Viruses, Serums, Toxins, and Analogous Products; General Requirements for Inactivated Bacterial Products

DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Parts 101 and 113

[Docket No. 92-201-2]

Viruses, Serums, Toxins, and Analogous Products; General

Requirements for Inactivated Bacterial Products

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Final rule.

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SUMMARY: We are amending the regulations to include a general standard

requirement for inactivated bacterial products that is consistent with

the general standard requirements [[Page 14354]] for live bacterial

products, killed virus vaccines, and live virus vaccines. We are also

including criteria and test concerning the identity of master seed.

Finally, the amendment provides a choice of the most appropriate test

methods, including identity tests, for the broad range of inactivated

bacterial products available today. The final rule is necessary to

update the current standards and provide uniform, relevant criteria for

inactivated bacterial products.

EFFECTIVE DATE: April 17, 1995.

FOR FURTHER INFORMATION CONTACT:

Dr. Richard E. Pacer, Senior Staff Veterinarian, Animal and Plant

Health Inspection Service, Biotechnology, Biologics, and Environmental

Protection, Veterinary Biologics, 4700 River Road Unit 148, Riverdale,

MD 20737-1228, (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

In accordance with the regulations in 9 CFR part 113, standard

requirements are prescribed for the licensing of veterinary biological

products. A standard requirement consists of specifications,

procedures, and test methods which define the standards of purity,

safety, potency, and efficacy for a given type of veterinary biological

product.

On March 1, 1994, we published in the Federal Register (59 FR 9681-

9682, Docket No. 92-201-1) a proposal to amend the regulations by

revising Sec. 113.100 to include the relevant criteria for evaluation

of the purity, safety, and identity of inactivated bacterial products.

In addition, we proposed to define the master seed concept as it

applies to inactivated bacterial products. This action was intended to

provide specific criteria for these inactivated bacterial products. We

also proposed to move certain definitions from Sec. 113.100 to part

101.

We solicited comments on our proposal for a 60-day period ending

May 2, 1994. We received one comment by that date. This comment was

from a licensed manufacturer of veterinary biological products. The

commenter's only concern was about the manufacture of inactivated

bacterial products for fish.

The commenter sought clarification of our requirement for safety

tests as proposed in Sec. 113.100(b). This requirement states that each

bacterial product shall be evaluated in mice and/or guinea pigs with

the exception that, if the product is specific for poultry, then the

safety test will be performed in poultry. The commenter suggested that

an exception similar to that for poultry should be considered for

products specifically intended for fish. We agree with the rationale of

the commenter because it would be more appropriate to evaluate the

safety of a biological product intended for fish in an aquatic species

than in a mammalian species. In response to the commenter, we have

amended the proposal by adding a new paragraph (b)(3) in Sec. 113.100

concerning fish and including other aquatic species or reptiles which

states: ``The product is recommended for fish, other aquatic species or

reptiles. In such instances, the product shall be safety tested in fish

or other aquatic species or reptiles as required by specific Standard

Requirement or Outline of Production for the product.'' We have also

made a slight change to the definitions to clarify the fact that the

defined products are inactivated bacterial products.

Therefore, with the exception of the above changes, we are adopting

the provisions of the proposal as a final rule.

Executive Order 12866 and Regulatory Flexibility Act

This rule has been reviewed under Executive Order 12866. The rule

has been determined to be not significant for purposes of Executive

Order 12866, and, therefore, has not been reviewed by the Office of

Management and Budget.

There are currently no general requirements for inactivated

bacterial products in the regulations. However, approximately 30

percent of the 114 currently licensed veterinary biologics companies

manufacture inactivated bacterial products. Many of these companies are

considered small entities and will benefit from the adoption of this

rule. The benefits of the rule include increased efficiency and reduced

time and expense in accomplishing the steps toward licensure of an

inactivated bacterial product. These benefits will be realized because

of ready access to clear requirements, uniformity and consistency in

product development, and the alleviation of unnecessary steps in

production of these type of products. These companies should not

experience any additional costs above those which they currently incur

to license an inactivated bacterial product as a result of adoption of

this rule.

Under these circumstances, the Administrator for the Animal and

Plant Health Inspection Service has determined that this action will

not have a significant economic impact on a substantial number of small

entities.

Executive Order 12778

This rule has been reviewed under Executive Order 12778, Civil

Justice Reform. This rule: (1) Preempts all State and local laws and

regulations that are in conflict with this rule; (2) has no retroactive

effect; and (3) does not require administrative proceedings before

parties may file suit in court challenging this rule.

Paperwork Reduction Act

This rule contains no information collection or recordkeeping

requirements under the Paperwork Reduction Act of 1980 (44 U.S.C. 3501

et seq.).

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.)

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 ad 113 are amended as follows:

PART 101--DEFINITIONS

1. The authority citation for part 101 continues to read as

follows:

Authority: 21 U.S.C. 151-159; 7 CFR 2.17, 2.51, and 371.2(d).

2. Section 101.3, is amended by adding, at the end of the section,

the following definitions to read as follows:

Sec. 101.3 Biological products and related terms.

* * * * *

(m) Bacterin. An inactivated bacterial product consisting of an

antigenic suspension of organisms or particulate parts of organisms,

representing a whole culture or a concentrate thereof, with or without

the unevaluated growth products, which has been inactivated as

demonstrated by acceptable tests written into the filed Outline of

Production for the product.

(n) Toxoid. An inactivated bacterial product which consists of a

sterile, antigenic toxin or toxic growth product, which has resulted

from the growth of bacterial organisms in a culture medium from which

the bacterial cells have been removed, which has been inactivated

[[Page 14355]] without appreciable loss of antigenicity as measured by

suitable tests, and which is nontoxic as demonstrated by acceptable

tests written into the filed Outline of Production.

(o) Bacterin-toxoid. An inactivated bacterial product which is

either:

(1) A suspension of organisms, representing a whole culture or a

concentrate thereof, with the toxic growth products from the culture

which has been inactivated without appreciable loss of antigenicity as

measured by suitable tests, the inactivation of organisms and toxins

being demonstrated by acceptable tests written into the filed Outline

of Production: Provided, That it shall contain cellular antigens and

shall stimulate the development of antitoxin; or

(2) A combination product in which one or more toxoids or bacterin-

toxoids is combined with one or more bacterins or one or more bacterin-

toxoids.

(p) Bacterial extract. An inactivated bacterial product which

consists of the sterile, nontoxic, antigenic derivatives extracted from

bacterial organisms or from culture medium in which bacterial organisms

have grown.

PART 113--STANDARD REQUIREMENTS

3. The authority citation for part 113 continues to read as

follows:

Authority: 21 U.S.C. 151-159; 7 CFR 217, 2.51, and 371.2(d).

4. In Sec. 113.100, the heading, introductory paragraph, and

paragraphs (a) through (d) are revised to read as follows:

Sec. 113.100 General requirements for inactivated bacterial products.

Unless otherwise prescribed in an applicable Standard Requirement

or in the filed Outline of Production, an inactivated bacterial product

shall meet the applicable requirements in this section.

(a) Purity tests. (1) Final container samples of completed product

from each serial and each subserial shall be tested for viable bacteria

and fungi as provided in Sec. 113.26.

(2) Each lot of Master Seed Bacteria shall be tested for the

presence of extraneous viable bacteria and fungi in accordance with the

test provided in Sec. 113.27(d).

(b) Safety tests. Bulk or final container samples of completed

product from each serial shall be tested for safety in young adult mice

in accordance with the test provided in Sec. 113.33(b) unless:

(1) The product contains material which is inherently lethal for

mice.

In such instances, the guinea pig safety test provided in

Sec. 113.38 shall be conducted in place of the mouse safety test.

(2) The product is recommended for poultry. In such instances, the

product shall be safety tested in poultry as defined in the specific

Standard Requirement or Outline of Production for the product.

(3) The product is recommended for fish, other aquatic species, or

reptiles. In such instances, the product shall be safety tested in

fish, other aquatic species, or reptiles as required by specific

Standard Requirement or Outline of Production for the product.

(c) Identity test. Methods of identification of Master Seed

Bacteria to the genus and species level by laboratory tests shall be

sufficient to distinguish the bacteria from other similar bacteria

according to criteria described in the most recent edition of

``Bergey's Manual of Systematic Bacteriology'' or the American Society

for Microbiology ``Manual of Clinical Microbiology''. If Master Seed

Bacteria are referred to by serotype, serovar, subtype, pilus type,

strain or other taxonomic subdivision below the species level, adequate

testing must be used to identify the bacteria to that level. Tests

which may be used to identify Master Seed Bacteria include, but are not

limited to:

(1) Cultural characteristics,

(2) Staining reaction,

(3) Biochemical reactivity,

(4) Fluorescent antibody tests,

(5) Serologic tests,

(6) Toxin typing,

(7) Somatic or flagellar antigen characterization, and

(8) Restriction endonuclease analysis.

(d) Ingredient requirements. Ingredients used for the growth and

preparation of Master Seed Bacteria and of final product shall meet the

requirements provided in Sec. 113.50. Ingredients of animal origin

shall meet the applicable requirements provided in Sec. 113.53.

* * * * *

Done in Washington, DC, this 13th day of March 1995.

Terry L. Medley,

Acting Administrator, Animal and Plant Health Inspection Service.

[FR Doc. 95-6648 Filed 3-16-95; 8:45 am]

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