Federal Register / Vol. 60, No. 52 / Friday, March 17, 1995 / Rules and Regulations 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 § 113.100, the heading,

introductory paragraph, and paragraphs

(a) through (d) are revised to read as

follows:

§ 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 § 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

§ 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 § 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 § 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 § 113.50.

Ingredients of animal origin shall meet

the applicable requirements provided in

§ 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]

BILLING CODE 3410–34–M

9 CFR Part 113

[Docket No. 93–057–2]

Viruses, Serums, Toxins, and

Analogous Products; Sampling of

Biological Products

AGENCY: Animal and Plant Health

Inspection Service, USDA.

ACTION: Final rule.

SUMMARY: We are amending the

regulations concerning the number of

representative samples of product that a

firm is required to submit to the Animal

and Plant Health Inspection Service for

testing at the National Veterinary

Services Laboratories, Ames, Iowa. The

amendment is applicable to diagnostic

test kits and Master Seeds and Cells,

and will codify provisions which are

not currently in the regulations.

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

The regulations in 9 CFR Part 113

contain standard requirements for

evaluating veterinary biological

products that are licensed by the

Animal and Plant Health Inspection

Service (APHIS), U.S. Department of

Agriculture, under the Virus-SerumToxin Act of 1913, as amended by the

Food Security Act of 1985. Licenses are

required to show that biological

products are pure, safe, potent, and

efficacious.

Purity and identify tests are

performed by the licensee and the

National Veterinary Services

Laboratories (NVSL) on master seed(s)

and master cell stock(s) used in the

production of veterinary biological

products. The licensee is also required

to perform tests on the completed

veterinary biological product for purity,

safety, and potency as prescribed in a

filed outline of production or applicable

standard requirements for the product

in accordance with § 113.5. The

licensee’s test results may be confirmed

by NVSL personnel using representative

biological product samples that the

manufacturer is required to submit to

APHIS in accordance with § 113.3.

Section 113.3 currently provides

licensees and permittees with criteria

for selection and submission of

veterinary biological products, such as
14356 Federal Register / Vol. 60, No. 52 / Friday, March 17, 1995 / Rules and Regulations

vaccines, bacterins, antiserums, and

toxoids to NVSL. Section 113.3,

however, does not state the number of

samples of diagnostic test kits and

master seeds and cells required by

NVSL for product evaluation. These

amendments specify that a minimum of

1 sample of a diagnostic test kit, 10

samples of bacterial master seeds, 13

samples of viral master seeds, and 36

milliliters of master cell stocks will be

required for evaluation at NVSL.

Finally, minor editorial changes are

made in § 113.309 to reflect

organizational changes within APHIS.

On March 24, 1994, we published in

the Federal Register (59 FR 13896–

13897, Docket No. 93–057–1) the

proposal to amend § 113.3.

We solicited comments for a 60-day

period ending May 23, 1994. Two

comments were received by that date.

Both comments were from licensed

manufacturers of veterinary biological

products. The commenters were in favor

of the proposed rule, but suggested

certain changes.

The first commenter felt that the 1

milliliter (ml) sample volume for master

seeds and cells was too restrictive and

suggested that a volume of ‘‘1 ml or

larger’’ be specified along with a

minimum total volume. Proposed

paragraph (c) of § 113.3 specified that ‘‘a

minimum individual volume of 1 ml

shall be submitted.’’ The proposed

wording thus did not restrict the total

volume to only 1 ml. In response to the

commenter, we have amended

§ 113.3(c)(3) as follows:

Thirty-six samples of at least 1 ml each or

six samples of at least 1 ml each, one sample

of at least 20 ml, and one sample of at least

10 ml of Master Cell Stocks. In the case of

Master Cell Stocks which are persistently

infected with a virus, an additional four

samples of at least 1 ml each are required. If

these persistently infected cell stocks are

intended for use in more than one species,

an additional two samples of at least 1 ml are

required for each additional species.

The second commenter requested

clarification regarding diagnostic test

kits when the final product packages

contains more than one microtiter test

plate. Several diagnostic test kits are

designed to use 96-well microtiter test

plates or 12- or 16-well microtiter test

strips. The proposed rule (§ 113.3(b)(7))

specified the submission of ‘‘two

samples of diagnostic test kits’’ as a

general rule and ‘‘a minimum of one

diagnostic kit’’ in the preamble of the

rule. As the commenter pointed out,

multiple test plates or test strips may be

packaged together with other test

reagents in a single product. In the case

of a product with multiple microtiter

test plates or test strips, APHIS would

not need to test all of the test plates or

test strips for proper evaluation of the

product. In response to the commenter,

we have amended § 113.3(b)(7) and

§ 113.3(e)(1) to require the submission

of a specified number of test plates or

test strips along with all other test

reagents as prescribed in a filed Outline

of Production when a diagostic test kit

contains multiple microtiter test plates

or test strips.

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 criteria in the

regulations which specify the number of

samples needed by NVSL to evaluate

diagnostic test kits and Master Seeds

and Cells. Almost all of the 114 licensed

veterinary biologics companies

currently submit samples of Master

Seeds and Cells to NVSL for testing. In

addition, at least 25 of these companies

produce veterinary diagnostic test kits

and submit samples of them to NVSL for

testing. Many of these companies would

be considered small entities. This rule

will benefit these entities by clarifying

the current requirements.

This rule will reduce the licensees’

time and expense in submitting samples

to the NVSL by specifying the number

of samples required, by increasing the

uniformity of sample submissions, and

by allowing for more efficient handling

of samples by licensees and APHIS

personnel. In addition, this amendment

could increase revenues for

manufacturers of veterinary diagnostic

test kits by allowing them to return

unrequested samples to inventory for

sale.

Under these circumstances, the

Administrator of 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 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 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 new

information collection or recordkeeping

requirements under the Paperwork

Reduction Act of 1980 (44 U.S.C. 3501

et seq.).

List of Subjects in 9 CFR Part 113

Animal biologics Exports, Imports,

Reporting and recordkeeping

requirements.

Accordingly, 9 CFR part 113 is

amended 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 2.17,

2.51, and 371.2(d).

2. In § 113.3, paragraphs (b)(7), (b)(8)

and (b)(9) are revised, paragraph (b)(10)

is removed, paragraph (c) is revised, and

new paragraphs (d) and (e) are added to

read as follows:

§ 113.3 Sampling of biological products.

* * * * *

(b) * * *

(7) Diagnostic test kits: Two samples

of diagnostic test kits. The licensee or

permittee will hold one of these selected

samples at the storage temperature

recommended on the label while

awaiting a request by the animal and

Plant Health Inspection Service to

submit the additional sample. If

submission is not requested by the

Animal and Plant Health Inspection

Service, the additional sample may be

returned to the serial inventory after the

serial is released. In the case of

diagnostic test kits in which final

packaging consists of multiple

microtiter test plates or strips, the

licensee or permittee may submit a

specified number of test plates or strips

along with all other test reagents as

prescribed in a filed Outline of

Production and retain a similar amount

as a second sample for submission upon

request. When the initial sample is not

representative of final packaging by the

licensee of permittee, e.g., does not

consist of all the microtiter test plates or

strips, the second sample is not eligible

to be returned to serial inventory after

the serial is released.

(8) Autogenous biologics: Ten samples

shall be selected from each serial of

autogenous biologic that exceeds 50

containers. No samples, other than those
Federal Register / Vol. 60, No. 52 / Friday, March 17, 1995 / Rules and Regulations 14357

required by paragraph (e) of this section,

are required for a serial of autogenous

biologic with 50 or fewer containers.

(9) Miscellaneous: The number of

samples from products not in the

categories provided for in paragraphs

(b)(1) through (b)(8) of this section shall

be prescribed in the filed Outline of

Production for the product.

(c) Prelicensing and Outline of

Production changes: Samples needed to

support a license application or a

change in the Outline of Production for

a licensed product shall be submitted

only upon request from the animal and

Plant Health Inspection Service. Except

for miscellaneous products specified in

paragraph (b)(9) of this section, the

number of such samples shall be at least

one and one-half times the number

prescribed for such product in

paragraph (b) of this section. Samples of

Master Seeds and Master Cell Stocks

with a minimum individual volume of

1 ml shall be submitted as follows:

(1) Ten samples of Bacterial Master

Seeds.

(2) Thirteen samples of viral Master

Seeds or nonviral Master Seeds

requiring cell culture propagation. For

Master Seeds isolated or passed in a cell

line different from the species of

intended use, an additional 2 samples

are required for each additional species.

For Master Seeds grown in cell culture

and intended for use in more than one

species, an additional 2 samples are

required for each additional species.

(3) Thirty-six samples of at least 1 ml

each or six samples of at least 1 ml each,

one sample of at least 20 ml, and one

sample of at least 10 ml of Master Cell

Stocks. In the case of Master Cell Stocks

which are persistently infected with a

virus, an additional four samples of at

least 1 ml each are required. If these

persistently infected cell stocks are

intended for use in more than one

species, an additional two samples of at

least 1 ml each are required for each

additional species.

(4) Four samples of the Master Cell

Stock + n (highest passage) cells.

(d) Sterile diluent: A sample of Sterile

Diluent shall accompany each sample of

product, other than Marek’s Disease

Vaccine, if such diluent is required to

rehydrate or dilute the product before

use. The volume of diluent shall be an

appropriate amount to rehydrate or

dilute the product. Samples of Sterile

Diluent prepared for use with Marek’s

Disease Vaccine shall be submitted

upon request from the Animal and Plant

Health Inspection Service.

(e) Reserve samples shall be selected

from each serial and subserial of

biological product. Such samples shall

be selected at random from final

containers of completed product by an

employee of the Department, of the

licensee, or of the permittee, as

designated by the administrator. Each

sample shall:

(1) Consist of 5 single-dose packages,

2 multiple-dose packages, or 2

diagnostic test kits, except that, in the

case of diagnostic test kits in which

final packaging consists of multiple

microtiter test plates or strips, a sample

may consist of a specified number of

test plates or strips along with all other

test reagents as prescribed in a filed

Outline of Production;

(2) Be adequate in quantity for

appropriate examination and testing;

(3) Be truly representative and in final

containers;

(4) Be held in a special compartment

set aside by the licensee or permittee for

holding these samples under

refrigeration at the storage temperature

recommended on the labels for 6

months after the expiration date stated

on the labels. The samples that are

stored in this manner shall be delivered

to the Animal and Plant Health

Inspection Service upon request.

(Approved by the Office of Management and

Budget under control number 0579–0013)

§ 113.309 [Amended]

3. In § 113.309, paragraph (c)(4), the

words ‘‘Veterinary Services’’ are

removed and the words ‘‘Animal and

Plant Health Inspection Service’’ are

added in their place.

Done in Washington, DC, this 13th day of

March 1995.

Terry L. Medley,

Acting Administrator, Animal and Plant

Health Inspection Service.

[FR Doc. 95–6649 Filed 3–16–95; 8:45 am]

Billing Code 3410–34–M

9 CFR Part 113

[Docket No. 92–132–2]

Viruses, Serums, Toxins, and

Analogous Products; Revision of

Standard Requirements

AGENCY: Animal and Plant Health

Inspection Service, USDA.

ACTION: Final rule.

SUMMARY: This rule amends the

Standard Requirements concerning Dog

Safety Testing; Canine Distemper

Vaccine, Killed Virus; Canine Hepatitis

Vaccine, Killed Virus; Canine

Adenovirus Type 2 Vaccine, Killed

Virus; Mink Enteritis Vaccine, Killed

Virus; Canine Hepatitis Vaccine, Live

Virus; Canine Adenovirus Type 2

Vaccine, Live Virus; and Canine

Distemper Vaccine, Live Virus. The

amendments are necessary because new

test methods and procedures have been

developed that can replace current test

requirements and increase the validity

of test results. The effect of the

amendments is to provide new test

methods and procedures and to relax

some of the restrictions currently in

effect. Also, the Standard Requirement

for Canine Distemper Vaccine (Ferret

Virulent) is removed because this

vaccine is no longer manufactured.

EFFECTIVE DATE: April 17, 1995.

FOR FURTHER INFORMATION CONTACT:

Dr. David A. Espeseth, Deputy Director,

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

The regulations in 9 CFR part 113

‘‘Standard Requirements’’, (referred to

below as the regulations) consist of test

methods, procedures, and criteria

established by the Animal and Plant

Health Inspection Service (APHIS) for

the evaluation of veterinary biological

products based upon their purity, safety,

potency, and efficacy. The Agency

periodically reviews the regulations and

amends test methods and procedures as

required to ensure that they are

consistent with current scientific

knowledge. On July 23, 1993, we

published in the Federal Register (see

58 FR 39467–39473, Docket No. 92–

132–1) a proposed rule to update the

regulations based upon current

scientific knowledge.

We solicited comments concerning

our proposal for a 60-day comment

period ending September 21, 1993. We

received four comments by that date.

One commenter fully supported the

proposal as written. Three commenters

suggested changes to certain sections

related to the Standard Requirements.

These comments are discussed below.

Two commenters suggested changes

to § 113.204. Both commenters

indicated that the portion of the

regulations dealing with the time(s) of

feces collection for virus detection

required clarification, and suggested

that feces collection at some point from

day 4 to 8 would be appropriate.

APHIS believes that the above

comments have merit. APHIS agrees

that feces collection early or late in the

collection period, or more than once, is

unnecessary. Therefore, APHIS has

revised the regulations in

§ 113.204(b)(2) to specify that feces are