Part

1250

Interstate conveyance sanitation.

1251-1299 [Reserved]

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 32048, 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

§ 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, Education, and Welfare and any other officer or employee of the Department of Health, Education, and Welfare to whom the authority involved has been delegated.

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

(d) "Bureau of Biologics" means the Bureau of Biologics 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 any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man:

(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:

(1) 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.

(1) 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.

(1) 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.

(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.

(1) "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 and which are designed to insure the continued safety, purity and potency of such products.

(0) 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 prescribed in § 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.

(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" 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 re

(a) Responsible head. A person shall be designated as the responsible head who shall exercise control of the establishment in all matters relating to compliance with the provisions of this subchapter, with authority to represent the manufacturer in all pertinent matters with the Bureau of Biologics, and 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 subchapter 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 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 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 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. § 600.11 Physical establishment, equip. ment, 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, inspection 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 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-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 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-bearing 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-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 identified 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