[Federal Register Volume 60, Number 95 (Wednesday, May 17, 1995)]
[Proposed Rules]
[Pages 26381-26384]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-12152]
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DEPARTMENT OF AGRICULTURE
9 CFR Parts 101 and 113
[Docket No. 94-051-1]
RIN 0579-AA66
Viruses, Serums, Toxins, and Analogous Products; In Vitro Tests
for Serial Release
AGENCY: Animal and Plant Health Inspection Service, USDA.
ACTION: Proposed rule.
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SUMMARY: We are proposing to amend the regulations regarding the use of
in vitro potency tests in place of animal tests for immunogenicity to:
change the title of the section; prescribe requirements for in vitro
immunoassays used to determine the relative antigen content of
inactivated biological products; require that such immunoassays be
parallel line assays based upon unexpired reference preparations;
require that in vitro tests for relative antigen content be converted
to parallel line assays within 2 years; specify procedures and
requirements for qualifying or requalifying reference preparations for
inactivated products; and add certain definitions to the regulations.
The effect of the amendment would be to standardize the methods
used to determine the relative potency of inactivated biological
products.
DATES: Consideration will be given only to comments received on or
before August 15, 1995.
ADDRESSES: Please send an original and three copies of your comments to
Docket No. 94-051-1, Regulatory Analysis and Development, PPD, APHIS,
Suite 3C03, 4700 River Road Unit 118, Riverdale, MD 20737-1238. Please
state that your comments refer to Docket No. 94-051-1. Comments
received may be inspected at USDA, room 1141, South Building, 14th
Street and Independence Avenue SW., Washington, DC, between 8 a.m. and
4:30 p.m., Monday through Friday, except holidays. Persons wishing to
inspect comments are requested to call ahead (202) 690-2817 to
facilitate entry into the comment reading room.
FOR FURTHER INFORMATION CONTACT:
Dr. David A. Espeseth, Deputy Director, Veterinary Biologics, BBEP,
APHIS, 4700 River Road Unit 148, Riverdale, MD 20737-1237, (301) 734-
8245.
SUPPLEMENTARY INFORMATION:
Background
The regulations pertaining to the testing of biologics provide that
no biological product shall be released (for sale) prior to the
completion of tests prescribed to establish the product to be pure,
safe, potent, and efficacious (9 CFR 113.5). Efficacy refers to the
specific ability of the product to effect the result for which it is
offered when used as recommended by the manufacturer. Studies conducted
to establish efficacy include immunogenicity tests in host animals
using product manufactured according to specific requirements which
include specifications for antigen content and/or animal potency. These
requirements apply to every serial of product which is produced.
Therefore, if a product has been tested for immunogenicity in animals
and shown to have the desired effect, it follows that subsequent
serials (batches) of the product manufactured to the same
specifications should also have the same effect.
Once immunogenicity is established in relation to a specific
minimum antigen content in a product, it should no longer be necessary
to test every subsequent serial for potency in animals if an evaluation
can be made with reasonable certainty of the relative antigen content
by testing the serial or subserial in an acceptable in vitro test
system. Therefore, when properly qualified and validated, in vitro
immunoassays that determine relative antigen content of the product can
serve as acceptable substitutes for potency tests that otherwise would
need to be performed in animals.
The regulations in 9 CFR 113.8 pertain to the use of in vitro tests
in place of animal tests for determining the potency of veterinary
biological products. Currently, the in vitro tests prescribed in
Sec. 113.8 which include determining the log10 virus titer and
performing live bacterial counts are only applicable to veterinary
biologicals which contain live microorganisms. The changes and test
procedures prescribed in this proposal would make Sec. 113.8 applicable
to both live and inactivated products by prescribing validity
requirements for in vitro test systems used, in place of animal tests,
to test for the potency of inactivated products.
We are proposing to amend the title of Sec. 113.8 to read: ``In
vitro potency tests for serial release.'' This change is intended to
clarify the fact that the in vitro procedures described in Sec. 113.8
are applicable to in vitro tests used to release serials or subserials
of veterinary biological products after the prescribed animal
protection studies required for licensing have been completed. In the
case of inactivated products, the proposal specifies that in vitro
immunoassays (test systems) which compare the relative antigen content
(relative potency) of a test serial to a reference preparation must be
parallel line assays using an unexpired reference preparation whose
potency has been correlated directly or indirectly to immunogenicity in
host animals.
In addition, the proposal would require: confirming the accuracy of
the protective dose established for live products 3 years after the
initiation of the host animal immunogenicity study; and confirming the
immunogenicity of reference preparations used in immunoassays for
inactivated biological products prior to their expiration. The
expiration date for a reference would be equal to the dating of the
product or as supported by data acceptable to APHIS.
APHIS is proposing these amendments because current requirements
for many of the immunoassays being used to release serials or
subserials of product do not have uniform validity criteria and do not
include a provision to confirm periodically the immunogenicity of the
reference used in such immunoassays. The proposed amendment would
standardize the requirements for in vitro potency tests for relative
antigen content and update and improve the reliability of such tests
that are currently included in filed outlines of production. The
proposed amendment does not specify a particular immunoassay provided
that it is a parallel line assay using an unexpired reference
preparation. While there is not a generally accepted ``best''
immunoassay, there is general agreement that an acceptable
[[Page 26382]] immunoassay must demonstrate linearity, specificity, and
reproducibility; and that the reference must be capable of eliciting a
protective immune response in animals for as long as it serves as the
reference.
APHIS has selected the parallel line assay because it demonstrates
linearity, specificity, and reproducibility, and also compares the
``similarity'' of the responses elicited by the test and reference
preparations in the immunoassay. APHIS feels that the ``similarity''
feature is critical to the acceptance of any in vitro immunoassay
purporting to measure relative antigenic content. We realize that the
proposed amendment would necessitate the revalidation of immunoassays
currently contained in some filed outlines of production and propose to
implement the requirements as set out below.
Firms with filed outlines of production for licensed products with
in vitro potency tests that are immunoassays that are not parallel line
assays would be allowed 2 years after the effective date of the final
rule to come into compliance with the proposed amendments. In the
interim, immunoassays, utilizing unexpired references, contained in
previously approved outlines of production would continue to be allowed
for serial release of previously licensed fractions but would not be
acceptable for fractions not previously licensed to the firm. Firms
with filed outlines of production for licensed product with in vitro
potency tests for relative antigen content would be required to use
unexpired references. References that have expired or that are about to
expire would need to be requalified or have the dating period extended
in accordance with protocols and time schedules acceptable to APHIS.
APHIS has determined that immunoassays that are not based on a
parallel line assay using an unexpired reference may not provide
reliable relative potency data in all instances. Such instances include
the determination of relative potency based on a reference preparation
that may have expired or the extrapolation of data based upon standard
curves that may not be proportional between serial and reference. These
amendments are being proposed in order to provide greater assurance
that a serial of product provides adequate potency in all instances.
We are also adding to the regulations in Sec. 101.5 definitions of
the term ``immunogenicity'', and the terms ``master reference'',
``working reference'', and ``qualifying serial'' as they apply to
reference preparations used in in vitro immunoassays.
Licensees, researchers, and scientists at the National Veterinary
Services Laboratories, U.S. Department of Agriculture, have cooperated
in the development of this proposed rule. We are therefore proposing to
amend Secs. 101.5 and 113.8 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 no significant for purposes of
Executive Order 12866, and therefore, has not been reviewed by the
Office of Management and Budget.
This proposed amendment, if adopted, would allow any valid in vitro
immunoassay to be used in determining the relative antigen content of
an inactivated veterinary biological product, provided that it
satisfies the parallel line criteria and that it is conducted using an
unexpired reference preparation that has been tested, directly or
indirectly, for immunogenicity in a manner acceptable to APHIS. This
amendment would affect all licensed manufacturers of veterinary
biologicals utilizing in vitro relative potency immunoassays for
determining the potency of inactivated products. This proposal,
however, does not impose any additional economic burden since the
testing of product for potency is already required under Sec. 113.5 of
the regulations and outlines of production are routinely amended and
updated. Section 113.5 specifies that no biological product shall be
released prior to the completion of tests prescribed in a filed outline
of production or standard requirement to establish that the product is
pure, safe, potent, and efficacious. In the absence of a standard
requirement prescribing a specific potency test for inactivated
products, the firms develop a potency test suitable for their product,
and designate such tests in the outline of production that is filed
with APHIS. Currently, firms are using host animal tests, laboratory
animal tests, and a variety of in vitro immunoassays as potency tests
for inactivated products. This proposed rule does not restrict the
firm's discretion to choose the most appropriate test for its product.
The proposed rule would only prescribe validity requirements for in
vitro immunoassays for relative potency. The overall effect of this
proposed amendment would be to standardize in vitro immunoassays that
are used to determine the potency of inactivated veterinary biological
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 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 12778
This proposed rule has been reviewed under Executive Order 12778,
Civil Justice Reform. If this proposed rule is adopted: (1) All State
and local laws and regulations that are in conflict with this rule will
be preempted; (2) no retroactive effect will be given to this rule; and
(3) administrative proceedings will not be required before parties may
file suit in court challenging this rule.
Paperwork Reduction Act
In accordance with the Paperwork Reduction Act of 1980 (44 U.S.C.
3501 et seq.), the information collection or recordkeeping
requirements included in this proposed rule have been approved by the
Office of Management and Budget (OMB), and there are no new
requirements. The assigned OMB control number is 0579-0013.
List of Subjects
9 CFR Part 101
Animal biologics.
9 CFR Part 113
Animal biologics, Exports, Imports, Reporting and recordkeeping
requirements.
Accordingly, 9 CFR parts 101 and 113 would be amended as follows:
PART 101--DEFINITIONS
1. The authority citation for part 101 would continue to read as
follows:
Authority: 21 U.S.C. 151-159; 7 CFR 2.17, 2.51, and 371.2(d).
2. Section 101.5 would be amended by adding new paragraphs (o),
(p), (q), and (r) to read as follows:
Sec. 101.5 Testing terminology.
* * * * *
(o) Master Reference. A Master Reference is a reference whose
potency is correlated, directly or indirectly, to host animal
immunogenicity. The Master Reference may be used as the working
reference in in vitro tests for relative potency. The Master Reference
[[Page 26383]] may also be used to establish the relative potency of a
serial of product used in requalification studies and to establish the
relative potency of working references. A Master Reference may be:
(1) A completed serial of vaccine or bacterin prepared in
accordance with a field Outline of Production;
(2) A purified preparation of the protective immunogen or antigen;
or
(3) A nonadjuvanted harvested culture of microorganisms.
(p) Working Reference. A Working Reference is the reference
preparation that is used in the in vitro test for the release of
serials of product. Working References may be:
(1) Master References; or
(2) Serials of product that have been prepared and qualified, in a
manner acceptable to APHIS, for use as reference preparations.
(q) Qualifying Serial. (1) A serial of biological product used to
test for immunogenicity when the Master or Working Reference is a
purified antigen or nonadjuvanted harvest material. Qualifying serials
shall be produced in accordance with the filed Outline of Production,
tested for immunogenicity in host animals in accordance with protocols
acceptable to Animal and Plant Health Inspection Service, and have a
geometric mean relative potency, when compared to the Master Reference,
of not greater than 1.0 as established by independent parallel line
assays with 5 or more replicates.
(2) Qualifying serials used to requalify or extend the dating
period of a Master Reference in a repeat immunogenicity test shall
satisfy all criteria prescribed above and, it addition, shall have been
prepared within 6 months of requalifying testing, i.e., the initiation
of the repeat immunogenicity test.
(r) Immunogenicity. The ability of a biological product to elicit
an immune response in animals as determined by test methods or
procedures acceptable to the Animal and Plant Health Inspection
Service.
PART 113--STANDARD REQUIREMENTS
3. The authority citation for part 113 would continue to read as
follows:
Authority: 21 U.S.C. 151-159; 7 CFR 2.17, 2.51, and 371.2(d).
4. Section 113.8 would be amended as follows:
a. The section heading would be revised to read as set forth below.
b. Paragraph (a) would be revised to read as set forth below.
c. Paragraph (b) the introductory text would be revised to read as
set forth below.
d. Paragraph (b)(5) would be revised to read as set forth below.
e. Paragraph (c) would be redesignated as paragraph (e) and new
paragraphs (c) and (d) would be added to read as set forth below.
f. In redesignated paragraph (e), in the introductory text, the
reference to ``paragraph (b)'' would be removed and ``Paragraphs (b)
and (c)'' would be added in its place. In paragraph (e)(4), the
reference to ``paragraphs (c)(1),'' would be removed and ``paragraphs
(e)(1),'' would be added in its place.
Sec. 113.8 In vitro potency tests for serial release.
(a) Master Seed which has been established as pure, safe, and
immunogenic shall be used for preparing seed for production as
specified in the Standard Requirements or in the filed Outline of
Production. The Administrator may exempt a product from a required
animal potency test for release when an evaluation can, with reasonable
certainty, be made by:
(1) Subjecting the master seed to the applicable requirements
prescribed in Secs. 113.64, 113.100, 113.200, and 113.300;
(2) Testing the Master Seed for immunogenicity in a manner
acceptable to the Animal and Plant Health Inspection Service (APHIS);
(3) Establishing a satisfactory potency for live products based on
the protective dose used in the Master Seed immunogenicity test plus an
adequate overage allowance for adverse conditions and test error; and
(4) For inactivated products, determining the potency of each
serial or subserial, or both, using an accepted test system. Acceptable
potency tests shall include:
(i) Determining the log10 live virus titer;
(ii) Determining the live bacterial count; or
(iii) For inactivated products, determining the relative antigen
content, as compared with a reference, using a parallel line
immunoassay.
(b) In the case of live products, each serial and subserial of
desiccated product derived from an approved Master Seed and bulk or
final container samples of each serial of completed liquid product
derived from an approved Master Seed shall be evaluated by a test
procedure acceptable to APHIS. On the basis of the results of the test,
as compared with the required minimum potency, each serial and
subserial shall either be released to the firm for marketing or
withheld from the market. The evaluation of such products shall be made
in accordance with the following criteria:
(1) * * *
* * * * *
(5) Exceptions. When a product is evaluated in terms other than
log10 virus titer or organism count, an appropriate difference
between the average potency value obtained in the retests and the
potency value obtained in the initial test shall be established for use
in paragraphs (b)(3) or (b)(4) of this section to evaluate such
products and shall be specified in the Product Standard Requirement or
filed Outline of Production.
(c) In the case of inactivated products, bulk or final container
samples of completed product from each serial derived from an approved
Master Seed, shall be evaluated for relative antigen content (potency),
as compared with a reference, by a parallel line immunoassay procedure
acceptable to APHIS. Firms currently using immunoassays which do not
meet the requirements of a parallel line assay shall have 2 years from
the effective date of the final rule to update their filed Outlines of
Production to be in compliance with this requirement. On the basis of
the results of such test procedures, each serial that meets the
required minimum potency shall be released to the firm for marketing;
each serial not meeting the required minimum potency shall be withheld
from the market. The evaluation of such products shall be made in
accordance with the following criteria:
(1) A test that results in no valid lines is considered a no test
and may be repeated.
(2) An initial test that results in valid lines that are not
parallel is considered a valid equivocal test. Release of the serial
may not be based on such test since the result cannot be termed
``satisfactory'' or ``unsatisfactory''.
(3) If the initial test shows that potency equals or exceeds the
required minimum potency, the serial is satisfactory without additional
testing.
(4) If the initial test is an equivocal test due to lack of
parallelism, the serial may be retested up to three times: Provided,
That, if the test is not repeated, the serial shall be deemed
unsatisfactory.
(i) If more than 50% of all valid repeat tests show that potency
equals or exceeds the required minimum potency, the serial is
satisfactory.
(ii) If greater than 50% of all valid repeat tests show either lack
of parallelism or that potency is less than the required minimum
potency, the serial is unsatisfactory. [[Page 26384]]
(5) If the initial test shows that potency is less than the
required minimum potency, the serial may be retested. If retested, two
additional tests, must be conducted: Provided, That, if the serial is
not retested, the serial shall be deemed unsatisfactory.
(i) If more than 50% of all valid tests show that potency equals or
exceeds the required minimum potency, the serial is satisfactory.
(ii) If more than 50% of all valid tests show either lack of
parallelism or that potency is less than the required minimum potency,
the serial is unsatisfactory.
(d) Repeat immunogenicity tests.
(1) The accuracy of the protective dose established for live
products in the Master Seed immunogenicty test and defined as live
virus titer or live bacterial count shall be confirmed in 3 years in a
manner acceptable to APHIS, unless use of the lot of Master Seed
previously tested is discontinued.
(2) All determinations of relative antigen content using parallel
line immunoassays shall be conducted with an unexpired reference. The
lot of reference used to determine antigenic content shall have an
initial dating period equal to the dating of the product or as
supported by data acceptable to APHIS. Prior to the expiration date,
such reference may be granted an extension of dating by confirming its
immunogenicity using a Qualifying Serial of product. Tests to establish
or confirm immunogenicity of references shall be conducted in a manner
acceptable to APHIS. The dating period of the Master Reference and
Working Reference may be extended as supported by data acceptable to
APHIS if the minimum potency of the Master Reference is determined to
be adequately above the minimum level needed to provide protection in
the host animal. If a new Master Reference is established, it shall be
allowed an initial dating period equal to the dating of the product or
as supported by data acceptable to APHIS.
* * * * *
Done in Washington, DC, this 11th day of May 1995.
Terry L. Medley,
Acting Administrator, Animal and Plant Health Inspection Services.
[FR Doc. 95-12152 Filed 5-16-95; 8:45 am]
BILLING CODE 3410-34-M
