Veterinary Biologics Guideline 3.7
Guideline for Preparation of Outlines of Production, Special Outlines and Summary of Changes for Veterinary Biologics

This page is part of the Guidance Document Repository (GDR).

Looking for related documents?
Search for related documents in the Guidance Document Repository

Table of Contents

I. Introduction

II. General Requirements

III. Outlines of Production

IV. Special Outlines

V. Revisions to Outlines of Production and Special Outlines

VI. Special Considerations for Manufacturers in the United States

VII. Templates

I. Introduction

The purpose of this document is to inform veterinary biologics manufacturers and importers of the requirements for the preparation and submission of Outlines of Production (OPs) and Special Outlines (SOs). This guideline is directed primarily at Canadian manufacturers and foreign manufacturers in countries other than the United States (U.S.). The OP and SO requirements for U.S. manufacturers differ in some aspects, and these differences are described in Section VI.

The OP for a veterinary biologic is a legally binding document, describing the manufacturing and testing methods that are followed by the manufacturer and that have been accepted by the Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA). In addition to the OP, most companies also prepare a set of SOs to describe culture media, reagents, and standardized or common procedures. Changes (revisions) made to an OP or SO are described in a Summary of Changes document that must accompany an OP or SO revision submission.

All revisions to OPs and SOs that relate to products serial released in Canada must be approved by the CCVB before their implementation at the manufacturer's level.

Manufacturers and importers of veterinary biologics are required to conform to a standard format as described in this guideline when preparing OPs, SOs, and Summaries of Changes. Templates with the recommended formats for OPs, SOs, and Summaries of Changes are provided in Section VII.

Legal Authority

The Health of Animals Regulations requires that the production, packaging, labelling, and testing of all veterinary biologics conform to the specifications written in the product outline (Outline of Production) of the product, which has been approved by CCVB.

Section 122.(1) Subject to subsection (2), every applicant for a permit to import a veterinary biologic into Canada shall include with his application

(b) a product outline

Section 126. Subject to section 127, every applicant for a product licence shall include with his application the material and information referred to in subsection 122(1).

Section 130. No person shall sell a veterinary biologic or any diluent to be used therewith if the veterinary biologic or diluent has been prepared, manufactured, preserved, packed, labelled or tested otherwise than in the manner described in the product outline.

II. General Requirements

A. Required Format

For all OPs, SOs, and Summaries of Changes, a 2.5 cm margin is required at the top, left, and right sides, and a margin of at least 5 cm at the bottom of all pages to ensure that the CCVB approval stamp does not obscure any text.

B. Number of Copies to be Submitted for Review

The versions of the OPs and SOs that are submitted to the CCVB for the Canadian licensing of any new veterinary biologic are considered drafts, until these documents are approved (dated CCVB stamp on each page). Companies are required to submit two original copies of the final drafts of the OP and SOs signed by an authorized person at the company. Subsequent to approval (CCVB stamp), one stamped approved copy will be returned to the company, and one stamped copy is retained in the files at CCVB.

III. Outlines of Production

A. Required Format

The content and standard format of OPs are distinct for the three main categories of veterinary biologics: 1) vaccines, bacterins, antigens, and toxoids; 2) veterinary diagnostic kits; and 3) antibody products. Section VII contains templates, outlining the section headings and information requirements for each of these three product types. All the section and subsection titles shown on the template must be written in the OP. If a certain section or subsection does not apply to the product involved, it is then necessary to write "N/A" or "not applicable."

1. Cover Page

The cover page for the OP should contain the manufacturer's name and address, the assigned product name, the CCVB product file number, the establishment licence number (Canadian manufacturer) or its equivalent (foreign manufacturer), and the date. Refer to the template provided in Section VII.A. The cover page does not count when numbering pages in the OP (i.e. page 1 is assigned to the first subsequent page).

2. Subsequent Pages

All subsequent pages of the OP should contain a header with the same information as the cover page, with the exception of the manufacturer's address (optional). The six main sections of the OP are indicated by capitalized roman numerals (I., II., III., IV., V., and VI.), and the subsections by capitalized letters (A., B., C., D., etc.). Subdivisions first use arabic numbers (1., 2., 3., 4., etc.), then lower case letters (a., b., c., d., etc.), and lastly, roman numbers in lower case letters (i., ii., iii., iv., etc. [e.g.: IV.B.3.d.vi.]). It is recommended to identify the section and subsection at the upper-left corner of a new page when the content of that section and subsection is continued from the previous page.

For further information regarding OP content and layout, refer to the templates provided in Section VII.B.1. (Vaccines, Bacterins, Antigens, and Toxoids); VII.B.2. (Veterinary Diagnostic Kits); or VII.B.3. (Antibody Products).

IV. Special Outlines

SOs are used to describe complex procedures or common procedures that are used for multiple products. These documents may be cited in OPs or other SOs to reduce the duplication of text and to simplify the format of these parent documents. SOs are often used to describe the compositions of media and common methods or techniques used to manufacture and test veterinary biologics. They should have a descriptive title and should be numbered consecutively. They are formatted similar to the text pages of the OP (see below).

Standard Operating Procedures (SOPs) are usually found acceptable as substitutes for SOs when they are signed and dated, even if their format differs from that of SOs. In this situation, two certified photocopies of all the SOPs associated with a product file for licensing (i.e. all SOPs referenced in the OP and in the main SOPs) must be submitted by the company to CCVB for review and approval. For the purpose of this guideline, companies approved to use SOPs, rather than SOs, should follow the procedures indicated for SOs, wherever applicable.

Note: The CCVB may request the preparation of SOs according to the format described in this guideline, if the SOPs submitted by the manufacturer are deemed unsatisfactory.

A. Required Format

Templates outlining the format and content of the cover page and subsequent pages of an SO are provided in Section VII.D.1 and VII.D.2, respectively.

B. Documentation on Materials of Animal Origin

For each product intended for manufacture or importation into Canada, a list must be supplied of all materials of animal origin (MAO) that have been either used directly in its production or have been in contact with any of its constituents during development and/or production. For each listed material, the manufacturer must indicate the country of origin of the source animals, the animal species, tissue of origin, supplier's name and address, and must provide a signed and dated supplier's certificate (or European Directorate for the Quality of Medicines [EDQM] Certificate of Suitability), indicating the actions taken to minimize the risk for contamination of their product by animal transmissible spongiform encephalopathy (TSE) agents (i.e. country of origin, animal species, health status of source animals). More information on the required MAO documentation can be found in the Veterinary Biologics Guideline 3.32: Guideline for Minimising the Risk of Introducing Transmissible Spongiform Encephalopathy Agents through Veterinary Biologics.

Documentation on MAO should be compiled into a SO. As with other SOs, the two original copies of the MAO SO are required. However, only one copy is required of the certificates of origin or of analysis and of the supplier's certificates. These supporting documents are placed in the appendices to the MAO SO, and are not stamped but kept on file at CCVB as mandatory information.

V. Revisions to Outlines of Production and Special Outlines

A. Frequency

It is recommended that companies perform an annual document review to identify any required changes to their OPs or SOs. All revisions to OPs and SOs related to products serial released in Canada must be approved by the CCVB prior to their implementation, regardless of whether they involve major or minor changes.

If the current stamped-approved version of an OP or SO includes pen-and-ink corrections made by the CCVB at the time of its approval, the manufacturer must incorporate these pen-and-ink corrections during the next revision.

B. Number of Copies

Manufacturers are required to submit two original copies of the revised pages of the OP or of the SO signed by an authorized person of the company, together with two signed original copies of the Summary of Changes.

C. Summary of Changes

The Summary of Changes is a separate document prepared by the company to list all changes (additions, removals, corrections) made to the OP or SO as part of the current revision. The location of the changes must be accurately identified, referencing sections and subsections, as page numbers may change from revision to revision. The Summary of Changes pages must have a header that includes the company's identification and the name of the product or the SO title. Only the date of the revision submitted for approval is required in the heading. If the Summary of Changes includes more than one page, pages are numbered starting with page 1. The Summary of Changes must be signed by an authorized company representative. Sections VII.C and VII.F. provide templates for Summary of Changes documents that must accompany an OP or SO revision.

D. Submission for Approval

The submission of revisions to OPs and SOs must include 1) a covering letter, 2) the revised pages, and 3) the signed Summary of Changes. For the submission of a revision to an OP, Form CFIA/ACIA 4720 - Application for Services, accompanied by the appropriate cost recovery fee, is also required.

The cover letter accompanying the revision submission package should highlight the major changes being sought for the OP or SO, and should identify any information submitted in support of the changes. Companies concurrently submitting revisions to multiple OPs should prepare a separate cover letter that is specific to each product file.

For partial revisions of previously approved OPs and SOs, each revised page must be signed by an authorized person of the company. For complete revisions, only the last page of the OP needs to be signed.

All pages, except the cover page of an OP and SO, contain a field in the heading to write the date of the superseded version. When only individual pages are being revised, the date of the previous CCVB-approved version of that page is written at "Supersedes." For a complete revision of an OP or SO, the date of the previous complete version approved by CCVB is written at "Supersedes." In addition, for a compete revision, the cover page of the OP or SO must be resubmitted with the words "Complete Revision," placed below the revision date on the cover page.

When the changes to a single revised page exceed the space available, the surplus text is transferred to a new page, bearing the same number followed by the letter "a." If more than one page is required for the change, additional pages retain the same number with consecutive letters "a," "b," "c," etc.

Under certain circumstances, major changes in the production of a veterinary biologic may warrant designation as a new veterinary biologic and thus require the submission of a new product file, rather than the filing of an OP revision for the existing licensed product. Comprehensive supporting data are typically required. Please contact the CCVB for advice if considering major production changes to a licensed veterinary biologic.

As stipulated in the CFIA Fees Notice, there is a cost recovery fee for the consideration of a revision to a previously approved OP. Revisions to draft OPs for veterinary biologics being evaluated for licensing by the CCVB are covered by the cost recovery fees paid for product licensing. If multiple OPs require the same non-technical minor changes (e.g. a change in company name, mailing address), all affected OPs can be revised for a single fee, provided the OP revisions are submitted together in one package, and the cover letter identifies the non-technical changes and certifies that no changes to the manufacturing or testing methods specified in the OPs have been made. There is no fee for the review or filing of SO revisions.

VI. Special Considerations for Manufacturers in the United States

When revisions to an OP or SO must be reviewed and approval by the U.S. Department of Agriculture Center for Veterinary Biologics (USDA-CVB) prior to their implementation by the manufacturer, and the OP or SO does not relate to a product that must be serial released by the CCVB, some differences exist with respect to how these documents should be prepared and submitted to the CCVB. These differences are described below.

OPs and SOs for products manufactured in the U.S., but serial released in Canada (e.g. products exported under the U.S. Export Reform and Enhancement Act, autogenous vaccines), and SOs describing testing that is performed exclusively for Canada (e.g. pseudorabies and bluetongue virus exclusion testing) require CCVB approval, and must be prepared and revised following the same procedures as those previously described for Canadian manufacturers. The special considerations described in this section, therefore, do not apply to these OPs and SOs.

A. Required Format

The CCVB will accept OPs, SOs, and Summary of Changes documents in the format required by the USDA-CVB.

B. Number of Copies

Only one copy (photocopy) of the OP and each referenced SO should be submitted to the CCVB for a new product licensing application. Similarly, only one copy of an OP or SO revision should be submitted.

For a SO written to provide information on MAO, if this SO is not approved by the USDA-CVB, but instead by CCVB, two original copies of the MAO SO are required, but only one copy of the certificates of origin or analysis and of the supplier's certificates contained in the appendices of the MAO SO is required.

C. Submission of Revisions

1. Documents

The following documents must be submitted to the CCVB for the filing of a revision to an OP or SO:

  1. Form CFIA/ACIA 5212 - Revisions to Outlines of Production and Special Outlines for Veterinary Biologics Licensed in the United States - no covering letter required;
  2. Form CFIA/ACIA 4720 with the applicable cost recovery fee according to article 10.(2) (unnecessary for SO revisions, as there are no fees for the filing of SO revisions);
  3. One photocopy of the revised pages or completely revised OP or SO, bearing the USDA-CVB's filed stamp;
  4. One photocopy of all corresponding Summary of Changes, bearing the USDA-CVB's filed stamp;
  5. One photocopy of all APHIS Form 2015: Transmittal of Labels and Circulars or Outlines showing the disposition of the USDA-CVB; and
  6. One copy of any applicable supporting data.

Form CFIA/ACIA 5212 for OP and SO revisions only applies in the following circumstances:

  1. OPs and SOs have already been filed at USDA-CVB; and
  2. OPs and SOs correspond to products already licensed in Canada (listed on an annual import permit).

Form CFIA/ACIA 5212 for OPs and SOs does not apply in the following circumstances:

  1. Submission of documents for the file of a new product submission under evaluation and not yet licensed in Canada;
  2. Products manufactured in the U.S. for export only to Canada and serials are released by CCVB; and
  3. MAO SO written for and approved by CCVB.

After the successful filing of an OP or SO revision, the submitted Form CFIA/ACIA 5212 is signed by a designated person at the CCVB and returned to the submitter. Comments arising from the CCVB's review of the OP or SO revision may be communicated to the manufacturer via the returned Form CFIA/ACIA 5212.

If the OP for a product that is licensed in Canada refers to the OP for a product that is unlicensed in Canada, OP revisions for the referenced OP must be submitted to the CCVB. Any OPs or SOs referenced within a referenced OP similarly must be submitted to the CCVB. If a revision to the parent OP is submitted, along with revisions to the referenced OPs, only one OP revision fee is charged.

2. Timing

a. Outlines of Production - The timing for submitting OP revisions to the CCVB depends on whether the revision involves a major change, or only minor changes. Any revisions to an OP involving a major change must be submitted to the CCVB immediately after its filing by the USDA-CVB. An OP revision involving only minor changes must be submitted to the CCVB within one year of its filing by the USDA-CVB. This allows companies to accumulate minor revisions and submit these to the CCVB together as part of an annual revision, or with the next revision involving a major change made in that year.

i. Major Changes - Major changes are those changes to an OP that can impact upon the purity, safety, potency, and/or efficacy of the product. Again, OP revisions involving a major change must be submitted to the CCVB for review and approval as soon as possible after their filing by the USDA-CVB. Major changes typically require the co-submission of supporting data or research reports.

Revisions to the items listed below (grouped according to product type; section of OP provided in brackets) are considered major changes.

Vaccines, Bacterins, Antigens, and Toxoids

  • master seeds (section I.A.)
  • master cell lots and materials of animal origin (MAO) (section II.C.)
  • method of inactivation, attenuation, or detoxification (section IV.A.)
  • composition of preservative, adjuvant, or stabilizing agent (section IV.B.)
  • method of antigen concentration or purification (section IV.C)
  • quantity of antigenic material per dose in final container (section IV.I.)
  • tests (section V.)
  • expiry date (section VI.C.)
  • use, dose, route of administration and precautions (section VI.D.)

Veterinary Diagnostic Kits

  • nature of polyclonal antibodies (section I.A.)
  • nature of monoclonal antibodies (section I.B.)
  • master seeds of micro-organisms used in the kit (section II.A.)
  • master cell lots and MAO (section II.B.)
  • extraction and characterization of the antigen (section II.C.)
  • standardization of antigen and acceptability criteria (sections II.D. and II.E.)
  • nature of positive and negative controls in the kit, including new lots (section III.A.)
  • nature of other reagents in the kit (sections III.B. and III.C.)
  • method of filling, spreading, or binding of the antigen or antibody (section IV.2.)
  • tests to verify the performance of the kit and its serial release (section V.C.)
  • nature of the reference panel members (section V.C.)
  • modification to the reference panel members (section V.C.1.)
  • expiry date (section VI.C.)
  • use, test limitations, and interpretation (section VI.D.)

Antibody Products

  • serological tests or other tests for the selection of animals (section I.B.)
  • antigens and micro-organisms used in the immunization (sections II.A., II.B., II.C. and II.D.)
  • culture media and cell lines used for the propagation (section II.F.)
  • preparation of the antigen, toxin or toxoid (section II.G.)
  • method of inactivation or detoxification (section II.G.)
  • characteristics and dose of the inoculum for the animals (sections III.A.1. and III.A.2.)
  • characteristics of an acceptable harvest and required tests (section III.A.6.)
  • statement on MAO (section III.A.6.a.)
  • composition of preservative (section IV.B.)
  • quantity of immunoglobulins per dose(s) in the final container (section IV.C.)
  • method of lyophilization, drying, pulverizing, etc. (section IV.H.)
  • testing (section V.)
  • expiry date (section VI.C.)
  • use, dose, route of administration and precautions (section VI.D.)

Note: Any changes to the sections identified above that involve simply correcting spelling, typographical or grammatical errors, rewording or reformatting the text, or modifying the nomenclature (technical or usual term); or that pertain to ingredients other than those listed above; or that represent minor adjustments to manufacturing procedures or equipment are considered to be minor changes to the OP.

ii. Minor Changes - Minor changes to an OP are those changes that are not likely to impact on the purity, safety, potency, and efficacy of the product. Again, OP revisions that include only minor changes must be submitted to the CCVB within one year of their filing by the USDA-CVB. Minor revisions to OPs are filed at CCVB with minimal review. The revisions done to sections of the OP, other than those identified in Section VI.C.2.a.i. of the present guideline, are considered minor revisions.

To allow the filing of OP minor revisions with minimal review, the manufacturer, or its designated official representative, must certify on Form CFIA/ACIA 5212 for a revision that the submitted revision does not include any major changes.

Multiple minor revisions to a single OP that are submitted together within one year after the USDA-CVB's filing of the oldest revision can be submitted for review by the CCVB under the same cost recovery fee.

b. Special Outlines - The timing for submitting SO revisions to the CCVB depends on the subject matter of the SO in question. Revisions to SOs that describe production methods, the MAO used during production, or the quality control testing of bulk or final veterinary biologics, should be submitted to CCVB for review as soon as possible after their filing by the USDA-CVB, and should be accompanied by supporting documentation, wherever applicable. Revisions to all other SOs must be submitted within one year of their filing by the USDA-CVB.

VII. Templates

Note: Although the explanations that follow the main heading (in parentheses) are pertinent to the expected content of the sections, they are provided as information only and thus must not appear in the OP submitted to CCVB.

VII.A. Outline of Production - Cover Page - All Products

Company Name (manufacturing site)
Street Address
City, Province
Postal Code
Country

Outline of Production

Product Name (Assigned Generic Name)

CCVB Product File Number: space

Canadian Veterinary Biologics Establishment Licence No. space
(or the Manufacturing Authorization or equivalent of the foreign country of origin)

Date: yyyy-mm-dd (year-month-day)

VII.B. Outline of Production - Subsequent Pages

1. Vaccines, bacterins, antigens and toxoids

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd
Supersedes: yyyy-mm-dd

Product Assigned Name
CCVB Product File Number

I. Composition of the Product

A. Micro-organisms used (List the micro-organisms used and indicate the isolation and passage history.)

B. Source and date of accession (Indicate for each micro-organism.)

C. Strains

D. Proportions of each strain or subunit in product

II. Cultures

A. Identification (Indicate the methods used to identify micro-organisms in master seed and production seed.)

B. Virulence and purity of cultures (Indicate the methods used to determine virulence and purity of cultures, as well as the range of subcultures for use in production.)

C. Composition of media used for seed and production cultures (Indicate composition and source of media and other materials of animal origin [cell culture, serum, eggs, birds or animals]. Also indicate methods used to determine that the above materials are free from contaminants.)

  1. Statement pertinent to materials of animal origin (to minimize contamination with agents of transmissible spongiform encephalopathies).

D. Character, size, and shape of containers used for growing cultures

E. Storage conditions for seed cultures

F. Methods for preparing suspensions for inoculation

G. Technique for inoculating seed and production media (Indicate the titre or concentration of inoculum and the volume of media for each container.)

H. Incubation times, temperatures, conditions

I. Character and amount of growth (Indicate expected characteristics of cultures [physical appearance], and any observations of possible contaminants.)

J. Method for attenuation

III. Harvest

A. Handling and preparation of cultures prior to harvest

B. Incubation (Minimum and maximum elapsed incubation time for cultures.)

C. Harvest techniques

D. Specifications for acceptable harvest

E. Handling of discarded material

F. Additional pertinent information

IV. Preparation of the Product

A. Inactivation, attenuation, or detoxification (Describe the method used.)

B. Preservative, adjuvant, or stabilizer (Describe the composition.)

C. Concentration and purification of product (Describe the methods used.)

D. Standardization of antigens concentration in product

E. Assembly of serials:

  1. Method (Describe method used to make a serial from lots of production material.)
  2. Volume of average serial
  3. Volume of maximum serial
  4. Additional pertinent information

F. Volume of fill (min/max for each vial size. Vial type.)

G. Filling and sealing (Describe method and technique of filling and sealing final containers.)

H. Lyophilization (Indicate method used, if applicable; maximum moisture.)

I. Amount of antigenic material per dose

V. Testing

A. Purity (Indicate test for freedom from residual live bacteria and contaminants; Test for viable bacteria, fungi, and mycoplasma, as described in the USDA-CVB 9-CFR 113.26, 113.27, 113.28 or equivalent method.)

B. Safety

C. Potency

D. Moisture determination for lyophilized products

E. Any other tests (For example: residual formaldehyde determination.)

VI. Post Preparatory Steps

A. Form and size of final containers

B. Sample collection and submission

C. Expiration date

D. Label recommendations (Indicate intended use, dose, route of administration, and precautions.)

E. Statement of confidentiality of information in production outline

Signature

Name, Title

2. Veterinary diagnostic test kits

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd
Supersedes: yyyy-mm-dd

Product Assigned Name
CCVB Product File Number

Introduction

(Brief description of the test: principle of the test [e.g. ELISA, immunoblot]; detection of antibody or antigen; samples for testing [e.g. whole blood, serum, faeces, lymph nodes, brain obex]; list of enclosed reagents, reference controls, and equipment; identification of components from elsewhere [for further manufacture]; general description of the test and its limits, including additional tests.)

I. Antibody Components

A. Production of polyclonal antibody:

  1. (Purchased components: list of suppliers, acceptability criteria and description of tests done to meet requirements.)
  2. (Components prepared by manufacturer: describe criteria [e.g. animals, age, weight, conditions]:
    1. Criteria before inoculation [clinical exam, serological tests to select animals, collection of negative control serum]
    2. Immunization of animals
      1. Description and dose of antigen; description of adjuvant
      2. Describe route [injection, per os, aerosol, immersion] and schedule of immunization
      3. Describe collection of samples to verify seroconversion, evaluation tests and acceptability criteria
      4. Indicate number and interval of collections, volume obtained and other pertinent information.)

B. Production of monoclonal antibody:

  1. Hybridoma components:
    1. (Purchased components: list of suppliers, acceptability criteria and description of tests to meet requirements.
    2. If prepared by manufacturer, identify the antigens used, immunization method, and animal species used.
    3. Identify the tissue of origin, and the procedures to harvest, isolate and identify the immune cells.
    4. Describe the source, the identity and the product secreted [light or heavy chain] by the master cell stock of the myeloma.
    5. Summarize the cloning and recloning procedures, with its characterization and propagation as needed.
    6. Describe as needed the procedure to establish and maintain lots of master cell stocks.
    7. Describe all other tests done on the myeloma cell line as required.)
  2. Production of monoclonal antibody:
    1. Describe method of production. Cell cultures: composition of media. In animals: describe their maintenance and procedure of passages.
    2. Indicate acceptability criteria of monoclonal antibody, including purity tests.
    3. Describe all tests or methods used to ensure uniformity between lots of monoclonal antibody. Include reaction conditions, equipment used and reactivity of component.
    4. Describe characterization procedures and include expected reactivity of all reference monoclonal antibodies.

C. Statement pertinent to material of animal origin (to minimize contamination with agents of transmissible spongiform encephalopathies [or in II.G. as appropriate.])

II. Preparation of Antigen

A. Identity (Specify names of micro-organisms or antigens used. If the master seed of the micro-organisms or antigens has been approved by the CFIA, specify details.)

B. Propagation (Describe steps, identification of cells used, medium composition, conditions of culture and harvest. Growth of micro-organism in embryonated eggs: indicate the source of eggs, the age, and the route of inoculation. Growth of micro-organism in cell lines: indicate details of tests and approval date by the CFIA.)

C. Extraction and characterization of antigen (Describe procedures.)

D. Inactivation of antigen (Describe method used.)

E. Standardization of antigen (Describe method used.)

F. Purchased antigen (Identify supplier and describe acceptability criteria [tests done by supplier and/or manufacturer].)

G. Statement pertinent to material of animal origin (to minimize contamination with agents of transmissible spongiform encephalopathies [or in I.C. as appropriate].)

III. Preparation of Standard Reagents

A. Positive and negative controls in the kit. (Provide a description. Purchased controls: list of suppliers and acceptability criteria.)

B. Conjugate(s) (Describe preparation and standardization. Purchased conjugates: list of suppliers and acceptability criteria.)

C. Substrate(s) (Describe preparation and standardization. Purchased substrates: list of suppliers and acceptability criteria.)

D. Buffers, diluents, and other reagents in the kit (Describe here or in a referenced special outline.)

IV. Preparation of the Product

(Describe methods used to standardize the bound antigens or antibodies in the kit, the reference antigens or antibodies, the negative and positive control sera, and the standardized reagents from their preparation/purchase until the assembly of the kit in their final containers. Include the data thereafter.)

  1. Composition and quantity of preservatives.
  2. Method of filling, spreading, or binding of the antigens or antibodies to the solid phase.
  3. Minimum and maximum volumes of filling (container of each reagent in the kit).
  4. Discarding method of unsatisfactory material.
V. Testing

(Refer to all applicable standardized requirements.)

A. Purity (Describe tests done on the kit for purity or make reference to a valid exemption.)

B. Safety (In vitro diagnostic kits are exempt from safety tests.)

C. Potency (Provide details of tests used to determine the relative reactivity of the kit including the minimum requirements for a satisfactory test. The standardized reference antigens and the control sera must be identified by unique codes or by lot numbers. Verifying the kit performance with a reference panel is mandatory for the serial release of the kit.)

  1. Reference panel (Indicate the number of panel members [about 20], their identification and their respective level of reactivity [negative, strong positive, weak positive, dubious].)
  2. Serial release (Briefly describe the test to verify the kit performance before the release of the serial.)
  3. Other tests (Describe as appropriate.)
VI. Post Preparatory Steps

A. Form and size of final containers (for each reagent in the kit)

B. Collection, storage and submission of samples

C. Expiration date

D. Label recommendations (Indication of the recommended use, interpretation of the results, limits of the test and precautions to follow.)

E. Statement of confidentiality of information in production outline.

Signature

Name, Title

3. Antibody products

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd
Supersedes: yyyy-mm-dd

Product Assigned Name
CCVB Product File Number

I. Donor Animals (Mammals, birds, fish)

A. Species, conditions, age, and health status.

B. Pre-immunization care (Exam, preparation, care, quarantine, tests, and treatment of the animals before starting the immunization. Collection of serum, egg, and/or secretion for negative control.)

C. Maintenance of the animals during the immunization (Housing, holding, handling, exercise, and monitoring once immunization has started.)

II. Antigen used for the Immunization

A. Antigens - Composition and characteristics of antigen(s) (Only killed antigens are authorized.)

  1. List of micro-organisms used and criteria of acceptance
  2. List of suppliers and date of accession for each micro-organism
  3. Strains
  4. Proportions of each micro-organism and strain

B. Identification methods (for each micro-organism and frequency of application.)

C. Virulence and purity of culture (or of the antigen with its characterization and subsequent maintenance. Number of sub-cultures or passages allowed for use in production.)

D. Attenuation (as appropriate, before using in production.)

E. Character, size, and shape of containers (used to grow the micro-organisms.)

F. Media used (For the master seeds cultures and production cultures, composition and subsequent reaction; may refer to a special outline by number.)

G. Preparation of the antigen or toxin or toxoid (Provide and full description of each step, along with procedures, and number these steps in sequence. Include all tests for each antigen, and specifications for character, identity, virulence, concentration, and standardization.)

III. Immunization of Animals

A. Description (Fully outline with particular attention to the following items.):

  1. Description and dose of antigen(s); description of adjuvant (source, assigned name, serial number, expiry)
  2. Route (injection, per os, aerosol, immersion) and schedule of immunization.
  3. Time required (for the immunization or hyperimmunization)
  4. Collection of samples and tests used (to verify seroconversion)
  5. Treatments (Describe any treatment of the animals between collection of samples)
  6. Verification tests (Indicate type of tests used to verify antibody level)
  7. Statement pertaining to material of animal origin (to minimize risk of contamination with agents of transmissible spongiform encephalopathies.)

B. Intervals of collections (period of time between last inoculation and the first collection of sample [e.g. blood, colostrum, eggs], and between collections.)

C. Collections (technique of collection; volume of collections; resting period between collections.)

IV. Preparation of the Product

A. Description (Describe fully, indicating each step of preparation [including sterilization, concentration and purification] from the first collection up to a bulk product with preservative ready for conditioning.)

B. Composition and proportion of preservatives (Indicate at what step of production these are added and the method used.)

C. Titration of antibodies or immunoglobulins (Describe the methods used.)

D. Discarding (disposition of unsatisfactory product and of any infectious material used in production)

E. Assembly of serials (Describe methods used to prepare a serial from lots of collected material; average volume of a serial; maximum volume of a serial.)

V. Testing

(Indicate the steps during the preparation of the product when samples are taken. Make reference to standardized requirements. Make a detailed list of required additional tests and specify the minimum requirements for acceptable tests.)

A. Purity (Confirmation of the absence of live pathogenic bacteria and residual contaminants. Use detecting test for live bacteria, fungi and mycoplasmas, as described in 9CFR 113.26, 113.27, 113.28 [USDA-CVB] or other equivalent methods.)

B. Safety

C. Potency

D. Determination of moisture level for lyophilized or dehydrated products

E. Other tests

VI. Post Preparatory Steps

A. Form and size of final containers

B. Methods and techniques of filling (filling of final containers. Volume of filling for each size of final containers.)

C. Collection and submission of samples (Indicate the steps when samples are collected.)

D. Expiry date

E. Recommendation pertaining to labelling (recommended use, dosage, route of administration for each target species, and precautions.)

F. Statement of confidentiality of information in production outline

Signature

Name, Title

VII.C. Summary of Changes of Outline of Production Revision

The following is an example of the format for documenting amendments to an OP that has already been approved by CCVB. When revisions are necessary, the amended production outline pages, along with a Summary of Changes, are submitted to CCVB for approval. Subsequent to approval, the amended pages are inserted into the OP to replace the original pages. The Summary of Changes is attached to the approved OP and serves as documentation for all changes that have been approved since the original OP was prepared.

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd

Product Assigned Name

Product identification (CCVB Product File Number or USDA-CVB Product Code)

Summary of Changes

Section - Description of Changes

II.B.3.c. - "Spelling of … corrected as per pen-and-ink change by CCVB"
III.A. - "Harvest method changed from … to …"
IV.A. - "Inactivating agent changed from … to …"
IV.E.1. - "Sentence rewritten to clarify method for …"
V.C. - "Potency test changed from … to …"
V.F. - "Deleted … "
VI.B. - "Added …"

Signature

Name, Title

VII.D. Special Outline - Cover Page

Company Name (manufacturing site)
Street Address
City, Province
Postal Code
Country

Special Outline Number: space

Title of Special Outline

Canadian Veterinary Biologics Establishment Licence No. space
(or the Manufacturing Authorization, or equivalent, of the foreign country of origin)

Date: yyyy-mm-dd (year-month-day)

VII.E. Special Outline - Subsequent Pages

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd
Supersedes: yyyy-mm-dd

Special Outline Number: space

Title (e.g. Method of preparation of the culture medium for Leptospira hardjo.)

Introduction: (Specify which products [list of CCVB product file numbers or USDA product codes with the assigned names of the products] make reference to this special outline.)

I.

II.

etc.

(Description of materials and methods.)

space

space

Statement of confidentiality of information in special outline

Signature

Name, Title

VII.F. Summary of Changes of Special Outline Revision

The following is an example of the format for documenting amendments to a SO already approved by CCVB. When revisions are necessary, the amended pages and a Summary of Changes are submitted to CCVB for approval. Subsequent to approval, the amended pages are inserted into the SO, to replace the original pages. The Summary of Changes is attached to the approved SO and serves as documentation for all changes that have been approved since the original SO was prepared.

-Page-

Manufacturer:
Can. Vet. Biol. Estab. Lic. No.
(or Foreign Estab. Lic. / city, country)
Date: yyyy-mm-dd

Special Outline Number: space



Title (e.g. Method of preparation of the culture medium for Leptospira hardjo.)

Summary of Changes

Section - Description of Changes

Introduction - "Spelling of … corrected as per pen-and-ink change by CCVB"
Introduction - "New product … added to the list"
II. - "Concentration of … changed from … to …"
III. - "Incubation time changed from … to …"
IV.B. - "Deleted … "
IV.C. - "Added …"

Signature

Name, Title

Date modified: