Source: https://www.ecfr.gov/cgi-bin/text-idx?mc=true&node=sg9.1.113_155.sg3&rgn=div7
Timestamp: 2020-08-07 15:38:37
Document Index: 41970774

Matched Legal Cases: ['§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113', '§113']

§113.64 General requirements for live bacterial vaccines.
When prescribed in an applicable Standard Requirement or in the filed Outline of Production, a live bacterial vaccine shall meet the requirements in this section.
(a) Purity test. Final container samples of completed product from each serial and subserial, and samples of each lot of Master Seed Bacteria shall be tested for the presence of extraneous viable bacteria and fungi in accordance with the test provided in §113.27(b).
(b) Safety tests. (1) Samples of completed product from each serial or first subserial and samples of each lot of Master Seed Bacteria shall be tested for safety in young adult mice in accordance with the test provided in §113.33(b) unless:
(i) The bacteria or agents in the vaccine are inherently lethal for mice.
(ii) The vaccine is recommended for poultry.
(2) Samples of completed product from each serial or first subserial of live bacterial vaccine shall be tested for safety in one of the species for which the product is recommended as follows:
(i) Live bacterial vaccine recommended for use in dogs shall be tested as provided in §113.40, except that dogs shall be injected with the equivalent of two doses of vaccine administered as recommended on the label.
(ii) Live bacterial vaccine recommended for use in cattle shall be tested as provided in §113.41, except that calves shall be injected with the equivalent of two doses of vaccine administered as recommended on the label.
(iii) Live bacterial vaccine recommended for use in sheep shall be tested as provided in §113.45.
(iv) Live bacterial vaccine recommended for use in swine shall be tested as provided in §113.44.
(c) Identity test. At least one of the identity tests provided in this paragraph shall be conducted for the Master Seed Bacteria and final container samples from each serial or first subserial of completed biological product. A known positive control (reference) provided or approved by Animal and Plant Health Inspection Service shall be included in such tests.
(1) Fluorescent antibody test. The direct fluorescent antibody staining technique shall be conducted using suitable smears of the vaccine bacteria. Fluorescence typical for the bacteria concerned shall be demonstrated. Fluorescence shall not occur in control smears treated with specific antiserum.
(2) Tube agglutination test. A tube agglutination test shall be conducted with a suitable suspension of the vaccine bacteria using the constant antigen decreasing serum method with specific antiserum. Agglutination typical for the bacteria shall be demonstrated. Agglutination shall not occur with negative serum used as a control in this test.
(3) Slide agglutination test. The rapid plate (slide) agglutination test shall be conducted with suitable suspensions of the vaccine bacteria using the hanging drop, slide or plate method, with specific antiserum. Agglutination typical for the bacteria shall be demonstrated by microscopic or macroscopic observation. Agglutination shall not occur with negative serum used as a control in this test.
(4) Characterization tests. Applicable biochemical and cultural characteristics shall be demonstrated as specified in the filed Outline of Production.
(d) Ingredient requirements. Ingredients used for the growth and preparation of Master Seed Bacteria and of live bacterial vaccine shall meet the requirements provided in §113.50. Ingredients of animal origin shall meet the applicable requirements provided in §113.53.
(e) Moisture content. The maximum percent moisture in desiccated vaccines shall be stated in the filed Outline of Production and shall be established by the licensee as follows:
(1) Prelicensing. Data obtained by conducting accelerated stability tests and bacterial counts shall be acceptable on a temporary basis.
(2) Licensed products. Data shall be obtained by determining the percent moisture and bacterial count at release and expiration on a minimum of 10 consecutive released serials.
(3) Final container samples of completed product from each serial and subserial must be tested for moisture content in accordance with the test provided in §113.29.
[48 FR 33476, July 22, 1983, as amended at 54 FR 19352, May 5, 1989; 56 FR 66784, Dec. 26, 1991; 68 FR 57608, Oct. 6, 2003]
§113.65 Brucella Abortus Vaccine.
Brucella Abortus Vaccine shall be prepared as a desiccated live culture bacterial vaccine from smooth colonial forms of the Brucella abortus organism, identified as Strain 19. Each serial and subserial shall be tested for purity, potency, and moisture content. A serial or subserial found unsatisfactory by a prescribed test shall not be released.
(a) Purity tests. Each serial and subserial shall be tested for purity as provided in this paragraph.
(1) Macroscopic and microscopic examination shall be made on bulk samples from production containers. If organisms not typical of Brucella abortus organisms are evident, the serial or subserial is unsatisfactory.
(2) Two final container vials of completed product shall be tested by inoculating one tube of Dextrose Andrades broth with gas tube and one tube of thioglycollate broth from each vial. The inoculated media shall be incubated at 35 to 37 °C for 96 hours. If growth not typical of Brucella abortus organisms is evident, the serial or subserial is unsatisfactory.
(3) Bacterial dissociation test. Final container samples of completed product from each serial and subserial shall be tested for bacterial dissociation. Smooth colonies are the desired form. Rough colonies are undesirable terminal dissociation forms. Intermediate and intermediate-to-rough are also undesirable.
(i) The sample container shall be rehydrated and streaked on one potato agar plate in such a manner as to produce confluent colonies. Artificial reflected light shall be used so that the rays pass through the plate at a 45 °angle.
(ii) If the vaccine contains more than 5 percent rough colonies or more than 15 percent total undesirable colonies, the serial or subserial is unsatisfactory. If organisms or growth not characteristic of Brucella abortus are found, the serial or subserial is unsatisfactory. The test may be repeated one time using double the number of samples: Provided, That, if the test is not repeated, the serial or subserial is unsatisfactory.
(b) Bacterial count requirements for reduced dose vaccine. Each serial and each subserial shall be tested for potency.
(1) Two final container vials of completed product shall be tested for the number of viable organisms per dose of rehydrated vaccine. A bacterial count per vial shall be made on tryptose agar plates from suitable dilutions using 1 percent peptone as a diluent. The inoculated media shall be incubated at 35 to 37 °C for 96 hours.
(2) If the average count of the two final container samples of freshly prepared vaccine contains less than 3.0 or more than 10.0 billion organisms per dose, the serial or subserial is unsatisfactory.
(3) If the average count on the initial test is less than the minimum or greater than the maximum required in paragraph (b)(2) of this section, the serial or subserial may be retested one time using four additional final container vials. The average count of the retest is determined. If the average count of the four vials retested is less than the required minimum or greater than the required maximum, the serial or subserial is unsatisfactory. If the average count of the four vials retested is within the required limits described in paragraph (b)(2) of this section, the following shall apply:
(i) If the average count obtained in the initial test is less than one-third or more than three times the average count obtained on the retest, the average count of the initial test shall be considered the result of test system error and the serial or subserial is satisfactory.
(ii) If the average count obtained in the initial test is one-third or more than the average retest count or three times or less than the average retest count, a new average count shall be determined from the counts of all six vials. If the new average is less than the minimum or greater than the maximum required in paragraph (b)(2) of this section, the serial or subserial is unsatisfactory.
(4) If tested at any time within the expiration period, each dose of rehydrated vaccine must contain at least 3.0 billion viable organisms per dose.
(c) Bacterial count requirements for standard vaccine. Each serial and subserial shall be tested for potency.
(1) Two final container samples shall be tested for the number of viable organisms per milliliter of rehydrated vaccine. One bacterial count per vial shall be made on tryptose agar plates from suitable dilutions using 1 percent peptone as a diluent. The inoculated media shall be incubated at 35 to 37 °C for 96 hours.
(2) If the average count of the two final container samples of freshly prepared vaccine does not contain at least 10 billion viable organisms per milliliter, the serial or subserial is unsatisfactory.
(3) If the initial bacterial count is less than 10 billion organisms per milliliter, the serial or subserial may be retested one time using four samples. If the average count of the four vials retested is less than the required minimum, the serial or subserial is unsatisfactory.
(4) If tested at any time within the expiration period, each milliliter of rehydrated vaccine does not contain at least 5 billion viable organisms per milliliter, the serial or subserial is unsatisfactory.
[39 FR 16857, May 10, 1974. Redesignated at 39 FR 25463, July 11, 1974, and amended at 40 FR 758, Jan. 3, 1975; 50 FR 23794, Jan. 6, 1985]
§113.66 Anthrax Spore Vaccine—Nonencapsulated.
Anthrax Spore Vaccine—Nonencapsulated shall be a live spore suspension prepared from nonencapsulated variants of Bacillus anthracis. Only Master Seed which has been established as pure, safe, and immunogenic shall be used for production. All serials of vaccine shall be prepared from the first through the fifth passage from the Master Seed.
(a) The Master Seed shall meet the applicable general requirements prescribed in §113.64 and the requirements in this section.
(b) Each lot of Master Seed shall be tested for immunogenicity as follows:
(1) Forty-two susceptible guinea pigs from the same source each weighing 400 to 500 grams, shall be used as test animals (30 vaccinates and 12 controls).
(2) An arithmetic mean spore count of vaccine produced from the highest passage of the Master Seed shall be established before the immunogenicity test is conducted. The guinea pigs used as vaccinates shall be injected as recommended on the label with a predetermined number of vaccine spores. To confirm the dosage, five replicate spore counts shall be conducted on a sample of the vaccine dilution used.
(3) Fourteen to fifteen days postvaccination the vaccinates and controls shall each be challenged with not less than 4,500 guinea pig LD50 of a virulent suspension of Bacillus anthracis furnished or approved by Animal and Plant Health Inspection Service and observed for 10 days.
(4) If at least 10 of the 12 controls do not die from Bacillus anthracis within the 10-day postchallenge observation period the test is invalid and may be repeated.
(5) If at least 27 of 30 of the vaccinates do not survive the 10-day postchallenge observation period, the Master Seed is unsatisfactory.
(6) An Outline of Production change shall be made before authority for use of a new lot of Master Seed shall be granted by Animal and Plant Health Inspection Service.
(c) Test Requirements for Release. Each serial and subserial shall meet the applicable general requirements prescribed in 9 CFR 113.64 and the requirements in this paragraph. Any serial or subserial found unsatisfactory by a prescribed test shall not be released.
(1) Safety test. Samples of completed product from each serial or first subserial shall be tested for safety in sheep or goats by the methods described in 9 CFR 113.45(a).
(2) Spore Count Requirements. Final container samples of completed product shall be tested for spore count. Samples shall be diluted in tenfold steps. Each dilution expected to yield 30 to 300 colonies per plate shall be plated in triplicate on tryptose agar, inverted, and incubated at 35 to 70 °C for 24 hours to 28 hours. Each plate having uniformly distributed colonies shall be counted and an average count determined. To be eligible for release, each serial and each subserial shall have a spore count sufficiently greater than that of the vaccine used in the immunogenicity test to assure that when tested at any time within the expiration period, each serial and subserial shall have a spore count of at least twice that used in the immunogenicity test but not less than 2,000,000 spores per dose.
[50 FR 23794, June 6, 1985, as amended at 56 FR 66784, Dec. 26, 1991; 72 FR 72564, Dec. 21, 2007]
§113.67 Erysipelothrix Rhusiopathiae Vaccine.
(a) The Master Seed shall meet the applicable requirements prescribed in §113.64 and the requirements in this section.
(c) Test requirements for release. Each serial and subserial shall meet the applicable requirements in §113.64 and the requirements in this paragraph. Any serial or subserial found unsatisfactory by a prescribed test shall not be released.
(1) Safety test. Samples of completed product from each serial or first subserial shall be tested for safety in young adult mice as prescribed in §113.33(b) and in swine as prescribed in §113.44.
(2) Bacterial count requirements. Final container samples of completed product from each serial and each subserial shall be tested for bacterial count using the method used in paragraph (b)(2) of this section. Two replicate titrations shall be conducted on each sample. To be eligible for release, each serial and subserial shall have a bacterial count sufficiently greater than that of the vaccine used in the immunogenicity test to assure that, when tested at any time within the expiration period, each serial and subserial shall have a bacterial count two times greater than that used in such immunogenicity test.
[50 FR 23795, June 6, 1985, as amended at 56 FR 66784, Dec. 26, 1991; 72 FR 72564, Dec. 21, 2007]
§113.68 Pasteurella Haemolytica Vaccine, Bovine.
Pasteurella Haemolytica Vaccine, Bovine, shall be prepared as a desiccated live culture bacterial vaccine of an avirulent or modified strain of Pasteurella haemolytica, identified as serotype 1. Only Master Seed which has been established as pure, safe, and immunogenic shall be used for vaccine production. All serials of vaccine shall be prepared from the first through the fifth passage from the Master Seed.
(1) Fifteen Pasteurella haemolytica susceptible calves shall be used as test animals (10 vaccinates and 5 controls) for each route of administration recommended on the label.
(2) An arithmetic mean count of the colony forming units from vaccine produced from the highest passage of the Master Seed shall be established before the immunogenicity test is conducted. The 10 calves to be used as vaccinates shall be injected as recommended on the label with a predetermined quantity of vaccine bacteria. The five control calves shall be held separately from the vaccinates. To confirm the dosage calculation, five replicate titrations on a sample of the bacterial vaccine used. Only plates containing between 30 and 300 colonies shall be considered a valid test.
(3) The vaccinates and controls shall be examined and their average body temperature determined prior to challenge. Fourteen to twenty-one days post vaccination, the vaccinates and controls shall each be challenged by the respiratory route with a (virulent) pneumonia producing Pasteurella haemolytica culture and observed for 4 to 7 days. The challenge culture and instructions for preparation for use shall be furnished or approved by the Animal and Plant Health Inspection Service.
(4) A satisfactory challenge shall be evidenced in the controls by progression of clinical signs consistent with respiratory system infection following challenge, including but not limited to lacrimation, mucoid nasal exudates, expiratory dyspnea, tachypnea, pulmonary rales, and cough possibly terminating in death; moribundity, depression with anorexia, diarrhea with substantial weight loss; or any combination of these symptoms.
(5) Lung lesion response to challenge will be assessed in all calves. Lung lesions will be assessed at necropsy in calves that succumb to challenge. Surviving calves will be euthanized on day 4 to 7 following challenge and lung lesions assessed at necropsy. Lung lesion scores will be used in the assessment of the response to challenge exposure. If a significant difference in lung lesion scores cannot be demonstrated between vaccinates and controls using a scoring system approved by the Animal and Plant Health Inspection Service, the Master Seed is unsatisfactory.
(c) Test requirements for release. Each serial and subserial shall meet the applicable general requirements prescribed in §§113.8 and 113.64 and the requirements in this paragraph. Any serial or subserial found unsatisfactory by a prescribed test shall not be released.
(1) Safety test. Samples of completed product from each serial or first subserial shall be tested for safety in calves as provided in §§113.41(a) and 113.41(b) except, that the equivalent of two doses of vaccine shall be used and administered in the manner recommended on the label.
(2) Bacterial count requirements. Final container samples of completed product shall be tested for bacterial count using the method used in paragraph (b)(2) of this section. Two replicate titrations shall be conducted on each serial and subserial. Each sample shall be rehydrated with accompanying sterile diluent to the volume indicated on the label. To be eligible for release, each serial and subserial shall have a bacterial count sufficiently greater than that of the vaccine used in the immunogenicity test to assure that, when tested at any time within the expiration period, each serial and subserial shall have a bacterial count at least two times greater than that used in the immunogenicity test.
[55 FR 35559, Aug. 31, 1990, as amended at 72 FR 72564, Dec. 21, 2007]
§113.69 Pasteurella Multocida Vaccine, Bovine.
(1) Safety Test. Samples of completed product from each serial or first subserial shall be tested for safety in calves as provided in §§113.41(a) and 113.41(b), except that the equivalent of two doses of vaccine shall be used and administered in the manner recommended on the label.
(2) Bacterial count requirements. Final container samples of completed product shall be tested for bacterial count using the method used in paragraph (b)(2) of this section. Two replicate titrations shall be conducted on each serial and subserial. Each sample shall be rehydrated with accompanying sterile diluent to the volume indicated on the label. To be eligible for release, each serial and subserial shall have a bacterial count sufficiently greater than that of the vaccine used in the immunogenicity test count per dose established to assure that, when tested at any time within the expiration period, each serial and subserial shall have a bacterial count at least two times greater than that used in the immunogenicity test.
[55 FR 35560, Aug. 31, 1990, as amended at 72 FR 72564, Dec. 21, 2007]
§113.70 Pasteurella Multocida Vaccine, Avian Isolate.
Pasteurella Multocida Vaccine, Avian Isolate, shall be prepared as a desiccated live culture of an avirulent or modified strain of Pasteurella multocida. Only Master Seed which has been established as pure, safe, and immunogenic shall be used for vaccine production.
(b) Each lot of Master Seed used for vaccine production shall be tested for immunogenicity in each species and for each serotype for which the Master Seed is claimed to give protection.
(1) Thirty Pasteurella multocida susceptible birds shall be used as test animals (20 vaccinates and 10 controls) for each bird species, route of administration, and serotype for which protection is claimed on the label.
(2) An arithmetic mean count of colony forming units from vaccine produced from the highest passage of Master Seed shall be established before the immunogenicity test is conducted. The 20 birds to be used as vaccinates shall be inoculated, as recommended on the label with a predetermined quantity of vaccine bacteria. The 10 control birds shall be held separately from the vaccinates. To confirm the dosage calculation, an arithmetic mean count shall be established by conducting five replicate titrations on a sample of the bacterial vaccine used. Only plates containing between 30 and 300 colonies shall be considered in a valid test.
(3) Not less than 14 days after vaccination, each of 20 vaccinates and each of 10 unvaccinated controls shall be challenged intramuscularly or by other methods acceptable to the Animal and Plant Health Inspection Service with a virulent Pasteurella multocida strain, for which protection is claimed, and observed daily for a 14 day post-challenge period.
(4) Eight or more of the unvaccinated controls must die for the test to be valid. If at least 16 of 20 of the vaccinates do not survive the 14-day postchallenge period, the Master Seed is unsatisfactory at the selected bacterial count.
(c) Test requirements for release. Each serial and subserial shall meet the applicable requirements in §§113.8 and 113.64 and the requirements in this paragraph. Any serial or subserial found unsatisfactory by a prescribed test shall not be released.
(1) Safety test. Samples of completed product from each serial or first subserial shall be tested for safety.
(i) Ten birds of a species for which the vaccine is recommended shall be given the equivalent of 10 doses each of the vaccine and observed for 10 days. If the vaccine is recommended for more than one species, only one species needs to be tested.
(ii) If unfavorable reactions attributable to the vaccine occur during the observation period in two or more of the test birds, the serial is unsatisfactory.
(iii) If unfavorable reactions occur which are not attributable to the test vaccine, the test is a No Test and may be repeated. If the results of the next test are not satisfactory, or if the test is not repeated, the serial shall be considered unsatisfactory.
[55 FR 35560, Aug. 31, 1990, as amended at 59 FR 19633, Apr. 25, 1994; 64 FR 43044, Aug. 9, 1999; 72 FR 72564, Dec. 21, 2007]
§113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.
Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be prepared from chlamydia-bearing cell culture fluids or embryonated chicken eggs. Only Master Seed which has been established as pure, safe, and immunogenic shall be used for vaccine production. All serials of vaccine shall be prepared from the first through the fifth passage from the Master Seed.
(a) The Master Seed shall meet the applicable requirements prescribed in §113.300 and the requirements in this section. Master Seed propagated in chicken embryos shall be tested for pathogens by the chicken embryo test prescribed in §113.37. If found unsatisfactory by any prescribed test, the Master Seed shall not be used.
(b) Each lot of Master Seed used for vaccine production shall be tested for immunogenicity. The immunogenicity of a selected dose from the lot of Master Seed shall be established as follows:
(1) Thirty feline pneumonitis susceptible cats shall be used as test animals (20 vaccinates and 10 controls). Blood samples shall be drawn and individual serum samples tested. The cats shall be considered suitable for use if all serums are negative for pneumonitis antibody in a complement fixation test or other test of equal sensitivity.
(2) A geometric mean titer of the dried vaccine produced from the highest passage of the Master Seed shall be established before the immunogenicity test is conducted. The 20 cats used as vaccinates shall be administered a predetermined quantity of vaccine by the method to be recommended on the label and the remaining 10 cats shall be held as controls. To confirm the dosage calculations, five replicate titrations shall be conducted on a sample of the vaccine dilution used. If two doses are used, five replicate confirming titrations shall be conducted on each dose.
(3) Fourteen or more days after the final dose of vaccine, the vaccinates and controls shall each be challenged intranasally with a minimum of 10,000 yolk sac LD50 of virulent feline pneumonitis furnished or approved by the Animal and Plant Health Inspection Service and observed each day for 28 days postchallenge. The rectal temperature of each animal shall be taken and the presence or absence of clinical signs noted and recorded each day.
(i) If less than 8 of 10 controls show clinical signs of feline pneumonitis infection other than fever, the test is a No Test and may be repeated.
(ii) If a significant difference in clinical signs other than fever or chlamydia shedding cannot be demonstrated between vaccinates and controls using a scoring system approved by the Animal and Plant Health Inspection Service, the Master Seed is unsatisfactory.
(4) An Outline of Production change must be made before authority for use of a new lot of Master Seed is granted by the Animal and Plant Health Inspection Service.
(c) Test requirements for release: Except for §113.300(a)(3)(ii), each serial and subserial shall meet the requirements prescribed in §113.300 and in this paragraph. Final container samples of completed product shall be tested. Any serial or subserial found unsatisfactory by a prescribed test shall not be released.
(1) The test for pathogens prescribed in §113.37 shall be conducted on each serial or one subserial of avian origin vaccine.
(2) Chlamydia titer requirements. Final container samples of completed product shall be tested for chlamydia titer using the titration method used in paragraph (b)(2) of this section. To be eligible for release, each serial and each subserial shall have a titer sufficiently greater than the titer of vaccine used in the immunogenicity test prescribed in paragraph (b) of this section to assure that when tested at any time within the expiration period, each serial and subserial shall have a titer 0.7 greater than that used in such immunogenicity test but not less than 2.5 ID50 per dose.
[55 FR 35561, Aug. 31, 1990, as amended at 56 FR 66786, Dec. 26, 1991; 72 FR 72564, Dec. 21, 2007]