[Federal Register: January 31, 2007 (Volume 72, Number 20)]
[Proposed Rules]
[Page 4467-4470]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr31ja07-18]
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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service
9 CFR Part 113
[Docket No. APHIS-2007-0001]
RIN 0579-AC28
Viruses, Serums, Toxins, and Analogous Products; Detection of
Avian Lymphoid Leukosis Virus
AGENCY: Animal and Plant Health Inspection Service, USDA.
ACTION: Proposed rule.
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SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act
regulations concerning testing for avian lymphoid leukosis in
veterinary biologics to specify that the test is for the detection of
extraneous replicating avian leukosis virus; require such testing to be
conducted using a procedure that will detect extraneous replicating
avian leukosis virus and that is acceptable to the Animal and Plant
Health Inspection Service; require firms to develop a procedure to test
for lymphoid leukosis virus contamination in the case of vaccine virus
cytopathic to chick embryo cell cultures; and specify the equivalent
inoculum dose of vaccine to be used when testing certain specified
chicken vaccines for lymphoid leukosis virus. These proposed changes
would update the testing for lymphoid leukosis virus contamination by
prescribing a test procedure that increases the probability of
detecting atypical lymphoid leukosis viruses such as those recently
found in a contaminated vaccine.
DATES: We will consider all comments that we receive on or before April
2, 2007.
ADDRESSES: You may submit comments by either of the following methods:
Federal eRulemaking Portal: Go to http://www.regulations.gov
, select ``Animal and Plant Health Inspection
Service'' from the agency drop-down menu, then click ``Submit.'' In the
Docket ID column, select APHIS-2007-0001 to submit or view public
comments and to view supporting and related materials available
electronically. Information on using Regulations.gov, including
instructions for accessing documents, submitting comments, and viewing
the docket after the close of the comment period, is available through
the site's ``User Tips'' link.
Postal Mail/Commercial Delivery: Please send four copies
of your
[[Page 4468]]
comment (an original and three copies) to Docket No. APHIS-2007-0001,
Regulatory Analysis and Development, PPD, APHIS, Station 3A-03.8, 4700
River Road Unit 118, Riverdale, MD 20737-1238. Please state that your
comment refers to Docket No. APHIS-2007-0001.
Reading Room: You may read any comments that we receive on this
docket in our reading room. The reading room is located in room 1141 of
the USDA South Building, 14th Street and Independence Avenue, SW.,
Washington, DC. Normal reading room hours are 8 a.m. to 4:30 p.m.,
Monday through Friday, except holidays. To be sure someone is there to
help you, please call (202) 690-2817 before coming.
Other Information: Additional information about APHIS and its
programs is available on the Internet at http://www.aphis.usda.gov.
FOR FURTHER INFORMATION CONTACT: Dr. Albert P. Morgan, Chief Staff
Officer, Operational Support Section, Center for Veterinary Biologics,
Licensing and Policy Development, APHIS, 4700 River Road Unit 148,
Riverdale, MD 20737-1228; (301) 734-8245.
SUPPLEMENTARY INFORMATION:
Background
The Virus-Serum-Toxin Act regulations in 9 CFR part 113 (referred
to below as the regulations) contain standard procedures and
requirements that are used to establish the purity, safety, potency,
and efficacy of veterinary biological products. The regulations in
Sec. Sec. 113.200 and 113.300 specify general requirements for killed
virus vaccine and live virus vaccine, respectively. The purity
requirements for avian origin vaccine prescribed under these
regulations specify that bulk or final container samples from each
serial of avian origin vaccine must be tested for lymphoid leukosis
virus contamination. Lymphoid leukosis viruses are ubiquitous in
chickens, causing the disease lymphoid leukosis, and are considered to
be potential contaminants of all biological products propagated in
substrates of chicken origin. Inoculation of chickens and, possibly,
other animals with veterinary biologics contaminated with lymphoid
leukosis viruses may cause neoplastic diseases. Six subgroups (A, B, C,
D, E, and J) of lymphoid leukosis viruses have been identified in
chickens, with subgroups A (most often) and B (less frequently) being
associated with disease. In order to ensure that biological products
propagated in substrates of chicken origin are not contaminated with
lymphoid leukosis viruses, veterinary biologics licensees and
permittees are required to test such products for contaminating
lymphoid leukosis viruses in accordance with the test procedure
specified in Sec. 113.31 of the regulations. The test procedure
specified in Sec. 113.31 is designed to detect contamination due to
extraneous replicating subgroup A and B lymphoid leukosis viruses which
are most often associated with disease in chickens. Biological products
found contaminated with lymphoid leukosis viruses are unsatisfactory.
Currently, the standard test procedure in Sec. 113.31 of the
regulations prescribes the complement-fixation (CF) test for detecting
lymphoid leukosis viruses in bulk pooled material or final container
samples of biological products propagated in substrates of chicken
origin. A negative CF test is considered evidence that the product is
free of contaminating lymphoid leukosis viruses.
Recently, however, in response to a reported finding of lymphoid
leukosis virus contaminated vaccine, the Center for Veterinary
Biologics and other laboratories, using an enzyme-linked immunosorbent
assay (ELISA), detected lymphoid leukosis virus in 7 out of 129 serials
of a commonly used chicken vaccine. The lymphoid leukosis virus
contaminant had not been detected when the serials were tested using
the CF test procedure specified in Sec. 113.31 of the regulations.
Prior to the reported finding, and confirmation of lymphoid leukosis
virus contamination in the seven serials mentioned above, the CF test
procedure prescribed in Sec. 113.31 had been considered suitable for
detecting previously known and/or classified lymphoid leukosis viruses.
However, the failure of the CF test to detect lymphoid leukosis virus
contamination in the vaccine suggests that the contaminant most likely
is a previously unknown and unclassified subgroup A-like (atypical)
lymphoid leukosis virus that cannot be detected using the standard CF
test procedure prescribed in Sec. 113.31, but can be detected using an
ELISA for the detection of avian leukosis virus. The inability of the
CF test to detect the lymphoid leukosis virus contamination that was
later found using an ELISA test procedure indicates that the ELISA has
a broader spectrum of specificity as compared to the CF test, and may
be more suitable for detecting previously unclassified atypical
lymphoid leukosis viruses.
The requirement to use the CF test procedure specified in Sec.
113.31 of the regulations to test for contaminating lymphoid leukosis
viruses was promulgated prior to the development of ELISA methodology.
Subsequent to the development of ELISA methodology and the licensing of
ELISA based avian leukosis virus test kits, APHIS has approved the use
of licensed ELISA kits to test for contaminating lymphoid leukosis
viruses in place of the CF test procedure. Such approvals were based on
side-by-side testing of the two methods that found the licensed ELISA
kits to be equivalent to the CF test procedure for detecting lymphoid
leukosis virus contamination in biological products.
However, because the contaminated vaccine test results indicate
that an ELISA will detect lymphoid leukosis virus contamination that
cannot be detected using the CF test procedure, APHIS has concluded
that the CF test procedure should no longer be specified for the
detection of lymphoid leukosis viruses in Sec. 113.31. In place of the
CF test procedure, veterinary biologics licensees and permittees would
be required to conduct a test that will detect extraneous replicating
avian leukosis virus and that is acceptable to APHIS as specified in
the product's filed Outline of Production.
We are proposing to change the title of Sec. 113.31 from
``Detection of avian lymphoid leukosis'' to ``Detection of extraneous
replicating avian leukosis virus'' to clarify the fact that the test is
for the detection of ``extraneous replicating'' avian leukosis virus
that causes the disease ``lymphoid leukosis'' in chickens. We would
also amend the introductory text of the section, where the current
regulations specify that the CF test shall be conducted, to state
simply that a test that will detect extraneous replicating avian
leukosis virus and that is acceptable to APHIS shall be conducted. We
expect that most manufacturers would specify a licensed ELISA kit for
such testing, but other methods may be available and could be used
provided they are acceptable to APHIS.
In the case of biological product containing virus that has been
propagated in substrates of chicken origin that cannot be tested for
lymphoid leukosis virus contamination because the vaccine virus is
cytopathic to chick embryo fibroblast cells, we would amend the
regulations to require the individual firm(s) to specify a procedure to
test such product for contaminating lymphoid leukosis viruses in the
filed Outline of Production.
Currently, Sec. 113.31 of the regulations provides that in the
case of cytopathic vaccine virus, the test for contaminating
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lymphoid leukosis viruses may be performed using a sample of another
(alternative) vaccine prepared the same week from material harvested
from each source flock used for the preparation of the product that
contains the cytopathic (questionable) vaccine virus. Because both the
questionable vaccine and the alternative vaccine would have been
prepared using common-source avian origin substrate, the expectation
was that if contaminating lymphoid leukosis viruses are not detected in
the alternative vaccine, there is a strong probability that the
questionable vaccine also is free of contaminating lymphoid leukosis
viruses. However, as we sought to determine the source of the lymphoid
leukosis virus found in the contaminated vaccine, we tested samples of
another vaccine prepared the same week from material harvested from the
same source flock(s) that provided the substrate used in the
preparation of the contaminated vaccine. Because the substrate used to
prepare both the contaminated vaccine and the vaccine used for the
alternative test were derived from a common source, we expected the
alternative vaccine to test positive for contaminating lymphoid
leukosis viruses; however, none of the alternative vaccine samples
tested positive for lymphoid leukosis viruses. These results indicate
that testing an alternative vaccine for contaminating lymphoid leukosis
viruses in place of a questionable vaccine does not ensure that a
contaminant, if present, will be detected and, thus, should be
discontinued. Therefore, when a vaccine cannot be tested for
contaminating lymphoid leukosis viruses because the vaccine virus is
cytopathic to the cells used for viral propagation, we are proposing to
require veterinary biologics manufacturers to specify a procedure to
test such vaccine for contaminating lymphoid leukosis viruses in the
product's filed Outline of Production. The specified procedure would
have to be acceptable to APHIS.
In addition, we propose to specify that the equivalent of 200 doses
of vaccine must be used as inoculum when testing bursal disease
vaccine, tenosynovitis vaccine, and reovirus vaccine for contaminating
lymphoid leukosis viruses. The current standard requirement specifies
that when vaccines are tested for lymphoid leukosis virus
contamination, the equivalent of 200 doses of Newcastle disease vaccine
or 500 doses of other vaccine for use in poultry, or 1 dose of vaccine
for use in other animals, shall be used as inoculum. Subsequent to
codifying the requirement to use the equivalent of 200 doses as
inoculum when testing Newcastle disease vaccine for contaminating
lymphoid leukosis viruses, we have identified additional poultry
vaccines for which the equivalent of 200 doses should be used as
inoculum when testing for contaminating lymphoid leukosis viruses.
APHIS now proposes to amend Sec. 113.31 by specifying that the
equivalent of 200 doses also shall be used as inoculum when testing
bursal disease vaccine, tenosynovitis vaccine, and reovirus vaccine for
contaminating lymphoid leukosis viruses.
These amendments are being proposed in order to update the
procedure used to detect lymphoid leukosis virus contamination in
biological products and ensure that such products are free of material
that adversely affects their safe use in animals.
Executive Order 12866 and Regulatory Flexibility Act
This proposed 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.
We are proposing to amend the regulations for detection of avian
lymphoid leukosis to require that a test that will detect extraneous
replicating avian leukosis virus and that is acceptable to APHIS shall
be conducted on all biological products containing virus that has been
propagated in substrates (starting material) of chicken origin.
Lymphoid leukosis is a disease of chickens caused by avian leukosis
viruses. Veterinary biologics containing virus that has been grown in
substrates of chicken origin are at risk for contamination with avian
leukosis viruses which, if present, are referred to as extraneous
replicating avian leukosis virus. Inoculation of chickens, and possibly
other animals, with vaccine contaminated with avian leukosis virus may
cause neoplastic disease. This proposed rule, if adopted, would allow
any valid method to be used for testing veterinary biologics for
extraneous replicating avian leukosis virus, provided that it is
acceptable to APHIS.
The proposed changes would affect all licensed manufacturers of
veterinary biologics who are required to test for the detection of
extraneous replicating avian leukosis virus. There are approximately
125 veterinary biologics establishments, and approximately 15 of these
establishments produce product that would be affected by this proposed
rule. According to the standards of the Small Business Administration,
most veterinary biologics establishments would be classified as small
entities. The proposed changes, however, would not impose any
additional economic burden since the regulations already require
vaccine propagated in substrates of chicken origin to be tested for
extraneous replicating avian leukosis virus; currently, the regulations
require firms to use the CF test procedure for such testing. This
proposed rule would discontinue required use of the CF test and instead
require a test that will detect extraneous replicating avian leukosis
virus and that is acceptable to APHIS to be conducted. In addition, the
proposed rule would require firms to specify a procedure to test for
extraneous replicating avian leukosis virus when questionable vaccine
cannot be tested because the vaccine virus is cytopathic to chick
embryo fibroblast cells; and would specify using the equivalent of 200
doses as inoculum when testing bursal disease, tenosynovitis, and
reovirus vaccines for contaminating lymphoid leukosis viruses. The
overall effect of this action would be to update the standard procedure
for detecting extraneous replicating avian leukosis virus in biological
products by prescribing a test procedure that has a greater probability
of detecting an atypical lymphoid leukosis virus such as was recently
found in contaminated vaccine.
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 proposed rule contains no new information collection or
recordkeeping requirements under the Paperwork
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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, we propose to 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 371.4.
2. Section 113.31 would be revised to read as follows:
Sec. 113.31 Detection of extraneous replicating avian leukosis virus.
A test that will detect extraneous replicating avian leukosis virus
and that is acceptable to the Animal and Plant Health Inspection
Service (APHIS) shall be conducted on all biological products
containing virus that has been propagated in substrates of chicken
origin: Provided, An inactivated viral product will be exempt from this
requirement if the licensee can provide data that demonstrates to APHIS
that the agent used to inactivate the vaccine virus would also
inactivate lymphoid leukosis virus.
(a) Propagation of extraneous lymphoid leukosis viruses shall be
done in chick embryo cell cultures or other substrate acceptable to
APHIS.
(1) Each vaccine virus cytopathic to the cell culture being used
shall be effectively neutralized, inactivated, or separated so that
minimal amounts of extraneous replicating lymphoid leukosis virus can
be propagated during the specified growth period. If the product cannot
be tested for extraneous replicating lymphoid leukosis virus because
the vaccine virus cannot be effectively neutralized, inactivated, or
separated, an alternative procedure acceptable to APHIS shall be
specified in the filed Outline of Production.
(2) When cell cultures are tested, 5 mL of the final cell
suspension as prepared for seeding of production cell cultures shall be
used as inoculum. When vaccines are tested, the equivalent of 200 doses
of cytopathic vaccine viruses, including Newcastle disease vaccine,
bursal disease vaccine, tenosynovitis vaccine, and reovirus vaccine, or
500 doses of other vaccines for use in poultry, or 1 dose of vaccine
for use in other animals shall be used as inoculum. Control cultures
shall be prepared from the same cell suspension as the cultures for
testing the vaccine.
(3) Uninoculated chick embryo fibroblast cell cultures shall act as
negative controls. One set of chick fibroblast cultures inoculated with
subgroup A virus and one set of chick fibroblast cultures inoculated
with subgroup B virus shall act as positive controls A and B,
respectively.
(4) The cell cultures shall be passed when necessary to maintain
viability, and samples harvested from each passage shall be tested for
group-specific antigen.
(b) A test that will detect extraneous replicating lymphoid
leukosis virus and that is acceptable to APHIS shall be used.
(1) All test materials, including positive and negative controls,
shall be stored at -60 [deg]C or colder until used in the test.
(2) The test procedure, including the cutoff value indicative of a
positive test for extraneous replicating lymphoid leukosis virus, shall
be specified in a filed Outline of Production or Special Outline.
(3) The detection of extraneous replicating lymphoid leukosis virus
at the first passage shall be considered suspicious and the sample
shall be further subcultured and tested to determine the presence of
extraneous replicating lymphoid leukosis virus.
(4) Biological products or primary cells that are found
contaminated with lymphoid leukosis viruses are unsatisfactory. Source
flocks from which contaminated material was obtained are also
unsatisfactory.
Done in Washington, DC this 25th day of January 2007.
Kevin Shea,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. E7-1528 Filed 1-30-07; 8:45 am]
BILLING CODE 3410-34-P