[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
