[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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