Timel blodic rise noted 8, Dec. XI his parturi conjugate, toxin, virus, bacterial cul- (iii) Desiccated biological products; IGIN PROBLE tural, or antigen to be used in test sys- samples shall be in final containers quirenett to tems but not for direct comparison and shall be randomly selected if deswith serials of biological products iccated in the final container. Biologiunder test. cal products desiccated in bulk shall rix Piso (d) Seed cultures are small quanti- be sampled at the end of the filling op ties of standard organisms to be propa- eration. Emper Reiz gated by the recipient to establish a (iv) Representative samples of each supply for use. serial or subserial in each shipment of Perringar imported biological products shall be (39 FR 21041, June 18, 1974, as amended at Perfringes 2 40 FR 758, Jan. 3, 1975) selected. (2) Comparable samples shall be $113.3 Sampling of biological products. used by Veterinary Services, the li censee, and the permittee for similar Each licensee and permittee shall tests. furnish representative samples of each (3) When bulk samples of completed serial or subserial of a biological prod product in liquid form are to be tested uct manufactured in the United States as prescribed in paragraph (a)(1) of or imported into the United States as this section, the number of such samprescribed in this section. Additional ples from each serial and the minisamples may be purchased in the open mum quantity of product to be promarket by a Veterinary Services repre vided in each sample shall be stated in sentative. the filed Outline of Production. (a) Either an employee of the De (b) Unless otherwise prescribed by Tal of a dis partment of Agriculture, of the licens the Deputy Administrator, the nufacturiee, or of the permittee, as designated number of final container samples to by the Deputy Administrator, or be selected from each serial and subperson under contract with the De serial shall be: partment shall select prerelease sam (1) Vaccines: ples of biological product in the (i) Twelve single-dose or six multinumber prescribed in paragraph (b) of ple-dose samples of live bacterial vacthis section. Each sample shall be cines; marked for identification by the (ii) Thirty single-dose or 20 multipleperson making the selection after dose samples of equine encephalomyewhich they shall be packaged by the litis vaccine (killed); (iii) Eighteen samples of live virus Services Laboratories; except that an rabies vaccine; employee or contractor of the Depart (iv) Six samples of coccidiosis vacment may forward or deliver the sam cine; ples to Veterinary Services Laborato (v) Sixteen samples of all other vacres if such action is deemed advisable cines. by the Deputy Administrator. (2) Bacterins and bacterin-toxoids. (1) Selection shall be made as fol (1) Twelve samples of single-fraction lows: bacterins and bacterin-toxoids. (1) Nonviable liquid biological prod (ii) Thirteen samples of double-fracucts-either bulk or final container tion bacterins and bacterin-toxoids. samples of completed product shall be (iii) Fourteen samples of triple-fracselected for purity, safety, or potency tion bacterins and bacterin-toxoids. tests. Biological product in final con- (iv) Fifteen samples of bacterins and tainer shall be selected to test for bacterin-toxoids containing more than viable bacteria and fungi. three fractions. (11) Viable liquid biological products; (3) Antiserums: Twelve samples of samples shall be in final containers antiserum recommended for large ani. and shall be randomly selected at the mals or 14 samples of antiserum recend of the filling operation. Bulk con ommended for small animals or the tainers of completed product may be number of reagent serum samples presampled when authorized by the scribed in the filed Outline of Produc. Deputy Administrator. tion for the product. mportelif sistent au cedures or permittee, for holding these sam- а AWA. NO 1876,48 (4) Antitoxins: Twelve samples of tetanus antitoxin or 11 samples of all other antitoxins. (5) Toxoids: Sixteen single-dose samples or thirteen multiple-dose samples of tetanus toxoid or twelve samples of all other toxoids. (6) Antigens: Twelve samples of poultry antigens or 20 samples of tuberculin or four samples of all other diagnostic antigens. (7) Miscellaneous: The number of samples from products not in the categories provided for in paragraph (b) (1), (2), (3), (4), (5), or (6) of this section shall be prescribed in the filed Outline of Production for the product. (8) Prelicensing and outline of production changes. Samples needed to support a license application or change in the Outline of Production for a licensed product shall be submitted only upon request from Veterinary Services. Such samples shall be double the number prescribed in this section for such product. (9) Sterile Diluent. A sample of Sterile Diluent shall accompany each sample of vaccine, other than frozen Marek's Disease Vaccine, if such diluent is required to rehydrate or dilute the vaccine before use. Samples of Sterile Diluent prepared for use with frozen Marek's Disease Vaccine shall be submitted upon request from Veterinary Services. (10) Autogenous biologics. Two samples from each serial of autogenous biologics shall be selected; Provided, That, if the serial exceeds 50 containers, 12 samples shall be selected. (c) Reserve samples shall be selected from each serial and subserial of every biological product. Such samples shall be selected at random from finished product by an employee of the Department, of the licensee, or of the permittee, as designated by the Deputy Administrator or a person under contract with the Department. Each sample shall: (1) Consist of 5 single dose or 2 multiple dose packages as the case may be; (2) Be adequate in quantity for appropriate examination and testing; (3) Be truly representative and in final containers; (4) Be held in a special compartment or equivalent set aside by the licensee 8 113.4 Exemptions to tests. (a) The test methods and procedures contained in all applicable Standard Requirements shall be complied with unless otherwise exempted by the Deputy Administrator and provided that such exemption is noted in the filed Outline of Production for the product. (b) Test methods and procedures by which the biological products shall be evaluated shall be designated in the Outline of Production for such prod. ucts. z then prior The De [38 FR 29887, Oct. 30, 1973] 8 113.5 General testing. (a) No biological product shall be released prior to the completion of tests prescribed in a filed Outline of Production or Standard Requirements for the product to establish the product to be pure, safe, potent, and efficacious. (b) Tests of biological products shall be observed by a competent employee of the manufacturer during all critical periods. A critical period shall be the time when certain specified reactions must occur in required tests to properly evaluate the results. (c) Records of all tests shall be kept in accordance with Part 116 of this chapter. Results of all required tests prescribed in the filed Outline of Production or the Standard Requirements for the product shall be submitted to Veterinary Services. Blank forms shall WUR emmended to 40 FR 20 ests. compilikit mpted by and prac holding te be furnished upon request to Veteri- be evaluated by tests applicable to ation at tes nary Services. each fraction. (d) When the initial or any subse- (b) When similar potency tests are s after the quent test is declared a “No test,” the required for more than one fraction of the labes i reasons shall be reported in the test a combination biological product, difred in this er records, the results shall not be con- ferent animals must be used to evaluered to be sidered as final, and the test may be ate each fraction except when written St. repeated. Standard Requirements or outlines of (e) When new test methods are de- production make provisions and set Zice of Ver veloped and approved by Veterinary forth conditions for use of the same ntroi numer Services, biological products tested animals for testing different fractions. thereafter shall be evaluated by such (c) When the same safety test is re37 FR 2410X methods, and if not found to be satis- quired for more than one fraction, re factory when so tested shall not be re- quirements are fulfilled by satisfac1973 , as a leased. tory results from one test of the comE, 1975 , 4988 (Approved by the Office of Management pleted product. 31. Dec 283 and Budget under control number 0579 (d) When an inactivated fraction(s) is used as a diluent for a live virus (44 U.S.C. 3506) fraction(s), the inactivated fraction(s) may be tested separately and the live (34 FR 18004, Nov. 4, 1969, as amended at 39 virus fraction(s) may be tested sepa FR 25463, July 11, 1974; 40 FR 45420, Oct. 2, s and protein 1975; 40 FR 46093, Oct. 6, 1975; 41 FR 6751, rately: Provided, That, the viricidal cicable Size Feb. 13, 1976; 48 FR 57473, Dec. 30, 1983] test requirements prescribed in $ 113.85 are complied with. moted as 8113.6 Veterinary Services testing. (e) Virus titrations for a multivirus A biological product shall with rea product shall be conducted by methEs noted in sonable certainty yield the results in ods which will quantitate each virus. ziction fixa tended when used as recommended or [34 FR 18004, Nov. 7, 1969, as amended at 40 suggested in its labeling or proposed FR 46093, Oct. 6, 1975) procedunt labeling prior to the expiration date. (a) The Deputy Administrator is au 8 113.8 Virus titrations in lieu of animal gmated D. thorized to cause a biological product, test for immunogenicity. or such a manufactured in the United States or (a) Master Seed Virus which has imported into the United States, to be examined and tested for purity, safety, been established as pure, safe, and impotency, or efficacy; in which case, the munogenic shall be used for preparing licensee or permittee shall withhold the production seed virus for vaccine such product from the market until a production when this requirement is determination has been made. included in the Standard Require(b) The final results of each test con ments for a virus vaccine. The Deputy ducted by the licensee and Veterinary Administrator may exempt a live virus Services shall be considered in evaluat vaccine from a required animal test ing a biological product. A serial or for release when an evaluation of the subserial which has been found unsa vaccine can with reasonable certainty tisfactory by a required test prescribed be made by: In a filed Outline of Production or (1) Subjecting the Master Seed Virus Standard Requirement is not in com to the applicable requirements prepliance with the regulations and shall scribed in § 113.135; and not be released for market. (2) Testing the Master Seed Virus for immunogenicity in a manner ac[34 FR 18004, Nov. 7, 1969, as amended at 40 FR 46420, Oct. 2, 1976; 40 FR 63378, Nov. 18, ceptable to Veterinary Services; and 1976; 41 FR 1751, Feb. 13, 1976) (3) Establishing a satisfactory virus titer based on a predetermined protec8 113.7 Multiple fractions. tive dose plus an adequate overage al lowance for adverse conditions; and (a) When a biological product contains more than one immunogenic (4) Conducting virus titrations on fraction, the completed product shall each serial and subserial in an accept ed titration test system. Jducts.sta? uiremena ed ine de et potenc (b) Each serial and subserial of live virus vaccines derived from an approved Master Seed Virus shall be evaluated by a laboratory virus titration test and the vaccine either released to the firm for marketing or withheld from the market on the basis of the results of the test when compared with the required minimum virus titer. Except as provided in paragraphs (b)(4) and (c) of this section, the evaluation of such products shall be made in accordance with paragraphs (b) (1), (2), and (3) of this section. (1) If the initial test shows the virus titer to equal or exceed the required minimum, the serial or subserial is satisfactory for virus titer without additional testing. (2) If the initial test shows the virus titer to be lower than the required minimum, the serial or subserial may be retested, using two new samples. The average (geometric mean) of titers obtained in the retests shall be determined. If the average titer is less than the required minimum, the serial or subserial is unsatisfactory without further consideration. (3) If the average titer is more than the required minimum, the following shall apply: (i) If the difference between the average titer obtained in the retests and the titer obtained in the initial test is 100.7 or greater, the initial titer may be considered a result of test system error and the serial or subserial considered satisfactory for virus titer. (ii) If the difference between the average titer obtained in the retests and the titer obtained in the initial test is less than 100.7, a new average shall be determined using the titers obtained in all tests. If the new average is below the required minimum, the serial or subserial is unsatisfactory. (4) Exceptions. When a product such as, but not limited to, Marek's Disease Vaccine is evaluated in terms other than logs, a range shall be established to substitute for use in paragraphs (b)(3) (i) and (ii) of this section. Marek's Disease Vaccine shall have a range of 300 PFU's. (c) Final container samples of completed product derived from Masteran potencu Seed Virus found immunogenic in ac- red from cordance with paragraph (a) of this mm of tb section and found satisfactory for zmolem is virus titer in accordance with paragraph (b) of this section may also be subjected to an animal potency test by Veterinary Services as provided in this anteste paragraph. Liquid vaccine and rehy. 2dl Produ drated desiccated vaccines shall be x xonsidere used according to label directions in. 21 Veterie cluding dose(s) and route of adminis. To additio tration. med for the (1) A one stage test using 20 vacci in test is nates and 5 controls or a two stage test using 10 vaccinates and 5 controls for at de pub each stage shall be used. Except as si Requir provided in paragraphs (c), (c)(1), (c)(2), and (c)(3) of this section, the finale pot tests shall be conducted in accordance wol the with the test protocol used in the product Master Seed Virus immunogenicity bil de mar test including the criteria used for botertion judging the specific response in the nation controls and vaccinates. (2) If at least 80 percent of the controls do not show specific responses to say such challenge, the test is inconclusive and is the may be repeated. If a vaccinate shows the specific responses to challenge ex. pected in the controls, the vaccinate shall be listed as a failure. (3) The results of the testing shall be only be evaluated according to the following table: CUMULATIVE TOTALS Fallures for Stage Failures for serials Number of tory seriale ata 107 1 10. 1 or loss......... 3 or moro. 4 or less..... 6 or more (4) When a serial has been found unsatisfactory for potency by the test provided in paragraphs (c) (1), (2), and (3) of this section, the serial shall be withheld from the market and the following actions taken: (1) The Deputy Administrator shall require that at least two additional serials prepared with the same Master Seed Virus be subjected to similar animal potency tests by Veterinary Services or the licensee or both. Cainer samt 5 section mit graphs (0 : uct. f this sentit immune criteris # respone. ces ercent of the ecific respect inconcia7 (ii) If another serial is found unsatis- the individual ingredients, they may derived ful factory for potency, the product shall be made from dehydrated mixtures ad immune be removed from the market while a which, when rehydrated with purified paragraph i reevaluation of the product is made water, have the same or equivalent und sets and the problem is resolved. composition as such media and have ccordance [40 FR 49296, Oct. 22, 1975) growth-promoting buffering, and oxygen tension-controlling properties cnimal porer 8 113.9 New potency test. equal to or better than such media. es as proti A potency test written into the filed The formulas for the composition of ed vaccine e Outline of Production for a product the culture media prescribed in vacinas de shall be considered confidential infor- $ $ 113.26 and 113.27 are set forth in label du mation by Veterinary Services until at the United States Pharmacopeia, 19th od route de least two additional product licenses Edition. are issued for the product or unless (b) The licensee shall test each test using di use of the test is authorized by the li- quantity of medium prepared at one s or a troske censee, in which case, such potency E and act test may be published as part of the time from individual ingredients and be used by Standard Requirement for the prod the first quantity prepared from each lot of commercial dehydrated medium (a) Until a potency test is published for growth-promoting qualities. If any cted in south as part of the Standard Requirement portion of a lot of commercial dehy. Focal met die for the product, reference to such a drated medium is held for 90 days or test shall be made in the filed Outline longer after being so tested, it shall be of Production and the test shall be retested before use. Two or more conducted. strains of micro-organisms that are ex(b) When a potency test has been acting in their nutritive requirements published as part of the Standard Re- shall be used. More than one dilution quirement, such test shall be conduct shall be used to demonstrate the adeed unless the product is specifically quacy of the medium to support the exempted as provided in $ 113.4. growth of a minimum number of to chalis (40 FR 14084, Mar. 28, 1975) micro-organisms. (c) The sterility of the medium shall 3 113.10 Testing of bulk material for be confirmed by incubating an adeexport only. quate number of test vessels and exWhen liquid product is prepared for amining each for growth. Additional export in large multiple-dose contain control may be used by incubation of ers as provided in $112.8 (d) or (e) of representative uninoculated test vesthis subchapter, samples of the bulk sels for the required incubation period material shall be subjected to all required test prescribed in the filed Out during each test. line of Production or standard Re (d) A determination shall be made quirements for the product. Samples by the licensee for each biological of concentrated liquid product shall be product of the ratio of inoculum to diluted to a volume equal to the con medium which shall result in suffitents of the sample times the concen cient dilution of such product to pretration factor prior to initiating poten vent bacteriostatic and fungistatic activity. The determination may be made by tests on a representative biological product for each group of comparable products containing identical preservatives at equal or lower concen8113.25 Culture media for detection of trations. Inhibitors or neutralizers of preservatives, approved by the Deputy (a) Ingredients for which standards Administrator, may be considered in are prescribed in the United States determining the proper ratio. [35 FR 16039, Oct. 13, 1970, as amended at ure he testys OTALS cy tests. STANDARD PROCEDURES bacteria and fungi. 37 FR 2430, Feb. 1, 1972; 41 FR 27715, July In lieu of preparing the media from 6, 1976) poth |