[Federal Register Volume 62, Number 110 (Monday, June 9, 1997)]
[Rules and Regulations]
[Pages 31329-31331]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14996]
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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service
9 CFR Part 113
[Docket No. 92-090-2]
Viruses, Serums, Toxins, and Analogous Products; Revision of
Standard Requirements for Clostridium Perfringens Types C and D Toxoids
and Bacterin-Toxoids
AGENCY: Animal and Plant Health Inspection Service, USDA.
ACTION: Final rule.
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SUMMARY: We are amending the regulations pertaining to the Standard
Requirements for Clostridium Perfringens Type C and Clostridium
Perfringens Type D toxoids and bacterin-toxoids. The amendments will
reduce the minimum number of rabbits required in order to pool their
serum for testing. This amendment will also clarify the method of
determining the test vaccine dose in rabbits based on the recommended
vaccine dosage in cattle and other host animal species.
These amended regulations will not change the accuracy of the
assays and, under certain circumstances, will reduce the number of
required tests as well as the number of mice needed for testing. The
amendment is necessary to make the potency assays conform more closely
to the revised standard requirements for Clostridium Novyi and
Clostridium Sordellii Bacterin-Toxoids and more economical to run when
combination products containing these fractions are tested.
EFFECTIVE DATE: July 9, 1997.
FOR FURTHER INFORMATION CONTACT: Dr. David A. Espeseth, Director,
Licensing and Policy Development, Center for Veterinary Biologics, VS,
APHIS, USDA, 4700 River Road Unit 148, Riverdale, MD 20737-1237, (301)
734-8245.
SUPPLEMENTARY INFORMATION:
Background
The regulations in 9 CFR part 113 pertain to standard requirements
for the preparation of veterinary biological products. A standard
requirement consists of test methods, procedures, and criteria
established by the Animal and Plant Health Inspection Service (APHIS)
to determine that a veterinary biological product is pure, safe,
potent, and efficacious and not worthless, dangerous, contaminated, or
harmful.
These regulations concerning potency testing of Clostridium
Perfringens Type C Toxoid and Bacterin-Toxoid in Sec. 113.111 and
Clostridium Perfringens Type D Toxoid and Bacterin-Toxoid in
Sec. 113.112 reduce certain test requirements and decrease the cost of
performing these tests. This has been accomplished without affecting
the accuracy and reliability of the tests.
On March 22, 1993, we published a proposed rule in the Federal
Register (58 FR 15301-15303, Docket No. 92-090-1) to amend the
regulations in Sec. 113.111 pertaining to Clostridium Perfringens Type
C Toxoid and Bacterin-Toxoid and in Sec. 113.112 pertaining to
Clostridium Perfringens Type D Toxoid and Bacterin-Toxoid.
We proposed to reduce the number of mice needed for serum
neutralization testing in certain circumstances. Also, the current test
method uses half of the recommended cattle or sheep dose. The proposed
rule provided for potency testing of product recommended for use in
host animal species other than cattle and sheep. The test method in the
proposed rule provided for recommendations for a variety of host animal
species by prescribing the use of half of the smallest host animal
dose.
Current regulations in Secs. 113.111(c) and 113.112(c) provide for
at least four of eight rabbits which are initially injected to be bled
in the potency determination of Clostridium Perfringens Type C Toxoid
and Bacterin-Toxoid and Clostridium Perfringens Type D Toxoid and
Bacterin-Toxoid. The amount of antitoxin found in the rabbit sera after
injection with the toxoid or bacterin-toxoid is proportional to the
potency of the antigen in the product tested.
The antitoxin response of vaccinated rabbits is measured by a toxin
neutralization assay in mice. A standard amount of Clostridium
perfringens Beta or Epsilon toxin is mixed with a designated amount of
the test rabbits' sera. The mixture is allowed to neutralize for one
hour. Swiss white mice are then injected with this toxin-sera mixture
to determine if the standard amount of toxin was neutralized by the
test rabbit sera. Since mice are particularly sensitive to these
toxins, the absence of mouse mortality indicates sufficient toxin
neutralization and thus an adequate antitoxin response in the rabbits
tested. The result would indicate an acceptable potency for the toxoid
or bacterin-toxoid antigen in the product tested.
Under the current regulations in Secs. 113.111(c) and 113.112(c),
if four to seven rabbits are bled for potency testing, the sera from
each rabbit must be assayed individually. This requires the use of at
least 20 to 35 mice (each rabbit serum is tested in a minimum of 5
mice) for serum neutralization testing as compared to a minimum of 5
mice with the single pooled serum sample which was proposed.
The proposed rule required the use of at least seven rabbits in
order for the sera to be pooled into a single sample. The potency test
would then be conducted on the single pooled sample. Pooling the serum
samples of seven instead of eight rabbits would reduce the number of
toxin-antitoxin neutralization tests required, the number of mice
needed, the time spent, and the expense of the procedure.
We solicited comments concerning our proposal for 60 days ending
May 21, 1993. We received six comments by that date from manufacturers
of animal health products and a national trade association. One of the
commenters supported the proposed rule as written, while five raised
specific issues concerning the proposed rule. Those comments are
discussed below.
One commenter expressed concern that, as proposed, the rule had the
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unintended effect of making the potency test requirements more
stringent. As a cure, the commenter recommended the use of half the
cattle dose for testing the potency of all Clostridium Perfringens
Toxoids.
Five other commenters also expressed concern about the proposed
reduction in the volume of rabbit inoculum to half the smallest host
animal dose. One firm indicated it would be forced to increase antigen
content in order to pass the more stringent requirement resulting from
a reduced volume of rabbit inoculum, with the possible negative effect
on host animal safety.
Three commenters indicated that the proposed inoculum volumes would
be incompatible with those in the recently revised standard
requirements for Clostridium Novyi and Clostridium Sordellii, which
permitted utilization of the same group of rabbits for testing of sheep
and cattle product fractions, the only two species addressed under that
standard requirement. One commenter indicated that there is no need to
change the volume of the rabbit inoculum under the current regulations.
Yet another commenter suggested that the volume of rabbit inoculum
should be half of the largest dose indicated on the label for any
species of animal for which the product is recommended. The commenter
argued that this suggestion would not affect the potency test procedure
for any licensed product, while it would address the dosage to be used
for alternate species not specifically addressed under the current
regulations, i.e., goats and swine.
In response to these comments, APHIS agrees that a volume of rabbit
inoculum that is half the largest host animal dose for any species of
animal for which the product is recommended is reasonable and also
provides for more general indications that are appropriate for products
not recommended for cattle or sheep. Reference to half of the largest
host animal dose would, in most cases, result in the same rabbit test
dosage that is used for testing these products in the current standard
requirement. The proposal to require half the smallest host animal dose
would have unnecessarily raised the potency requirement for some
products and, in contrast to statements made in the proposed rule,
would have resulted in test procedures that were not consistent with
recent standard requirements for products containing Clostridium novyi
and Clostridium sordellii. Therefore, in response to these comments, we
are amending the regulations in Secs. 113.111 and 113.112, paragraph
(c)(2), to allow the use of half the largest recommended dose in host
animals for the rabbit potency testing for any species of animal for
which the product is recommended. The change in the proposed rule will,
in most cases, retain the potency test requirement for these products
at the same level as in the current standard requirement while
recognizing products that would be used in animals other than cattle or
sheep.
In further response to the comment that the standard requirement
for Clostridium Perfringens should be consistent with those of
Clostridium Novyi and Clostridium Sordellii, APHIS notes that the
recently amended standard requirements for Clostridium Novyi and
Clostridium Sordellii require that the strain of rabbit used for
potency testing be acceptable to APHIS. APHIS believes that, for
consistency, the requirement should apply equally to Clostridium
Perfringens. Therefore, in response to this comment, we are adding the
requirement in Secs. 113.111 and 113.112, paragraph (c)(2), that the
strain of rabbit used for potency testing Clostridium Perfringens be
acceptable to APHIS.
Therefore, based on the rationale set forth in the proposed rule
and in this document, we are adopting the provisions of the proposal as
a final rule, with the changes discussed in this document.
Executive Order 12866 and Regulatory Flexibility Act
This 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.
There are currently some 19 veterinary biologics establishments
that may be affected by this rule. According to the Small Business
Administration regulations, many of them would be classified as small
entities.
This rule will result in a reduction of the number of mice required
to perform potency assays. The reduction in the number of mice needed
will result in a reduction in the total cost of the assays. Therefore,
the rule should provide an economic benefit to producers of veterinary
biologics. In addition, this rule clarifies the dosage of rabbit
inoculum to be used in potency tests for products recommended for
species other than cattle or sheep.
Retests may be indicated if less than 80 percent of control mice,
inoculated with standard antitoxin and 10 L+ doses of
standard toxin, die in the neutralization test. However, since the
testing of the pooled serum sample requires fewer mice as compared to
testing individual serum samples, the number of mice required for a
retest will be less.
Manufacturers, as well as the National Veterinary Services
Laboratories, will benefit from the revisions since they will improve
efficiency and reduce costs but will not change the accuracy of the
assays.
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.)
Executive Order 12988
This 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 which must be exhausted
prior to a judicial challenge to the provisions of this rule.
Paperwork Reduction Act
This rule contains no new information collection or record keeping
requirements under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501
et seq.).
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. Section 113.111 is amended by revising paragraphs (c)(2),
(c)(3)(i), (c)(3)(ii), (c)(3)(iii), and (c)(5)(iii) to read as set
forth below, and by removing paragraph (c)(5)(iv).
Sec. 113.111 Clostridium Perfringens Type C Toxoid and Bacterin-
Toxoid.
* * * * *
(c) * * *
(2) Each of at least eight rabbits of a strain acceptable to APHIS,
each
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weighing 4-8 pounds, shall be injected subcutaneously with not more
than half of the largest recommended dose for any species indicated on
the product label. A second equivalent dose shall be given not less
than 20 days nor more than 23 days after the first dose.
(3) * * *
(i) At least seven rabbits are required to make an acceptable serum
pool.
(ii) Equal quantities of serum from each rabbit shall be combined
and tested as a single pooled serum.
(iii) If less than seven rabbits are available, the test is invalid
and shall be repeated: Provided, That, if the test is not repeated, the
serial shall be declared unsatisfactory.
* * * * *
(5) * * *
(iii) If any mice inoculated with the mixture of serum with 10
L doses of Standard Toxin die, the serum is considered to
contain less than 10 International Units per ml, and the serial is
unsatisfactory.
3. Section 113.112 is amended by revising paragraphs (c)(2),
(c)(3)(i), (c)(3)(ii), (c)(3)(iii), and (c)(5)(iii) to read as set
forth below, and by removing paragraph (c)(5)(iv).
Sec. 113.112 Clostridium Perfringens Type D Toxoid and Bacterin-
Toxoid.
* * * * *
(c) * * *
(2) Each of at least eight rabbits of a strain acceptable to APHIS,
each weighing 4-8 pounds, shall be injected subcutaneously with not
more than half of the largest recommended dose for any species
indicated on the product label. A second equivalent dose shall be given
not less than 20 days nor more than 23 days after the first dose.
(3) * * *
(i) At least seven rabbits are required to make an acceptable serum
pool.
(ii) Equal quantities of serum from each rabbit shall be combined
and tested as a single pooled serum.
(iii) If less than seven rabbits are available, the test is invalid
and shall be repeated: Provided, That, if the test is not repeated, the
serial shall be declared unsatisfactory.
* * * * *
(5) * * *
(iii) If any mice inoculated with the mixture of serum with 10
L doses of Standard Toxin die, the serum is considered to
contain less than 2 International Units per ml, and the serial is
unsatisfactory.
Done in Washington, DC, this 3rd day of June 1997.
Donald W. Luchsinger,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 97-14996 Filed 6-6-97; 8:45 am]
BILLING CODE 3410-34-P
