[Federal Register Volume 67, Number 66 (Friday, April 5, 2002)]
[Proposed Rules]
[Pages 16327-16329]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-8260]


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 Proposed Rules
                                                 Federal Register
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 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
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  Federal Register / Vol. 67, No. 66 / Friday, April 5, 2002 / Proposed 
Rules  

[[Page 16327]]


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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 113

[Docket No. 01-091-1]


Viruses, Serums, Toxins, and Analogous Products; Standard 
Requirements for Determination of Residual Free Formaldehyde Content of 
Biological Products

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 for the determination of residual free formaldehyde in 
veterinary biologics. This amendment would specify that such 
determinations be made using the ferric chloride method, and that the 
residual free formaldehyde content be measured in grams per liter . We 
are proposing this amendment because the ferric chloride method has 
been adopted as an international standard by scientific experts and 
regulatory authorities in the United States, Canada, Japan, and the 
European Union. The effect of the proposed amendment would be to reduce 
the differences in technical requirements for veterinary biologics 
among regulatory agencies in different countries and further ensure the 
safety and shelf life of veterinary biologics by adopting a method 
which has been standardized and accepted internationally.

DATES: We will consider all comments we receive that are postmarked, 
delivered, or e-mailed by June 4, 2002.

ADDRESSES: You may submit comments by postal mail/commercial delivery 
or by e-mail. If you use postal mail/commercial delivery, please send 
four copies of your comment (an original and three copies) to: Docket 
No. 01-091-1, 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. 01-091-1. If you use e-mail, 
address your comment to [email protected]. Your comment must 
be contained in the body of your message; do not send attached files. 
Please include your name and address in your message and ``Docket No. 
01-091-1'' on the subject line.
    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.
    APHIS documents published in the Federal Register, and related 
information, including the names of organizations and individuals who 
have commented on APHIS dockets, are available 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 Development, 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 113 (referred 
to below as the regulations) prescribe standard requirements for the 
preparation and testing of veterinary biological products. Standard 
requirements consist of test methods, procedures, and criteria that 
define the standards for purity, safety, potency, and efficacy for a 
given type of veterinary biological product. When a standard procedure 
for testing veterinary biological products is validated and approved by 
the Animal and Plant Health Inspection Service (APHIS) for general use, 
it is proposed for codification in the regulations. Sections 113.100 
and 113.200 of the regulations prescribe the requirement for 
determination of residual free formaldehyde content in inactivated 
bacterial products and killed virus vaccines, respectively.
    In this document, we are proposing to amend the regulations for 
determination of residual free formaldehyde content in inactivated 
bacterial products and killed virus vaccines.
    Typically, pathogenic microorganisms or toxins are used in the 
formulation of veterinary biologics. In order to ensure that such 
products are safe and free from undue local and systemic reactions and 
cannot replicate and cause disease in the host, the microorganisms may 
be inactivated or killed. Formalin solution (formaldehyde) is one of 
several chemical compounds that may be used to inactivate the 
microorganisms or toxins used in the formulation of veterinary 
biologics. However, because of its toxicity, excess formaldehyde that 
remains in the product after inactivation is complete may cause 
undesirable secondary effects when the product is administered to the 
host, or result in residues in meat intended for human consumption. 
Therefore, in order to minimize the undesirable secondary effects 
associated with the use of formaldehyde as an inactivation agent, 
excess levels of formaldehyde that persist in veterinary biologics 
after inactivation is complete must be neutralized. Neutralization of 
excess formalin:
     Ensures that residual formalin will not inactivate other 
products used in combination,
     Prolongs product shelf life, and
     Provides an extra margin of safety relative to local and/
or systemic reactions and residues in meat for human consumption.
    Sodium bisulfite is the chemical compound most veterinary biologics 
manufacturers use to neutralize residual free formaldehyde in their 
products. After neutralization is complete, the level of free 
formaldehyde remaining in the neutralized preparation must be 
determined. Of the several methods that may be used to estimate 
residual free formaldehyde content in formalin-inactivated veterinary 
biologics that are treated with sodium bisulfite, the ferric chloride 
titration method and the basic fuchsin reagent method are the most 
accurate. The basic fuchsin test is currently specified in 
Secs. 113.100 and 113.200 of the regulations under the general 
requirements for inactivated bacterial products and the general 
requirements for killed virus vaccines, respectively. However, it may 
not be the

[[Page 16328]]

best method for all products. Studies show that the basic fuchsin test 
may overestimate the amount of residual free formaldehyde in formalin-
inactivated vaccine neutralized with sodium bisulfite, based on the 
calculated amount of sodium bisulfite needed to neutralize the volume 
of formaldehyde added to the product during inactivation.
    Those same studies showed that the ferric chloride method estimated 
the amount of residual free formaldehyde in formalin-inactivated 
vaccine neutralized with sodium bisulfite to be closer to the amount 
that would be determined by calculation based on the volume of 
formaldehyde added during inactivation. Other countries that receive 
these products as exports have required vaccine manufacturers to test 
for residual free formaldehyde content by other methods in addition to 
using the basic fuchsin test. Some manufacturers may be using two or 
more test methods in order to satisfy the regulatory requirements of 
other countries.
    Therefore, in an attempt to harmonize requirements for 
determination of residual free formaldehyde in veterinary biologics, 
the International Cooperation on Harmonization of Technical 
Requirements for the Registration of Veterinary Medicinal Products 
(VICH) is recommending that regulatory authorities cooperating in the 
VICH initiative adopt a harmonized procedure for determination of 
residual free formaldehyde content that is based on the ferric chloride 
method. (VICH is a unique project that brings together regulatory 
authorities of the United States, the European Union, and Japan and 
representatives from the animal health industry in the three regions to 
harmonize technical requirements for veterinary products as a means of 
reducing the differences in technical requirements for veterinary drugs 
and biologics among regulatory agencies in different countries.) The 
ferric chloride method described in this proposed rule was validated by 
a collaborative study involving 11 laboratories in the United States, 
Canada, Japan, and the European Union.
    APHIS is proposing to implement the recommendations of the VICH by 
amending the regulations in Secs. 113.100 and 113.200 concerning 
general requirements for inactivated bacterial products and general 
requirements for killed virus vaccines. We are proposing to require 
bulk or final container samples of completed inactivated bacterial 
products and killed virus vaccines from each serial to be tested for 
residual free formaldehyde content using the ferric chloride method in 
place of the basic fuchsin test that is currently specified. We are 
also proposing that the maximum allowable residual free formaldehyde 
content of veterinary biologics be measured in grams per liter (g/L) 
instead of the currently specified equivalent percent or parts per 
million. Under the present regulations, inactivated bacterial products 
which are found satisfactory using the viricidal activity test 
prescribed in Sec. 113.35 are not required to be tested pursuant to 
Sec. 113.100. This provision would remain unchanged.
    Licensed biologics manufacturers currently use the basic fuchsin 
method for determining residual free formaldehyde content of products 
that they produce. However, they are allowed to use alternative methods 
when they are more suited to a particular product being tested or to 
satisfy the regulatory requirements prescribed by other countries.
    The ferric chloride method for determination of residual free 
formaldehyde content proposed in this document is a harmonized method 
that regulatory authorities in the United States, the European Union, 
Japan, and Canada agree is the most accurate of the two best available 
methods for determining residual free formaldehyde content of 
veterinary biologics. It was selected because it is a familiar, 
commonly used procedure that does not require special equipment or 
reagents, should yield reproducible results in all laboratories, and 
should eliminate the need for veterinary biologics manufacturers to 
perform two or more tests to determine if their products contain excess 
levels of free formaldehyde. If necessary, however, veterinary 
biologics manufacturers would be allowed an exemption under Sec. 113.4 
of the regulations to use other test methods for determining residual 
free formaldehyde content of their products based on specific 
requirements or characteristics of the test material.

Determination of Residual Free Formaldehyde Content of Biological 
Products

    We are proposing to amend the regulations to specify that the 
requirements in Secs. 113.100 and 113.200 pertain to using the ferric 
chloride method to determine the free formaldehyde content of 
veterinary biological products. A footnote in each of these sections 
would provide an address from which the procedure for performing the 
ferric chloride test could be obtained. The basis for this proposed 
amendment is the collaborative and comparative study performed by 
APHIS, other VICH members, and the animal health industry to validate 
the ferric chloride method and earn its recognition as a VICH 
recommended harmonized procedure.

Materials and Equipment

    The proposed change to the regulations in Secs. 113.100 and 113.200 
would require the use of analytical grade chemical reagents and a 
spectrophometer capable of measuring absorbance at a wavelength of 628 
nm. Other commonly used and readily available laboratory equipment and 
supplies also would be required.

Compliance

    Veterinary biologics manufacturers that determine residual free 
formaldehyde content in desiccated biological products by a method that 
is not the ferric chloride method that would be required under this 
proposed rule would be allowed 1 year after the effective date of the 
final rule to come into compliance or to request an exemption under 
Sec. 113.4 of the regulations.
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.
    We are proposing to amend the Virus-Serum-Toxin Act regulations for 
determination of residual free formaldehyde content in biological 
products to require that such free formaldehyde determinations be made 
using the ferric chloride method, which determines residual free 
formaldehyde content by measuring the quantity of coloring matter in 
solution by the quantity of light absorbed in passing through the 
solution. In addition, we are proposing that the maximum allowable 
residual free formaldehyde content of veterinary biologics be measured 
in grams per liter rather than the currently specified equivalent 
percent or parts per million. The effect of this action would be to 
provide a standardized method which has been shown to be more accurate 
than the presently used basic fuchsin method and which has been 
standardized and adopted internationally.
    This proposed rule would affect all licensed manufacturers of 
veterinary biologics that test inactivated bacterial products and 
killed virus vaccines for free formaldehyde content.Currently, there 
are approximately 135 veterinary

[[Page 16329]]

biologics establishments, including permittees. According to the 
standards of the Small Business Administration, most veterinary 
biologics establishments would be classified as small entities.
    This proposed rule should not impose any additional testing or 
economic burden on these manufacturers because manufacturers currently 
test their products for free formaldehyde content using the basic 
fuchsin and other methods, and the reagents and equipment necessary to 
perform the ferric chloride test for free formaldehyde content that 
would be required under this proposed rule should be comparable in 
cost.
    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 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, Reporting and recordkeeping 
requirements.

    Accordingly, we propose to amend 9 CFR parts 113 as follows:

PART 113--STANDARD REQUIREMENTS

    1. The authority citation for part 113 continues to read as 
follows:

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

    2. In Sec. 113.100, paragraph (f) is revised to read as follows:


Sec. 113.100  General requirements for inactivated bacterial products.

* * * * *
    (f) If formaldehyde is used as the inactivating agent, and the 
serial has not been found satisfactory by the viricidal activity test, 
bulk or final container samples of completed product from each serial 
must be tested for residual free formaldehyde content using the ferric 
chloride test.\2\ Firms currently using tests for residual free 
formaldehyde content other than the ferric chloride test have until 
[Insert date 1 year from effective date of the final rule] to update 
their Outline of Production to be in compliance with this requirement.
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    \2\ The procedures for performing the ferric chloride test for 
residual free formaldehyde may be obtained from USDA, APHIS, Center 
for Veterinary Biologics-Laboratory, 100 Dayton Road, P.O. Box 844, 
Ames, IA 50010.
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    (1) The residual free formaldehyde content of biological products 
containing clostridial antigens must not exceed 1.85 grams per liter 
(g/L).
    (2) The residual free formaldehyde content of bacterins, bacterin-
toxoids, and toxoids, other than those containing clostridial antigens, 
must not exceed 0.74 grams per liter (g/L).
    3. In Sec. 113.200, paragraph (f) is revised to read as follows:


Sec. 113.200  General requirements for killed virus vaccines.

* * * * *
    (f) Formaldehyde content. If formaldehyde is used as the killing 
agent, the residual free formaldehyde content must not exceed 0.74 
grams per liter (g/L) as determined using the ferric chloride test.\3\ 
Firms currently using tests for residual free formaldehyde content 
other than the ferric chloride test have until [Insert date 1 year from 
effective date of the final rule] to update their Outline of Production 
to be in compliance with this requirement.
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    \3\ The procedures for performing the ferric chloride test for 
residual free formaldehyde may be obtained from USDA, APHIS, Center 
for Veterinary Biologics-Laboratory, 100 Dayton Road, P.O. Box 844, 
Ames, IA 50010.

    Done in Washington, DC, this 1st day of April 2002.
Bobby R. Acord,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 02-8260 Filed 4-4-02; 8:45 am]
BILLING CODE 3410-34-U