[Code of Federal Regulations]
[Title 9, Volume 1]
[Revised as of January 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 9CFR114.9]
[Page 781-785]
TITLE 9--ANIMALS AND ANIMAL PRODUCTS
CHAPTER I--ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF
AGRICULTURE
PART 114_PRODUCTION REQUIREMENTS FOR BIOLOGICAL PRODUCTS
--Table of Contents
Sec. 114.9 Outline of Production guidelines.
Each Outline of Production shall be prepared in accordance with the
applicable directions provided in this section.
(a) General requirements. (1) The original and not more than four
copies of each Outline of Production or special outline or revised pages
of either shall be prepared on heavy paper (8.5 x
11) of a type receptive to permanent stamp ink.
(2) The name of the biological product (or component), the
establishment license number, and the date prepared shall appear on a
front cover page and each page of the Outline of Production or special
outline. The name of the licensee (or foreign manufacturer) shall appear
on the front cover page.
(3) The pages shall be numbered in the upper center. At least 1\1/2\
inch margin shall be left at the top of the first page and a 2 inch
margin at the bottom of each page for the Animal and Plant Health
Inspection Service stamp.
(4) Amended pages shall be numbered the same as those being
superseded. They shall bear the date prepared and refer to the date on
the pages being superseded. If one replacement page supersedes more than
one page, the new page shall indicate same, but if several replacement
pages are added to supersede one page, the page number followed by
letters shall be used.
(5) The last page of the original and one copy of either a new or a
completely rewritten Outline of Production and each page revised
separately shall be signed in the lower left corner by the authorized
representative of the licensee (or foreign producer). Stamped or
facsimile signatures are not acceptable.
(6) A summary of changes shall appear on an attached page and refer
to each page, paragraph, or subparagraph being changed.
(7) Transmittal forms shall be used for the original and subsequent
revisions. Blank forms shall be available upon request to Animal and
Plant Health Inspection Service.
(b) Special outline. An outline describing the preparation of a
component of a biological product or an operation performed in the
preparation of a biological product may be required if such special
outline could be referred to in Outlines of Production to eliminate
repetition. Each special outline shall be identified by number and shall
not be used until accepted and filed by Animal and Plant Health
Inspection Service.
(c) Outline of Production for anti-serum, antitoxin, and normal
serum
[[Page 782]]
shall be written according to the following:
Outline Guide for Production of Antiserum and Antitoxin and Normal Serum
License No. Name of Product Date
I. Serum animals. A. Species, conditions, age, and general health.
B. Examination, preparation, care, quarantine, tests, and treatment
of animals before injections are started.
C. Holding, handling, exercising, and monitoring the condition of
animals after injections are started.
II. Antigens. A. Composition and character of the antigen.
1. Micro-organisms.
2. Source and date of accession of each micro-organism.
3. Strains.
4. Proportions of each micro-organism and strain.
B. Identification methods used for each micro-organism and frequency
with which these methods are applied.
C. Virulence and purity of cultures or antigen and the determination
and maintenance thereof. Range of subcultures or passages to be used in
production.
D. Attenuation, if any, before use for production purposes.
E. Character, size, and shape of containers used for growing micro-
organisms.
F. Media used for stock, seed, and antigen cultures (composition and
reaction of). May refer to a special outline by number.
G. Preparation of the antigen or toxin and toxoid. Complete and full
description of each step and its manner of accomplishment and number
these steps in sequence. Include all tests for each antigen, and the
specifications for character, identity, virulence, concentration, and
standardization.
III. Immunization of animals. A. Outline fully with special
attention given to the following:
1. Character and dose of the antigen.
2. Method and frequency of injections.
3. Time required for immunization or hyperimmunization.
4. Preliminary bleedings and tests, if any, to ascertain quality of
serum.
5. All other similar matters, including treatments between
bleedings.
B. Period of time elapsing between last injection and first
bleeding; and between bleedings.
C. Technique of bleeding operations; volume of blood collected at
each bleeding; and period of rest.
IV. Preparation of the biological product. A. Describe fully and
show each step of preparation from the first bleeding to the completion
of the preserved product in bulk containers prior to filling of final
containers.
B. Composition of the preservative and proportions used. Indicate at
which step of production, and the method used in adding the
preservative.
C. Agglutination and complement-fixation titers and the methods of
their determinations.
D. Disposition of unsatisfactory biological products and infective
materials not used in production.
E. Assembly of units to make a serial; volume of the average serial;
and the volume of the maximum serial.
V. Testing. Indicate the stages in the preparation of the biological
product at which samples are collected. Refer to all applicable Standard
Requirements. Outline all additional tests in detail and state minimum
requirements for each satisfactory test.
A. Purity.
B. Safety.
C. Potency.
D. Other tests.
VI. Post preparatory steps.
A. Form and size of final containers in which the product is to be
distributed.
B. Methods and techniques of filling final containers. Volume of
fill for each size final container.
C. Collection, storage, and submission of representative samples.
Indicate at which steps in the production these samples are taken.
D. Expiration date based on the earliest date of harvest and the
date of the last satisfactory potency test.
E. Use, dosage, and route of administration for each animal species
for which it is recommended.
F. Include any additional pertinent information.
(d) Outline of Production for vaccines, bacterins, antigens, and
toxoids shall be written according to the following:
Outline Guide for Vaccines, Bacterins, Antigens, and Toxoids
License No. Name of Product Date
I. Composition, etc., of the product. A. Micro-organisms used. Give
the isolation and passage history.
B. Source and date of accession of each micro-organism.
C. Strains.
D. Proportions of each strain.
II. Cultures. A. Brief description of methods of identifying each
micro-organism and the frequency with which these methods are applied.
B. Virulence and purity of cultures and the determination and
maintenance thereof. Range of subcultures or passages to be used in
production.
C. Composition and reaction of media used for seed and production
cultures. Include the
[[Page 783]]
source of eggs, tissue, or cell cultures, and the tests to determine
that eggs, tissues, and cells are free of contamination.
D. Character, size, and shape of containers used for growing
cultures.
E. Storage conditions of seed cultures.
F. Methods of preparing suspensions for seeding or inoculation.
G. Technique of inoculating (1) seed media; (2) production media.
Titer or concentration of inoculum, and the volume of medium for each
size and type of culture container.
H. Period of time and conditions for incubation and degree of
temperature used for each micro-organism or group of micro-organisms.
I. Character and amount of growth; observation as to contamination
of growth.
J. Method of attenuation, if any, before used for production
purposes.
III. Harvest. A. Handling and preparation of cultures and media
(including eggs) before removal of micro-organisms or tissues for
production purposes.
B. Minimum and maximum period of time elapsing from time of
inoculation until harvest.
C. Technique of harvesting micro-organisms or tissues (specify) for
production purposes.
D. Specifications for acceptable harvest material.
E. Handling of discarded material not used in production.
F. Include any additional pertinent information.
IV. Preparation of the product. Describe fully and show each step of
preparation from harvest of antigen containing tissues or production
cultures to the completion of the finished product in final containers.
In describing the preparation of the product, emphasize the following:
A. Method of inactivation, attenuation, or detoxification.
B. Composition of preservative, adjuvant or stabilizer, and
proportions used stated in such a manner that the concentration can be
calculated; stage and method of addition.
C. Method and degree of concentration.
D. If product is standardized to give concentration of antigen, show
procedures and calculations.
E. 1. Assembly of units to make a serial (illustrate by example).
2. Volume of average serial.
3. Volume of maximum serial.
4. Any other pertinent information.
F. Volume of fill for each size vial. Type of vial if unusual.
G. Method and technique of filling and sealing of final containers.
H. Desiccation, including moisture control. Give maximum percent
moisture.
I. Amount of antigenic material per dose or doses in final
container.
V. Testing. Indicate the stages in the preparation of the biological
product at which the samples are collected. Refer to all applicable
Standard Requirements. Outline all additional tests in detail and state
the minimum requirement for each satisfactory test.
A. Purity.
B. Safety.
C. Potency.
D. Moisture, if desiccated.
E. Any other tests.
VI. Post preparatory steps. A. Form and size of final containers in
which the product is to be distributed.
B. Collection, storage, and submission of representative samples.
Indicate at which steps in the production these samples are taken.
C. Expiration date based on the earliest date of harvest and the
date of the last satisfactory potency test. If applicable, give the date
of lyophilization.
D. Use, dosage, and route of administration for each animal species
for which the biological product is recommended.
(e) Outlines of Production for allergenic extracts shall be written
according to the following:
Outline Guide for Allergenic Extracts
License No. Name of Product Date
I. Composition of the product. A. Source and type of raw material.
B. Weight/volume concentration.
II. Preparation of the product. A. Describe fully and show each step
of preparation to the completion of the finished product in true
containers. In describing the preparation of the product, emphasize the
following:
1. Method of extraction.
2. Composition of preservative, adjuvant or stabilizer, and
proportions used; stage and method of addition.
3. Method and degree of concentration.
4. Standardization of the product.
5. (a) Assembly of units to make a serial.
(b) Volume of average serial.
(c) Maximum serial.
6. Volume of fill for each size vial.
7. Method and technique of filling and sealing of final containers.
8. Amount material per dose or doses in final container.
III. Testing. Indicate the stages in the preparation of the
biological product at which the samples are collected. Refer to all
applicable Standard Requirements. Outline all additional tests in detail
and state the minimum requirement for each satisfactory test.
A. Purity.
B. Safety.
C. Potency.
D. Any other tests.
E. Include any additional pertinent information.
[[Page 784]]
IV. Post preparatory steps. A. Form and size of final containers in
which the product is to be distributed.
B. Collection, storage, and submission of representative samples.
Indicate at which steps in the production these samples are taken.
C. Expiration date based on the earliest date of harvest and the
date of the last satisfactory potency test.
D. Use, dosage, and route of administration for each animal species
for which the biological product is recommended.
(f) Outlines of Production for diagnostic test kits based on
antigen-antibody reactions, and other diagnostics whose production
methods are amenable to description as described herein shall be written
according to the following requirements:
Outline Guide for Diagnostic Test Kits
License No. Name of product Date
Introduction
Provide a brief description of the kit as follows:
1. Principle of the test (ELISA, latex agglutination, etc.).
2. Antigen or antibody detection test.
3. Sample(s) used for testing (serum, whole blood, tears, etc.).
4. List reagents, references, and equipment included.
5. Identify materials obtained under split manufacturing agreements.
6. General description of test interpretations and their
limitations, including followup tests.
I. Antibody Components
A. Production of polyclonal antibody components.
1. If purchased, list suppliers, criteria for acceptability, and
describe all tests performed after receipt to determine that
specifications have been met.
2. If produced in-house, describe the species, age, weight,
conditions, and general health of all animals used in antiserum
production.
a. Preinjection considerations:
Describe the examination, preparation, care, quarantine procedures,
and treatments administered before immunization(s). Describe all tests
used to determine suitability for use. Describe the preparation of any
standard negative serum(s) collected prior to immunization.
b. Immunization of animals.
i. Describe the character and dose of the antigen; if adjuvant is
used provide details on its preparation. If commercial product is used
include its true name as shown on the label, the manufacturer, serial
number, and expiration date.
ii. Describe the method and schedule for immunizations.
iii. Describe the method for harvesting and evaluating the
immunization product, including tests for acceptability.
iv. Provide number and intervals between harvests, volume obtained,
and any other pertinent information.
B. Production of Monoclonal Antibody Components.
1. Hybridoma components:
a. If hybridoma components are purchased, list suppliers and
criteria for acceptability; if tests are performed after receipt,
describe fully.
b. If hybridomas are prepared inhouse, identify the antigen(s) used,
describe the immunization scheme, and the species of animal used.
c. Identify the tissue of origin, and the procedures for harvesting,
isolating, and identifying the immune cells.
d. Describe the source, identity, and the product secreted (light or
heavy chain) by the parent Myeloma Cell Line.
e. Summarize cloning and recloning procedures, including clone
characterization and propagation, if appropriate.
f. If appropriate, describe procedures for establishing and
maintaining seed lots.
g. Describe any other pertinent tests or procedures performed on the
hybridoma cell line.
2. Antibody production:
a. Describe the production method. If produced in cell culture,
animal serum additives must conform to 9 CFR 113.53. If produced in
animals, describe fully including husbandry practices and passage
procedures.
b. Provide the criteria for acceptable monoclonal antibody,
including tests for purity.
c. Describe all tests or other methods used to ensure uniformity
between production lots of monoclonal antibody. Include all reaction
conditions, equipment used, and reactivity of the component.
d. Describe all characterization procedures and include the expected
reactivity of all reference monoclonal antibodies.
II. Antigen Preparation
A. Identify the microorganism(s) or antigen being used. If
previously approved Master Seed virus, bacteria, or antigen derived
therefrom is used, provide pertinent information on the testing
performed, and details of dates of United States Department of
Agriculture confirmatory tests and approval, as appropriate.
B. Describe all propagation steps, including identification of cell
cultures, media ingredients, cell culture conditions, and harvest
methods. For antigen produced in eggs,
[[Page 785]]
give the egg source, age, and route of inoculation. If cell lines are
being used, give dates of testing and approval as specified in 9 CFR
113.52.
C. Describe procedures used for extracting and characterizing the
antigen.
D. Describe the method used to standardize the antigen.
E. If the antigen is purchased, identify the supplier and describe
the criteria for acceptable material, including all tests performed by
the producer and/or the recipient to determine acceptability.
III. Preparation of Standard Reagents
A. Describe the positive and negative controls included in the kit.
If purchased, list suppliers and criteria for acceptance.
B. Describe the preparation and standardization of the conjugate(s).
If purchased, list suppliers and criteria for acceptance.
C. Describe the preparation and standardization of the substrate(s).
If purchased, list suppliers and criteria for acceptance.
D. Identify buffers, diluents, and other reagents included in the
kit. The preparation of these components may be described in this
section or in filed Special Outlines.
IV. Preparation of the Product
Fully describe methods used to standardize antigens, reference
standards, positive control serum, negative control serum, and standard
reagents from production/purchase to completion of finished product in
final containers, including the following:
1. Composition and quantity of preservative in each.
2. Method of filling, plating, or attaching the antigen or antibody
component to a solid phase.
3. Minimum and maximum acceptable fill volumes for each final
container of reagent included in the kit.
4. The disposition of unsatisfactory material.
V. Testing
Refer to all applicable standard requirements.
A. Purity.
Describe all tests of the kit for purity or specify the exemption as
provided in 9 CFR 113.4.
B. Safety.
In vitro products are exempt from safety tests.
C. Potency.
Provide details of tests used to determine the relative reactivity
of the kit including minimum requirements for a satisfactory test.
Reference standards and control serum used for this purpose should be
identified by unique codes or lot numbers.
VI. Postpreparatory Steps
A. Describe the form and size of final containers of each reagent/
component included in the kit.
B. Describe the collection, storage, and submission of
representative samples. Refer to 9 CFR 113.3(b)(7).
C. Specify the expiration date. Refer to 9 CFR 114.13.
D. Provide details of recommendations for use, including all
limitations, qualifications, and interpretation of results.
E. Submit confidentiality statement identifying specific parts of
the outline containing information, the release of which would cause
harm to the submitter.
(Approved by the Office of Management and Budget under control number
0579-0013)
[39 FR 16869, May 10, 1974, as amended at 48 FR 57473, Dec. 30, 1983; 56
FR 20124, May 2, 1991; 56 FR 66784, Dec. 26, 1991]