into any State or possession of the United States and shall specify that it is issued upon the condition that the licensee will permit the inspection during all reasonable hours of the establishment by any officer, agent, or employee of the Department of Health, Education, and Welfare authorized by the Secretary of the Department of Health, Education, and Welfare for such purpose.

§ 73.23 Samples for each importation.

Random samples of each importation, obtained by the Collector of Customs and forwarded to the Director, Division of Biologics Standards, shall be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment shall accompany the shipment for forwarding with the samples to the Director, Division of Biologics Standards. For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Division of Biologics Standards accompanies each shipment. [33 F.R. 367, Jan. 10, 1968]

ESTABLISHMENT INSPECTION

SOURCE: §§ 73.30 to 73.32 appear at 25 F.R. 3400, Apr. 20, 1960, unless otherwise noted. § 73.30 Inspectors.

Inspections shall be made by an officer of the Public Health Service having special knowledge of the methods used in the manufacture and control of products and designated for such purpose by the Surgeon General or by any officer, agent, or employee of the Department of Health, Education, and Welfare specifically designated for such purpose by the Secretary.

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 license, 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.

§ 73.32

Duties of inspector. The inspector shall:

(a) Call upon the active head of the establishment, stating the object of his visit,

(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 manufacture 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, Division of Biologics Standards, 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 § 73.37,

(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.

[25 F.R. 3400, Apr. 20, 1960, as amended at 26 F.R. 5755 June 28, 1961; 29 F.R. 13387, Sept. 26, 1964]

with authority to enforce or to direct the enforcement of discipline and the performance of assigned functions by employees engaged in the manufacture of products. The responsible head shall have an understanding of the scientific principles and the techniques involved in the manufacture of products. The responsible head shall have the responsibility for the training of employees in manufacturing methods and for their being informed concerning the application of the pertinent provisions of this part to their respective functions.

(b) Other 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 part to their respective functions. Personnel shall include such professionally trained persons as are necessary to insure the competent performance of all manufacturing processes.

on

personnel (1)

(c) Restrictions 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 sporebearing organisms. Persons working with viruses pathogenic for man or with spore-bearing 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 busi

ness 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. [26 F.R. 5752, June 28, 1961]

73.36 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 twenty minutes by saturated steam or by an attained temperature of 170°C. maintained for two 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, in

spection for cleanliness. All surfaces that come in contact with products shall be clean and free of extraneous material. 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 clincial 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-bearing pathogenic microorganisms are not involved and provided the space is thoroughly cleaned and disinfected before the manufacture of products is resumed.

(2) Spore-bearing organisms for supplemental sterilization procedure control test. Spore-bearing organisms used as an additional control in sterilization procedures may be introduced into areas used for the manufatcure of products, only for the purposes of the test and only immediately before use for such purposes: Provided, That (1) the organism is not pathogenic for man and does not produce pyrogens or toxins, (ii) the organism does not grow at or below 37° C. within a two-week period, (iii) the culture is demonstrated to be pure, (iv) test cultures are not transferred to culture media in areas used for the manufacture

of products, (v) each culture be labeled with the name of the microorganism and the statement "Caution: microbial spores. See directions for storage, use and disposition", and (vi) the container of each such culture is designed to withstand handling without breaking.

(3) Work with spore-bearing organisms. Except as provided in the previous paragraph, all work with spore-bearing microorganisms shall be done in an entirely separate building: Provided, That such work may be done in a portion of a building used in the manufacture of products not containing spore-bearing microorganisms if such portion is completely walled-off and is constructed so as to prevent contamination of other areas and if entrances to such portion are independent of the remainder of the building. All vessels, apparatus and equipment used for spore-bearing microorganisms shall be permanently identifled and reserved exclusively for use with those organisms. Materials destined for further manufacturing may be removed from such an area only under conditions which will prevent the introduction of spores into other manufacturing areas.

(4) Live vaccine processing. Space used for processing a live vaccine shall not be used for any other purpose during the processing period for that vaccine and such space shall be decontaminated prior to initiation of the processing. Live vaccine processing areas shall be isolated from and independent of any space used for any other purpose by being either in a separate building, in a separate wing 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 part. 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) Smallpox vaccine production animals. Animals used for the manufacture of smallpox vaccine shall be thoroughly cleaned with soap and water at the beginning of the quarantine and at its conclusion. The animals shall not be vaccinated in areas most likely to be contaminated with feces.

(6) Reporting of certain diseases. In cases of actual or suspected infection with foot and mouth disease, glanders, tentanus, 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, Division of Biologics Standards.

(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 part, 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 part, 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 § 73.50 et seq., 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.

[26 F.R. 5752, June 28, 1961, as amended at 29 F.R. 13387, Sept. 26, 1964; 31 F.R. 14000, Nov. 2, 1966; 33 F.R. 367, Jan. 10, 1968; 33 F.R. 855, Jan. 24, 1968]

tailed 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, Division of Biologics Standards, to recall for failure to conform with the standards prescribed in the regulations of this part, 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, Division of Biologics Standards, 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