Veterinary Biologics Guideline 3.1-1
Guidance for Preparation of New Product Licensing (Registration) Submissions for Veterinary Biologics Manufactured in Canada

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Table of Contents

I. Introduction

The purpose of this guideline is to provide information to Canadian veterinary biologics (VB) manufacturers regarding the preparation and submission of documents for the licensing (registration) of VB in Canada. The Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA) is responsible for licensing VB, including veterinary vaccines, colostrum, antibody products and test kits for the diagnosis of infectious diseases, manufactured and/or distributed in Canada under the legal authority of the Health of Animals Act and the Health of Animals Regulations.

The related New Product Submission Checklist, as well as the appropriate Veterinary Biologics Guidelines, should be consulted when preparing a new product submission (NPS) for licensing a VB in Canada.

The CFIA is subject to Canadian legislation, including the Access to Information Act and the Privacy Act, as well as administrative procedures and court orders. The CFIA will treat all information received from VB manufacturers and importers, including confidential proprietary business information, in accordance with such legislation, administrative procedures and court orders.

The process for licensing a new VB that is manufactured in Canada has several steps (i.e. phased review). Each step must be approved by the CCVB before a manufacturer can proceed further with the licensing process. The following is an example of the phased review and approval of a new veterinary vaccine manufactured in Canada:

  1. Pre-licensing inspection of the new manufacturing facility and associated documents. The approval of a new manufacturing facility may not be finalized until the final phase of review and approval of the first new VB.
  2. Review of administrative documents such as a draft Outline of Production (OP), related special outlines (SO), standard operating procedures (SOP), proof of concept data, draft labels, data on Master Seeds (MS) and Master Cells (MC), protocols for laboratory safety and efficacy studies, Manufacturer Serial Release Test Report (MSRTR) template and other applicable data and documents. Authorization to submit samples of MS and MC to a laboratory acceptable to CCVB for confirmatory testing.
  3. Review of confirmatory test results for MS and MC, authorization to introduce MS and MC into the production facility for the preparation of pilot or pre-licensing serials (PLS), and authorization to conduct safety and efficacy studies in target animals in containment.
  4. Review of manufacturer's PLS data, review and acceptance of laboratory safety and efficacy reports, and other applicable data and documents. Authorization to submit samples of PLS to a laboratory acceptable to CCVB for confirmatory testing.
  5. Review and acceptance of PLS data from manufacturer and a laboratory acceptable to CCVB, review of the protocol and environmental assessment (if applicable) for target animal field safety study, and other applicable data and documents. Authorization to conduct a field safety study in target animals.
  6. Review and acceptance of data from the field safety study, data on stability, final OP, SO, SOP and labels, and other applicable data and documents to support purity, potency, safety and efficacy of the new VB. Approval of the new VB in accordance with the Health of Animals Act and Regulations and any specific conditions and restrictions determined during the review process.

A similar phased review is completed for other types of VB such as antibody products and diagnostic kits for infectious diseases. Contact the CCVB for more details.

The Canadian veterinary biologics regulations and/or guidance may be modified or updated periodically to reflect changes in technical standards or developments in the international harmonization of regulatory requirements for veterinary biologics. Manufacturers and importers are, therefore, encouraged to consult Veterinary Biologics Guideline 3.4E: Guideline for Pre-Submission Consultation Meetings and Advance Notification of New Product Licensing Submissions prior to preparing a NPS, to assist in determining whether or not a pre-submission meeting or teleconference with the CCVB will be necessary.

II. Legal Authority

Health of Animals Act

Health of Animals Regulations, Part XI

III. Definitions

"Veterinary biologic" means:

  1. a helminth, protozoa or micro-organism;
  2. a substance or mixture of substances derived from animals, helminths, protozoa or micro-organisms; or
  3. a substance of synthetic origin

that is manufactured, sold or represented for use in restoring, correcting or modifying organic functions in animals or for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or the symptoms thereof, in animals (section 2, Health of Animals Act).

VB include vaccines, bacterins, bacterin-toxoids, colostrum, antibody products and test kits for the diagnosis of infectious diseases in animals.

"Licensing" or "Registration" means regulatory approval from the CCVB to manufacture, distribute and/or sell VB in Canada.

IV. General Guidance

A. General Criteria for Product Acceptability

  1. The product must be pure, safe, potent and efficacious.
  2. Each biologically active component must be relevant to infectious animal disease conditions and animal genetics in Canada.
  3. The product must be manufactured in a facility acceptable to the CCVB.
  4. The product must be produced and tested in accordance with generally accepted good manufacturing practices and quality assurance standards.

B. Reasons to Refuse Manufacture and/or Distribution of a Product in Canada

  1. Products containing components originating from countries where foot-and-mouth disease, rinderpest, African swine fever, African horse sickness, and other diseases foreign to Canada are endemic.
  2. Products for the prevention or diagnosis of diseases which are under a CFIA control or eradication program or for use against animal diseases foreign to Canada, such as hog cholera, bluetongue, vesicular stomatitis, and pseudorabies. Some exceptions may be granted if deemed in the best interest of the success of the control or eradication program.
  3. Products which may not be in the best interest of, or which may be contrary to, public health control or survey programs, such as live Brucella species vaccine in calves.
  4. Modified live products which have residual virulence, such as virulent strains of infectious laryngotracheitis virus or virulent Newcastle disease virus.

C. General Considerations Concerning a New Product Submission

  1. The process for licensing VB manufactured in Canada involves a phased review of documents.
  2. A completed New Product Submission Checklist must accompany each NPS.
  3. Each NPS must include a brief justification for use of the veterinary biologic in Canada. Statements must be supported by scientific references and/or opinions expressed by professional associations, or a written statement prepared by the manufacturer. Rationales should be submitted on company letterhead, dated and signed by the person preparing the rationale.
  4. All required documents for the NPS should be placed in binders, arranged using the New Product Submission Checklist as a table of contents and with corresponding section dividers (tabs) identifying the documents.
  5. The use of double-sided photocopies for protocols and reports of support studies, including data, is recommended to reduce the volume of paper submitted.
  6. Files of breakout products (e.g. various combinations of multivalent vaccines) should be submitted at the same time in order that they may be evaluated concurrently.
  7. All documents must be submitted in English or in French.
  8. Various restrictions and conditions may be applied once licensing is complete. These restrictions and conditions will be listed on the Veterinary Biologics Product Licence, and explained in supplemental correspondence as required.

D. Submission Requirements

  1. Product Manufactured in Canada

    The manufacturer must specify in the cover letter whether the product will be distributed in Canada only, exported only, or distributed in Canada and abroad.

    1. For Distribution in Canada

      In addition to a complete product file, the licensing of a veterinary biologic manufactured in Canada for distribution in Canada requires the satisfactory inspection of the manufacturing facilities, approval of the master seeds, approval of pre-licensing serials and post-licensing release of all serials by the CCVB. All Canadian manufacturers are required to have a Canadian Veterinary Biologics Establishment Licence (Can. Vet. Biol. Estab. Lic.). Products licensed for distribution in Canada are eligible for export, provided they meet the requirements of the importing country.

    2. For Export Only

      In addition to a complete product file, the licensing of a VB manufactured in Canada for export requires the satisfactory inspection of the manufacturing facilities and approval of the master seeds by the CCVB. For a Canadian product to be licensed for export only, the Canadian manufacturer is required to submit an official document to the CCVB confirming the regulatory status of the product in the importing country (or any other attestation deemed acceptable by the CCVB) stipulating that the product meets all the requirements and is authorized for marketing and distribution in the destination country. Canadian manufacturers of products for export only are required to have a Can. Vet. Biol. Estab. Lic. A product licensed for export only is not eligible for distribution in Canada.

  2. Special Circumstances

    Other cases not mentioned above will be evaluated on a case-by-case basis. The CCVB should be contacted for more details.

V. Required Forms

  1. Form CFIA/ACIA 4720 - Application for Services
  2. Form CFIA/ACIA 1503 - Veterinary Biologic Information

VI. Facility and Personnel Requirements

All VB intended for distribution and use in Canada, or for export to other countries, must be manufactured in a facility approved by CCVB. The approval of a new VB manufacturing facility involves a review of the facility, personnel, manufacturing and quality control/quality assurance documents, and a pre-licensing inspection of all premises where manufacturing, testing, preservation, packaging, labelling, storage and distribution of VB are performed.

Please consult Veterinary Biologics Guidelines 3.28E: Guideline for Personnel Requirements for a list of required documents related to Personnel. Please contact CCVB for a list of required documents related to facility requirements.

VII. Manufacturing and Testing Protocols

A. General Considerations

Manufacturers must prepare and submit two copies of an OP and related SO in the Canadian format. Refer to Veterinary Biologics Guideline 3.7E: Guideline for Preparation of Outlines of Production, Special Outlines and Summary of Changes for Veterinary Biologics for more details. The OP may cite internationally accepted regulatory requirements such as parts 101 to 123 of the United States Department of Agriculture's Title 9 Code of Federal Regulations (9 CFR), the European Pharmacopoeia (Ph. Eur.) or the World Organisation for Animal Health (OIE) Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2010. Once the OP and SO are approved and stamped as satisfactory, one copy of each will be retained on file with the CCVB, and one copy will be returned to the manufacturer.

Additional testing by a laboratory acceptable to CCVB may be required.

B. Contract Manufacturing

VB may be contract manufactured in whole or in part in a facility that has been previously approved by the CCVB for the manufacture of VB. In this case, the manufacturer presenting the licensing submission must provide a flow chart indicating the source(s) of all antigens and/or other components. The manufacturer presenting the licensing submission is also responsible for ensuring that all relevant and up-to-date OP and SO are received by the CCVB.

C. Master Seeds and Master Cell Stocks

The following information is required:

  1. Master cell stock data: Identity (species, cell type) karyology, freedom from extraneous agents.
  2. Master seed data: Identity (genus, species, biotype), purity, back passage studies of modified live vaccines.
  3. Data on the genetic characterization if the product is biotechnology-derived.

Upon CCVB request, samples of master seed and master cell stocks must be submitted to a laboratory acceptable to CCVB for confirmatory testing.

Manufacturers holding a Can. Vet. Biol. Estab. Lic. must obtain permission from the CCVB before introducing any new master seeds or any new cell cultures into the production area.

D. Materials of Animal Origin Documentation

In order to protect the Canadian public and the Canadian animal herd from transmissible spongiform encephalopathies (TSEs) and from other infectious animal diseases foreign to Canada, all materials of animal origin used in the production of VB must be sourced from countries and animals acceptable to the CCVB.

More information on specific requirements can be found in Veterinary Biologics Guideline 3.32E: Guideline for Minimising the Risk of Introducing Transmissible Spongiform Encephalopathy Agents Through Veterinary Biologics.

VIII. Labelling

Draft Canadian labels should accompany each NPS. Labels include vial labels, cartons, package inserts and all other printed information distributed with the product.

A. For Distribution in Canada

Labelling may be presented in English, French or both. If both languages are used, all information must appear in both languages.

B. For Export Only

If the labels are written in a language other than English or French, the manufacturer must supply a certified translation in English or in French. A document from the regulatory authority of the importing country indicating approval of the label claims is also required.

C. For Distribution in Canada and for Export

A language other than English or French may not appear on the labels unless all of the label information is also included in both English and French.

If the importing country does not allow multiple languages on the product labels, two sets of labels must then be prepared according to sections VIII.A and VIII.B above, and submitted to the CCVB for approval.

IX. Supporting Data

Data must be provided to support the purity, potency, safety and efficacy of the product and to support label claims. Please refer to the appropriate New Product Submission Checklist when collecting this data.

Studies supporting efficacy and safety must be conducted with serials equivalent to the final product described in the submitted OP. All reports must be dated and signed by the study investigator and by the quality assurance personnel of the manufacturer. Only one copy of each supporting document is required. Copies of pertinent reprints (scientific publications) are required if these are referred to in the reports. Individual animal data for all the animals used in the studies are required; however, these data can be presented in summary tables. The use of double-sided photocopies is recommended to reduce the volume of paper submitted. Please review the NPS for accuracy and completeness before submitting it to the CCVB.

Any later amendments, including additions and corrections, to a signed and dated research report should be prepared as new, signed and dated documents detailing the changes and referencing the original report.

Copies of bench records may be required by the CCVB.

A. For Distribution in Canada

For products manufactured and distributed in Canada, only preliminary data will be submitted with the initial product file. A phased review is carried out. The Canadian manufacturer is required to obtain preliminary approval from CCVB of protocols for major studies supporting potency, efficacy and safety before undertaking these studies.

A Permit to Release Veterinary Biologics is required from CCVB for the use of experimental products or unapproved products in field studies outside of biocontainment facilities or if experimental animals are intended for food. An environmental assessment may also be required when novel micro-organisms or biotechnology-derived products are used.

B. For Export Only

For products manufactured in Canada for export only, the Canadian manufacturer is required to submit data to support the safety of the product, the purity of the master seeds and the master cell stocks, OP, SO and labels. Copies of documents indicating acceptance of the product from the regulatory authorities of the importing country are also required.

X. Summary Test Results

Manufacturers must submit summary test results to verify uniformity, and serial-to-serial consistency of production serials. These data demonstrate the manufacturer's ability to consistently manufacture serials that meet OP specifications.

The test results must be submitted to the CCVB on a Manufacturer's Serial Release Test Report. Test references on serial release test result forms must cite the current OP and SO as filed with the CCVB.

Canadian manufacturers must keep production records for all serials of manufactured products.

A. For Distribution in Canada

For new products, manufacturers must provide summary test results from three consecutive pre-licensing serials. Upon CCVB request, samples of these serials must be submitted to a laboratory acceptable to CCVB for confirmatory testing.

Post-licensing serial release testing by a laboratory acceptable to CCVB may be required. All serials must be released by the CCVB prior to distribution.

B. For Export Only

Manufacturer’s summary test results from pre-licensing serials may be required by the CCVB. There is no requirement for confirmatory testing.

XI. Environmental Assessment and Risk Evaluation

The manufacturer is required to present an evaluation of the environmental impact of any novel or biotechnology-derived product.

The CFIA may also prepare a risk assessment, alone or in consultation with other governmental organizations, especially if the micro-organism could be harmful to humans, any animal species or the environment.

XII. Appendices

The following documents constitute part of this guideline and are appended. The appropriate document is sent to the CCVB along with a submission for the licensing of a new VB.

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