```

[Federal Register: September 17, 2010 (Volume 75, Number 180)]
[Proposed Rules]               
[Page 56916-56919]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17se10-19]                         

-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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.
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

    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
```