113.450—General requirements for antibody products.
Unless otherwise prescribed in a Standard Requirement or in a filed Outline of Production, all antibody products shall meet the applicable requirements of this section.
(a) Terminology.
The following terms in the regulations and standards concerning antibody products shall mean:
Antibody. An immunoglobulin molecule, having a precise glycoprotein structure, produced by certain cells of the B lymphocyte lineage in response to antigenic stimulation, and functioning to specifically bind and influence the antigens that induced its synthesis.
IgG (Immunoglobulin G). One of the several recognized classes of structurally related glycoproteins whose representatives include all known antibodies.
Monoclonal. Produced by, or derived from, the offspring of a single common progenitor cell.
Failure of passive transfer. A condition of neonates characterized by an abnormally low concentration of circulating maternal IgG.
(1) Virus-specific products.
The true name of a virus-specific product shall: include the term “antibody,” specify the disease for which the product is intended, and indicate the type of animal that supplied the component antibodies. If the antibodies are monoclonal, the term “monoclonal” shall be used. Example: “Duck Virus Hepatitis Antibody, Duck Origin.”
(2) Bacterium-specific products.
The true name of a bacterium-specific product shall: include the term “antibody” if the component antibodies are directed against a nontoxin antigen or the term “antitoxin” if the component antibodies are directed against toxin, specify the organism against which the product is intended, and indicate the type of animal that supplied the component antibodies. If the antibodies are monoclonal, the term “monoclonal” shall be used. Example: “Escherichia Coli Monoclonal Antibody, Murine Origin.”
(3) Failure of passive transfer products.
The true name of a product for treatment of failure of passive transfer shall include the term “IgG” and indicate the type of animal that supplied the component IgG. Example: “Bovine IgG.”
(4) Combination products.
The true name of a product for treatment of failure of passive transfer as well as for the prevention and/or alleviation of a specific viral or bacterial disease shall be named according to the nomenclature prescribed above for virus-specific or bacterium-specific products.
(c) Animals.
All animals used in the production of antibody products shall be healthy. Their health status shall be determined by physical examination by, or under the direct supervision of, a licensed veterinarian and by tests for infectious diseases. Such animals shall be maintained at licensed establishments: Provided, That cows maintained at Grade A dairies (or the equivalent) that are not injected with antigens for the purpose of stimulating the production of specific antibodies and that are used only for the purpose of supplying lacteal secretions are exempt from being maintained at a licensed establishment.
(1)
No animal shall be used while showing clinical signs of disease. The presence of minor localized injuries or lesions (contusions, lacerations, burns, etc.) without body temperature elevation and without significant pain and distress shall not be construed as clinical evidence of disease.
(2)
Before first use and on a regular basis, all animals used in the manufacture of antibody products shall be individually subjected to applicable tests for infectious diseases. Records of all test results shall be maintained. An animal which tests positive for an infectious disease shall not be used in the manufacture of antibody products. Retests shall be conducted as deemed necessary by the Administrator.
(C)
Brucellosis at a laboratory approved by APHIS. Horses with standard agglutination titers of 1:50 or less can be used for production. Horses with standard agglutination titers equal to or greater than 1:100 may be tested by the Rivanol or card tests. Reactors to these supplemental tests shall not be used for production. Nonreactors to the supplemental tests shall be retested after 30 days. If the supplemental tests are negative and the agglutination titer has not increased, the animal may be used for production. Otherwise, the animal is unsatisfactory for this purpose.
(ii)
Horses shall be retested annually for EIA and, if housed or pastured with any other species, shall be retested annually for brucellosis.
(A)
Tuberculosis by an accredited veterinarian: Provided, That cattle at Grade A dairies supplying only lacteal secretions need only be tested for tuberculosis in accordance with applicable Milk Ordinances or similar laws or regulations.
(B)
Brucellosis at a laboratory approved by APHIS. Cattle with standard agglutination titers of 1:50 or less can be used for production. Cattle with standard agglutination titers equal to or greater than 1:100 may be tested by the Rivanol or card tests. Reactors to these supplemental tests shall not be used for production. Nonreactors to the supplemental tests shall be retested after 30 days. If the supplemental tests are negative and the agglutination titer has not increased, the animal may be used for production; otherwise, the animal is unsatisfactory for this purpose. Cattle at Grade A dairies supplying only lacteal secretions need not be tested individually for brucellosis if a portion of their secretions contribute to the herd milk pool tested as required by the brucellosis ring test. An animal of a herd testing positive by this test shall not be used in production.
(iv)
Cattle shall be retested annually for both tuberculosis and brucellosis. Cattle at Grade A dairies supplying only lacteal secretions need only be tested for tuberculosis in accordance with applicable Milk Ordinances or similar laws or regulations. Cattle at Grade A dairies supplying only lacteal secretions need not be tested individually for brucellosis if a portion of their secretions contribute to the herd milk pool tested as required by the brucellosis ring test. An animal of a herd testing positive by this test shall not be used in production.
(v)
For other species, appropriate tests and the frequency with which they are applied shall be specified in the filed Outline of Production for the product.
(vi)
If a positive result is obtained on any prescribed test, the positive animal(s) shall be removed from the herd and the remaining animals retested. Production shall not be renewed until a negative herd test is obtained not less than 28 days following removal of the positive animal(s).
(vii)
Negative animals shall be maintained separate and apart from untested or positive animals of any species. Production animals shall not be used for any other purpose, such as testing, work, or recreation.
(d) Collection procedures.
Blood, lacteal secretions, and egg material shall be collected as described in the filed Outline of Production for the product.
(e) Ingredient handling and processing.
Blood derivatives (serum, plasma, etc.), lacteal secretions, and egg material used in the production of antibody products shall be subjected to an appropriate procedure for the inactivation of potential contaminating microorganisms. The procedure shall be one of those described below and specified in the filed Outline of Production for the product: Provided, That another procedure may be substituted if demonstrated to be at least as effective by data acceptable to APHIS and specified in the filed Outline of Production for the product. These data are expected to come from a study comparing the effectiveness of the established and substitute procedures against a satisfactory battery of potential contaminating microorganisms.
(1)
Blood derivatives of equine origin shall be heated at 58.0-59.0° C for 60 minutes, and blood derivatives of bovine, porcine, or other origin shall be heated at 58.0-59.0° C for 30 minutes. In lieu of heat treatment, blood derivatives of any origin may be treated with at least 2.5 megarads of ionizing radiation, with a maximum radiation dosage specified in the filed Outline of Production for the product.
(2)
Lacteal secretions shall be heated as described in paragraph (e)(1) of this section, or shall be pasteurized at either 72° C for 15 seconds or 89° C for 1 second using appropriate equipment. In lieu of the heat treatment regimens prescribed, lacteal secretions may be treated with at least 2.5 megarads of ionizing radiation, with a maximum radiation dosage specified in the Outline of Production for the product.
(3)
Egg material shall be heated at 58.0-59.0° C for 30 minutes, or treated with at least 2.5 megarads of ionizing radiation, with a maximum radiation dosage specified in the filed Outline of Production for the product.
(4)
Blood derivatives, lacteal secretions, and egg material shall not contain preservatives at the time of heat treatment, and immediately after heat treatment shall be cooled to 7° C or lower.
(5)
Licensees shall keep detailed records as to each batch treated and each serial of product prepared for marketing. Recording charts shall bear full information concerning the material treated and tests made of the equipment used for treatment.
(f) Preservatives.
Liquid antibody products, except those immediately frozen following preparation and maintained in a frozen state until time of use, shall contain at least one preservative from the following list, within the range of concentration set forth:
(g) Antigens for hyperimmunization.
If animals are hyperimmunized to generate antibodies for a product for the prevention and/or alleviation of a specific infectious disease, and a USDA-licensed veterinary biological product is not employed for this purpose, the following shall apply:
(i)
Bacterial Master Seeds shall be tested for purity and identity as prescribed for live bacterial vaccines in § 113.64.
(ii)
Viral Master Seeds shall be tested for purity and identity as prescribed for live virus vaccines in § 113.300.
(2)
The maximum allowable passage level of the hyperimmunizing antigen shall be the passage level of the antigen used to generate product shown to be efficacious and shall not exceed 10 passages from the Master Seed.
(h) Purity tests.
Final container samples of each serial and each subserial shall be tested for viable bacteria and fungi as follows:
(1)
Dried products for parenteral administration and liquid products shall be tested as prescribed in § 113.26.
(2)
For dried products for oral administration, 10 final container samples shall be reconstituted with sterile water at the volume recommended on the label and tested for the following contaminants:
(i) Coliforms.
One milliliter of each rehydrated sample shall be pipetted into a 100×15 mm petri dish and 10-15 ml of violet red bile agar at 45-50° C added. The plate shall be manipulated to coat its entirety with the agar-sample mixture and allowed to stand until the mixture solidifies. The plate shall then be incubated at 35° C for 24 hours. A positive control plate and a negative control plate shall be prepared at the same time and in the same manner as the plates containing samples of the serial. All plates shall be examined at the end of the incubation period. If characteristic growth is observed on the negative control plate, or no characteristic growth is observed on the positive control plate, the test shall be considered inconclusive and may be repeated. If characteristic growth is observed on any of the 10 plates containing samples of the serial, one retest to rule out faulty technique may be conducted on samples from 20 final containers. If characteristic growth is observed on any of the retest plates, or if a retest is not initiated within 21 days of the completion of the original test, the serial or subserial is unsatisfactory.
(ii) Salmonellae.
One milliliter of each rehydrated sample shall be pipetted into a 100×15 mm petri dish and 10-15 ml of brilliant green agar at 45-50° C added. The dish shall be manipulated to coat its entirety with the agar-sample mixture and allowed to stand until the mixture solidifies. The plate shall then be incubated at 35° C for 24 hours. A positive control plate and a negative control plate shall be prepared at the same time and in the same manner as the plates containing samples of the serial. All plates shall be examined at the end of the incubation period. If characteristic growth is observed on the negative control plate, or no characteristic growth is observed on the positive control plate, the test shall be considered inconclusive and may be repeated. If characteristic growth is observed on any of the 10 plates containing samples of the serial, one retest to rule out faulty technique may be conducted on samples from 20 final containers. If characteristic growth is observed on any of the retest plates, or if a retest is not initiated within 21 days of the completion of the original test, the serial or subserial is unsatisfactory.
(iii) Fungi.
One milliliter of each rehydrated sample shall be pipetted into a 100×15 mm petri dish and 10-15 ml of appropriately acidified potato dextrose agar at 45-50° C added. The plate shall be manipulated to coat its entirety with the agar-sample mixture and allowed to stand until the mixture solidifies. The plate shall then be incubated at 20-25° C for 5 days. A positive control plate and a negative control plate shall be prepared at the same time and in the same manner as the plates containing samples of the serial. All plates shall be examined at the end of the incubation period. If growth is observed on the negative control plate, or no growth is observed on the positive control plate, the test shall be considered inconclusive and may be repeated. If growth is observed on any of the 10 plates containing samples of the serial, one retest to rule out faulty technique may be conducted on samples from 20 final containers. If growth is observed on any of the retest plates, or if a retest is not initiated within 21 days of the completion of the original test, the serial or subserial is unsatisfactory.
(iv) Total bacterial count.
One milliliter of each rehydrated sample, undiluted or diluted as prescribed in the Outline of Production, shall be pipetted into a 100×15 mm petri dish and 10-15 ml of tryptone glucose extract agar at 45-50° C added. The plate shall be manipulated to coat its entirety with the agar-sample mixture and allowed to stand until the mixture solidifies. The plate shall then be incubated at 35° C for 48 hours. A positive control plate and a negative control plate shall be prepared at the same time and in the same manner as the plates containing samples of the serial. All plates shall be examined at the end of the incubation period. If growth is observed on the negative control plate, or no growth is observed on the positive control plate, the test shall be considered inconclusive and may be repeated. If the average number of bacterial colonies on the 10 plates containing samples of the serial exceeds that specified in the filed Outline of Production for the product, one retest to rule out faulty technique may be conducted on samples from 20 final containers. If the average number of bacterial colonies on the retest plates exceeds that specified in the filed Outline of Production for the product, or if a retest is not initiated within 21 days of the completion of the original test, the serial or subserial is unsatisfactory.
(i) Safety tests.
Bulk or final container samples of each serial shall be tested as prescribed in § 113.33(b). Dried product shall be reconstituted as indicated on the label and 0.5 ml injected per mouse.