VB-GL-3.1.1: Preparation of new product licensing (registration) submissions for veterinary biologics manufactured in Canada

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1. 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 Canadian VB manufacturers, 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 (phased review). Each step must be approved by the CCVB before a Canadian VB 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:

  • Pre-licensing inspection of the new Canadian VB manufacturing facility and associated documents
    • The approval of a new VB manufacturing facility will not be finalized until the final phase of review and approval of the company's first new VB product
  • 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)
      • The CCVB may require the submission of MS and MC samples to a laboratory acceptable to CCVB for confirmatory testing
    • protocols for laboratory safety and efficacy studies
    • Manufacturer's serial release test report (MSRTR) template and
    • other applicable data and documents
  • 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
  • Review of manufacturer's PLS data, review and acceptance of laboratory safety and efficacy reports, and other applicable data and documents
    • The CCVB may require the submission of PLS samples to a laboratory acceptable to CCVB for confirmatory testing
  • 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
  • Review and acceptance of data from the field safety study, data on product 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
  • Issuance of a veterinary biologics product licence and, for a new VB establishment, a veterinary biologics establishment licence

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. Canadian VB manufacturers are, therefore, encouraged to consult VB-GL-3.4: 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. Prospective new Canadian VB manufacturers should engage the CCVB in discussions early in the facility and VB product design process.

1.1 Legal authority

2. Definitions

Licensing (or registration)
means regulatory approval from the CCVB to manufacture, distribute and/or sell VB in Canada.
Veterinary biologic (section 2, Health of Animals Act)

means a thing 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 its symptoms – in animals and that is

  • a helminth, protozoa or micro-organism
  • a substance or mixture of substances derived from animals, helminths, protozoa, micro-organisms or plants, or
  • a substance of synthetic origin

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

3. General guidance

3.1 General criteria for VB product acceptability

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

3.2 Reasons to refuse manufacture and/or distribution of a VB product in Canada

  • Products containing components originating from countries where foot-and-mouth disease, African swine fever, African horse sickness, or other diseases foreign to Canada are endemic
  • Products for the prevention or diagnosis of diseases under a CFIA control or eradication program or for use against animal diseases foreign to Canada, such as hog cholera, bluetongue, vesicular stomatitis, or pseudorabies
    • Some exceptions may be granted if deemed in the best interest of the success of the control or eradication program, or to support emergency preparedness by the CFIA
  • Products that may not be in the best interest of, or contrary to, public health control or survey programs
  • Modified live virus (MLV) products with residual virulence, such as virulent strains of infectious laryngotracheitis virus
  • MLV products with a known risk of the vaccine strain reverting to virulence under field conditions, such as porcine reproductive and respiratory syndrome virus MLV vaccines
  • Products which were previously manufactured in Canada and for various reasons (for example, pharmacovigilance concerns; product no longer relevant to infectious animal disease conditions) are no longer considered suitable for use in Canada

3.3 General considerations concerning a new product submission

  • The CCVB accepts new product submissions in an electronic format
    • The applicant can submit a licensing application through a file hosting service by advance arrangement with the CCVB
    • The applicant may also mail in the licensing submission on a USB memory device or on DVD, accompanied by a printed cover letter
  • A completed new product submission checklist specific for the type of product must accompany each NPS; refer to the Appendix for the appropriate checklist
  • A detailed Index of submission contents must list all documents by title, file name, version and date (yyyymmdd)
  • Each NPS must include a brief justification for use of the veterinary biologic in Canada,  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
  • All required documents for the NPS should be arranged using the new product submission checklist as guidance and in the order listed on the index of submission contents
    • For electronic submissions, a folder structure corresponding to section dividers (tabs) may be set up
      • Document file names should clearly specify the contents, for example, report, protocol, correspondence, amendment, safety, etc.
      • If multiple documents are compiled into 1 PDF file, then each document should be bookmarked and identified accordingly
  • Files of breakout products (for example, various combinations of multivalent vaccines) should be submitted at the same time in order that they may be evaluated concurrently if possible
  • All documents, protocols, reports and correspondence must be submitted in English or in French
  • Proposed draft labelling material must be bilingual (English and French)
  • Various restrictions and conditions may be applied once licensing is complete; these will be listed on the veterinary biologics product licence, and explained in supplemental correspondence as required

3.4 Submission requirements

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.

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.

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.

Special circumstances

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

4. Required forms

5. 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. Companies intending to design and build VB manufacturing facilities should contact the CCVB early in the facility design process. Consult VB-GL-3.34: Requirements for veterinary biologics facilities.

Consult VB-GL-3.28: Requirements for personnel involved in the manufacturing, testing, and importation of veterinary biologics for a list of required documents related to personnel.

6. Manufacturing and testing protocols

6.1 General considerations

Manufacturers must prepare the OP and any related SO in the Canadian format. Refer to VB-GL-3.7: 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 (WOAH; founded as Office International des Épizooties (OIE)) Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2010. Once the OP and SO are approved and digitally stamped as satisfactory, an approved copy will be returned to the manufacturer.

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

6.2 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.

6.3 Master seeds and master cell stocks

Data must be provided to support identity, purity, safety and stability of the master seed and master cell stocks. The following information is required:

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

More information on specific requirements for master seeds and master cells can be found in  VB-GL-3.22: Master seed stocks, master cell stocks and serial requirements. More information on specific requirements for master seed and master cells derived from biotechnology can be found in VB-GL-3.2: Regulation of biotechnology-derived veterinary biologics.

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

A complete list of all micro-organisms handled in the same facilities where the VB will be prepared must be submitted to the CCVB.

VB manufacturers holding or seeking to hold 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.

6.4 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 VB-GL- 3.32: Minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics.

7. Labelling

Draft Canadian labels should accompany each NPS. Labels include vial labels, cartons, package inserts and all other printed information distributed with the product. Information on specific requirements and permissible formats and texts on labelling can be found in VB-GL-3.3: Labelling of veterinary biologics.

7.1 For distribution in Canada

Labelling must be presented in English and French.

7.2 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.

7.3 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, 2 sets of labels must then be prepared according to sections 7.1 and 7.2 above, and submitted to the CCVB for approval.

8. Supporting data

Data must be provided to support the purity, potency, safety and efficacy of the product and to support label claims. Refer to the appropriate new product submission checklist when collecting this data.

Protocols for laboratory and containment safety and efficacy studies must be submitted for review and approval in advance of the study start date. 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; each page of the report must be numbered.. All study deviations must be attached to the report; the implication of the deviation on the final study outcome must be explained and justified. Assays used to assess study outcomes must be carried out according to validated methodologies. Results must be statistically sound and methodology explained. 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. 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.

8.1 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.

8.2 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. An environmental assessment may also be required when novel micro-organisms or biotechnology-derived products are used.

9. 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.

9.1 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.

9.2 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.

10. 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.

11. 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.

Product submission checklists

Veterinary biologics template