[Federal Register Volume 75, Number 180 (Friday, September 17, 2010)]
[Proposed Rules]
[Pages 56916-56919]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-23186]
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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service
9 CFR Parts 101 and 114
[Docket No. APHIS-2009-0028]
RIN 0579-AD06
Viruses, Serums, Toxins, and Analogous Products; Expiration Date
Required for Serials and Subserials and Determination of Expiration
Date of Product
AGENCY: Animal and Plant Health Inspection Service, USDA.
ACTION: Proposed rule; withdrawal and reproposal.
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SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act
regulations concerning expiration dating to clarify that the expiration
date of a serial or subserial of a veterinary biologic should be
computed from the date of the initiation of the first potency test. We
also propose to require the expiration dating period (stability) of a
product to be confirmed by conducting a real-time stability study with
a stability-indicating assay; require stability monitoring of products
after licensing; and specify a single standard for determining the
expiration date for veterinary biologics in place of the current
standard that specifies different procedures for products contingent
upon whether they consist of viable or nonviable organisms. These
amendments would update and clarify the regulations concerning
expiration dating and establish a single uniform standard for
determining the stability of veterinary biological products. This
proposed rule replaces a previously published proposed rule, which we
are withdrawing as part of this document.
DATES: We will consider all comments that we receive on or before
November 16, 2010.
ADDRESSES: You may submit comments by either of the following methods:
Federal eRulemaking Portal: Go to (http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=APHIS-2009-0028) to submit or view comments
and to view supporting and related materials available electronically.
Postal Mail/Commercial Delivery: Please send one copy of
your comment to Docket No. APHIS-2009-0028, 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-2009-0028.
Reading Room: You may read any comments that we receive on
Regulations.gov (see the link above) or 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 of
Operational Support, 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 Virus-Serum-Toxin Act regulations in 9 CFR part 114,
``Production Requirements for Biological Products'' (referred to below
as the regulations), include requirements applicable to computing
expiration dates and determining expiration dating periods (stability)
for veterinary biologics. Currently, Sec. 114.12 of the regulations
requires each serial or subserial of veterinary biological product
prepared in a licensed establishment to be given an expiration date,
and Sec. 114.13 provides that the expiration date for each product
shall be computed from the date of the initiation of the potency test.
The computed expiration date of a serial or subserial of biological
product is inextricably linked to the stability of such product. The
expiration date of a veterinary biologic designates the end of the
period during which such product, when properly stored and handled, can
be expected with reasonable certainty to
[[Page 56917]]
be efficacious. The most precise determination of the stability of a
veterinary biologic occurs when the potency of such product is measured
at the end of its predicted shelf life (expiration date). Typically,
however, products are licensed and serials or subserials are released
for marketing before the first production serials reach the end of
their predicted shelf life.
Thus, prior to licensure, licensees and permittees must submit
preliminary stability data that provides a level of confidence that the
product will remain efficacious throughout the dating period shown on
its labeling. Typically, such data is obtained by subjecting the
product to extreme temperatures for a specified time period and
measuring the relative strength of each fraction by conducting a
potency test. Products that pass the potency test are licensed with the
provision that the dating period must be confirmed by real-time
stability testing at the end of the predicted shelf life. Currently,
the requirement prescribed under Sec. 114.13 of the regulations for
confirming stability is contingent upon whether a product consists of
viable or nonviable organisms. For products consisting of viable
organisms, each serial must be tested for potency at release and at the
approximate expiration date until a statistically valid stability
record has been established; for nonviable biological products, each
serial presented in support of licensure (prelicensing serials) must be
tested for potency at release and at or after the dating requested.
Products with satisfactory potency tests at the beginning and end of
dating are considered to be efficacious throughout the requested dating
period. Current science, however, considers stability estimates based
on potency tests conducted at the beginning and end of dating (a two-
point profile) to be inaccurate and imprecise.
To address this situation, on April 28, 2005, we published in the
Federal Register (70 FR 21985-21987, Docket No. 04-064-1) a proposed
rule\1\ to amend the regulations concerning expiration dating to
require veterinary biologics licensees and permittees to confirm the
proposed expiration dating period of products by potency testing
serials on multiple occasions throughout the proposed dating period.
The proposed rule also would have required stability data to be
submitted to the Animal and Plant Health Inspection Service (APHIS) for
review and filing; the stability data approved for filing date to be
specified in the filed Outline of Production; and a plan for monitoring
the stability of the product and the suitability of its proposed dating
period.
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\1\ To view the proposed rule and the comments we received, go
to (http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=APHIS-2005-0041).
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We solicited comments on our proposal for 60 days ending on June
27, 2005. We received six comments by that date. The comments were from
three licensed manufacturers, two national trade associations
representing manufacturers of animal health products, and a
professional association. All of the commenters agreed with the need to
establish a uniform standard for determining expiration dating;
however, most expressed concern that the proposed rule lacked detail,
and suggested that such detail be added and the rule reproposed.
In response to these comments, we have provided specifics that we
believe address the perceived ambiguity in the proposed rule.
Therefore, we are withdrawing the April 22, 2005, proposed rule
referenced above and replacing it with the proposed changes described
in this document. The proposed requirements for determining expiration
dating that would apply to each licensee and permittee that prepares
and distributes veterinary biologics are described below.
Definitions
The regulations in 9 CFR part 101 contain the definitions of terms
used in the regulations concerning veterinary biologics. The proposed
changes to part 114 of the regulations would make it necessary for us
to add a definition in Sec. 101.5 for a term used in the proposed
regulations: Stability-indicating assay. We would define stability-
indicating assay as a validated quantitative analytical procedure (in
vitro or live animal test) that can detect changes over time in the
pertinent properties of a veterinary biologic.
Expiration Date Required for a Serial
We are proposing to change the title of Sec. 114.12 from
``Expiration date required'' to ``Expiration date required for a
serial.'' In addition, we propose to amend this section by adding the
wording ``computed from the date of the initiation of the first potency
test.'' These changes are intended to clarify the fact that the
requirements in this section pertain to serials or subserials of
product, and that APHIS interprets the ``date of the initiation of the
potency test'' to mean the on-test date of the first potency test
conducted on a serial or subserial. This interpretation is consistent
with the APHIS policy in that regard.
Determination of the Expiration Dating Period of a Product
We are proposing to change the title of Sec. 114.13 from
``Expiration date determination'' to ``Determination of the expiration
dating period of a product.'' This change would clarify the fact that
the requirements in that section pertain to determining the stability
of a product rather than the expiration date of a serial or subserial
of such product. The proposed revision of this section would:
Prescribe a single, uniform standard for determining the
stability of veterinary biologics in place of the current standards,
which prescribe different procedures for products consisting of viable
and nonviable organisms;
Remove the wording ``computed from the date of the
initiation of the potency test'' and providing that the expiration
dating period of a product would be based on the testing of production
serials beginning on the day of filling into final containers or the
date final formulation of the product if such date is specified in the
filed Outline of Production;
Require testing of serials or subserials using a
stability-indicating assay on multiple occasions throughout the
predicted dating period in place of the current requirement, which only
requires potency testing at the beginning and end of the dating period
in order to confirm stability;
Require the stability data to be submitted to APHIS for
review and filing and the approved for filing date to be specified in
section VI of the filed Outline of Production; and
Require the periodic testing of serials or subserials to
monitor the stability and suitability of the approved dating period.
APHIS is proposing these amendments because it has been shown that
the potency of most veterinary biologics degrade in a nonlinear
fashion, which may cause potency to degrade more quickly than
previously estimated. Testing on only two occasions would be reasonable
only if potency loss has a strictly linear pattern, and this is usually
not the case. Thus, when confirming the dating period, APHIS is
proposing to require the stability of a product to be evaluated as a
function of time by requiring serials to be tested on multiple
occasions with a stability-indicating assay.
The changes and test procedures prescribed in this proposal would
update and standardize expiration date determination for veterinary
biologics in Sec. Sec. 114.12 and 114.13 by establishing a single,
uniform standard for all products
[[Page 56918]]
based on testing and monitoring with a stability-indicating assay.
Executive Order 12866 and Regulatory Flexibility Act
This proposed rule has been determined to be significant for the
purposes of Executive Order 12866 and, therefore, has been reviewed by
the Office of Management and Budget.
This proposed rule would amend the Virus-Serum-Toxin Act
regulations in Sec. Sec. 114.12 and 114.13 concerning expiration dates
and the determination of the stability of veterinary biologics to:
Change the title of the sections; clarify that the ``date of the
initiation of the potency test'' is the on-test date of the first
potency test conducted on a serial or subserial; require veterinary
biologics licensees and permittees to evaluate the stability of
veterinary biologics as a function of time by testing serials for
potency on multiple occasions with a stability-indicating assay
throughout and after their proposed dating period; require the
stability data approved for filing date to be specified in the filed
Outline of Production; and require monitoring of the stability of the
product and the suitability of its dating period. In addition, the
proposed changes to the regulations are consistent with the
recommendations of the collaborative initiative by regulatory
authorities and industry associations known as International
Cooperation on Harmonization of Technical Requirements for the
Registration of Veterinary Medicinal Products (VICH). VICH is concerned
with harmonization of technical requirements for the registration of
veterinary medicinal products among three regions: The European Union,
Japan, and the United States. The proposed stability testing guidelines
are consistent with those adopted by VICH as an international standard
for the generation and submission of stability data for veterinary
medicinal products. The overall benefit of these proposed amendments
would be to reduce the differences in technical requirements for
veterinary biologics among regulatory agencies in different countries.
This proposed rule would affect all licensed manufacturers of
veterinary biologics. Currently, there are approximately 125 veterinary
biologics manufacturers, including permittees. According to the
standards of the Small Business Administration, most veterinary
biologics establishments are small entities. Relative to the baseline
of the existing regulations in Sec. Sec. 114.12 and 114.13, we do not
believe that the changes we are proposing would result in new or
additional effects on small entities subject to the regulations, as the
current testing protocols would not change; we are simply clarifying
those existing protocols. All veterinary biologics manufacturers are
currently required to confirm the expiration dating of the products
that they produce and to submit the data to APHIS for review and
filing. In addition, the proposed requirements to test serials of
product on multiple occasions when confirming expiration dating, and to
monitor stability post-licensing are not expected to have a significant
economic impact because most veterinary biologics manufacturers
routinely test and monitor the stability of products throughout their
dating period.
Under the changes to the regulations described in this proposed
rule, veterinary biologics with a 2-year dating period would require 7
test occasions, for a total of 21 tests of 3 serials. To confirm
expiration dating under current regulations, many licensees may be
required to test 10 serials twice, a total of 20 tests. This is about
the same number of tests. The most recent data compiled by APHIS show
that over one 3-year period, 101 veterinary biologics manufacturers
submitted 105 stability studies to the Center for Veterinary Biologics,
an average per manufacturer of 1 every 3 years. The proposed amendment
to the regulations would not necessitate an increase in the number of
stability studies required to be performed, or an increase in
associated testing costs, as these proposed changes will primarily
apply to newly licensed products.
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 category 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 where they are necessary to address local disease conditions
or eradication programs. However, where safety, efficacy, purity, and
potency of biological products are concerned, it is the Agency's intent
to occupy the field. This includes, but is not limited to, the
regulation of labeling. Under the Act, Congress clearly intended that
there be national uniformity in the regulation of these products. There
are no administrative proceedings which must be exhausted prior to a
judicial challenge to the regulations under this rule.
Paperwork Reduction Act
This proposed rule contains no new information collection or
recordkeeping requirements under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520).
List of Subjects
9 CFR Part 101
Animal biologics.
9 CFR Part 114
Animal biologics, Reporting and recordkeeping requirements.
0
Accordingly, we propose to amend 9 CFR parts 101 and 114 as follows:
PART 101--DEFINITIONS
0
1. The authority citation for part 101 continues to read as follows:
Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.
0
2. Section 101.5 is amended by adding new paragraph (s) to read as
follows:
Sec. 101.5 Testing terminology.
* * * * *
(s) Stability-indicating assay. A stability-indicating assay is a
validated quantitative analytical procedure that can detect changes
over time in the pertinent properties of the product.
PART 114--PRODUCTION REQUIREMENTS FOR BIOLOGICAL PRODUCTS
0
3. The authority citation for part 114 continues to read as follows:
Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.
0
4. Section 114.12 is revised to read as follows:
Sec. 114.12 Expiration date required for a serial.
Unless otherwise provided for in a Standard Requirement or filed
Outline of Production, each serial or subserial of biological product
prepared in a licensed establishment shall be given an expiration date
computed from the date of the initiation of the first potency test. A
licensed biological product shall be considered worthless under the
Virus-Serum-Toxin Act after the expiration date appearing on the label.
[[Page 56919]]
0
5. Section 114.13 is revised to read as follows:
Sec. 114.13 Determination of the expiration dating period of a
product.
An expiration dating period determined by the stability of each of
its fractions shall be assigned to each product. Stability shall be
determined with a stability-indicating assay that can detect changes
over time in the pertinent properties of the product. Stability
criteria include the specifications for potency at release, potency
throughout the dating period, and the length of the dating period. When
tested at any time during the dating period, the potency of the product
shall not be less than the minimum specified in the filed Outline of
Production. Prior to licensure, the licensee shall propose an
expiration dating period for the product based on preliminary data
available about the stability of each of its fractions. If the
preliminary stability data are acceptable, the product may be licensed
with the provision that the proposed expiration dating period must be
confirmed by conducting a real-time stability study with a stability-
indicating assay as follows:
(a) In the case of a newly licensed product with acceptable
preliminary stability data and the real-time stability study is not
conducted in animals, at least three production serials of the product
shall be selected and tested during the proposed dating period. Each
serial shall be tested beginning on the day of filling into final
containers or the date of final formulation specified in the filed
Outline of Production, and at the following intervals:
(1) Every 3 months during the first year of storage,
(2) Every 6 months during the second year of storage, and
(3) Annually thereafter throughout the proposed dating period.
(b) In the case of a newly licensed product with acceptable
preliminary stability data and the real-time stability study is
conducted in animals, at least three production serials shall be tested
as follows:
(1) One test per serial shall be conducted beginning on the day of
filling into final containers or the date of final formulation
specified in the filed Outline of Production.
(2) One test per serial shall be conducted at thebe end of the
proposed dating period.
(3) One test per serial shall be conducted between the initial and
final test, but at a different interval for each serial.
(c) In the case of a newly licensed product, and licensed products
whose stability studies were completed prior to [Effective date of
final rule], a real-time stability study conducted with a stability-
indicating assay in accordance with paragraphs (a) or (b) of this
section shall be completed in support of changes to one of the
stability criteria or for major changes to the potency test.
(d) In the case of a licensed product with an unconfirmed
expiration dating period that is tested in animals with a test that is
not a stability-indicating assay, the following shall apply:
(1) Testing involving the use of a non-stability-indicating assay
specified in the filed Outline of Production to confirm the expiration
dating period for such product shall be completed by [Date 42 months
after effective date of the final rule], or
(2) Subsequent to [Date 42 months after effective date of the final
rule], such testing to confirm expiration dating shall be completed
with a stability-indicating assay. Products not meeting the requirement
to confirm the expiration dating with a stability-indicating assay
shall be withheld from the market.
(e) At the completion of the real-time stability study to confirm
or change expiration dating, the data shall be submitted to Animal and
Plant Health Inspection Service for approval for filing and the
approved for filing date shall be specified in section VI of the filed
Outline of Production at the next revision.
(f) For products licensed subsequent to [Effective date of the
final rule], the licensee or permittee shall submit a plan to monitor
the stability of the product and the suitability of its dating period
that includes regularly testing serials for potency with a stability-
indicating assay during and at the end of dating.
Done in Washington, DC, this 3\rd\ day of September 2010.
John Ferrell,
Deputy Under Secretary for Marketing and Regulatory Programs.
[FR Doc. 2010-23186 Filed 9-16-10: 10:57 am]
BILLING CODE 3410-34-S