[Federal Register Volume 61, Number 194 (Friday, October 4, 1996)]
[Rules and Regulations]
[Pages 51771-51777]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-25501]


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DEPARTMENT OF AGRICULTURE
9 CFR Part 113

[Docket No. 92-124-2]


Viruses, Serums, Toxins, and Analogous Products; Antibody 
Products

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Final rule.

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SUMMARY: This rule amends the regulations by revising the designation 
for a group of standard requirements from ``Blood Origin Products'' to 
``Antibody Products;'' revising five of the six existing standard 
requirements in the group; removing the sixth; and adding a new 
standard requirement for products intended for the treatment of failure 
of passive transfer. These amendments are necessary in order to update 
the standard requirements for veterinary biological products and to 
provide for their regulation in a manner that is more consistent with 
current scientific knowledge and understanding.

EFFECTIVE DATE: November 4, 1996

FOR FURTHER INFORMATION CONTACT: Dr. David A. Espeseth, Deputy 
Director, Veterinary Biologics, BBEP, APHIS, 4700 River Road Unit 148, 
Riverdale, MD 20737-1237, (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

    In accordance with the regulations in 9 CFR part 113 (hereinafter 
referred to as ``the regulations''), standard requirements are 
prescribed for the preparation of veterinary biological products. A 
standard requirement consists of specifications, procedures, and test 
methods that define the standards of purity, safety, potency, and 
efficacy for a veterinary biological product. Where a standard 
requirement for a product does not exist, production procedures and 
specifications for purity, safety, and potency of a biological product 
are provided in an Outline of Production filed with the Animal and 
Plant Health Inspection Service (APHIS). For consistency of review and 
uniformity of standards, standard requirements are codified in the 
regulations.
    In recent years, the number of license applications received by 
APHIS for antibody products has increased substantially. Historically, 
the antibody source material for most of these products has been blood. 
Increasingly, however, the Agency is being presented with products for 
licensure that are derived from other sources such as colostrum, milk, 
and eggs. Standard requirements for many of these products are not 
codified in the regulations, and many of the products are not 
adequately addressed by the general requirements for blood origin 
products in Sec. 113.450.
    On July 23, 1993, we published in the Federal Register (58 FR 
39462-39467, Docket No. 92-124-1) a proposed rule that would update the 
regulations to provide more consistent licensing standards and more 
appropriate product-indication statements that, in turn, should provide 
greater guidance to manufacturers and lead to more reliable products.
    We solicited comments concerning our proposal for 60 days ending 
September 21, 1993. We received twelve sets of comments by that date. 
They were from eight manufacturers of veterinary biological products, 
three consultants, and a national trade association.
    One commenter asked what the impact of the rule would be on a 
product that is currently licensed by APHIS as a veterinary biological 
but for which no biologic-type claim (i.e., a claim that a product 
functions through an immunologic mechanism to diagnose, prevent, or 
alleviate animal disease) is made, overtly or by implication. The 
commenter noted that the proposed regulations do not seem to 
specifically address this category of product. In response to the 
commenter, APHIS notes that these type of products were licensed at the 
request of producers for use in the nonspecific treatment of anemia, 
hemorrhage, or shock that may follow injury to horses. The regulations 
referred to such products as ``normal serum.'' This regulation does not 
specifically address normal serum because it is not a product which is 
required to be licensed. Therefore, no new licenses shall be issued for 
normal serum, which is not intended to affect the immune mechanism. 
APHIS will work with the producers of any such product that may be 
currently licensed to resolve any questions involving these type of 
products. No change to the regulations is made in response to this 
comment.
    One commenter criticized the proposed nomenclature for products 
intended for the treatment of failure of passive transfer (FPT) 
proposed in Sec. 113.450(b)(3). The commenter asserted that to refer to 
these products as ``IgG'' is misleading because such products may 
contain ``many other protective factors.'' In response to the 
commenter, APHIS believes the nomenclature proposed for products for 
the treatment of FPT is appropriate for this category of biological 
product. The reason for this is that FPT is most commonly defined as a 
below normal level of circulating, maternally derived immunoglobulin G 
(IgG) in the neonate, the awareness that IgG is measured in the 
establishment of product efficacy and potency, and the understanding 
that the ``other protective factors'' (i.e., substances other than 
immunoglobulins) cited are at best very poorly characterized. No change 
to the regulations is made in response to this comment.
    Three commenters suggested other changes to proposed 
Sec. 113.450(c). Two of the commenters stated that the proposed 
regulations precluded the use of slaughterhouse blood as an antibody

[[Page 51772]]

source and opined that the proposed restriction is unwarranted. APHIS 
believes that, unless slaughtered animals are from a herd that is 
maintained at a licensed establishment, physically examined, and tested 
to ensure freedom from infectious disease, their blood is unacceptable 
as a source of antibody. In this respect, the proposed regulations 
differ little from the current regulations. Assurance of the health of 
donor animals is necessary to reduce the risk of product contamination 
from infectious agents. No change to the regulations is made in 
response to these comments.
    The other commenter addressed the provision in proposed 
Sec. 113.450(c) that would exempt cattle from Grade A dairies supplying 
lacteal secretions for the manufacture of a veterinary antibody product 
from being maintained at a licensed establishment. The commenter 
recommended that the exemption be broadened to include cattle from 
Grade B dairies. In response to the commenter, APHIS notes that while 
Grade A dairies are required to conform to the provisions of the Food 
and Drug Administration's Grade ``A'' Pasteurized Milk Ordinance, the 
regulations that apply to dairies supplying Manufacturing Grade milk 
are less uniform and usually less stringent. In addition, monitoring of 
``Grade B'' dairies is significantly less rigorous. Exempting Grade A 
dairies in Sec. 113.450(c) strikes an appropriate balance between 
assuring pure, safe, and efficacious products and recognizing that 
maintenance of a dairy herd of sufficient size at a licensed 
establishment would be an economic burden. No change to the regulations 
is made in response to this comment.
    Three commenters provided remarks concerning proposed 
Sec. 113.450(e). One commenter felt that the specified radiation dose 
should be reduced from 3.0 megarads to at least 2.5 megarads to be more 
consistent with published information in this area. APHIS agrees with 
this comment. In addition, we believe the rules should allow a narrow 
range in the level of radiation, since it is often difficult to assure 
that an exact radiation dose will be delivered. In response to this 
comment, the regulations in Secs. 113.450(e)(1), 113.450(e)(2), and 
113.450(e)(3) are revised to indicate that the level of ionizing 
radiation to which applicable source material must be subjected shall 
be at least 2.5 megarads, and that a maximum radiation dosage is to be 
specified in the Outline of Production, based on data for that product.
    The second commenter stated that the proposed treatment methods for 
the inactivation of extraneous agents would be too limited and that 
other methods of treatment should be considered by the Agency. In 
response to the commenter, APHIS agrees that other procedures may be as 
or more effective than those proposed. We agree that other procedures 
may be more appropriate for some source materials and that greater 
flexibility is needed. We are therefore amending the introductory 
paragraph of proposed Sec. 113.450(e) to allow the use of another 
procedure, provided it is demonstrated to be at least as effective by 
data acceptable to APHIS and the procedure chosen is described in the 
filed Outline of Production for the product. Data submitted should 
demonstrate the alternative procedure is at least as effective against 
a battery of potential contaminating pathogenic microorganisms as the 
thermal- and irradiation-treatment methods specified.
    The third commenter asserted that treatment of certain source 
materials is unnecessary because of the manner in which the materials 
are obtained. The commenter added that for certain materials, the 
proposed irradiation regimen would be acceptable (i.e., it would not 
render the materials unsuitable for use in production) only if the 
materials were manipulated in special, costly ways prior to treatment. 
In response to the commenter, the proposed regulations are the same as 
the current regulations in requiring treatment of source materials. 
APHIS believes that treatment that is demonstrated to be effective in 
eliminating viable pathogenic microorganisms is an essential component 
of an established protocol to ensure that an antibody product poses 
minimal risk for transmitting a potential pathogen. Regarding the claim 
that irradiation is unsuitable for certain substances, APHIS believes 
that ionizing radiation at the levels prescribed may impact the 
physical character of some source materials. Many of these materials, 
however, may be successfully heat treated. Because some source 
materials may not be amenable to either heating or exposure to ionizing 
radiation, APHIS believes flexibility should be provided in the 
regulations to permit the use of other procedures, provided that they 
can be shown to be as effective as the proposed methods for the 
intended purpose. As explained above, we have amended Sec. 113.450(e) 
to provide such flexibility.
    One commenter expressed opposition to the regulations in proposed 
Sec. 113.450(h)(2) that require that any retest for purity of dried 
products for oral administration be conducted within 21 days of the 
original test. The commenter stated that ``valid circumstances may 
arise that prevent a test from being restarted within the 21 day time 
frame.'' In response to the commenter, we believe that some time limit 
must be prescribed, that it would be improper to allow a very long 
period of time to elapse before retesting, and that the proposed period 
would, in almost all situations, prove acceptable to the manufacturer. 
If we are presented with legitimate ``valid circumstances'' by a 
manufacturer, an extension of the time period for retest could be 
considered under the provisions of Sec. 113.4. No change to the 
regulations is made in response to this comment.
    Ten commenters expressed opinions concerning proposed Sec. 113.499, 
which refers to products for the treatment of FPT. Eight of the 
commenters felt it was inappropriate to restrict the recommendation of 
a product to use only in neonates of the same species as that of 
antibody origin. It appears that five of the commenters misinterpreted 
the regulations, incorrectly interpreting them to mean that the 
restriction extended to all antibody products, not just to products 
intended for the treatment of FPT. In response to the three commenters 
who correctly interpreted the restriction to apply only to products 
intended for the treatment of FTP, APHIS believes its position is 
appropriate. An acceptable FPT product is one that, at the recommended 
dose, raises the serum IgG concentration of maternal-IgG-deficient 
neonates by a specified minimum amount. This increase in serum IgG 
concentration might be expected to confer a significant degree of 
protection against a broad spectrum of potential pathogens. With few 
exceptions, however, true broad-spectrum protection by FPT products has 
not been demonstrated. Furthermore, the potency test for such products, 
conducted to ensure that a dose of product has at least a minimum 
quantity of IgG, does not measure the ability of the product to protect 
against or alleviate disease. Upon considering factors such as antibody 
functionality, antibody half-life, and the spectrum of antibody 
activity, the Agency believes that the meaningful clinical efficacy of 
heterologous (i.e., derived from a different species) FPT products is 
simply too uncertain to warrant their licensure. No change to the 
regulations is made in response to these comments.
    One commenter stated that the proposed requirement that 
parenterally administered products for the treatment of FPT should be 
recommended for use only in animals 120 hours of age or less would be 
too restrictive. In response to the commenter, APHIS notes that some

[[Page 51773]]

manufacturers of parenterally-administered FPT products have 
recommended that the products be used in animals of virtually any age, 
even though FPT is limited to neonatal animals. We believed that the 
inclusion in the proposed regulations of a prohibition against 
recommending such products for use in older animals would aid in 
preventing misuse of the product. However, we agree that the proposed 
rule may have been too restrictive in this regard. Therefore, in 
response to the comment, APHIS has revised the regulations in 
Sec. 113.499 to specify that parenterally administered products for the 
treatment of FPT be recommended for use only in neonatal animals.
    Two commenters expressed concern with the regulations in proposed 
Sec. 113.499(a) pertaining to the establishment of an IgG Reference 
Product. One commenter stated that ``IgG Reference Product'' and ``IgG 
Species Standard'' should be more clearly defined and that requiring 
the establishment of an IgG Reference Product was inappropriate. The 
commenter described an alternative method for establishing product 
efficacy and ensuring adequate potency of production serials that was 
not entirely clear. In response to the commenter, we have amended the 
regulations to define more completely ``IgG Reference Product'' and 
``IgG Species Standard''. In further response to the commenter, we 
believe that, based on the high degree of variability between radial 
immunodiffusion (RID) kits for IgG, an IgG Reference Product must be 
qualified (i.e., shown through efficacy testing to be an acceptable 
potency test reference).
    The other commenter stated that the proposed requirement that dose 
size be based on body weight should be eliminated. The commenter 
asserted that because FPT products are usually marketed in a single 
dose size for all animals for which they are intended, and labels for 
veterinary biologics are required to state that the entire contents of 
a container must be used when first opened, portions of containers will 
often have to be discarded. The commenter also believed that the 
preparation of an IgG Species Standard would be improper because a 
standard appropriate for one species would not be appropriate for 
another. In response to the commenter, we acknowledge that 
historically, recommended dosages of FPT products have not been linked 
to body weight and that consumers have come to expect this. As a 
result, we are amending the regulations to indicate that an IgG 
Reference Product may be established with a single-dose size for all 
animals, as long as the animals used are at or near the maximum weight 
for neonates of the species. Regarding the IgG Species Standard, it is 
not APHIS' intent to have a single standard for all species. Different 
standards would be prepared for calves, foals, pigs, and so on.
    In addition to the comments received, APHIS is making the following 
changes to the regulations for clarity. APHIS notes that the test media 
specified in proposed Secs. 113.450(h)(2)(i) and 113.450(h)(2)(ii) are 
quite selective. It is possible, however, that an occasional 
noncoliform or nonSalmonella growth may appear on one or more test 
plates. To allow for this possibility, the regulations under these 
sections are revised to change the term ``growth'' to ``characteristic 
growth'' to indicate that the purity test is intended to screen for the 
growth of specified bacteria.
    APHIS also notes that some antibody source materials--for example, 
whey from cheese making operations--may contain high levels of 
innocuous bacteria, and that biological products made from these 
materials may contain so many bacteria per dose that rehydrated product 
would have to be further diluted to do a meaningful total bacterial 
count as proposed in Sec. 113.450(h)(2)(iv). To allow for this, the 
regulations are revised to provide for an appropriate dilution of the 
rehydrated sample prior to its addition to the test plates.
    APHIS further notes that the regulations in Secs. 113.499(a) and 
113.499(c) may not make it clear whether one IgG measurement is to be 
obtained from each of five radial immunodiffusion (RID) plates or if 
five IgG measurements may be obtained from just one, or possibly two, 
RID plates. In addition, APHIS believes that five IgG measurements of 
each of the paired serum samples to qualify an IgG Reference Product is 
unnecessary. The regulations are revised to specify that ``five IgG 
measurements'' be made (Sec. 113.499(a)(6) and (c)) and to replace the 
proposed five replicate tests with one concurrent test for paired serum 
samples (Sec. 113.499(a)(5)).
    In addition, APHIS notes that because the RID assay is 
semiquantitative, five IgG measurements of two samples instead of one, 
as proposed, should be made for retests for potency of serials of FPT 
products. The regulations are revised in Sec. 113.499(c) to specify 
that two samples of a serial be included in a retest instead of one. 
This is consistent with retest requirements for other product types.
    Therefore, based on the rationale set forth in the proposed rule 
and in this document, we are adopting the provisions of the proposed 
rule as a final rule, with the changes discussed in this document. The 
agency will review, on a case-by-case basis, within one year after the 
effective date of this rule, products that may be affected by this rule 
to ensure that such products come into conformance by the end of the 
review period.

Executive Order 12866 and Regulatory Flexibility Act

    This rule has been reviewed under Executive Order 12866. The rule 
has been determined to be not significant for the purposes of Executive 
Order 12866 and, therefore, has not been reviewed by the Office of 
Management and Budget.
    The amendments to the regulations should, in most instances, either 
have no significant economic impact or have a positive economic impact. 
For example, manufacturers will not be restricted to pasteurization for 
the treatment of source materials. Where this final rule may have a 
negative economic impact on manufacturing, such impact should be 
minimal. A negative impact may arise because this rule prohibits 
recommendations for cross-species use of FPT products. Notification, 
however, that such a prohibition was being considered was given by 
APHIS over 7 years ago.
    Sections 113.450 through 113.455 are amended to reflect current 
scientific understanding and to establish uniform standards for 
antibody products made from substances other than blood. One such 
amendment is the provision for use of other procedures for eliminating 
potential contaminating microorganisms. The Agency believes the 
amendment is important because the Agency intends to require that all 
antibody products be subjected to an appropriate procedure for 
inactivation of potential contaminating microorganisms or another 
procedure demonstrated to be equally effective in eliminating viable 
pathogenic microorganisms. Currently, equine plasma products are 
exempted from heat treatment by approval of Outlines of Production. At 
the time this exemption was given, no other products were available for 
treatment of FPT in foals and it was believed that plasma-based 
products were not amenable to heat treatment. Certain equine FPT 
products that are now licensed are subjected to a treatment step in 
their manufacture. The Agency believes that no special benefit 
associated with the biologic-type claim has been demonstrated for 
plasma-based products to offset the added risk associated with no 
procedure for elimination. The amendment will give the manufacturers

[[Page 51774]]

of antibody products derived from equine plasma the option to use other 
procedures for such products provided they are demonstrated to be 
equally effective as heat or irradiation treatment by data acceptable 
to APHIS.
    Section 113.499 is added to provide standards for products for the 
treatment of failure of passive transfer. The addition of the provision 
in this section that restricts the use of such products to the same 
species as that of antibody origin will economically impact the one 
manufacturer of an FPT product currently approved for cross-species 
use. The firm was notified over 7 years ago of our intent to establish 
such regulations that would restrict the recommendations for use of its 
product. The Agency believes the firm has been given adequate notice to 
provide compelling efficacy and potency data or prepare for the removal 
of the cross-species recommendation from labeling and advertising. 
Given the length of time from notification, we believe the loss of the 
recommendation should result in minimal economic loss to the producer.
    The addition of Sec. 113.499 may initially increase the cost to 
some FPT product manufacturers as necessary label changes are made and 
IgG Reference Products are qualified. This is not unexpected when a 
standard requirement is codified. No negative economic impact beyond 
that initially incurred is anticipated. Firms will be given one year 
from the effective date of this rule to come into compliance with it.
    We do not expect any increase in cost to the other biologics 
manufacturers affected by this rule.
    Under these circumstances, the Administrator of the Animal and 
Plant Health Inspection Service has determined that this action will 
not have a significant economic impact on a substantial number of small 
entities.

Executive Order 12372

    This program/activity is listed in the Catalog of Federal Domestic 
Assistance under No. 10.025 and is subject to Executive Order 12372, 
which requires intergovernmental consultation with State and local 
officials. (See 7 CFR part 3015, subpart V.)

Paperwork Reduction Act

    This rule contains no new information collection or recordkeeping 
requirements under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.).

Executive Order 12988

    This final rule has been reviewed under Executive Order 12988, 
Civil Justice Reform. It is not intended to have retroactive effect. 
This rule would not preempt any State or local laws, regulations, or 
policies, unless they present an irreconcilable conflict with this 
rule. There are no administrative procedures that must be exhausted 
prior to a judicial challenge to the provisions of this rule.

Regulatory Reform

    This action is part of the President's Regulatory Reform 
Initiative, which, among other things, directs agencies to remove 
obsolete and unnecessary regulations and to find less burdensome ways 
to achieve regulatory goals.

List of Subjects in 9 CFR Part 113

    Animal biologics, Exports, Imports, Reporting and recordkeeping 
requirements.
    Accordingly, 9 CFR part 113 is amended as follows:

PART 113--STANDARD REQUIREMENTS

    1. The authority citation for part 113 continues to read as 
follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.2(d).

    2. The undesignated center heading preceding Sec. 113.450 is 
revised to read ``ANTIBODY PRODUCTS''.
    3. Section 113.450 is revised to read as follows:


Sec. 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.
    (b) Nomenclature. Antibody products shall be named as follows:
    (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

[[Page 51775]]

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.
    (i) Before first use, horses shall be tested as follows for:
    (A) Equine infectious anemia (EIA) at a laboratory approved by 
APHIS.
    (B) Piroplasmosis, dourine, and glanders at the National Veterinary 
Services Laboratories.
    (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.
    (iii) Before first use, cattle shall be tested as follows for:
    (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 deg. C for 60 minutes, and blood derivatives of bovine, porcine, 
or other origin shall be heated at 58.0-59.0 deg. 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 deg. C for 
15 seconds or 89 deg. 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 deg. 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 deg. 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:
    (1) Phenol 0.25 to 0.55 percent, or
    (2) Cresol 0.10 to 0.30 percent, and/or
    (3) Thimerosal 0.01 to 0.03 percent, or
    (4) Other preservative(s) specified in the filed Outline of 
Production for the product.
    (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:
    (1) For each antigen, a Master Seed shall be established.
    (i) Bacterial Master Seeds shall be tested for purity and identity 
as prescribed for live bacterial vaccines in Sec. 113.64.
    (ii) Viral Master Seeds shall be tested for purity and identity as 
prescribed for live virus vaccines in Sec. 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

[[Page 51776]]

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 Sec. 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  x  15 mm petri dish and 10-15 ml of violet red 
bile agar at 45-50 deg. 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 deg. 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  x  15 mm petri dish and 10-15 ml of brilliant 
green agar at 45-50 deg. 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 deg. 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  x  15 mm petri dish and 10-15 ml of appropriately 
acidified potato dextrose agar at 45-50 deg. 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 deg. 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  x  15 mm petri dish and 10-15 
ml of tryptone glucose extract agar at 45-50 deg. 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 deg. 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 Sec. 113.33(b). Dried product shall be 
reconstituted as indicated on the label and 0.5 ml injected per mouse.
    4. In Sec. 113.451, paragraphs (b) and (c) are removed, paragraph 
(d) is redesignated paragraph (b), and the introductory text of the 
section is revised to read as follows:


Sec. 113.451  Tetanus Antitoxin.

    Tetanus Antitoxin is a specific antibody product containing 
antibodies directed against the toxin of Clostridium tetani. Each 
serial shall meet the applicable general requirements provided in 
Sec. 113.450 and paragraph (a) of this section, and be tested for 
potency as provided in paragraph (b) of this section. Any serial found 
unsatisfactory by a prescribed test shall not be released.
* * * * *
    5. In Sec. 113.452, the section heading, introductory text of the 
section, and paragraph (a) are revised; paragraph (b) is removed; 
paragraph (c) is redesignated as new paragraph (b); and newly 
redesignated paragraph (b) introductory text, paragraphs (b)(1) and 
(b)(3) are revised to read as follows:


Sec. 113.452  Erysipelothrix Rhusiopathiae Antibody.

    Erysipelothrix Rhusiopathiae Antibody is a specific antibody 
product containing antibodies directed against one or more somatic 
antigens of Erysipelothrix rhusiopathiae. Each serial shall be tested 
as provided in this section. Any serial found unsatisfactory by a 
prescribed test shall not be released.
    (a) Each serial shall meet the applicable general requirements 
provided in Sec. 113.450.
    (b) Potency test. Bulk or final container samples of completed 
product from each serial shall be tested using the two-stage test 
provided in this section.
    (1) In the first stage, each of 40 Swiss mice, each weighing 16 to 
20 grams, shall be injected subcutaneously with 0.1 ml of product 
(dried product shall be rehydrated according to label directions). 
Twenty-four hours postinjection, the injected mice and 10 additional 
mice designated controls shall be challenged subcutaneously with the 
same culture of Erysipelothrix rhusiopathiae.
* * * * *
    (3) The mice injected with product shall be observed for 10 days 
postchallenge and all deaths recorded.

[[Page 51777]]

The second stage shall be required when 7-10 of the mice injected with 
product die in the first stage. The second stage shall be conducted in 
a manner identical to the first stage.
* * * * *


Sec. 113.453  [Removed and Reserved]

    6. Section 113.453 is removed and reserved.
    7. In Sec. 113.454, the introductory text of the section and 
paragraph (a) are revised; paragraph (b) is removed; paragraph (c) is 
redesignated as new paragraph (b); and the introductory text of newly 
designated paragraph (b) is revised to read as follows:


Sec. 113.454  Clostridium Perfringens Type C Antitoxin.

    Clostridium Perfringens Type C Antitoxin is a specific antibody 
product containing antibodies directed against the toxin of Clostridium 
perfringens Type C. Each serial shall be tested as provided in this 
section. Any serial found unsatisfactory by a prescribed test shall not 
be released.
    (a) Each serial shall meet the applicable general requirements 
provided in Sec. 113.450.
    (b) Potency test. Bulk or final container samples of completed 
product from each serial shall be tested using the toxin-neutralization 
test for Beta Antitoxin provided in this section. Dried products shall 
be rehydrated according to label directions.
* * * * *
    8. In Sec. 113.455, the introductory text of the section and 
paragraph (a) are revised; paragraph (b) is removed; paragraph (c) is 
redesignated as new paragraph (b); and the introductory text of newly 
redesignated paragraph (b) is revised to read as follows:


Sec. 113.455  Clostridium Perfringens Type D Antitoxin.

    Clostridium Perfringens Type D Antitoxin is a specific antibody 
product containing antibodies directed against the toxin of Clostridium 
perfringens Type D. Each serial shall be tested as provided in this 
section. Any serial found unsatisfactory by a prescribed test shall not 
be released.
    (a) Each serial shall meet the applicable general requirements 
provided in Sec. 113.450.
    (b) Potency test. Bulk or final container samples of completed 
product from each serial shall be tested using the toxin-neutralization 
test for Epsilon Antitoxin provided in this section. Dried products 
shall be rehydrated according to label directions.
* * * * * * *


Secs. 113.456 through 113.498  [Added and Reserved]

    9. New Secs. 113.456 through 113.498 are added and reserved.
    10. New Sec. 113.499 is added to read as follows:


Sec. 113.499  Products for treatment of failure of passive transfer.

    A product for the treatment of failure of passive transfer (FPT) 
shall contain a specified minimum quantity of IgG per dose and shall be 
recommended for use only in neonates of the same species as that of 
antibody origin. A product for oral administration shall not be 
recommended for use in animals more than 24 hours of age, while one for 
parenteral administration shall only be recommended for use in neonatal 
animals. Each serial shall meet the applicable general requirements 
provided in Sec. 113.450 and be tested for potency as provided in this 
section. Any serial found unsatisfactory by a prescribed test shall not 
be released.
    (a) Qualification of an IgG Reference Product. An IgG Reference 
Product (reference) shall be a serial of product that is manufactured 
according to the filed Outline of Production, properly qualified, and 
used to assess the potency of subsequent product serials, as described 
in paragraph (c) below. The reference shall be qualified as follows:
    (1) At least 20 newborn, colostrum-deprived animals of the species 
for which the product is recommended shall be randomly selected.
    (2) Blood samples shall be taken from each animal.
    (3) Each animal shall be administered one dose of reference by the 
recommended route and shall be observed for 24 hours.
    (i) Any adverse reactions shall be recorded.
    (ii) The dosage of reference administered to each animal shall be 
in accordance with label directions. Label directions may indicate a 
single dosage regardless of weight, in which case the animals in the 
study shall be at or near the maximum weight for neonates of the 
species.
    (4) After 24 hours, blood samples shall be taken from each animal.
    (5) Pretreatment and post treatment serum IgG concentrations shall 
be concurrently determined for each animal using a radial 
immunodiffusion (RID) method acceptable to APHIS and described in the 
filed Outline of Production for the product.
    (6) Concurrently, using the same method, five IgG measurements 
shall be made on an IgG Species Standard supplied or approved by APHIS. 
The IgG Species Standard shall be a preparation that contains IgG 
specific for the species in question at a concentration acceptable to 
APHIS.
    (7) For an IgG Reference Product to be satisfactory, all animals 
used to qualify the reference must remain free of unfavorable product-
related reactions and at least 90 percent of the paired serum samples 
must reflect an increase in IgG concentration (posttreatment minus 
pretreatment concentration) equal to or greater than the IgG 
concentration of the IgG Species Standard.
    (b) Antibody functionality. Prior to licensure, the prospective 
licensee shall perform a neutralization study, or another type of study 
acceptable to APHIS, to demonstrate functionality of product antibody.
    (c) Potency. Bulk or final container samples of completed product 
from each serial shall be tested for IgG content as provided in this 
paragraph. Samples of the test serial and of an IgG Reference Product 
established in accordance with paragraph (a) of this section shall be 
concurrently tested for IgG content by the RID method referred to in 
paragraph (a)(5) of this section. Five IgG measurements shall be made 
on each. If the IgG level per dose of the test serial does not meet or 
exceed that of the reference, one complete retest, involving five IgG 
measurements on both the reference and two samples of the test serial, 
may be conducted. If, upon retest, the average IgG level per dose of 
the two samples of the test serial does not meet or exceed that of the 
reference, or if a retest is not conducted, the serial is 
unsatisfactory.

    Done in Washington, DC, this 30th day of September 1996.
A. Strating,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 96-25501 Filed 10-3-96; 8:45 am]
BILLING CODE 3410-34-P