifier necessary to provide for effective tracking of the devices;

(ii) The date the device was shipped by the manufacturer;

(iii) The name, address, and telephone number of the multiple distributor;

(iv) The name, address, telephone number, and social security number (if available) of the patient using the device, unless not released by the patient under § 821.55(a);

(v) The location of the device;

(vi) The date the device was provided for use by the patient;

(vii) The name, address, and telephone number of the prescribing physician; and

(viii) If and when applicable, the date the device was returned to the manufacturer, permanently retired from use, or otherwise permanently disposed of.

(b) A manufacturer of a tracked device shall keep current records in accordance with its standard operating procedure of the information identified in paragraphs (a)(1), (a)(2) and (a)(3)(i) through (a)(3)(iii) of this section on each tracked device released for distribution for as long as such device is in use or in distribution for use.

(c) A manufacturer of a tracked device shall establish a written standard operating procedure for the collection, maintenance, and auditing of the data specified in paragraphs (a) and (b) of this section. A manufacturer shall make this standard operating procedure available to FDA upon request. A manufacturer shall incorporate the following into the standard operating procedure:

(1) Data collection and recording procedures, which shall include a procedure for recording when data which is required under this part is missing and could not be collected and the reason why such required data is missing and could not be collected;

(2) A method for recording all modifications or changes to the tracking system or to the data collected and maintained under the tracking system, reasons for any modification or change, and dates of any modification or change. Modification and changes included under this requirement include modifications to the data (including termination of tracking), the data format, the recording system, and the file maintenance procedures system; and

(3) A quality assurance program that includes an audit procedure to be run for each device product subject to tracking, at not less than 6-month intervals for the first 3 years of distribution and at least once a year thereafter. This audit procedure shall provide for statistically relevant sampling of the data collected to ensure the accuracy of data and performance testing of the functioning of the tracking system.

(d) When a manufacturer becomes aware that a distributor, final distributor, or multiple distributor has not collected, maintained, or furnished any record or information required by this part, the manufacturer shall notify the FDA district office responsible for the area in which the distributor, final distributor, or multiple distributor is located of the failure of such persons to comply with the requirements of this part. Manufacturers shall have taken reasonable steps to obtain compliance by the distributor, multiple distributor, or final distributor in question before notifying FDA.

(e) A manufacturer may petition for an exemption or variance from one or more requirements of this part according to the procedures in § 821.2 of this chapter.

[58 FR 43447, Aug. 16, 1993, as amended at 67 FR 5951, Feb. 8, 2002; 78 FR 58822, Sept. 24, 2013]

§ 821.30 Tracking obligations of persons other than device manufacturers: distributor requirements.

(a) A distributor, final distributor, or multiple distributor of any tracked device shall, upon purchasing or otherwise acquiring any interest in such a device, promptly provide the manufacturer tracking the device with the following information:

(1) The name and address of the distributor, final distributor or multiple distributor;

(2) The unique device identifier (UDI), lot number, batch number, model number, or serial number of the device or other identifier used by the manufacturer to track the device;

(3) The date the device was received;

(4) The person from whom the device was received;

(5) If and when applicable, the date the device was explanted, the date of the patient's death, or the date the device was returned to the distributor, permanently retired from use, or otherwise permanently disposed of.

(b) A final distributor, upon sale or other distribution of a tracked device for use in or by the patient, shall promptly provide the manufacturer tracking the device with the following information:

(1) The name and address of the final distributor,

(2) The unique device identifier (UDI), lot number, batch number, model number, or serial number of the device or other identifier used by the manufacturer to track the device;

(3) The name, address, telephone number, and social security number (if available) of the patient receiving the device, unless not released by the patient under § 821.55(a);

(4) The date the device was provided to the patient or for use in the patient;

(5) The name, mailing address, and telephone number of the prescribing physician;

(6) The name, mailing address, and telephone number of the physician regularly following the patient if different than the prescribing physician; and

(7) When applicable, the date the device was explanted and the name, mailing address, and telephone number of the explanting physician, the date of the patient's death, or the date the device was returned to the manufacturer, permanently retired from use, or otherwise permanently disposed of.

(c)(1) A multiple distributor shall keep written records of the following each time such device is distributed for use by a patient:

(i) The unique device identifier (UDI), lot number, batch number, model number, or serial number of the device or other identifier used by the manufacturer to track the device;

(ii) The name, address, telephone number, and social security number (if available) of the patient using the device;

(iii) The location of the device, unless not released by the patient under § 821.55(a);

(iv) The date the device was provided for use by the patient;

(v) The name, address, and telephone number of the prescribing physician;

(vi) The name, address, and telephone number of the physician regularly following the patient if different than the prescribing physician; and

(vii) When applicable, the date the device was permanently retired from use or otherwise permanently disposed of.

(2) Except as required by order under section 518(e) of the act, any person who is a multiple distributor subject to the recordkeeping requirement of paragraph (c)(1) of this section shall, within 5 working days of a request from the manufacturer or within 10 working days of a request from FDA for the information identified in paragraph (c)(1) of this section, provide such information to the manufacturer or FDA.

(d) A distributor, final distributor, or multiple distributor shall make any records required to be kept under this part available to the manufacturer of the tracked device for audit upon written request by an authorized representative of the manufacturer.

(e) A distributor, final distributor, or multiple distributor may petition for an exemption or variance from one or more requirements of this part according to the procedures in § 821.2.

[58 FR 43447, Aug. 16, 1993, as amended at 67 FR 5951, Feb. 8, 2002; 78 FR 58822, Sept. 24, 2013]

§ 821.50 Availability.

(a) Manufacturers, distributors, multiple distributors, and final distributors shall, upon the presentation by an FDA representative of official credentials and the issuance of Form FDA 482 at the initiation of an inspection of an establishment or person under section 704 of the act, make each record and all information required to be collected and maintained under this part and all records and information related to the events and persons identified in such records available to FDA personnel.

(b) Records and information referenced in paragraph (a) of this section shall be available to FDA personnel for purposes of reviewing, copying, or any other use related to the enforcement of the act and this part. Records required to be kept by this part shall be kept in a centralized point for each manufacturer or distributor within the United States.

[58 FR 43447, Aug. 16, 1993, as amended at 65 FR 43690, July 14, 2000]

§ 821.55 Confidentiality.

(a) Any patient receiving a device subject to tracking requirements under this part may refuse to release, or refuse permission to release, the patient's name, address, telephone number, and social security number, or other identifying information for the purpose of tracking.

(b) Records and other information submitted to FDA under this part shall be protected from public disclosure to the extent permitted under part 20 of this chapter, and in accordance with § 20.63 of this chapter, information contained in such records that would identify patient or research subjects shall not be available for public disclosure except as provided in those parts.

(c) Patient names or other identifiers may be disclosed to a manufacturer or other person subject to this part or to a physician when the health or safety of the patient requires that such persons have access to the information. Such notification will be pursuant to agreement that the record or information will not be further disclosed except as the health aspects of the patient requires. Such notification does not constitute public disclosure and will not trigger the availability of the same information to the public generally.

[58 FR 43447, Aug. 16, 1993, as amended at 67 FR 5951, Feb. 8, 2002]

§ 821.60 Retention of records.

Persons required to maintain records under this part shall maintain such records for the useful life of each tracked device they manufacture or distribute. The useful life of a device is the time a device is in use or in distribution for use. For example, a record may be retired if the person maintaining the record becomes aware of the fact that the device is no longer in use, has been explanted, returned to the manufacturer, or the patient has died.

§ 822.1 What does this part cover?

This part implements section 522 of the Federal Food, Drug, and Cosmetic Act by providing procedures and requirements for postmarket surveillance of class II and class III devices that meet any of the following criteria:

(a) Failure of the device would be reasonably likely to have serious adverse health consequences;

(b) The device is intended to be implanted in the human body for more than 1 year;

(c) The device is intended to be used outside a user facility to support or sustain life. If you fail to comply with requirements that we order under section 522 of the Federal Food, Drug, and Cosmetic Act and this part, your device is considered misbranded under section 502(t)(3) of the Federal Food, Drug, and Cosmetic Act and you are in violation of section 301(q)(1)(C) of the Federal Food, Drug, and Cosmetic Act; or

(d) The device is expected to have significant use in pediatric populations.

[67 FR 38887, June 6, 2002, as amended at 88 FR 16880, Mar. 21, 2023]

§ 822.2 What is the purpose of this part?

The purpose of this part is to implement our postmarket surveillance authority to maximize the likelihood that postmarket surveillance plans will result in the collection of useful data. These data can reveal unforeseen adverse events, the actual rate of anticipated adverse events, or other information necessary to protect the public health.

§ 822.3 How do you define the terms used in this part?

Some of the terms we use in this part are specific to postmarket surveillance and reflect the language used in the statute (law). Other terms are more general and reflect our interpretation of the law. This section of the part defines the following terms:

(a) Act means the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 301 et seq., as amended.

(b) Designated person means the individual who conducts or supervises the conduct of your postmarket surveillance. If your postmarket surveillance plan includes a team of investigators, as defined below, the designated person is the responsible leader of that team.

(c) Device failure means a device does not perform or function as intended, and includes any deviation from the device's performance specifications or intended use.

(d) General plan guidance means agency guidance that provides information about the requirement to conduct postmarket surveillance, the submission of a plan to us for approval, the content of the submission, and the conduct and reporting requirements of the surveillance.

(e) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

(f) Investigator means an individual who collects data or information in support of a postmarket surveillance plan.

(g) Life-supporting or life-sustaining device used outside a device user facility means that a device is essential to, or yields information essential to, the restoration or continuation of a bodily function important to the continuation of human life and is used outside a hospital, nursing home, ambulatory surgical facility, or diagnostic or outpatient treatment facility. A physician's office is not a device user facility.

(h) Manufacturer means any person, including any importer, repacker, and/or relabeler, who manufactures, prepares, propagates, compounds, assembles, processes a device, or engages in any of the activities described in § 807.3(d) of this chapter.

(i) Postmarket surveillance means the active, systematic, scientifically valid collection, analysis, and interpretation of data or other information about a marketed device.

(j) Prospective surveillance means that the subjects are identified at the beginning of the surveillance and data or other information will be collected from that time forward (as opposed to retrospective surveillance).

(k) Serious adverse health consequences means any significant adverse experience related to a device, including device-related events that are life-threatening or that involve permanent or long-term injuries or illnesses.

(l) Specific guidance means guidance that provides information regarding postmarket surveillance for specific types or categories of devices or specific postmarket surveillance issues. This type of guidance may be used to supplement general guidance and may address such topics as the type of surveillance approach that is appropriate for the device and the postmarket surveillance question, sample size, or specific reporting requirements.

(m) Surveillance question means the issue or issues to be addressed by the postmarket surveillance.

(n) Unforeseen adverse event means any serious adverse health consequence that either is not addressed in the labeling of the device or occurs at a rate higher than anticipated.

(o) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20 of this chapter. A UDI is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

[67 FR 38887, June 6, 2002, as amended at 78 FR 58823, Sept. 24, 2013]

§ 822.4 Does this part apply to me?

If we have ordered you to conduct postmarket surveillance of a medical device under section 522 of the Federal Food, Drug, and Cosmetic Act, this part applies to you. We have the authority to order postmarket surveillance of any class II or class III medical device, including a device reviewed under the licensing provisions of section 351 of the Public Health Service Act, that meets any of the following criteria:

(a) Failure of the device would be reasonably likely to have serious adverse health consequences;

(b) The device is intended to be implanted in the human body for more than 1 year;

(c) The device is intended to be used to support or sustain life and to be used outside a user facility; or

(d) The device is expected to have significant use in pediatric populations.

[67 FR 38887, June 6, 2002, as amended at 88 FR 16880, Mar. 21, 2023]

§ 822.5 How will I know if I must conduct postmarket surveillance?

We will send you a letter (the postmarket surveillance order) notifying you of the requirement to conduct postmarket surveillance. Before we send the order, or as part of the order, we may require that you submit information about your device that will allow us better to define the scope of a surveillance order. We will specify the device(s) subject to the surveillance order and the reason that we are requiring postmarket surveillance of the device under section 522 of the act. We will also provide you with any general or specific guidance that is available to help you develop your plan for conducting postmarket surveillance.

§ 822.6 When will you notify me that I am required to conduct postmarket surveillance?

We will notify you as soon as we have determined that postmarket surveillance of your device is necessary, based on the identification of a surveillance question. This may occur during the review of a marketing application for your device, as your device goes to market, or after your device has been marketed for a period of time.

§ 822.7 What should I do if I do not agree that postmarket surveillance is appropriate?

(a) If you do not agree with our decision to order postmarket surveillance for a particular device, you may request review of our decision by:

(1) Requesting a meeting with the Director of the Office that issued the order for postmarket surveillance;

(2) Seeking internal review of the order under § 10.75 of this chapter;

(3) Requesting an informal hearing under part 16 of this chapter; or

(4) Requesting review by the Medical Devices Dispute Resolution Panel of the Medical Devices Advisory Committee.

(b) You may obtain guidance documents that discuss these mechanisms from the Center for Devices and Radiological Health's (CDRH's) Web site (http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHOmbudsman/default.htm.).

[67 FR 38887, June 6, 2002, as amended at 72 FR 17399, Apr. 9, 2007; 78 FR 18233, Mar. 26, 2013; 85 FR 18843, Apr. 2, 2020; 88 FR 16880, Mar. 21, 2023]

§ 822.8 When, where, and how must I submit my postmarket surveillance plan?

You must submit your plan to conduct postmarket surveillance within 30 days of the date you receive the postmarket surveillance order. For devices regulated by the Center for Biologics Evaluation and Research, send your submission to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. For devices regulated by the Center for Drug Evaluation and Research, send your submission to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B, Ammendale Rd., Beltsville, MD 20705-1266. For devices regulated by the Center for Devices and Radiological Health, send your submission to the Document Mail Center, 10903 New Hampshire Ave., Bldg. 66, Rm. G609, Silver Spring, MD 20993-0002. When we receive your original submission, we will send you an acknowledgment letter identifying the unique document number assigned to your submission. You must use this number in any correspondence related to this submission.

[87 FR 17950, Mar. 29, 2022]

§ 822.9 What must I include in my submission?

Your submission must include the following:

(a) Organizational/administrative information:

(1) Your name and address;

(2) Generic and trade names of your device;

(3) Name and address of the contact person for the submission;

(4) Premarket application/submission number and device identifiers for your device;

(5) Table of contents identifying the page numbers for each section of the submission;

(6) Description of the device (this may be incorporated by reference to the appropriate premarket application/submission);

(7) Product codes and a list of all relevant model numbers; and

(8) Indications for use and claims for the device;

(b) Postmarket surveillance plan;

(c) Designated person information;

(1) Name, address, and telephone number; and

(2) Experience and qualifications.

[67 FR 38887, June 6, 2002, as amended at 78 FR 58823, Sept. 24, 2013]

§ 822.10 What must I include in my surveillance plan?

Your surveillance plan must include a discussion of:

(a) The plan objective(s) addressing the surveillance question(s) identified in our order;

(b) The subject of the study, e.g., patients, the device, animals;

(c) The variables and endpoints that will be used to answer the surveillance question, e.g., clinical parameters or outcomes;

(d) The surveillance approach or methodology to be used;

(e) Sample size and units of observation;

(f) The investigator agreement, if applicable;

(g) Sources of data, e.g., hospital records;

(h) The data collection plan and forms;

(i) The consent document, if applicable;

(j) Institutional Review Board information, if applicable;

(k) The patient followup plan, if applicable;

(l) The procedures for monitoring conduct and progress of the surveillance;

(m) An estimate of the duration of surveillance;

(n) All data analyses and statistical tests planned;

(o) The content and timing of reports.

§ 822.11 What should I consider when designing my plan to conduct postmarket surveillance?

You must design your surveillance to address the postmarket surveillance question identified in the order you received. You should consider what, if any, patient protection measures should be incorporated into your plan. You should also consider the function, operating characteristics, and intended use of your device when designing a surveillance approach.

§ 822.12 Do you have any information that will help me prepare my submission or design my postmarket surveillance plan?

Guidance documents that discuss our current thinking on preparing a postmarket surveillance submission and designing a postmarket surveillance plan are available on the Center for Devices and Radiological Health's website, the Food and Drug Administration main website, and from the Food and Drug Administration, Center for Devices and Radiological Health, Office of Policy, Guidance and Policy Development, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 5431, Silver Spring, MD 20993-0002. They do not establish legally enforceable rights or responsibilities and do not legally bind you or FDA. You may choose to use an approach other than the one set forth in a guidance document, as long as your alternative approach complies with the relevant statutes (laws) and regulations. If you wish, we will meet with you to discuss whether an alternative approach you are considering will satisfy the requirements of the act and regulations.

[75 FR 20915, Apr. 22, 2010, as amended at 87 FR 17950, Mar. 29, 2022]

§ 822.13 [Reserved]

§ 822.14 May I reference information previously submitted instead of submitting it again?

Yes, you may reference information that you have submitted in premarket submissions as well as other postmarket surveillance submissions. You must specify the information to be incorporated and the document number and pages where the information is located.

§ 822.15 How long must I conduct postmarket surveillance of my device?

The length of postmarket surveillance will depend on the postmarket surveillance question identified in our order. We may order prospective surveillance for a period up to 36 months; longer periods require your agreement. If we believe that a prospective period of greater than 36 months is necessary to address the surveillance question, and you do not agree, we will use the Medical Devices Dispute Resolution Panel to resolve the matter. You may obtain guidance regarding dispute resolution procedures from the Center for Devices and Radiological Health's (CDRH') Web site (http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHOmbudsman/default.htm.). The 36-month period refers to the surveillance period, not the length of time from the issuance of the order.

[72 FR 17400, Apr. 9, 2007, as amended at 78 FR 18233, Mar. 26, 2013]

§ 822.16 What will you consider in the review of my submission?

First, we will determine that the submission is administratively complete. Then, in accordance with the law, we must determine whether the designated person has appropriate qualifications and experience to conduct the surveillance and whether the surveillance plan will result in the collection of useful data that will answer the surveillance question.

§ 822.17 How long will your review of my submission take?

We will review your submission within 60 days of receipt.

§ 822.18 How will I be notified of your decision?

We will send you a letter notifying you of our decision and identifying any action you must take.

§ 822.19 What kinds of decisions may you make?

If your plan: | Then we will send you: | And you must:

(a) Should result in the collection of useful data that will address the postmarket surveillance question | An approval order, identifying any specific requirements related to your postmarket surveillance | Conduct postmarket surveillance of your device in accordance with the approved plan

(b) Should result in the collection of useful data that will address the postmarket surveillance question after specific revisions are made or specific information is provided | An approvable letter identifying the specific revisions or information that must be submitted before your plan can be approved | Revise your postmarket surveillance submission to address the concerns in the approvable letter and submit it to us within the specified timeframe. We will determine the timeframe case-by-case, based on the types of revisions or information that you must submit

(c) Does not meet the requirements specified in this part | A letter disapproving your plan and identifying the reasons for disapproval | Revise your postmarket surveillance submission and submit it to us within the specified timeframe. We will determine the timeframe case-by-case, based on the types of revisions or information that you must submit

(d) Is not likely to result in the collection of useful data that will address the postmarket surveillance question | A letter disapproving your plan and identifying the reasons for disapproval | Revise your postmarket surveillance submission and submit it to us within the specified timeframe. We will determine the timeframe case-by-case, based on the types of revisions or information that you must submit

§ 822.20 What are the consequences if I fail to submit a postmarket surveillance plan, my plan is disapproved and I fail to submit a new plan, or I fail to conduct surveillance in accordance with my approved plan?

The failure to have an approved postmarket surveillance plan or failure to conduct postmarket surveillance in accordance with the approved plan constitutes failure to comply with section 522 of the act. Your failure would be a prohibited act under section 301(q)(1)(C) of the act, and your device would be misbranded under section 502(t)(3) of the act. We have the authority to initiate actions against products that are adulterated or misbranded, and against persons who commit prohibited acts. Adulterated or misbranded devices can be seized. Persons who commit prohibited acts can be enjoined from committing such acts, required to pay civil money penalties, or prosecuted.

§ 822.21 What must I do if I want to make changes to my postmarket surveillance plan after you have approved it?

You must receive our approval in writing before making changes in your plan that will affect the nature or validity of the data collected in accordance with the plan. To obtain our approval, you must submit the request to make the proposed change and revised postmarket surveillance plan to the applicable address listed in § 822.8. You may reference information already submitted in accordance with § 822.14. In your cover letter, you must identify your submission as a supplement and cite the unique document number that we assigned in our acknowledgment letter for your original submission, specifically identify the changes to the plan, and identify the reasons and justification for making the changes. You must report changes in your plan that will not affect the nature or validity of the data collected in accordance with the plan in the next interim report required by your approval order.

[87 FR 17950, Mar. 29, 2022]

§ 822.22 What recourse do I have if I do not agree with your decision?

(a) If you disagree with us about the content of your plan or if we disapprove your plan, or if you believe there is a less burdensome approach that will answer the surveillance question, you may request review of our decision by:

(1) Requesting a meeting with the individual who issued the order for postmarket surveillance;

(2) Seeking internal review of the order under § 10.75 of this chapter;

(3) Requesting an informal hearing under part 16 of this chapter; or

(4) Requesting review by the Medical Devices Dispute Resolution Panel of the Medical Devices Advisory Committee.

(b) You may obtain guidance documents that discuss these mechanisms from the Center for Devices and Radiological Health's (CDRH's) Web site.

[67 FR 38887, June 6, 2002, as amended at 72 FR 17400, Apr. 9, 2007; 85 FR 18443, Apr. 2, 2020]

§ 822.23 Is the information in my submission considered confidential?

We consider the content of your submission confidential until we have approved your postmarket surveillance plan. After we have approved your plan, the contents of the original submission and any amendments, supplements, or reports may be disclosed in accordance with the Freedom of Information Act. We will continue to protect trade secret and confidential commercial information after your plan is approved. We will not disclose information identifying individual patients. You may wish to indicate in your submission which information you consider trade secret or confidential commercial.

§ 822.24 What are my responsibilities once I am notified that I am required to conduct postmarket surveillance?

You must submit your plan to conduct postmarket surveillance to us within 30 days from receipt of the order (letter) notifying you that you are required to conduct postmarket surveillance of a device. The manufacturer shall commence surveillance not later than 15 months after the day the order was issued.

[88 FR 16880, Mar. 21, 2023]

§ 822.25 What are my responsibilities after my postmarket surveillance plan has been approved?

After we have approved your plan, you must conduct the postmarket surveillance of your device in accordance with your approved plan. This means that you must ensure that:

(a) Postmarket surveillance is initiated in a timely manner;

(b) The surveillance is conducted with due diligence;

(c) The data identified in the plan is collected;

(d) Any reports required as part of your approved plan are submitted to us in a timely manner; and

(e) Any information that we request prior to your submission of a report or in response to our review of a report is provided in a timely manner.

§ 822.26 If my company changes ownership, what must I do?

You must notify us within 30 days of any change in ownership of your company. Your notification should identify any changes to the name or address of the company, the contact person, or the designated person (as defined in § 822.3(b)). Your obligation to conduct postmarket surveillance will generally transfer to the new owner, unless you and the new owner have both agreed that you will continue to conduct the surveillance. If you will continue to conduct the postmarket surveillance, you still must notify us of the change in ownership.

§ 822.27 If I go out of business, what must I do?

You must notify us within 30 days of the date of your decision to close your business. You should provide the expected date of closure and discuss your plans to complete or terminate postmarket surveillance of your device. You must also identify who will retain the records related to the surveillance (described in subpart G of this part) and where the records will be kept.

§ 822.28 If I stop marketing the device subject to postmarket surveillance, what must I do?

You must continue to conduct postmarket surveillance in accordance with your approved plan even if you no longer market the device. You may request that we allow you to terminate postmarket surveillance or modify your postmarket surveillance because you no longer market the device. We will make these decisions on a case-by-case basis, and you must continue to conduct the postmarket surveillance unless we notify you that you may stop your surveillance study.

§ 822.29 May I request a waiver of a specific requirement of this part?

You may request that we waive any specific requirement of this part. You may submit your request, with supporting documentation, separately or as a part of your postmarket surveillance submission to the address in § 822.8.

§ 822.30 May I request exemption from the requirement to conduct postmarket surveillance?

You may request exemption from the requirement to conduct postmarket surveillance for your device or any specific model of that device at any time. You must comply with the requirements of this part unless and until we grant an exemption for your device. Your request for exemption must explain why you believe we should exempt the device or model from postmarket surveillance. You should demonstrate why the surveillance question does not apply to your device or does not need to be answered for the device for which you are requesting exemption. Alternatively, you may provide information that answers the surveillance question for your device, with supporting documentation, to the address in § 822.8.

§ 822.31 What records am I required to keep?

You must keep copies of:

(a) All correspondence with your investigators or FDA, including required reports;

(b) Signed agreements from each of your investigators, if your surveillance plan uses investigators, stating the commitment to conduct the surveillance in accordance with the approved plan, any applicable FDA regulations, and any conditions of approval for your plan, such as reporting requirements;

(c) Your approved postmarket surveillance plan, with documentation of the date and reason for any deviation from the plan;

(d) All data collected and analyses conducted in support of your postmarket surveillance plan; and

(e) Any other records that we require to be maintained by regulation or by order, such as copies of signed consent documents, evidence of Institutional Review Board review and approval, etc.

§ 822.32 What records are the investigators in my surveillance plan required to keep?

Your investigator must keep copies of:

(a) All correspondence between investigators, FDA, the manufacturer, and the designated person, including required reports.

(b) The approved postmarket surveillance plan, with documentation of the date and reason for any deviation from the plan.

(c) All data collected and analyses conducted at that site for postmarket surveillance.

(d) Any other records that we require to be maintained by regulation or by order.

§ 822.33 How long must we keep the records?

You, the designated person, and your investigators must keep all records for a period of 2 years after we have accepted your final report, unless we specify otherwise.

§ 822.34 What must I do with the records if the sponsor of the plan or an investigator in the plan changes?

If the sponsor of the plan or an investigator in the plan changes, you must ensure that all records related to the postmarket surveillance have been transferred to the new sponsor or investigator and notify us within 10 working days of the effective date of the change. You must provide the name, address, and telephone number of the new sponsor or investigator, certify that all records have been transferred, and provide the date of transfer.

§ 822.35 Can you inspect my manufacturing site or other sites involved in my postmarket surveillance plan?

We can review your postmarket surveillance programs during regularly scheduled inspections, inspections initiated to investigate recalls or other similar actions, and inspections initiated specifically to review your postmarket surveillance plan. We may also inspect any other person or site involved in your postmarket surveillance, such as investigators or contractors. Any person authorized to grant access to a facility must permit authorized FDA employees to enter and inspect any facility where the device is held or where records regarding postmarket surveillance are held.

§ 822.36 Can you inspect and copy the records related to my postmarket surveillance plan?

We may, at a reasonable time and in a reasonable manner, inspect and copy any records pertaining to the conduct of postmarket surveillance that are required to be kept by this regulation. You must be able to produce records and information required by this regulation that are in the possession of others under contract with you to conduct the postmarket surveillance. Those who have signed agreements or are under contract with you must also produce the records and information upon our request. This information must be produced within 72 hours of the initiation of the inspection. We generally will redact information pertaining to individual subjects prior to copying those records, unless there are extenuating circumstances.

§ 822.37 Under what circumstances would you inspect records identifying subjects?

We can inspect and copy records identifying subjects under the same circumstances that we can inspect any records relating to postmarket surveillance. We are likely to be interested in such records if we have reason to believe that required reports have not been submitted, or are incomplete, inaccurate, false, or misleading.

§ 822.38 What reports must I submit to you?

You must submit interim and final reports as specified in your approved postmarket surveillance plan. In addition, we may ask you to submit additional information when we believe that the information is necessary for the protection of the public health and implementation of the act. We will also state the reason or purpose for the request and how we will use the information.

§ 830.3 Definitions.

As used in this part:

Automatic identification and data capture (AIDC) means any technology that conveys the unique device identifier or the device identifier of a device in a form that can be entered into an electronic patient record or other computer system via an automated process.

Center Director means the Director of the Center for Devices and Radiological Health or the Director of the Center for Biologics Evaluation and Research, depending on which Center has been assigned lead responsibility for the device.

Device package means a package that contains a fixed quantity of a particular version or model of a device.

Expiration date means the date by which the label of a device states the device must or should be used.

FDA, we, or us means the Food and Drug Administration.

Federal Food, Drug, and Cosmetic Act means 21 U.S.C. 321 et seq., as amended.

Finished device means any device or accessory to any device that is suitable for use or capable of functioning.

Global Unique Device Identification Database (GUDID) means the database that serves as a repository of information to facilitate the identification of medical devices through their distribution and use.

Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in § 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.

Issuing agency means an organization accredited by FDA to operate a system for the issuance of unique device identifiers.

Label has the meaning set forth in section 201(k) of the Federal Food, Drug, and Cosmetic Act.

Labeler means:

(1) Any person who causes a label to be applied to a device with the intent that the device will be commercially distributed without any subsequent replacement or modification of the label; and

(2) Any person who causes the label of a device to be replaced or modified with the intent that the device will be commercially distributed without any subsequent replacement or modification of the label, except that the addition of the name of, and contact information for, a person who distributes the device, without making any other changes to the label, is not a modification for the purposes of determining whether a person is a labeler.

Lot or batch means one finished device or more that consist of a single type, model, class, size, composition, or software version that are manufactured under essentially the same conditions and that are intended to have uniform characteristics and quality within specified limits.

Shipping container means a container used during the shipment or transportation of devices, and whose contents may vary from one shipment to another.

Small business means a medical device manufacturer with 500 or fewer employees, or a medical device relabeler or repackager with 100 or fewer employees.

Specification means any requirement with which a device must conform.

Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and use by meeting the requirements of § 830.20. A UDI is composed of:

(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and the labeler of that device; and

(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when included on the label of the device:

(i) The lot or batch within which a device was manufactured;

(ii) The serial number of a specific device;

(iii) The expiration date of a specific device;

(iv) The date a specific device was manufactured.

(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.

Universal product code (UPC) means the product identifier used to identify an item sold at retail in the United States.

Version or model means all devices that have specifications, performance, size, and composition, within limits set by the labeler.

§ 830.10 Incorporation by reference.

(a) Certain material is incorporated by reference into this part with the approval of the Director of the Federal Register in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. To enforce any edition other than that specified in this section, the Food and Drug Administration must publish notice of change in the Federal Register and the material must be available to the public. All approved material is available for inspection at the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, 301-827-6860, and is available from the source listed in paragraph (b) of this section. Copies are also available for purchase from the American National Standards Institute (ANSI), mailing address: ANSI, Attn: Customer Service Department, 25 West 43rd St., 4th floor, New York, NY 10036, phone: 212-642-4980, and may be ordered online at http://webstore.ansi.org/. The material is also available for inspection at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030 or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

(b) International Organization for Standardization (ISO), mailing address: ISO, Attn: ISO Central Secretariat, 1, ch. de la Voie-Creuse, Case postale 56, CH-1211 Geneva 20, Switzerland, phone (dialing from the United States): 011-41-22-749-0111, and may be ordered online at http://www.standardsinfo.net.

(1) ISO/IEC 646:1991(E), Information technology—ISO 7-bit coded character set for information interchange (third edition; December 15, 1991), into §§ 830.20(c) and 830.100(b);

(2) ISO/IEC 15459-2:2006(E), Information technology—Unique identifiers—Part 2: Registration procedures (second edition; March 1, 2006), into §§ 830.20(b) and 830.100(b);

(3) ISO/IEC 15459-4:2008(E), Information technology—Unique identifiers—Part 4: Individual items (second edition; July 15, 2008), into §§ 830.20(b) and 830.100(b);

(4) ISO/IEC 15459-6:2007(E), Information technology—Unique identifiers—Part 6: Unique identifier for product groupings (first edition; June 15, 2007), into §§ 830.20(b) and 830.100(b).

[78 FR 58823, Sept. 24, 2013, as amended at 88 FR 45067, July 14, 2023]

§ 830.20 Requirements for a unique device identifier.

A unique device identifier (UDI) must:

(a) Be issued under a system operated by FDA or an FDA-accredited issuing agency;

(b) Conform to each of the following international standards:

(1) ISO/IEC 15459-2, which is incorporated by reference at § 830.10;

(2) ISO/IEC 15459-4, which is incorporated by reference at § 830.10; and

(3) ISO/IEC 15459-6, which is incorporated by reference at § 830.10.

(c) Use only characters and numbers from the invariant character set of ISO/IEC 646, which is incorporated by reference at § 830.10.

[78 FR 58825, Sept. 24, 2013]

§ 830.40 Use and discontinuation of a device identifier.

(a) Only one device identifier from any particular system for the issuance of unique device identifiers (UDIs) may be used to identify a particular version or model of a device. A particular version or model may be identified by UDIs from two or more systems for the issuance of UDIs.

(b) A device identifier shall be used to identify only one version or model.

(c) In the event that a version or model of a device is discontinued, its device identifier may not be reassigned to another device. If a discontinued version or model is re-introduced and no changes have been made that would require the use of a new device identifier, the device identifier that was previously in use may be used to identify the device.

(d) In the event that an issuing agency relinquishes or does not renew its accreditation, you may continue to use a previously issued UDI until such time as § 830.50 requires you to assign a new device identifier.

[78 FR 58825, Sept. 24, 2013]

§ 830.50 Changes that require use of a new device identifier.

(a) Whenever you make a change to a device that is required to bear a unique device identifier (UDI) on its label, and the change results in a new version or model, you must assign a new device identifier to the new version or model.

(b) Whenever you create a new device package, you must assign a new device identifier to the new device package.

[78 FR 58825, Sept. 24, 2013]

§ 830.60 Relabeling of a device that is required to bear a unique device identifier.

If you relabel a device that is required to bear a unique device identifier (UDI), you must:

(a) Assign a new device identifier to the device, and

(b) Keep a record showing the relationship of the prior device identifier to your new device identifier.

[78 FR 58825, Sept. 24, 2013]

§ 830.100 FDA accreditation of an issuing agency.

(a) Eligibility. A private organization may apply for accreditation as an issuing agency.

(b) Accreditation criteria. FDA may accredit an organization as an issuing agency, if the system it will operate:

(1) Will employ unique device identifiers (UDIs) that meet the requirements of this part to adequately identify a device through its distribution and use;

(2) Conforms to each of the following international standards:

(i) ISO/IEC 15459-2, which is incorporated by reference at § 830.10;

(ii) ISO/IEC 15459-4, which is incorporated by reference at § 830.10;

(iii) ISO/IEC 15459-6, which is incorporated by reference at § 830.10.

(3) Uses only characters and numbers from the invariant character set of ISO/IEC 646, which is incorporated by reference at § 830.10.

(4) Will be available to all users according to a single set of consistent, fair, and reasonable terms and conditions.

(5) Will protect against conflicts of interest between the issuing agency (and its officers, employees, and other agents) and labelers (and their officers, employees, and other agents) seeking to use UDIs that may impede the applicant's ability to independently operate a fair and neutral identifier system.

§ 830.110 Application for accreditation as an issuing agency.

(a) Application for initial accreditation. (1) An applicant seeking initial FDA accreditation as an issuing agency shall notify FDA of its desire to be accredited by sending a notification by email to: GUDIDSupport@fda.hhs.gov, or by correspondence to: UDI Regulatory Policy Support, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 3293, Silver Spring, MD 20993-0002.

(2) FDA will provide the applicant with additional information to aid in submission of an application for approval as an issuing agency, together with an email address for submission of an application.

(3) The applicant shall furnish to FDA, via email to the email address provided in paragraph (a)(1) of this section, an application containing the following information, materials, and supporting documentation:

(i) Name, address, and phone number of the applicant;

(ii) Detailed descriptions of any standards or criteria the applicant will apply to participating labelers;

(iii) A detailed description of the guidelines that govern assignment of a unique device identifier (UDI) to a device;

(iv) A detailed description of the review and decisionmaking process the applicant will apply when determining whether a particular labeler may use the applicant's UDI system, including:

(A) Copies of the application forms, guidelines, instructions, and other materials the applicant will send to medical device labelers who wish to use the applicant's unique device identification system;

(B) Policies and procedures for notifying a labeler of deficiencies in its use of UDIs;

(C) Procedures for monitoring a labeler's correction of deficiencies in its use of UDIs;

(D) Policies and procedures for suspending or revoking a labeler's use of the applicant's UDI system, including any appeals process.

(v) Description of the applicant's electronic data management system with respect to its review and decision processes and the applicant's ability to provide electronic data in a format compatible with FDA data systems;

(vi) Fee schedules, if any, together with an explanation of any fee waivers or reductions that are available;

(vii) Detailed information regarding any financial or other relationship between the applicant and any labeler(s) or governmental entity(ies); and

(viii) Other information required by FDA to clarify the application for accreditation.

(b) Application for renewal of accreditation. An accredited issuing agency that intends to continue to serve as an issuing agency beyond its current term shall apply to FDA for renewal or notify FDA of its plans not to apply for renewal in accordance with the following procedures and schedule:

(1) At least 9 months before the date of expiration of its accreditation, an issuing agency shall inform FDA, at the address given in paragraph (a)(1) of this section, of its intent to seek renewal.

(2) FDA will notify the issuing agency of the relevant information, materials, and supporting documentation that we will require the issuing agency to submit as part of the renewal procedure. We will tailor these requirements to reflect our experience with the issuing agency during the current and any prior period of accreditation. We will limit our request to the types of the information required by paragraph (a)(3) of this section, and we will require less information if experience shows that we need only a subset of that information.

(3) At least 6 months before the date of expiration of its accreditation, an issuing agency shall furnish to FDA, at the email address we provide, a copy of a renewal application containing the information, materials, and supporting documentation requested by FDA in accordance with paragraph (b)(2) of this section.

(4) Any issuing agency that does not plan to renew its accreditation shall so notify FDA at the address given in paragraph (a)(1) of this section at least 9 months before the expiration of the issuing agency's term of accreditation and shall include a description of its plans for allowing continued use of UDIs issued prior to the expiration of the current term of accreditation.

(c) FDA action on an application for initial or renewal accreditation. (1) FDA will conduct a review and evaluation to determine whether the applicant meets the requirements of this subpart and whether the UDI system proposed by the applicant will meet the requirements of this subpart.

(2) Within 60 days of receipt of an application for accreditation, FDA will notify the applicant of any deficiencies in its application and will request correction of those deficiencies within 60 days. The applicant may request an extension if it needs additional time to correct deficiencies in its application. If the deficiencies are not resolved to FDA's satisfaction within the specified time period, the application for accreditation as an issuing agency may be denied.

(3) FDA shall notify the applicant whether the application for accreditation has been granted or denied. That notification shall list any conditions of approval or state the reasons for denial.

(4) If FDA denies an application, we will advise the applicant of the circumstances under which a denied application may be resubmitted.

(5) If FDA does not reach a final decision on a renewal application before the expiration of an issuing agency's current accreditation, the approval will be deemed extended until FDA reaches a final decision on the application.

(d) Relinquishment of accreditation. If an issuing agency decides to relinquish its accreditation before expiration of the current term of accreditation, it shall submit a letter of such intent to FDA, at the address provided in paragraph (a)(1) of this section, at least 9 months before relinquishing its accreditation.

(e) Notice of termination of accreditation. An issuing agency that does not apply for renewal of its accreditation, is denied renewal of accreditation by FDA, or relinquishes its accreditation and duties before expiration of the current term of accreditation, shall notify all labelers that are using the issuing agency's UDI system, in a manner and time period approved by FDA, of the date that the issuing agency will cease to serve as an FDA-accredited issuing agency.

(f) Term of accreditation. The initial term of accreditation for an issuing agency shall be for a period of 3 years. An issuing agency's term of accreditation may be periodically renewed for a period of 7 years.

[78 FR 58825, Sept. 24, 2013, as amended at 81 FR 11429, Mar. 4, 2016; 85 FR 18443, Apr. 2, 2020]

§ 830.120 Responsibilities of an FDA-accredited issuing agency.

To maintain its accreditation, an issuing agency must:

(a) Operate a system for assignment of unique device identifiers (UDIs) that meets the requirements of § 830.20;

(b) Make available information concerning its system for the assignment of UDIs;

(c) Maintain a list of labelers that use its system for the assignment of UDIs and provide FDA a copy of such list in electronic form by December 31 of each year;

(d) Upon request, provide FDA with information concerning a labeler that is employing the issuing agency's system for assignment of UDIs; and

(e) Remain in compliance with the eligibility and accreditation criteria set forth in § 830.100.

§ 830.130 Suspension or revocation of the accreditation of an issuing agency.

FDA may suspend or revoke the accreditation of an issuing agency if FDA finds, after providing the issuing agency with notice and opportunity for an informal hearing in accordance with part 16 of this chapter, that the issuing agency or any officer, employee, or other agent of the issuing agency:

(a) Has been guilty of misrepresentation or failure to disclose required information in obtaining accreditation;

(b) Has failed to fulfill the responsibilities outlined in § 830.120;

(c) Has failed to protect against conflicts of interest that may impede the issuing agency's ability to independently operate a fair and neutral identifier system;

(d) In the operation of the issuing agency, has engaged in any anticompetitive activity to restrain trade; or

(e) Has violated or aided and abetted in the violation of any regulation issued under section 510(e) or section 519(f) of the Federal Food, Drug, and Cosmetic Act.

§ 830.200 When FDA will act as an issuing agency.

(a) During any period where there is no accredited issuing agency, FDA will act as an issuing agency.

(b) If FDA determines that a significant number of small businesses would be substantially and adversely affected by the fees required by all accredited issuing agencies, FDA will act as an issuing agency.

(c) FDA may, in its discretion, act as an issuing agency if we determine it is necessary for us to do so to ensure the continuity or the effectiveness of the system for the identification of medical devices.

(d) FDA may, in its discretion, act as an issuing agency if we determine it is appropriate for us to do so in order to facilitate or implement an alternative granted under § 801.55 of this chapter.

§ 830.210 Eligibility for use of FDA as an issuing agency.

When FDA acts as an issuing agency, any labeler will be permitted to use FDA's unique device identification system, regardless of whether the labeler is considered a small business.

§ 830.220 Termination of FDA service as an issuing agency.

(a) FDA may end our services as an issuing agency if we determine that the conditions that prompted us to act no longer exist and that ending our services would not be likely to lead to a return of the conditions that prompted us to act.

(b) If FDA has ended our services as an issuing agency, a labeler may continue to use a device identifier assigned under FDA's unique device identification system until such time as § 830.50 requires the use of a new device identifier.

§ 830.300 Devices subject to device identification data submission requirements.

(a) In general. The labeler of a device must provide the information required by this subpart for each version or model required to bear a unique device identifier (UDI).

(b) Voluntary submission of information. If a labeler voluntarily includes a UDI on the label of a device under § 801.40, the labeler may also voluntarily submit information concerning that device under this part.

(c) Exclusions. FDA may reject or remove any device identification data where:

(1) The device identifier submitted does not conform to § 830.20;

(2) The information concerns a device that is neither manufactured in the United States nor in interstate commerce in the United States,

(3) The information concerns a product that FDA determines is not a device or a combination product that includes a device constituent part,

(4) The information concerns a device or a combination product that requires, but does not have, FDA premarket approval, licensure, or clearance;

(5) A device that FDA has banned under section 516 of the Federal Food, Drug, and Cosmetic Act; or

(6) FDA has suspended the accreditation of the issuing agency that operates the system used by the labeler.

§ 830.310 Information required for unique device identification.

The contact for device identification designated under § 830.320(a) shall provide FDA with the following information concerning each version or model of a device required to bear a unique device identifier (UDI) on its label:

(a) Concerning the labeler:

(1) The name of the labeler;

(2) A telephone number or email address that will allow FDA to communicate with the contact for device identification designated under § 830.320(a); and

(3) The name of each issuing agency whose system is used by the labeler to assign UDIs used by the labeler.

(b) Concerning each version or model of a device with a UDI on its label:

(1) The device identifier portion of the UDI assigned to the version or model;

(2) When reporting a substitution of a new device identifier that will be used in lieu of a previously reported identifier, the device identifier that was previously assigned to the version or model;

(3) If § 801.45 of this chapter requires the device to bear a UDI as a permanent marking on the device itself, either:

(i) A statement that the device identifier that appears as a permanent marking on the device is identical to that reported under paragraph (b)(1) of this section, or

(ii) The device identifier portion of the UDI that appears as a permanent marking on the device;

(4) The proprietary, trade, or brand name of the device as it appears on the label of the device;

(5) Any version or model number or similar reference that appears on the label of the device;

(6) If the device is labeled as sterile, a statement to that effect;

(7) If the device is labeled as containing natural rubber latex that contacts humans, or is labeled as having packaging containing natural rubber latex that contacts humans, as described by §§ 801.437(b)(1), 801.437(b)(3), and 801.437(f) of this chapter, a statement to that effect;

(8) Whether a patient may be safely exposed to magnetic resonance imaging, nuclear magnetic resonance imaging, or magnetic resonance tomography while using the device, or while the device is implanted in patient.

(9) If the device is available in more than one size, the size of the particular version or model, together with the unit of measure, as it appears on the label of the device;

(10) The type of production identifiers that appear on the label of the device;

(11) The FDA premarket submission number of a cleared or approved device, or a statement that FDA has by regulation exempted the device from premarket notification;

(12) The FDA listing number assigned to the device;

(13) The Global Medical Device Nomenclature (GMDN) term or code for the device;

(14) The total number of individual devices contained in the device package.

§ 830.320 Submission of unique device identification information.

(a) Designation of contact for device identification. Each labeler must designate an individual to serve as the point of contact with FDA on matters relating to the identification of medical devices marketed by the labeler. The contact for device information is responsible for ensuring FDA is provided with all information required by this part. The contact for device information may authorize an issuing agency or any other person to provide information to FDA on behalf of the labeler.

(b) Information shall be submitted via electronic means. All information required by this subpart shall be submitted electronically to FDA's Global Unique Device Identification Database (GUDID) in a format that we can process, review, and archive, unless the labeler has obtained a waiver from electronic submission of unique device identifier (UDI) data.

(c) Waiver from electronic submission. (1) A labeler may request a waiver from electronic submission of UDI data by submitting a letter addressed to the appropriate Center Director explaining why electronic submission is not technologically feasible; send the request by email to: udi@fda.hhs.gov, or by correspondence to: UDI Regulatory Policy Support, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 3293, Silver Spring, MD 20993-0002.

(2) If the establishment where the labeler is located has obtained a waiver from electronic submission of registration and listing information under section 510(p) of the Federal Food, Drug, and Cosmetic Act, the labeler is deemed to have a waiver from electronic submission of UDI data.

(3) A labeler that has a waiver from electronic submission of UDI data must send a letter containing all of the information required by § 830.310, as well as any ancillary information permitted to be submitted under § 830.340 that the labeler wishes to submit, within the time permitted by § 830.330, addressed to: UDI Regulatory Policy Support, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm. 3293, Silver Spring, MD 20993-0002.

[78 FR 58826, Sept. 24, 2013, as amended at 85 FR 18443, Apr. 2, 2020]

§ 830.330 Times for submission of unique device identification information.

(a) The labeler shall submit to FDA the information required by § 830.310 no later than the date the label of the device must bear a unique device identifier under § 801.20 of this chapter.

(b) The labeler of a device shall submit to FDA an update to the information required by § 830.310 whenever the information changes. The updated information must be submitted no later than the date a device is first labeled with the changed information. If the information does not appear on the label of a device, the updated information must be submitted within 10 business days of the change.

§ 830.340 Voluntary submission of ancillary device identification information.