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ATCC strains of microorganisms described in this section are available from the American Type Culture Collection, 10801 University Blvd., Manassas, VA 20110. Periodic tests shall be performed to verify the integrity of the test organisms in accordance with §610.18 (a) and (b). The results of these periodic tests shall be recorded and retained in accordance with §600.12(b) of this chapter.
(iii) Storage and maintenance of cultures of test organisms. Cultures of the test organisms used to determine the growth-promoting qualities of the medium shall be stored in a manner that will prevent cross contamination or loss of identity, at a temperature and by a method that will retain the initial characteristics of the organisms and ensure freedom from contamination and deterioration. If the test organisms are stored in the freeze-dried state, or frozen, they shall be reconstituted or thawed, whichever is applicable, and plated periodically to verify the colony count of the suspension. If the test suspensions are stored in a state other than freeze-dried or frozen, they shall be plated, and a colony count shall be performed at the time of each growth-promoting quality test to assure that not more than 100 organisms are used per test vessel. The results of tests for verification of the colony count shall be recorded and retained in accordance with §600.12(b) of this chapter.
(iv) Storage and condition of media. A medium shall not be used if the extent of evaporation affects its fluidity, nor shall it be reused in a sterility test of the product. Fluid Thioglycollate Medium shall be stored in the dark at room temperature if the vessels are unsealed. Sealed vessels shall be stored at the manufacturer's specified storage temperature. Fluid Thioglycollate Medium shall not be used if more than the upper one-third of the medium has acquired a pink color. The medium may be restored once by heating on a steam bath or in free-flowing steam until the pink color disappears. The design of the test vessel for Fluid Thioglycollate Medium shall provide favorable aerobic and anaerobic conditions for growth of the microorganisms throughout the test period. Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25 °C. Unsealed vessels of either medium may be stored for more than 10 days at the proper temperature, provided they are tested monthly for growth-promotion and found to be satisfactory. Sealed vessels of either medium may be stored at the proper temperature for a period of time not to exceed 1 year, provided they are tested for growth-promotion every 3 months and found to be satisfactory. The results of such testing shall be recorded and retained in accordance with §600.12(b) of this chapter.
(v) Criteria for a satisfactory growth-promoting quality test. (a) One hundred or fewer organisms of each strain tested shall be used. The test is satisfactory if evidence of growth appears within 7 days in all vessels inoculated. If a lot of medium fails to support the growth of any test organism, or if the test results show that more than 100 organisms of a strain were used or are necessary to promote growth in the lot of medium being tested, or if the growth is not a pure culture of the test organism, a second test may be performed. If it fails the second test, the lot of medium shall be rejected.
(b) Inoculated Fluid Thioglycollate Medium shall be incubated at 30 to 35 °C for 7 days. If the test medium is to be used in determining the sterility of a product containing a mercurial preservative, a second test shall be performed in accordance with paragraph (e)(2)(v)(a) of this section, except that the test shall be incubated at 20 to 25 °C for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated at 20 to 25 °C for 7 days. The sterility of each lot of medium shall be confirmed by the incubation of uninoculated control test vessels for 7 days at the temperature(s) for that particular medium. The lot of medium is satisfactory if no growth is observed in the control test vessels within the incubation period. The tests for growth-promoting qualities of culture media may be performed simultaneously with sterility testing of biological products, provided the sterility test is considered invalid if the test medium shows no growth response.
(vi) Volume of culture medium. The volume of each culture medium shall be determined for each bulk and final container sterility test required for each product. The ratio of the volume of inoculum to the volume of culture medium shall result in a dilution of the product that is not bacteriostatic or fungistatic, except for products to be tested by membrane filtration. The volume of inhibitors or neutralizers of preservatives added should be considered in determining the proper ratio of inoculum/medium. Vessels of the product-medium mixture(s) and control vessels of the medium shall be inoculated with dilutions of cultures of bacteria or fungi which are viable in the product being tested, and incubated at the appropriate temperature for no less than 7 days.
(f) Membrane filtration. Bulk and final container material or products containing oil products in water-insoluble ointments may be tested for sterility using the membrane filtration procedure set forth in the United States Pharmacopeia (23d Revision, 1995), section entitled “Test Procedures Using Membrane Filtration,” pp. 1689 to 1690, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, or available for inspection at the Center for Drug Evaluation and Research's Division of Medical Library, 5600 Fishers Lane, rm. 11B–40, Rockville, MD, 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.php). Except that:
(1) The test samples shall conform with paragraph (d) of this section; and
(2) In addition, for products containing a mercurial preservative, the product shall be tested in a second test using Fluid Thioglycollate Medium incubated at 20 to 251/2C in lieu of the test in Soybean-Casein Digest Medium.
(g) Exceptions. Bulk and final container material shall be tested for sterility as described above in this section, except as follows:
(1) Different sterility tests prescribed. When different sterility tests are prescribed for a product in this subchapter.
(2) Alternate incubation temperatures. Two tests may be performed as prescribed in paragraph (a)(1)(i) of this section, one test using an incubation temperature of 18 to 22 °C, the other test using an incubation temperature of 30 to 37 °C, in lieu of performing one test using an incubation temperature of 30 to 35 °C, provided that growth-promoting quality tests have been performed at these temperatures.
(3) [Reserved]
(4) Test precluded or not required. (i) The tests prescribed in this section need not be performed for Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.
(ii) Where a manufacturer submits data which the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, finds adequate to establish that the mode of administration, the method of preparation, or the special nature of the product precludes or does not require a sterility test or that the sterility of the lot is not necessary to assure the safety, purity, and potency of the product, the Director may exempt a product from the sterility requirements of this section subject to any conditions necessary to assure the safety, purity, and potency of the product.
(5) Number of final containers more than 20, less than 200. If the number of final containers in the filling is more than 20 or less than 200, the sample shall be no less than 10 percent of the containers.
(6) Number of final containers—20 or less. If the number of final containers in a filling is 20 or less, the sample shall be two final containers, or the sample need be no more than one final container, provided (i) the bulk material met the sterility test requirements and (ii) after filling, it is demonstrated by testing a simulated sample that all surfaces to which the product was exposed were free of contaminating microorganisms. The simulated sample shall be prepared by rinsing the filling equipment with sterile 1.0 percent peptone solution, pH 7.1 ±0.1, which shall be discharged into a final container by the same method used for filling the final containers with the product.
(7) Samples—large volume of product in final containers. For Albumin (Human) and Plasma Protein Fraction (Human), when the volume of product in the final container is 50 milliliters or more, the final containers selected as the test sample may contain less than the full volume of product in the final containers of the filling from which the sample is taken: Provided, That the containers and closures of the sample are identical with those used for the filling to which the test applies, and the sample represents all stages of that filling.
(8) Diagnostic biological products not intended for injection. For diagnostic biological products not intended for injection, (i) only the Fluid Thioglycollate Medium test incubated at 30 to 35 °C is required, (ii) the volume of material for the bulk test shall be no less than 2.0 milliliters, and (iii) the sample for the final container test shall be no less than three final containers if the total number filled is 100 or less, and, if greater, one additional container for each additional 50 containers or fraction thereof, but the sample need be no more than 10 containers.
(9) Immune globulin preparations. For immune globulin preparations, the test samples from the bulk material and from each final container need be no more than 2.0 ml.
(h) Records. The records related to the testing requirements of this section shall be prepared and maintained as required by §§211.167 and 211.194 of this chapter.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41 FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26, 1990; 62 FR 48175, Sept. 15, 1997; 67 FR 9587, Mar. 4, 2002; 69 FR 18803, Apr. 9, 2004; 70 FR 14985, Mar. 24, 2005] § 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 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.
[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] § 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]
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