[Federal Register Volume 66, Number 137 (Tuesday, July 17, 2001)]
[Proposed Rules]
[Pages 37194-37197]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-17802]


 ========================================================================
 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. 66, No. 137 / Tuesday, July 17, 2001 / 
Proposed Rules  

[[Page 37194]]



DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 113

[Docket No. 98-099-1]


Viruses, Serums, Toxins, and Analogous Products; Erysipelothrix 
Rhusiopathiae Bacterin

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 
standard requirement for Erysipelothrix Rhusiopathiae Bacterin to 
specify that those requirements apply only to bacterins recommended for 
use in swine and turkeys, to require that the immunogenicity of such 
bacterins be demonstrated in a host animal protection study, to 
establish ``protection to market weight/age'' as the minimum duration 
of immunity requirement, and to replace the current mouse protection 
potency test used for serial release with an in vitro potency test. We 
are proposing these changes as a result of our evaluation that showed 
that some swine vaccinated with Erysipelothrix Rhusiopathiae Bacterins 
that meet the current standard requirement may be diagnosed with acute 
erysipelas infection before they reach market age. These actions would 
update the regulations by standardizing the efficacy and duration of 
immunity requirements, provide for the use of a validated serial 
release potency test, and ensure that serials that pass the serial 
release potency test will also protect swine and turkeys to market 
weight.

DATES: We invite you to comment on this docket. We will consider all 
comments that we receive by September 17, 2001.

ADDRESSES: Please send four copies of your comment (an original and 
three copies) to: Docket No. 98-099-1, 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. 98-099-1.
    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, between 8 a.m. and 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 Staff 
Officer, Operational Support Section, Center for Veterinary Biologics, 
Licensing and Policy Development, APHIS, USDA, 4700 River Road Unit 
148, Riverdale, MD 20737-1228; (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

    Standard requirements are prescribed in 9 CFR part 113 for the 
preparation and testing of certain veterinary biological products. A 
standard requirement consists of test methods, procedures, and criteria 
that define the standards of purity, safety, potency, and efficacy for 
a veterinary biological product. The regulations in 9 CFR 113.119 
specify purity, safety, and potency requirements for Erysipelothrix 
Rhusiopathiae Bacterin.
    Although purity, safety, and potency requirements for 
Erysipelothrix Rhusiopathiae Bacterin are specified in Sec. 113.119 of 
the standards, they do not prescribe the requirements by which such 
bacterin must be evaluated for immunogenicity and duration of immunity. 
Most of the currently available Erysipelothrix Rhusiopathiae Bacterins 
were licensed on the basis of host animal protection studies performed 
in either swine or turkeys. In the typical host animal protection 
study, swine or turkeys were vaccinated with Erysipelothrix 
Rhusiopathiae Bacterin and challenged with virulent Erysipelothrix 
rhusiopathiae culture 2 to 4 weeks post vaccination. The elapsed time 
between the completion of the immunization regimen and the 
administration of the challenge culture establishes the duration of 
vaccinal immunity. Therefore, 2 to 4 weeks' protection would be the 
demonstrated duration of immunity provided by Erysipelothrix 
Rhusiopathiae Bacterin licensed in accordance with the requirements 
currently specified in the regulations in Sec. 113.119.
    Currently, the serial release potency test prescribed in 
Sec. 113.119 is a mouse protection relative potency assay in which an 
Erysipelothrix Rhusiopathiae Bacterin (Unknown) and an Erysipelothrix 
rhusiopathiae standard reference bacterin (Standard) are compared in 
their ability to protect mice challenged with a virulent Erysipelothrix 
rhusiopathiae culture. The mouse potency test measures the relative 
strength of the Unknown as compared to the Standard and provides an 
indication of the ability of the Unknown to protect swine against 
erysipelas. The Standard used in the mouse potency test must have been 
shown to protect swine against erysipelas. The Unknown is considered to 
be potent enough to protect swine against erysipelas if it passes the 
mouse protection test.
    Based on the current standards, it was expected that a serial of 
Erysipelothrix Rhusiopathiae Bacterin would protect swine or turkeys 
until they reached market weight/age if it passed the mouse protection 
test. However, we have received complaints that swine vaccinated with 
Erysipelothrix Rhusiopathiae Bacterin at an early age were being 
diagnosed with erysipelas before reaching market weight/age. In 
response to these complaints, we evaluated four representative 
Erysipelothrix Rhusiopathiae Bacterins recommended for use in swine and 
found that three of the four failed to protect swine at 22 weeks of 
age, which is the age at which most swine are marketed. We did not 
evaluate Erysipelothrix Rhusiopathiae Bacterin recommended for use in 
turkeys for duration of immunity.
    On the basis of our evaluation of Erysipelothrix Rhusiopathiae 
Bacterins, we concluded that the mouse protection serial release 
potency test using the Erysipelothrix rhusiopathiae standard reference 
bacterin should be discontinued. This is because all of the

[[Page 37195]]

serials that failed to protect swine to market weight had passed the 
mouse protection relative potency test required for serial release. 
Western blot analyses performed on Erysipelothrix rhusiopathiae 
cultures used in our studies provided evidence that mice and swine 
recognize different immunogens. This may account for the failure in our 
analysis.
    As a result of our findings, we are proposing to amend the 
regulations in Sec. 113.119 to require that Erysipelothrix 
Rhusiopathiae Bacterin be tested for immunogenicity and duration of 
immunity in swine and/or turkeys. As a serial release potency test, we 
are proposing to require each serial of Erysipelothrix Rhusiopathiae 
Bacterin to be: (1) Tested for relative antigen content (potency) as 
compared with an unexpired Erysipelothrix rhusiopathiae reference 
bacterin by an in vitro parallel line immunoassay or other procedure 
acceptable to APHIS, or (2) evaluated in animals using antibody titers 
or other animal test data previously correlated to host animal 
protection as evidence of immunogenicity.
    We are also proposing to specify that the requirements prescribed 
in Sec. 113.119 pertain to Erysipelothrix Rhusiopathiae Bacterins for 
use in swine and turkeys. The basis for this proposed amendment is a 
host animal vaccination challenge study conducted by APHIS in which 6-
week old pigs vaccinated with Erysipelothrix Rhusiopathiae Bacterin 
were protected against challenge with a virulent Erysipelothrix 
rhusiopathiae culture at 22 weeks of age.

Immunogenicity

    We are further proposing that Erysipelothrix Rhusiopathiae 
Bacterins be evaluated for immunogenicity in swine and/or turkeys as 
appropriate. Thirty Erysipelothrix rhusiopathiae-susceptible swine and/
or turkeys (20 vaccinates and 10 controls) of the youngest age 
recommended on the label would be vaccinated with an Erysipelothrix 
Rhusiopathiae Bacterin (master reference bacterin or qualifying serial, 
as defined in the regulations in Sec. 101.5) by each route of 
administration recommended on the label.

Protection to Market Weight/Age (Duration of Immunity)

    The proposed changes to the regulations in Sec. 113.119 would also 
require Erysipelothrix Rhusiopathiae Bacterin to protect vaccinates 
against the characteristic signs of erysipelas until they reach market 
weight, which occurs at approximately 22 weeks of age for swine and 14 
weeks of age for turkeys. To demonstrate protection and duration of 
immunity, swine used in the immunogenicity study would be challenged 
with a virulent culture of Erysipelothrix rhusiopathiae at 22 weeks of 
age or older, while turkeys would be challenged with a virulent culture 
of Erysipelothrix rhusiopathiae at 14 weeks of age or older.

Potency

    Under this proposed rule, each serial would have to be evaluated 
for relative antigen content by a direct or indirect in vitro parallel 
line immunoassay using a monospecific antibody that has been shown to 
provide passive protection in animals after challenge with virulent 
Erysipelothrix rhusiopathiae. Alternatively, potency could also be 
determined by measuring serologic response in animals, provided that 
such response had been correlated to protection in a host animal 
immunogenicity study using a protective protein.

Reagents

    In order to facilitate the development of Erysipelothrix 
Rhusiopathiae Bacterin that provides the host animal protection and 
duration of immunity specified in this proposed rule, APHIS will supply 
reagent (monospecific antibody) produced by the hybridoma cell line 
ERHU1-B60-91, which is the same cell line that produced the antisera 
used to demonstrate passive protection and to purify the protein used 
to demonstrate active protection in the host animal vaccination-
challenge study conducted by APHIS that serves as the basis for this 
proposed rule. If they prefer, firms could develop their own reagents 
for use in satisfying the requirements specified in this proposed rule. 
However, we believe that the use of APHIS-supplied reagent would 
greatly reduce the expenditure of time and resources needed to develop 
a potency test that would ensure that the product provides the duration 
of immunity that would be required by this proposed rule.

Safety

    Currently, the regulations require each serial of biological 
product containing Erysipelothrix rhusiopathiae to be tested for safety 
in guinea pigs in accordance with Sec. 113.38. However, for consistency 
with the regulations for other bacterins, we are proposing that each 
serial of biological product containing Erysipelothrix rhusiopathiae 
immunogen be tested for safety in mice in accordance with Sec. 113.33.

Currently Licensed Bacterins

    Veterinary biologics manufacturers that produce Erysipelothrix 
Rhusiopathiae Bacterin under the present standards would be allowed 1 
year after the effective date of the final rule to come into 
compliance. In the interim, we would allow such manufacturers to 
continue to release serials of Erysipelothrix Rhusiopathiae Bacterins 
using the current standards, provided that such serials of product are 
shown to be effective and the labels for such products specify the 
demonstrated duration of immunity.

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 regulations regarding the standard 
requirement for Erysipelothrix Rhusiopathiae Bacterins to require that 
such bacterins be shown to protect vaccinated swine and/or turkeys at 
least to market weight based on vaccination-challenge studies conducted 
in host animals. We are also proposing to replace the mouse protection 
(potency) test used for serial release with an in vitro parallel line 
immunoassay because we have data that demonstrate that some 
Erysipelothrix Rhusiopathiae Bacterins that pass the mouse potency test 
do not protect animals to market weight (normally reached at 22 weeks 
of age for swine and 14 weeks of age for turkeys) when used as 
directed. The effect of these actions would be to standardize the 
duration of immunity and potency test requirements for Erysipelothrix 
Rhusiopathiae Bacterins and ensure that serials that pass the potency 
test also protect animals to market weight.
    This proposed rule would affect all licensed manufacturers of 
veterinary biologics that produce Erysipelothrix Rhusiopathiae 
Bacterins. Currently, there are approximately 135 veterinary biologics 
establishments, and approximately 45 of these establishments produce 
Erysipelothrix Rhusiopathiae Bacterins. According to the standards of 
the Small Business Administration, most veterinary biologics 
establishments would be classified as small entities.
    This proposed rule would require each manufacturer of 
Erysipelothrix Rhusiopathiae Bacterins to incur the expense of 
developing an Erysipelothrix

[[Page 37196]]

Rhusiopathiae Bacterin that provides the duration of immunity specified 
in this proposed rule. However, the cost of developing such a bacterin 
would be greatly reduced if manufacturers use the reagents developed 
and provided by APHIS. In addition, the in vitro potency test specified 
in this proposed rule would result in a reduction in the number of 
animals used for serial release testing and would also reduce the time 
and personnel costs associated with animal care and housing.
    Veterinary biologics manufacturers that produce Erysipelothrix 
Rhusiopathiae Bacterin under the present standards would be allowed 1 
year after the effective date of the final rule to come into 
compliance. In the interim, we would allow such manufacturers to 
continue to release serials of Erysipelothrix Rhusiopathiae Bacterins 
using the current standards, provided that such serials of product are 
shown to be effective and the labels for such products specify the 
demonstrated duration of immunity.
    We do not have an alternative option to this proposed rule because 
swine and turkey producers need a vaccine that offers protection until 
the animals reach market weight. However, we believe that, in the long 
term, expended developmental costs would be recovered and manufacturers 
would actually realize a savings, as the cost of purchasing, feeding, 
and housing the animals needed to test Erysipelothrix Rhusiopathiae 
Bacterins, as currently required, would be reduced and/or eliminated by 
utilizing nonanimal (in vitro) potency tests for serial release as 
proposed in this document.
    This proposed rule would not require manufacturers to use the same 
monospecific antibodies that APHIS used in the host animal protection 
study. However, manufacturers may use the reagents developed by APHIS 
to facilitate their ability to comply with the requirements specified 
in this proposed rule or develop their own.
    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 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 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 113.119 would be revised to read as follows:


Sec. 113.119  Erysipelothrix Rhusiopathiae Bacterin.

    Erysipelothrix Rhusiopathiae Bacterin must be produced from a 
culture of Erysipelothrix rhusiopathiae or a culture expressing 
protective proteins from Erysipelothrix rhusiopathiae that are 
inactivated and nontoxic. Each serial of biological product containing 
Erysipelothrix rhusiopathiae immunogen must meet the applicable 
requirements of Sec. 113.100 and must be tested for purity, safety, 
potency, and immunogenicity as prescribed in this section. A serial 
found unsatisfactory by any prescribed test may not be released. The 
requirements in this section apply to bacterins used in swine and 
turkeys. Firms currently producing Erysipelothrix rhusiopathiae 
bacterin that does not satisfy the immunogenicity and/or duration of 
immunity requirement will have 1 year from the effective date of this 
rule to be in compliance with this requirement unless granted an 
extension by the Administrator based on a showing by the firm that it 
has made a good faith effort with due diligence to achieve compliance.
    (a) Erysipelothrix Rhusiopathiae Bacterins must be tested for 
immunogenicity as follows:
    (1) For Erysipelothrix Rhusiopathiae Bacterins recommended for use 
in swine or turkeys, 30 Erysipelothrix rhusiopathiae-susceptible 
animals (20 vaccinates and 10 controls) of the youngest age recommended 
on the label must be used as test animals for each route of 
administration.
    (2) A master reference (as defined in Sec. 101.5 of this chapter) 
must be established before the immunogenicity test is conducted. The 
method of production and conditions of storage of the master reference 
must be described in the outline of production filed with the Animal 
and Plant Health Inspection Service (APHIS). The 20 animals used as 
vaccinates must be injected as recommended on the label with either the 
master reference or a qualifying serial (as defined in Sec. 101.5 of 
this chapter). The vaccinates and controls must be examined and their 
body temperature determined daily for 3 days prior to challenge. At 22 
weeks of age or older for swine or 14 weeks or age or older for 
turkeys, the vaccinates and controls must be challenged with a virulent 
Erysipelothrix rhusiopathiae culture and observed for 7 days. The 
challenge culture and instructions for preparation and use must be 
obtained from APHIS.
    (3) A satisfactory challenge in swine will be evidenced in the 
controls by a high body temperature or clinical signs, including, but 
not limited to, acute illness with hyperemia of the abdomen and/or 
ears, possibly terminating in sudden death; moribundity, with or 
without skin lesions; depression with anorexia, stiffness, and/or joint 
involvement; or any combination of these symptoms and lesions. If at 
least 8 of the 10 controls do not show characteristic signs of 
erysipelas during the observation period, including, but not limited 
to, a body temperature of at least 105.6  deg.F on at least 2 
consecutive days, the test will be considered inconclusive. However, 
control swine that meet the requirements for susceptibility, except for 
high body temperature, will be considered susceptible if Erysipelothrix 
rhusiopathiae organisms are isolated from the blood, spleen, or other 
organs.
    (4) A satisfactory challenge in turkeys will be evidenced in the 
controls by a generalized septicemia accompanied by the isolation of 
Erysipelothrix rhusiopathiae organisms from the joints or organs. If at 
least 8 of the 10 controls do not show characteristic signs or 
demonstrate other evidence of infection during the observation period, 
the test will be considered inconclusive.
    (5) To demonstrate immunity after challenge, at least 80 percent of 
the vaccinates must remain free of clinical signs, and the body 
temperature of 80

[[Page 37197]]

percent of the swine must not exceed 104.6  deg.F on 2 or more 
consecutive days.
    (6) The allowable dating of the master reference previously 
qualified as specified in paragraph (a)(2) of this section is the same 
as the dating of a serial of product or as approved by APHIS. The 
expiration date and the lot number of the master reference must be 
specified in the filed outline of production. The dating of the master 
reference may be extended by confirming its stability in accordance 
with Sec. 113.8 prior to the expiration date specified in the filed 
outline of production.
    (7) The master reference may be requalified by one of the following 
methods:
    (i) Performing an immunogenicity test as specified in paragraph 
(a)(1) through (a)(5) of this section, except that the number of test 
animals may be reduced to 10 vaccinates and 5 controls, provided that 8 
of 10 vaccinates and 4 of 5 controls meet the criteria specified in 
paragraphs (a)(3), (a)(4), and (a)(5) of this section.
    (ii) Immunologic methods not requiring vaccination and challenge 
(e.g., serology) may be used to demonstrate the stability of a 
reference if the immunologic response was initially correlated to 
protection during the immunogenicity test. For a satisfactory test, 5 
of 5 controls must remain seronegative at a 1:2 dilution, and 80 
percent of the vaccinates must demonstrate bioequivalent serologic 
titers when compared to the protective titers established during the 
immunogenicity test. The length of the serologic study need not be the 
same as the immunogenicity test if adequate data acceptable to APHIS 
exist to correlate the serologic response earlier after vaccination 
than the immunogenicity test with protection at market weight.
    (iii) A purified protein from Erysipelothrix rhusiopathiae that has 
been shown to elicit a protective response to challenge with virulent 
Erysipelothrix rhusiopathiae in swine may be used to requalify a 
working reference or qualify a new working reference. Such protein must 
be prepared by immunoaffinity purification methods using monospecific 
antisera or by other purification methods acceptable to APHIS. The 
purity and potency of a purified protein master reference must be well-
characterized by in vitro methods such as high-performance liquid 
chromatography, protein quantification methods, immunoblot analyses, 
and/or other methods acceptable to APHIS. The immunogenicity of a 
purified protein master reference must be directly established or 
indirectly established using a qualifying serial of product as provided 
in Sec. 113.8 and paragraphs (a)(3), (a)(4), and (a)(5) of this 
section.
    (8) An outline of production and data acceptable to APHIS must be 
approved for filing before authorization for the use of a new lot of 
master reference, a new lot of working reference, or a requalified 
master reference is granted.
    (b) Test requirements for release. Each serial of Erysipelothrix 
Rhusiopathiae Bacterin must meet the applicable requirements of 
Sec. 113.100 and must be tested for purity, safety, and potency as 
prescribed in this section. A serial found unsatisfactory by any 
prescribed test is not eligible for release.
    (1) Purity test. Final container samples of completed product from 
each serial must be tested for viable bacteria and fungi as prescribed 
in Sec. 113.26.
    (2) Safety test. Bulk or final container samples of completed 
product from each serial must be tested for safety as provided in 
Sec. 113.33(b).
    (3) Potency test. In accordance with Sec. 113.8(c), bulk or final 
container samples of completed product from each serial derived from an 
approved master seed must be evaluated for relative antigen content 
(potency) by the procedure specified in the filed outline of production 
as compared with an unexpired reference (which has been shown directly 
or indirectly to elicit acceptable duration of immunity) by a direct or 
indirect parallel line immunoassay. Potency may also be evaluated by 
measuring serologic response in animals that has been correlated to 
protection provided by a protective protein or other procedure 
acceptable to APHIS. The immunoassay must use a monoclonal antibody or 
monospecific antibody that has been shown to impart passive protection 
in animals following challenge with virulent Erysipelothrix 
rhusiopathiae.
    (i) For a valid potency assay, at least two replications of at 
least six dilutions of the reference must be compared to at least two 
replications of at least six dilutions of each test serial on the same 
microtitration plate.
    (ii) When comparing the test serial to the master reference by a 
relative potency method, a satisfactory test must have a minimum 
relative potency greater than or equal to 1.0. A relative potency of 
1.0 is based on the antigen concentration of the master reference or 
qualifying serial of vaccine used in the host animal duration of 
immunity efficacy trial specified in paragraphs (a)(3), (a)(4), and 
(a)(5) of this section or on the serologic response to a protective 
immunogen elicited by the master reference or qualifying serial.
    (iii) On the basis of the results of such tests, each serial that 
meets the required minimum relative potency of greater than or equal to 
1.0 will be released for marketing. Each serial that does not meet the 
required minimum potency must be withheld from the market.
    (c) Products without the required duration of immunity. This 
section's requirement that an Erysipelothrix Rhusiopathiae Bacterin 
provide 22 weeks' duration of immunity in swine and 14 weeks' duration 
of immunity in turkeys will become effective 1 year after the 
publication of the final rule. Producers of Erysipelothrix 
Rhusiopathiae Bacterin may use the 1-year interval between the date of 
publication of the final rule and its effective date to update their 
products to provide the required duration of immunity. During this 1-
year period, Erysipelothrix Rhusiopathiae Bacterins that do not protect 
vaccinates to market age (22 weeks for swine and 14 weeks for turkeys) 
may continue to be marketed if the labels for such products specify the 
duration of immunity demonstrated in the host animal protection study 
required for licensing. At the end of this 1-year period, 
Erysipelothrix Rhusiopathiae Bacterins that do not provide the minimum 
specified protection must be withheld from the market until they comply 
with the requirements of this section.

    Done in Washington D.C., this 11th day of July 2001.
Bobby R. Acord,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 01-17802 Filed 7-16-01; 8:45 am]
BILLING CODE 3410-34-U