of a building, or in quarters at the blind end of a corridor and shall include adequate space and equipment for all processing steps up to filling into final containers. Test procedures which potentially involve the presence of microorganisms other than the vaccine strains, or the use of tissue culture cell lines other than primary cultures, shall not be conducted in space used for processing live vaccine.

(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 pyrogenfree.

(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, Bureau of Biologics.

(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 (1) 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.

After

(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. 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.

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, Bureau of Biologics, 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, Bureau of Biologics, 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.

§ 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 (Human), Antihemophilic Plasma (Human), Cryoprecipitated Antihemophilic Factor (Human), Platelet Concentrate (Human) Red Blood Cells (Human), Single Donor Plasma (Human), Source Plasma (Human), Normal Human Plasma and

Product:

SO

re

Allergenic Products prepared to physician's prescription. Samples tained 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 packageequivalent 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 Bureau of Biologics. Exceptions may be authorized by the Director, Bureau of Biologics, 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.

[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 4304, Jan. 29, 1975]

§ 600.14 Reporting of errors.

The Director, Bureau of Biologics, shall be notified promptly of errors or accidents in the manufacture of products that may affect the safety, purity, or potency of any product.

§ 600.15 Temperatures during shipment.

The following products shall be maintained during shipment at the specified temperatures: (a) Products.

Temperature

-18° C or colder. 10° C or colder.

Do.

Do.

Do.

Do.

Between 20° and 24° C if suspended in 30 to 50 milliliters of plasma, or between 1° and 10° C if suspended in 20 to 30 milliliters of plasma. 0° C or colder.

Do.

Do.

Do.

-65° C or colder.

Between 1° and 10° C.

10° C or colder. Do.

-18° C or colder. 0° C or colder.

-5° C or colder.

Between 1° and 10° C.

0° C or colder.

(b) Exemptions. Exemptions or modifications shall be made only upon written approval, in the form of an amendment of the product license, issued by the Director, Bureau of Biologics.

139 FR 39872, Nov. 11, 1974, as amended at 40 FR 4304, Jan. 29, 1975]

Subpart C-Establishment Inspection § 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, Education, and Welfare specifically designated for such purpose by the Secretary. § 600.21 Time of inspection.

The inspection of an establishment for which a license is pending need not be made until the establishment is in operation and is manufacturing the complete product for which a product license is desired. In case the license is denied following inspection for the original 11cense, no reinspection need be made until assurance has been received that the faulty conditions which were the basis of the denial have been corrected. An inspection of each licensed establishment shall be made at least once each year. Inspections may be made with or without notice, and shall be made during regular business hours unless otherwise directed.

(b) Interrogate the proprietor or other personnel of the establishment as he may deem necessary,

(c) Examine the details of location, construction, equipment and maintenance, including stables, barns, warehouses, manufacturing laboratories. bleeding clinics maintained for the collection of human blood, shipping rooms. record rooms, and any other structure or appliance used in any part of the manufacture of a product,

(d) Investigate as fully as he deems necessary the methods of propagation, processing, testing, storing, dispensing. recording, or other details of manufac

ture and distribution of each licensed product, or product for which a license has been requested, including observation of these procedures in actual operation,

(e) Obtain and cause to be sent to the Director, Bureau of Biologics, adequate samples for the examination of any product or ingredient used in its manufacture,

(f) Bring to the attention of the manufacturer any fault observed in the course of inspection in location, construction, manufacturing methods, or administration of a licensed establishment which might lead to impairment of a product,

(g) Inspect and copy, as circumstances may require, any records required to be kept pursuant to § 600.12.

(h) Certify as to the condition of the establishment and of the manufacturing methods followed and make recommendations as to action deemed appropriate with respect to any application for license or any license previously issued.

Changes to be reported.

Subpart B-Establishment Licensing 601.10 Establishment licenses; issuance and conditions.

601.11 Registration of blood banks and other firms collecting, manufacturing, preparing, or processing human blood or blood products.

Subpart C-Product Licensing

601.20 Product licenses; issuance and conditions.

AUTHORITY: Sec. 215, 58 Stat. 690, as amended; 42 U.S.C. 216. Sec. 351, 58 Stat. 702, as amended; 42 U.S.C. 262, unless otherwise noted.

SOURCE: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.

CROSS REFERENCES: For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see 39 CFR Parts 124 and 125, esp. § 125.2. Subpart A-General Provisions

§ 601.1

Two forms of licenses.

There shall be two forms of licenses establishment and product.

§ 601.2 Application for establishment and product licenses: procedure for filing.

To obtain a license for any establishment or product, the manufacturer shall make application to the Director, Bureau of Biologics, on forms prescribed for such purpose, and in the case of an application for a product license, shall submit data derived from laboratory and clinical studies which demonstrate that the manufactured product meets prescribed standards of safety, purity and potency. a full description of manufacturing methods, data establishing stability of the product through the dating period, sample(s) representative of the product to be sold, bartered or exchanged or offered, sent, carried or brought for sale. barter or exchange, summaries of results of tests performed on the lot(s) represented by the submitted sample(s), and specimens of the labels enclosures and containers proposed to be used for the product. An application for license shall not be considered as filed until all pertinent information and data shall have been received from the manufacturer by the Bureau of Biologics.

§ 601.3 License forms.

(a) Establishment license. The establishment license form shall be prescribed by the Commissioner of Food and Drugs and shall include:

(1) The name and address of the manufacturer.

(2) The name and address of the establishment.

(3) The names and addresses of all locations of the establishment.

(4) The license number.

(5) The date of issuance.

(b) Product license. The product 11cense form shall be prescribed by the Commissioner of Food and Drugs and shall include:

(1) The name and address of the manufacturer.

(2) The name and address of the establishment.

(3) The name and address of each loIcation at which the product is manufactured.

(4) The license number of the establishment.

(5) The proper name of the product, with additional specifications, if any. which may be approved or required for additional labeling purposes.

A license shall be issued by the Secretary upon the recommendation of the Commissioner of Food and Drugs and upon the determination by the Commissioner of Food and Drugs that the establishment or the product, as the case may be, meets the standards established by the regulations in this subchapter as herein prescribed or hereafter amended. Licenses shall be valid until suspended or revoked. An establishment or product license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products or of intention to discontinue the manufacture of a particular product for which a license is held. The Commissioner of Food and Drugs shall recommend to the Secretary that a license be suspended or revoked whenever he finds, after notice and opportunity for hearing, that (a) Food and Drug Administration inspectors 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, or that (b) manufacturing