VB-GL-3.1.2: Preparation of new product licensing (registration) submissions for veterinary biologics manufactured and/or licensed in the United States

On this page

• 1. Introduction
  • 1.1 Legal authority
• 2. Definitions
• 3. General guidance
  • 3.1 Criteria for VB product acceptability
  • 3.2 Reasons to refuse licensure and/or importation of a VB product in Canada
  • 3.3 Considerations concerning a new product submission
  • 3.4 Submission requirements
• 4. Required forms and licences
• 5. Facility and personnel requirements
• 6. Manufacturing and testing protocols
  • 6.1 General considerations
  • 6.2 Bulk products and products for further manufacture
  • 6.3 Master seeds and master cell stocks
  • 6.4 Materials of animal origin documentation
• 7. Labelling
• 8. Supporting data
  • 8.1 Products manufactured and licensed in the U.S.
  • 8.2 Products manufactured under FDA-EREA and unlicensed in the U.S.
  • 8.3 Products manufactured in countries other than Canada and the U.S., and imported through a U.S. permittee
• 9. Summary test results
  • 9.1 Products manufactured and/or licensed in the U.S.
  • 9.2 Products manufactured and unlicensed in the U.S.
  • 9.3 Live vaccines for use in ruminants
  • 9.4 Live vaccines for use in pigs
• 10. Environmental assessment and risk evaluation
• 11. Importations
  •  11.1 Designated importer
  •  11.2 Import permit
  •  11.3 Canada border services agency invoice
• 12. Appendices

1. Introduction

The purpose of this guideline is to provide information to U.S. 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 U.S. VB manufacturers and Canadian VB importers, including confidential proprietary business information, in accordance with such legislation, administrative procedures and court orders.

A NPS should be submitted to the CCVB after the licensing process is complete in the U.S. All documents pertaining to product licensing must be submitted at the same time. Under certain special circumstances, a NPS may be considered for evaluation by the CCVB prior to final licensing in the U.S. if the VB product is novel to Canada and addresses an emerging and priority need for a VB to manage an infectious disease situation. Contact the CCVB for more details and to determine eligibility. 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. U.S. VB manufacturers and Canadian VB importers 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.

1.1 Legal authority

• Health of Animals Act
• Health of Animals Regulations, Part XI

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 Criteria for VB product acceptability

• The product must be pure, safe, potent and efficacious
• The product must be licensed by the USDA-CVB in the U.S
• 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 licensure and/or importation 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 foreign animal diseases, 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 imported into Canada and for various reasons (for example, pharmacovigilance concerns; product no longer relevant to infectious animal disease conditions) are no longer considered suitable for importation into Canada

3.3 Considerations concerning a new product submission

• Licensing must be complete in the U.S. before a NPS will be considered for evaluation by the CCVB
  • Some exceptions may be made for reviews concurrent with the USDA-CVB, or for conditionally licensed products requested in support of a CFIA animal disease control or eradication program
• The CCVB accepts new VB 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 restrictions and conditions will be listed on the veterinary biologics product licence and on the veterinary biologics import permit, and explained in supplemental correspondence as required

3.4 Submission requirements

Products manufactured and licensed in the U.S.

A VB manufactured and licensed in the U.S. may be licensed in Canada, provided the conditions listed in section 3 above are met. The CCVB does not routinely repeat manufacturer inspections, master seed testing, pre-licensing serial testing or post-licensing serial release that has already been completed by the USDA-CVB. Official documentation of these activities must be included with the NPS and will be reviewed by the CCVB.

Products manufactured and unlicensed in the U.S.

A VB manufactured in the U.S. under the Food and Drugs Administration Export Reform and Enhancement Act of 1996 (FDA-EREA) (refer to the USDA's Veterinary Services Memorandum Number 800.94 – PDF (26 kb)), may be licensed (registered) in Canada. The NPS review will follow the process as for a VB product manufactured in Canada. The licensed VB product will be subject to post-licensing serial release by the CCVB as a condition of importation. The CCVB will inspect U.S. VB establishments manufacturing VB product for Canada under FDA-EREA.

Products manufactured in countries other than Canada and the U.S. and imported through a U.S. permittee

The requirements for licensing this type of VB are the same as those for VB manufactured and licensed in the U.S. Such VB must be shipped directly from the permittee's address in the U.S.

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 and licences

• Form CFIA/ACIA 4720 – Application for Services
• Form CFIA/ACIA 1503 – Veterinary biologic information
  • Only an authorized person at the manufacturing site in the U.S. or at the permittee in the U.S. can sign this form
• Form CFIA/ACIA 1493 – Application for permit to import licensed veterinary biologics into Canada
  • This form must be signed by the designated Canadian importer
• U.S. veterinary biological establishment license
  • Manufacturers in the U.S. must submit a copy of their U.S. Veterinary Biological Establishment License, as well as that of other U.S. manufacturers supplying product "for further manufacture" (FFM)
• US veterinary biological product license
  • Manufacturers in the U.S. must provide a copy of their U.S. Veterinary Biological Product License

In the case of FFM-products, a copy of the U.S. Veterinary Biological Product License from the other manufacturers is also required.

U.S. permittees must provide a copy of their U.S. Veterinary Biological Product Permit.

5. Facility and personnel requirements

All VB intended for importation into Canada must be manufactured in a facility licensed and inspected by the USDA-CVB. The approval of a new VB facility by the CCVB involves a review of the facility, personnel, manufacturing and quality control/quality assurance documents. These facilities may be periodically inspected by the CCVB. 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 and permittees in the U.S. must provide one copy of the most recent version of each relevant Outline of Production (OP) and related Special Outlines (SO) that have been filed with the USDA-CVB. The Animal and Plant Health Inspection Services (APHIS) Form 4039 and corresponding Summary of Changes (or alternatively, a print-out of the tracked changes) must also be submitted with each outline. All subsequent updates to submitted OP and SO must be submitted to the CCVB as soon as they are filed by the USDA-CVB. Refer to VB-GL-3.7: Preparation of outlines of production, special outlines and summary of changes for veterinary biologics.

If a referenced OP or SO is already on file with the CCVB, the manufacturer must indicate in which CCVB VB product file or under which company code the document is filed.

6.2 Bulk products and products for further manufacture

For VB formulated from bulk vaccine manufactured at another facility, the manufacturer should also provide a flow chart indicating the source(s) of all antigens and/or components. The manufacturer submitting the NPS is responsible for ensuring that all up-to-date and relevant OP and SO are received by the CCVB from the manufacturer(s) of the bulk component(s).

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

Manufacturers handling pathogens foreign to Canada must provide the CCVB with information regarding the identity and handling of these pathogens. The CCVB will conduct a risk assessment to evaluate the risk of cross-contamination.

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.

Labelling must be presented in English and French. A third language may not appear on the labels unless all information is already included in English and French.

It is recommended that manufacturers submit drafts of the proposed French label text for CCVB evaluation prior to printing final copies of the labels.

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.

Studies supporting efficacy and safety must be conducted with serials equivalent to the final VB described in the submitted OP. Depending on the specific VB, an efficacy and/or field safety study conducted in Canada may be required by the CCVB. 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. Assays to measure study outcomes must be carried out according to validated methodologies. Results must be statistically sound and the statistical methodology explained. A copy of each pertinent reprint (scientific publication) is required if it is referred to in the report. Individual animal data for all the animals used in the studies are required; however, these data can be presented in summary tables. Figures, tables and graphs produced in colour must be submitted in colour. 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.

All correspondence between the manufacturer and the USDA-CVB pertaining to the approval of data and studies submitted to support the NPS must be submitted to the CCVB with the NPS.

8.1 Products manufactured and licensed in the U.S.

The following documents are required:

• Final study protocols that have been approved by the USDA-CVB
• Final study reports, including all supporting data
• Correspondence from the USDA-CVB concerning these protocols and reports
• Additional data may be required on a case-by-case basis

8.2 Products manufactured under FDA-EREA and unlicensed in the U.S.

These requirements are the same as for VB manufactured in Canada.

8.3 Products manufactured in countries other than Canada and the U.S., and imported through a U.S. permittee

Supporting data requirements are the same as for a VB manufactured and licensed in the U.S. Only serials released by the USDA-CVB are eligible for importation to Canada.

9. Summary test results

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

In the case of breakout VB of already licensed combination vaccines, only the results from one pre-licensing serial are required.

9.1 Products manufactured and/or licensed in the U.S.

The test results must be submitted on the APHIS Form 2008 – Veterinary Biologics Production and Test Report and clearly show the USDA-CVB disposition.

9.2 Products manufactured and unlicensed in the U.S.

Only serials released by the CCVB are eligible for importation. 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 at CCVB.

9.3 Live vaccines for use in ruminants

The manufacturer is required to demonstrate that live viral vaccines for use in ruminants are free from bluetongue virus (BTV) contamination. Refer to VB-GL-3.6: Bluetongue virus exclusion testing of veterinary biologics for more details. If the manufacturer has not been granted an exemption for BTV testing (verification of all master seed viruses and master cell stocks, along with the exclusive use of irradiated ruminant sera/non-ruminant sera for production), testing of each serial for BTV is required as an additional condition on the import permit.

9.4 Live vaccines for use in pigs

The manufacturer is required to demonstrate that live viral vaccines for use in pigs are free from pseudorabies (Aujesky's disease) virus (PRV) contamination. Refer to VB-GL-3.31: Pseudorabies virus exclusion testing of veterinary biologics for more details. If the manufacturer has not been granted an exemption for PRV testing (verification of all master seed viruses and master cell stocks), submission to CCVB of test results for each serial are required before the issuance of an import permit restricted to each serial. The use of irradiated sera for production is also required to prevent contamination with other viruses that can infect swine (for example, bovine viral diarrhea virus).

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. Importation

The issuance of an annual import permit, or addition of a product to an existing import permit, corresponds to the licensing in Canada of the product manufactured and/or licensed in the U.S.

11.1 Designated importer

A Canadian VB importer must be designated by the U.S. VB manufacturer (Form CFIA/ACIA 1503), and approved by CCVB before an import permit will be issued. The facilities of designated Canadian importers are inspected prior to the issuance of the import permit and periodically thereafter by the Veterinary Biologics Operations (VBO) group.

11.2 Import permit

• An annual permit to import veterinary biologics is issued for the majority of VB which have been found acceptable for importation, and which do not require special tests or pre-clearance
  • This permit is valid for up to one year and must be renewed every year before June 30
• U.S. VB manufacturers are required to update all of their files of licensed VB before submitting an application to CCVB to renew their annual import permit

11.3 Canada border services agency invoice

A copy of this invoice must be kept on record by the designated importer for all VB imported into Canada (on single entry or annual permit). This information may be requested on occasion. It is used for summary statistics only, and is kept strictly confidential.

12. 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 Manufactured and/or Licensed in the U.S.

Product submission checklists

• Vaccines, immunomodulators, and prescription products
• Allergenic extracts, serum, or plasma products
• Autogenous vaccines
• Antibody products
• Diagnostic kits
• Export only
• For further manufacture (FFM)

Veterinary biologics template

• Manufacturer's serial release test report