A general safety test for the detection of extraneous toxic contaminants shall be performed on biological products intended for administration to humans. The general safety test is required in addition to other specific tests prescribed in the additional standards for individual products in this subchapter, except that, the test need not be performed on those products listed in paragraph (g) of this section. The general safety test shall be performed as specified in this section, unless: Modification is prescribed in the additional standards for specific products, or variation is approved as a supplement to the product license under § 610.9.
(a)Product to be tested. The general safety test shall be conducted upon a representative sample of the product in the final container from every final filling of each lot of the product. If any product is processed further after filling, such as by freeze-drying, sterilization, or heat treatment, the test shall be conducted upon a sample from each filling of each drying chamber run, sterilization chamber, or heat treatment bath.
(b)Test animals. Only overtly healthy guinea pigs weighing less than 400 grams each and mice weighing less than 22 grams each shall be used. The animals shall not have been used previously for any test purpose.
(c)Procedure. The duration of the general safety test shall be 7 days for both species, except that a longer period may be established for specific products in accordance with § 610.9. Once the manufacturer has established a specific duration of the test period for a specific product, it cannot be varied subsequently, except, in accordance with § 610.9. Each test animal shall be weighed and the individual weights recorded immediately prior to injection and on the last day of the test. Each animal shall be observed every working day. Any animal response including any which is not specific for or expected from the product and which may indicate a difference in its quality shall be recorded on the day such response is observed. The test product shall be administered as follows:
(1)Liquid product or freeze-dried product which has been reconstituted as directed on the label. Inject intraperitoneally 0.5 milliliter of the liquid product or the reconstituted product into each of at least two mice, and 5.0 milliliters of the liquid product or the reconstituted product into each of at least two guinea pigs.
(2)Freeze-dried product for which the volume of reconstitution is not indicated on the label. The route of administration, test dose, and diluent shall be as approved in accordance with § 610.9. Administer the test product as approved on at least two mice and at least two guinea pigs.
(3)Nonliquid products other than freeze-dried product. The route of administration, test dose, and diluent shall be as in accordance with § 610.9. Dissolve or grind and suspend the product in the approved diluent. Administer the test product as approved on at least two mice and at least two guinea pigs.
(d)Test requirements. A safety test is satisfactory if all animals meet all of the following requirements:
(1) They survive the test period.
(2) They do not exhibit any response which is not specific for or expected from the product and which may indicate a difference in its quality.
(3) They weigh no less at the end of the test period than at the time of injection.
(1)First repeat test. If a filling fails to meet the requirements of paragraph (d) of this section in the initial test, a repeat test may be conducted on the species which failed the initial test, as prescribed in paragraph (c) of this section. The filling is satisfactory only if each retest animal meets the requirements prescribed in paragraph (d) of this section.
(2)Second repeat test. If a filling fails to meet the requirements of the first repeat test, a second repeat test may be conducted on the species which failed the test: Provided, That 50 percent of the total number of animals in that species has survived the initial and first repeat tests. The second repeat test shall be conducted as prescribed in paragraph (c) of this section, except that the number of animals shall be twice that used in the first repeat test. The filling is satisfactory only if each second repeat test animal meets the requirements prescribed in paragraph (d) of this section.
(1) The test prescribed in this section need not be performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF, Platelets, Plasma, or Cellular Therapy Products.
(2) For products other than those identified in paragraph (g)(1) of this section, a manufacturer may request from 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), an exemption from the general safety test. The manufacturer must submit information as part of a biologics license application submission or supplement to an approved biologics license application establishing that because of the mode of administration, the method of preparation, or the special nature of the product a test of general safety is unnecessary to assure the safety, purity, and potency of the product or cannot be performed. The request must include alternate procedures, if any, to be performed. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, upon finding that the manufacturer's request justifies an exemption, may exempt the product from the general safety test subject to any condition necessary to assure the safety, purity, and potency of the product.
[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 19403, Apr. 20, 1998; 63 FR 41718, Aug. 5, 1998; 68 FR 10160, Mar. 4, 2003; 70 FR 14984, Mar. 24, 2005]
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