[Federal Register Volume 70, Number 81 (Thursday, April 28, 2005)]
[Proposed Rules]
[Pages 21985-21987]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-8516]


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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 114

[Docket No. 04-064-1]


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.

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SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act 
regulations to require licensees and permittees to confirm the proposed 
expiration dating period of products by potency testing serials on 
multiple occasions throughout the proposed dating period, rather than 
only at release and at the approximate expiration date as is currently 
required. We would require that those stability test data be submitted 
to the Animal and Plant Health Inspection Service for review and 
filing, and that the approval date be specified in a filed Outline of 
Production. In addition, after a product is licensed and its dating 
period confirmed, the licensee or permittee would have to submit a plan 
to monitor the stability of the product and the suitability of its 
dating period; that plan would have to include regular testing of 
serials for potency during and at the end of dating. The proposed 
changes would help clarify the distinction between specifying an 
expiration date for an individual serial of a product and establishing 
the appropriate expiration dating period for the product. The effect of 
these proposed changes would be to establish a single uniform standard 
for determining expiration dates for veterinary biological products.

DATES: We will consider all comments that we receive on or before June 
27, 2005.

ADDRESSES: You may submit comments by any of the following methods:
     EDOCKET: Go to http://www.epa.gov/feddocket to submit or 
view public comments, access the index listing of the contents of the 
official public docket, and to access those documents in the public 
docket that are available electronically. Once you have entered 
EDOCKET, click on the ``View Open APHIS Dockets'' link to locate this 
document.
     Postal Mail/Commercial Delivery: Please send four copies 
of your comment (an original and three copies) to Docket No. 04-064-1, 
Regulatory Analysis and Development, PPD, APHIS, Station 3C71, 4700 
River Road Unit 118, Riverdale, MD 20737-1238. Please state that your 
comment refers to Docket No. 04-064-1.
     Federal eRulemaking Portal: Go to http://www.regulations.gov and follow the instructions for locating this 
docket and submitting comments.
    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: You may view APHIS documents published in the 
Federal Register and related information on the Internet at http://www.aphis.usda.gov/ppd/rad/webrepor.html.

FOR FURTHER INFORMATION CONTACT: Dr. Albert P. Morgan, Chief of 
Operational Support, Center for Veterinary Biologics, Licensing and 
Policy

[[Page 21986]]

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 designating the 
expiration date of a serial or subserial of veterinary biologics and 
determining the expiration dating period (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 determined in 
accordance with the requirements prescribed in Sec.  114.13 of the 
regulations. The regulations in Sec.  114.13 require the expiration 
date described under Sec.  114.12 to be computed from the date of the 
initiation of the potency test.
    The expiration date of a product designates the end of the period 
during which a biological product, when properly stored and handled, 
can be expected, with reasonable certainty, to be efficacious. Thus, 
the most precise determination of the expiration date occurs when the 
product is tested at the end of its predicted shelf life. However, the 
typical product may be released for distribution and sale before its 
dating period is confirmed, which necessitates a mechanism for 
predicting the product's shelf life. Prior to licensure, the stability 
of each fraction of a product must be determined by methods acceptable 
to Animal and Plant Health Inspection Service (APHIS). Typically, such 
methods involve subjecting the product to extreme temperatures and 
measuring its relative strength by conducting a potency test. Products 
that pass the potency test are licensed with the provision that such 
expiration dates must be confirmed by real-time testing as follows: For 
products consisting of viable organisms each (prelicensing) serial 
shall 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 (prelicensing) 
serial presented in support of licensure shall be tested for potency at 
release and at or after the dating requested.
    We are proposing to amend the title of Sec.  114.12 to read: 
``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 potency test'' and remove it from Sec.  114.13 
where it is currently found. This change is intended to clarify the 
fact that the expiration date of a serial, and not the dating period of 
a product, is computed from the date of the initiation of the potency 
test.
    We are proposing to amend the title of Sec.  114.13 to read: `` 
Determination of the expiration dating period of a product.'' This 
change will show that it deals with a product's dating period rather 
than the expiration date of a serial. The proposed revision of this 
section would define a single uniform standard for determining the 
dating period for all veterinary biologics; require the expiration 
dating periods of a product to be confirmed by testing serials or 
subserials on multiple occasions throughout their dating period in 
place of the current requirement which only requires testing at the 
beginning and end of the dating period in order to confirm stability; 
require a report of the expiration dating period testing to be 
submitted to APHIS for review and filing and the date of approval to be 
specified in section VI of the filed Outline of Production; and after 
the dating period has been approved, require that the stability of the 
product and the suitability of the dating period be monitored by 
regularly testing serials during and after their dating period.
    APHIS is proposing these amendments because it has been shown that 
the potency of most veterinary biologics degrades in a nonlinear 
fashion, which could result in their potency reaching its lowest point 
during the middle of the dating period rather than at the end. 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, APHIS 
is proposing to evaluate a product's stability as a function of time by 
requiring serials to be tested on multiple occasions when confirming 
the dating period, and thereafter by monitoring stability on a regular 
basis.
    The proposed amendment would update and standardize testing to 
establish/confirm the stability of veterinary biologics and improve the 
reliability of expiration dating periods currently specified on the 
labeling of veterinary biologics, thereby providing greater assurance 
that the product, when properly stored and handled, will be 
efficacious. We are therefore proposing to amend Sec. Sec.  114.12 and 
114.13 as set forth below.

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.
    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; require veterinary biologics 
licensees and permittees to evaluate the stability of veterinary 
biologics as a function of time by testing serials for potency 
throughout and after their proposed dating period beginning at the date 
of final formulation; require that the expiration dating period be 
determined by testing serials for potency on multiple occasions 
throughout and after the proposed dating period; require that a report 
of the results of the testing to confirm expiration dating be submitted 
to APHIS for review and filing and that the date of approval be 
specified in the filed Outline of Production; and require monitoring of 
the stability of the product and the suitability of the dating period. 
The overall effect of these proposed amendments would be to establish a 
single uniform standard for confirming the expiration dating period of 
veterinary biologics.
    This proposed rule would affect all licensed manufacturers of 
veterinary biologics. Currently, there are approximately 152 veterinary 
biologics manufacturers, including permittees. According to the 
standards of the Small Business Administration, most veterinary 
biologics establishments are small entities. We believe that this 
proposed rule would not have a significant effect on small entities 
because all veterinary biologics manufacturers are currently required 
to confirm the expiration dating of the products that they produce and 
to submit a report to APHIS for review and filing. In addition, the 
proposed requirements to test serials on multiple occasions when 
confirming expiration dating and to require post-licensing stability 
monitoring are not expected to have a significant effect, as most 
veterinary biologics manufacturers routinely test and monitor the 
stability of products throughout their dating period.
    Under these circumstances, the Administrator of the Animal and 
Plant Health Inspection Service has determined that this action would 
not

[[Page 21987]]

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 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 Reduction Act of 1995 
(44 U.S.C. 3501 et seq.).

List of Subjects in 9 CFR Part 114

    Animal biologics, Reporting and recordkeeping requirements.

    Accordingly, we propose to amend 9 CFR part 114 as follows:

PART 114--PRODUCTION REQUIREMENTS FOR BIOLOGICAL PRODUCTS

    1. The authority citation for part 114 would continue to read as 
follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.4.

    2. Section 114.12 would be 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 must 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 subsequent to the expiration date appearing on 
the label.
    3. Section 114.13 would be revised to read as follows:


Sec.  114.13  Determination of the expiration dating period of a 
product.

    (a) An expiration dating period shall be assigned to each product. 
When tested at any time during the dating period, the potency of the 
product must not be less than the minimum specified in the filed 
Outline of Production.
    (b) Prior to licensure, a proposed expiration dating period for the 
product should be determined by assessing the stability of each of its 
fractions by methods acceptable to Animal and Plant Health Inspection 
Service. The proposed dating period must be confirmed by testing the 
serials for potency on multiple occasions throughout the proposed 
dating period beginning at the date of final formulation specified in 
the filed Outline of Production. A report of the study should be 
submitted to Animal and Plant Health Inspection Service for review and 
filing and the date of approval should be specified in section VI of 
the filed Outline of Production.
    (c) After the product is licensed and its dating period confirmed, 
the licensee or permittee must submit a plan to monitor the stability 
of the product and the suitability of its dating period that includes 
regularly testing serials for potency during and at the end of dating.
    (d) Subsequent changes in the dating period for a product may be 
granted, based on the submission of a study to support a revision of 
the Outline of Production.

    Done in Washington, DC, this 22nd day of April 2005.
W. Ron DeHaven,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 05-8516 Filed 4-27-05; 8:45 am]
BILLING CODE 3410-34-P