[Federal Register Volume 64, Number 42 (Thursday, March 4, 1999)]
[Proposed Rules]
[Pages 10400-10402]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5358]
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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service
9 CFR Part 113
[Docket No. 97-103-1]
Viruses, Serums, Toxins, and Analogous Products; Update of
Incorporation by Reference for Rabies Vaccine
AGENCY: Animal and Plant Health Inspection Service, USDA.
ACTION: Proposed rule.
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SUMMARY: We are proposing to amend the regulations pertaining to the
standard requirements for rabies vaccine, killed virus, so that they
incorporate the latest edition of a guide to laboratory techniques. The
regulations currently refer to the previous edition of that guide,
which was published in 1973. This proposed action would ensure that the
latest edition of the guide is incorporated by reference and used in
conducting potency tests during the production of rabies vaccines.
DATES: Consideration will be given only to comments received on or
before May 3, 1999.
ADDRESSES: Please send an original and three copies of your comments to
Docket No. 97-103-1, Regulatory Analysis and Development, PPD, APHIS,
Suite 3C03, 4700 River Road Unit 118, Riverdale, MD 20737-1238. Please
state that your comments refer to Docket No. 97-103-1. Comments
received may be inspected at USDA, room 1141, South Building, 14th
Street and Independence Avenue SW., Washington, DC, between 8 a.m. and
4:30 p.m., Monday through Friday, except holidays. Persons wishing to
inspect comments are requested to call ahead on (202) 690-2817 to
facilitate entry into the comment reading room.
FOR FURTHER INFORMATION CONTACT: Dr. David A. Espeseth, Special
Assistant to
[[Page 10401]]
the Deputy Administrator, Veterinary Services, Center for Veterinary
Biologics, Licensing and Policy Development, VS, APHIS, 4700 River Road
Unit 148, Riverdale, MD 20737-1231, (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.
``Laboratory Techniques in Rabies,'' which is a guide to laboratory
techniques for rabies research and diagnosis and for the production of
vaccine and immunoglobulin and which is published by the World Health
Organization (WHO), is incorporated by reference into the Code of
Federal Regulations at 9 CFR 113.209(b)(1). In 1996, the WHO published
a fourth edition of ``Laboratory Techniques in Rabies'' (edited by F.X.
Meslin, M.M. Kaplan, and H. Koprowski), but the incorporation by
reference in Sec. 113.209(b)(1) still refers to the 1973 third edition
of that guide. Therefore, we are proposing to amend the regulations in
Sec. 113.209(b)(1) so that they refer to the fourth edition of
``Laboratory Techniques in Rabies'' in order for the latest version to
be incorporated by reference and used.
The regulations in Sec. 113.209(b)(1) currently refer to potency
tests conducted in accordance with the ``NIH Test For Potency''
contained in the third edition of ``Laboratory Techniques in Rabies.''
Because the fourth edition of ``Laboratory Techniques in Rabies''
provides two different methods of conducting the NIH test--a ``standard
test'' and a ``modified NIH test''--we would amend Sec. 113.209(b)(1)
to specify that it is the standard NIH test for potency that must be
used.
With regard to potency tests, the third sentence of
Sec. 113.209(b)(1) currently states that the volumetric method of
calculation must be used and that the challenge dose must contain
between 5 and 50 LD50. The required challenge dose has been
changed in the fourth edition and is now between 12 and 50
LD50. That change in the international standard came about
as a result of extensive statistical work that showed the 12 and 50
LD50 range to be a more sound measurement for the challenge
dose in an animal test system. Because the standard NIH test is a
volumetric method, it is not necessary to specify that the volumetric
method of calculation be used. Further, because the criteria for an
appropriate challenge are fully described in the fourth edition of
``Laboratory Techniques in Rabies,'' it is also not necessary to
describe the challenge dose. Therefore, we are proposing to remove the
third sentence of Sec. 113.209(b)(1).
The fourth edition of ``Laboratory Techniques in Rabies'' states
that the Challenge Virus Standard (CVS) to be used as the challenge in
the NIH test is available from the national control authority, which in
the United States is APHIS' Center for Veterinary Biologics-Laboratory
(CVB-L). A pool of CVS material at a given passage level is established
at the CVB-L, which supplies seed from this pool to all producers of
inactivated veterinary rabies vaccine. For use as the challenge
material, the producer makes one mouse passage from the seed supplied
by the CVB-L. This ensures that all producers are using challenge
material at the same passage level. As stated in the fourth edition, in
a valid NIH test for calculating potency, the reference vaccine
dilutions must be such that at the lowest dilution (highest dose) 70
percent of the mice survive after challenge, and at the highest
dilution (lowest dose) 70 percent of the mice die after challenge.
The fourth edition of ``Laboratory Techniques in Rabies'' also
indicates that each country's national control authority should supply
the reference vaccine for the NIH test. The national control authority
is responsible for preparing a national reference vaccine that is
calibrated against the International Standard. For U.S. producers of
veterinary rabies vaccine, the supplier of the reference vaccine is the
CVB-L. The reference produced by the CVB-L is calibrated against the
current WHO International Standard
to a final potency of 1.0 International
Unit per mL (IU/mL). This reference vaccine is available upon request
from
the CVB-L.
Miscellaneous
In updating the incorporation by reference, we would also revise
Sec. 113.209(b)(1) so that it conforms to the requirements of the
Office of the Federal Register (OFR) regarding the proper language of
incorporation. Specifically, we would amend that paragraph to provide,
in accordance with the OFR's regulations in 1 CFR 51.9(b), information
regarding the publication's authors and its reference number; state
that the incorporation by reference has been approved by the Director
of the Federal Register in accordance with 5 U.S.C. 552(a); and state
that copies of ``Laboratory Techniques in Rabies'' may be obtained from
WHO and may be reviewed at APHIS' offices in Riverdale, MD, or at the
Office of the Federal Register in Washington, DC.
We would also remove an outdated footnote in Sec. 113.209(d)(3).
That outdated footnote refers the reader to ``footnote 1 to
Sec. 113.129(b),'' but Sec. 113.129 and its footnote no longer exist in
part 113. (Section 113.129 was redesignated as Sec. 113.209 in a final
rule published in the Federal Register on August 31, 1990 (55 FR 35556-
35563, Docket No. 89-151).) However, the now-absent footnote did
provide details regarding the incorporation by reference that is the
subject of this proposed rule. Therefore, we are proposing to replace
the footnote in Sec. 113.209(d)(3) with text informing the reader that
the fourth edition of ``Laboratory Techniques in Rabies'' is
incorporated by reference at Sec. 113.209(b)(1).
Executive Order 12866 and Regulatory Flexibility Act
This proposed 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.
In accordance with the Regulatory Flexibility Act, we have
considered the potential impacts of this proposed action on small
entities. We have identified four producers of rabies vaccine as the
entities potentially affected by this proposed rule. Those producers
fall into one of two standard industrial classification (SIC)
categories, either SIC 2836 (Biological Products, Except Diagnostic
Substances) or SIC 2834 (Pharmaceutical Preparations). According to
Small Business Administration (SBA) criteria, a business in SIC 2836 is
considered to be a small entity if it has 500 or fewer employees, and a
business in SIC 2834 is considered to be a small entity if it has 750
or fewer employees. Under those criteria, none of the four producers
identified are small entities.
``Laboratory Techniques in Rabies'' is a guide to laboratory
techniques for rabies research and diagnosis and for the production of
vaccine and immunoglobulin that is incorporated by reference into the
standard requirements regulations in 9 CFR 113.209(b)(1). This proposed
rule would amend those regulations so that the language used in the
guide's incorporation by reference is correct and to ensure that the
current
[[Page 10402]]
edition of the guide is incorporated by reference and used.
The testing required under Sec. 113.209(b)(1) would remain the same
as is currently conducted. However, some retesting may be required due
to change in the international standard for the LD50 of the
challenge dose. We expect that the cost of a retest, which is estimated
to be approximately $2,400 for the mice and animal care, would have
minimal economic impact on the producers of rabies vaccines, none of
which are small entities under SBA criteria.
Under these circumstances, the Administrator of the Animal and
Plant Health Inspection Service has determined that this action would
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 proposed 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. The Virus-Serum-Toxin Act does not provide 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 recordkeeping
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, Incorporation by reference,
Reporting and recordkeeping requirements.
Accordingly, we would amend 9 CFR part 113 as follows:
PART 113--STANDARD REQUIREMENTS
1. The authority citation for part 113 would continue to read as
follows:
Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.2(d).
2. In Sec. 113.209, paragraphs (b)(1) and (d)(3) would be revised
to read as follows:
Sec. 113.209 Rabies Vaccine, Killed Virus.
* * * * *
(b) * * *
(1) The preinactivation virus titer must be established as soon as
possible after harvest by at least five separate virus titrations. A
mean relative potency value of the vaccine to be used in the host
animal potency test must be established by at least five replicate
potency tests conducted in accordance with the standard NIH test for
potency in chapter 37 of ``Laboratory Techniques in Rabies,'' Fourth
Edition (1996), edited by F.X. Meslin, M.M. Kaplan, and H. Koprowski,
World Health Organization, Geneva, Switzerland (ISBN 92 4 154479 1).
The provisions of chapter 37 of ``Laboratory Techniques in Rabies,''
Fourth Edition (1996), are the minimum standards for achieving
compliance with this section and are incorporated by reference. These
provisions state that the challenge virus standard to be used as the
challenge in the NIH test and the reference vaccine for the test are
available from the national control authority. In the United States,
that authority is the Animal and Plant Health Inspection Service's
Center for Veterinary Biologics-Laboratory, located at 1800 Dayton
Avenue, P.O. Box 844, Ames, IA 50010; phone (515) 239-8331; fax (515)
239-8673. This incorporation by reference was approved by the Director
of the Federal Register in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies may be obtained from the World Health Organization
Publications Center USA, 49 Sheridan Avenue, Albany, NY 12210. Copies
may be inspected at the Animal and Plant Health Inspection Service,
Center for Veterinary Biologics, Licensing and Policy Development, 4700
River Road, Riverdale, MD, or at the Office of the Federal Register,
800 North Capitol Street, NW., suite 700, Washington, DC.
* * * * *
(d) * * *
(3) Potency test. Bulk or final container samples of completed
product from each serial must be tested for potency by tests conducted
in accordance with the standard NIH test for potency in Chapter 37 of
``Laboratory Techniques in Rabies,'' Fourth Edition (1996), which is
incorporated by reference at paragraph (b)(1) of this section. The
relative potency of each serial must be at least equal to that used in
an approved host animal immunogenicity test.
Done in Washington, DC, this 26th day of February 1999.
Joan M. Arnoldi,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 99-5358 Filed 3-3-99; 8:45 am]
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