[Federal Register Volume 67, Number 150 (Monday, August 5, 2002)]
[Proposed Rules]
[Pages 50606-50608]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-19669]


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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. 150 / Monday, August 5, 2002 / 
Proposed Rules  

[[Page 50606]]



DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 113

[Docket No. 01-067-1 ]


Viruses, Serums, Toxins, and Analogous Products; Determination of 
Moisture Content in Desiccated 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 moisture content in desiccated 
biological products to specify that such determinations be made using 
the harmonized gravimetric method adopted by the International 
Cooperation on Harmonization of Technical Requirements for the 
Registration of Veterinary Medicinal Products that expresses moisture 
content as the percentage of weight a product loses during a drying 
cycle, and to require that the maximum percentage of moisture permitted 
for a satisfactory test must be specified in a filed Outline of 
Production. We are proposing this change in order to replace the 
variety of tests for moisture determination that are currently 
described by manufacturers in Outlines of Production filed with the 
Animal and Plant Health Inspection Service with a test recognized as an 
international standard by scientific experts and regulatory authorities 
in the United States, Japan, and the European Union. In addition, we 
are proposing to amend sections of the regulations pertaining to 
general requirements for live bacterial vaccines and general 
requirements for live virus vaccines to specify the gravimetric method 
when testing for moisture content. These actions would update the 
regulations by providing a uniform method of determining moisture 
content in desiccated products and ensure the stability of that product 
during its dating period.

DATES: We will consider all comments that we receive on or before 
October 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. 01-067-1, 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. 01-067-1. 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. 
01-067-1'' 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, Licensing and Policy Development, Center for 
Veterinary Biologics, 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 113 (referred 
to below as the regulations) contain requirements for the preparation 
and testing of certain veterinary biological products. Section 113.29 
of the regulations sets forth the requirement for determination of 
moisture content in desiccated biological products.
    In this document, we are proposing to amend the regulations 
regarding the determination of moisture content in desiccated 
biological products. Residual moisture in desiccated biological 
products is related to the stability of these products during their 
dating period. Under the current regulations in Sec. 113.29, a uniform 
method for determining residual moisture is not prescribed. Rather, 
biologics manufacturers establish an acceptable range for moisture for 
each of their products and test for moisture content using approved 
procedures specified in a filed Outline of Production. This allows 
biologics manufacturers to utilize test procedures that may be unique 
to specific products.
    Three common methods are generally recognized for use in 
determining residual moisture:
     The titrimetric method, also known as the Karl Fischer 
method, which involves titration of the water content of a sample and 
comparison with a standard curve that has been created by titrating 
different volumes of water;
     The azeotropic method, which measures change in the 
composition (weight) of a mixture after it is boiled under a given 
pressure; and
     The gravimetric method, which expresses residual moisture 
as a percentage of weight a product loses during a drying cycle.
    Although the gravimetric method or some variation thereof is used 
by most of the veterinary biologics manufacturers licensed by the U.S. 
Department of Agriculture (USDA) to test for residual moisture, the 
other methods may also be used if they are prescribed as a required 
test by regulatory authorities in other countries that receive these 
products as exports. Some manufacturers may be using two or more test 
methods in order to satisfy the regulatory requirements of other 
countries.
    Currently, each manufacturer describes its own test for moisture 
content in its filed Outline of Production. Because of the variety of 
assay procedures specified in Outlines of Production and the conditions 
that exist in the different laboratories performing the procedures, 
even a subtle difference in conditions or technique can cause large 
variations in measured moisture content and raise questions concerning 
the stability of the

[[Page 50607]]

product. When performing moisture determinations, control of all 
critical factors that may affect an assay is important. The validity of 
the assay and the quality of the product during its dating period are 
greatly dependent on control of all factors critical to the assay. The 
use of a uniform method for determining the moisture content would 
allow for the control of all the critical factors that are part of the 
assay.
    Therefore, in an attempt to harmonize residual moisture testing in 
countries with similar regulatory requirements, 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 determining residual moisture that is based on 
the gravimetric method. (VICH is a unique project that brings together 
regulatory authorities of the United States, 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 agreement by VICH to recommend adoption of a harmonized 
gravimetric procedure was preceded by collaborative and comparative 
testing by regulatory agencies and representatives of the veterinary 
biologics industry to validate the method.\1\ The harmonized procedure 
has been adopted in this proposed rule.
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    \1\ We published a notice in the Federal Register on January 24, 
2001 (65 FR 7614-7615, Docket No. 00-123-1), regarding the draft 
guideline ``Testing of Residual Moisture'' developed by VICH. The 
notice included information on how a copy of the draft guideline 
could be obtained from APHIS. The VICH harmonized gravimetric method 
can be viewed on the Internet at http://vich.eudra.org/htm/
guidelines.htmt3.
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    We are proposing to implement the recommendation of the VICH by 
amending the regulations in Sec. 113.29 concerning determination of 
moisture content in desiccated biological products. We are proposing to 
require that final container samples of completed desiccated biological 
products be tested for residual moisture using the harmonized 
gravimetric method. We also are proposing to require that the maximum 
allowable moisture content for each product must be specified in the 
Outline of Production approved for filing by the Animal and Plant 
Health Inspection Service (APHIS). The majority of USDA-licensed 
biologics manufacturers currently specify a gravimetric method for 
determining residual moisture in their Outlines of Production. However, 
manufacturers are allowed to customize the assay procedure to 
accommodate conditions that are most suitable to a particular product. 
Therefore, while most manufacturers express moisture content as a 
percentage of weight a product loses during a drying cycle, the methods 
used to determine the percentage of weight loss are not uniform and, 
therefore, not easily duplicated or confirmed by other laboratories. 
This proposed rule would establish a uniform test method applicable to 
all products that are tested for moisture content.
    The residual moisture assay proposed in this document would apply 
to final container samples of completed product for all desiccated 
vaccines. It was selected because it is a familiar, commonly used 
procedure that does not require special equipment or reagents, and 
should yield reproducible results in all laboratories. However, 
manufacturers would be allowed an exemption under Sec. 113.4 of the 
regulations to use other test methods based on specific requirements or 
characteristics of the test material.

Determination of Moisture Content in Desiccated Biological Products

    We are proposing to amend the regulations to specify that the 
requirements in Sec. 113.29 pertain to using a VICH harmonized 
gravimetric method to determine the moisture content of desiccated 
biological products. 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 gravimetric 
method and earn its recognition as a VICH-recommended, harmonized 
procedure. In addition, we propose to amend the regulations in 
Secs. 113.64 and 113.300 to specify the gravimetric method as the 
applicable procedure for determining moisture content.

Materials and Equipment

    The proposed change to the regulations in Sec. 113.29 would require 
the use of a heat-regulated vacuum oven with air-drying device attached 
to the inlet valve, a balance with a rated precision of  
0.1 mg, and other commonly used and readily available laboratory 
equipment.

Compliance

    Veterinary biologics manufacturers that determine moisture content 
in desiccated biological products by a method other than the 
gravimetric method that would be required by 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 moisture content in desiccated biological products to 
require that such moisture determinations be made using a VICH 
harmonized gravimetric method that determines residual moisture by 
measuring the percentage of weight a product loses during a product 
drying cycle. In addition, we are proposing to specify the gravimetric 
method as the applicable test for moisture content for live bacterial 
and live viral vaccines. The effect of this action would be to provide 
a standardized method for the determination of moisture content in 
desiccated biological products and ensure that such moisture 
determinations are uniform and reproducible.
    This proposed rule would affect all licensed manufacturers of 
veterinary biologics that test desiccated vaccines for moisture 
content. Currently, there are approximately 135 veterinary 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 the regulations 
currently require manufacturers to specify an assay procedure for 
moisture content in their filed Outline of Production, and most 
manufacturers currently specify the gravimetric method, or some 
variation thereof, as the test procedure that they are using. In 
addition, manufacturers would have the ability to request an exemption 
to use other test methods based on specific requirements or 
characteristics of the test material.
    Under these circumstances, the Administrator of the Animal and 
Plant Health Inspection Service has determined that this action would 
not

[[Page 50608]]

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 part 113 as follows:
    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 113.29 would be revised to read as follows:


Sec. 113.29  Determination of moisture content in desiccated biological 
products.

    Methods provided in this section must be used when a determination 
of moisture content in desiccated biological products is prescribed in 
an applicable Standard Requirement or in the filed Outline of 
Production for the product. Firms currently using methods other than 
those provided in this section for determining the moisture content in 
desiccated biological products have until [Insert date 1 year from 
effective date of the final rule] to update their Outlines of 
Production to be in compliance with this requirement.
    (a) Final container samples of completed product shall be tested. 
The weight loss of the sample due to drying in a vacuum oven shall be 
determined. All procedures should be performed in an environment with a 
relative humidity less than 45 percent. The equipment necessary to 
perform the test is as follows:
    (1) Cylindrical weighing bottles with airtight glass stoppers.
    (2) Vacuum oven equipped with validated thermometer and thermostat. 
A suitable air-drying device should be attached to the inlet valve.
    (3) Balance, accurate to 0.1 mg (rated precision  
0.01mg).
    (4) Desiccator jar equipped with phosphorous pentoxide, silica gel, 
or equivalent.
    (5) Desiccated vaccine in original sealed vial. Sample and control 
should be kept at room temperature in their original airtight 
containers until use.
    (b) Test procedure:
    (1) Thoroughly cleaned and labeled sample-weighing bottles with 
stoppers should be allowed to dry at 60  3  deg.C under 
vacuum at less than 2.5 kPa.
    (i) Transfer hot bottles and stoppers into the desiccator and allow 
to cool to room temperature.
    (ii) After bottles have cooled, insert stoppers and weigh and 
record the weights of the bottles as ``A.''
    (iii) Return weighing bottles to the desiccator.
    (2) Remove the sample container seal.
    (i) Using a spatula, break up the sample plug and transfer the 
required amount of sample to the previously tared weighing bottle.
    (ii) Insert the stopper and weigh and record the weights of the 
weighing bottles as ``B.''
    (3) Place the weighing bottle with the stopper at an angle in the 
vacuum oven. Set the vacuum to < 2.5 kPa and the temperature to 60 
 3  deg.C.
    (4) After a minimum of 3 hours of drying time, turn off the vacuum 
pump and allow dry air to bleed into the oven until the pressure inside 
the oven is equalized with the prevailing atmospheric pressure.
    (5) While the bottle is still warm, replace the stopper in its 
normal position and transfer the weighing bottle to the desiccator .
    (i) Allow a minimum of 2 hours for the weighing bottle to cool to 
room temperature or for its weight to reach equilibrium.
    (ii) Weigh, and record the weight as ``C.''
    (6) Calculate the percentage of moisture in the original sample as 
follows:

(B-C)/(B-A) x (100) = Percentage of residual moisture, where:
A = tare weight of weighing bottle
B-A = weight of sample before drying
B--C = weight of sample after drying

    (7) The results are considered satisfactory if the percentage of 
residual moisture is less than or equal to the manufacturer's 
specification.
    3. In Sec. 113.64, paragraph (e) would be amended by adding a new 
paragraph (e)(3) as follows:


Sec. 113.64  General requirements for live bacterial vaccines.

* * * * *
    (e) * * *
    (3) Final container samples of completed product from each serial 
and subserial must be tested for moisture content in accordance with 
the test provided in Sec. 113.29.
    4. Section 113.300 would be amended by revising paragraph (e) as 
follows:


Sec. 113.300  General requirements for live virus vaccines.

* * * * *
    (e) Moisture content. (1) The maximum moisture content in 
desiccated vaccines must be stated in the filed Outline of Production.
    (2) Final container samples of completed product from each serial 
or subserial must be tested for moisture content in accordance with the 
test prescribed in Sec. 113.29.

    Done in Washington, DC, this 30th day of July 2002.
Peter Fernandez,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 02-19669 Filed 8-2-02; 8:45 am]
BILLING CODE 3410-34-P