Licensing Requirements for Veterinary Biologics - Overview
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Veterinary biologics (VB) are animal health products such as vaccines, antibody products for administration to animals and test kits, that are used for the prevention, treatment, or diagnosis of infectious diseases in animals, including domestic livestock, poultry, pets, wildlife, and fish. In Canada, VB are regulated by the Canadian Food Inspection Agency. The authority for regulating VB in Canada is provided by the Health of Animals Act and Regulations. The Canadian Centre for Veterinary Biologics (CCVB) has been delegated the responsibility for regulating the manufacture, testing, licensing, labelling, import, export, distribution and sale of veterinary biologics.
VB program activities include the licensing of VB products based on satisfactory manufacturing and testing data, permitting the restrictive and conditional use of autogenous vaccines and unlicensed VB in Canada, inspection and approval of VB manufacturers and importer facilities and post-licensing serial release. The VB program requirements are described in the regulations and in technical and interpretive VB Guidelines and Memoranda which are available from the CCVB.
Veterinary biologics are evaluated on the basis of fulfilment of four criteria: purity, potency, safety and efficacy. It is the responsibility of the manufacturer to provide data to demonstrate that each product meets these licensing criteria.
A risk-based approach is used to evaluate the safety of the product in target and non-target species, humans and the environmentReference 1. Other federal departments, such as Health Canada or Fisheries and Oceans Canada, are consulted during the assessment process, when human health issues or national fish health concerns may be involved.
Manufacturers and researchers intending to develop and scale up experimental vaccines for licensing are encouraged to consult with the CCVB early in the product development process, so that the research data and quality assurance documentation are consistent and meet Canadian regulatory requirements.In addition to conforming to the Health of Animals Act and Regulations, all VB development projects must meet the standards and requirements for biosafety and animal care described in the Canadian Biosafety HandbookReference 2 and the Canadian Council on Animal Care's GuidelinesReference 3.
Definitions for veterinary biologics
Veterinary biologic 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 products include, but are not limited to, vaccines, bacterins, bacterin-toxoids, subunit protein vaccines, plasmid DNA vaccines, replicons, antibody products for administration to animals, immunomodulators, allergenic extracts and diagnostic kits.
Production Outline (Outline of Production, OP) means a detailed description of
- the process followed in preparing a veterinary biologic and any diluent,
- the tests used to establish the purity, safety, potency, and efficacy of a veterinary biologic, and satisfactory results for the tests
- the methods and procedures to be employed in handling, storing, administering, and testing a veterinary biologic.
Safety means the freedom from properties causing undue local or systemic reactions, when used as recommended.
Purity means quality of a biologic prepared to a final form and relatively free of extraneous micro-organisms and extraneous material, as determined by established test methods and approved in the production outline.
Potency is a measure of the relative strength of a biologic when tested by established methods which are documented in the production outline. It should correlate to the immunogenicity / efficacy of the biologic.
Efficacy is a measure of the specific protective capacity of the biologic when used according to label recommendations.
Stages in the development, field testing and licensing of veterinary biologics
The movement of a VB from contained laboratory research, to a fully licensed product for distribution and sale, follows four stages:
Stage 1. Preliminary laboratory research, done in containment, to support proof of concept of the VB. Research must comply with the Canadian Biosafety HandbookReference 2 and the Canadian Council on Animal Care's GuidelinesReference 3.
Stage 2. Controlled experiments, done in containment, using a prototype VB in target and non-target species. Protocols are pre-approved by the CCVB. Research must comply with the Canadian Biosafety HandbookReference 2 and the Canadian Council on Animal Care's GuidelinesReference 3. Studies are done to validate the VB dose, claim, safety, efficacy, indication, administration and required precautions.
Stage 3. Limited field trial in target species under confined conditions. A request for approval to conduct a field safety study in the target animal species under field conditions requires a complete licensing submission for the VB product, including satisfactory safety and efficacy data from Stages 1 and 2. For regulatory purposes, confinement is a condition under which the movement of experimental animals is limited within a designated outdoor environmental zone of control with designated borders or limits. The field trial protocol identifying the study sites must be pre-approved by the CCVB. The CCVB may also inspect the field trial sites to monitor compliance.
Prior to authorization of field use of certain new products, such as modified live veterinary biologics and those derived from biotechnology, an in-depth environmental assessment will be required to comply with the regulations for environmental safety assessment of veterinary biologics under the Health of Animals Regulations. Evaluation will be on a case-by-case basis.
Stage 4. Licensure The final stage involves submission and approval of the field study report, labels and Outline of Production, and resolution of any and all outstanding issues with respect to VB purity, safety, potency and efficacy, so as to complete all licensing requirements.
Licensing requirements and process
Veterinary Biologics Establishment Licence
Veterinary biologics licensed for sale, use or distribution in Canada must be manufactured at a facility that has been inspected and approved by the CCVB. On approval of the facility, a Veterinary Biologics Establishment Licence is issued. The VB facility, its quality management program and controls, production records and other related documents are inspected periodically to monitor compliance with the regulations.
Veterinary Biologics Product Licence
Veterinary biologics are licensed by issuance of a Veterinary Biologics Product Licence (for products manufactured in Canada), or a Permit to Import Veterinary Biologics (for products manufactured outside Canada). To initiate the licensing process for a prototype vaccine with demonstrated proof of concept, the manufacturer's regulatory liaison submits a new VB product licensing dossier containing the items described below.
Also referred to as an Outline of Production (OP), this detailed document describes manufacturing methods and testing procedures. It is considered a contract in which the manufacturer stipulates how the product will be produced and tested in a consistent manner. The production outline is divided into six sections that include the following information:
- microorganism(s), source, isolation and passage history, strains present and proportion of each strain
- culture conditions, composition of media and storage conditions
- technique for harvesting of the microorganism(s)
- description of assembly of the serial
- finished product tests and testing criteria for purity, potency, safety and efficacy and other quality control tests
- label recommendations (use, route of administration and dosage) and precaution statements. A confidentiality statement to protect business information is also provided.
Labels must contain the following information:
- the assigned or scientific name
- manufacturer's name, address and contact information
- Establishment Licence Number, if applicable
- serial number and expiry date
- directions for use
- all components, including antigens and preservatives
- quantity of veterinary biologic in the container, expressed in metric units or doses
- storage temperature expressed in metric units and
- withdrawal period, if applicable.
Supporting documentation and data
Data must be provided to demonstrate safety, purity, potency and efficacy. Studies supporting efficacy and safety must be conducted with serials equivalent to the final product described in the submitted OP. The label recommendations for use and indication of the VB must be based on statistically valid data submitted by the manufacturer. The expiry date must be supported by stability studies for product stored at the recommended temperature and potency tested at the expiry date.
Summary Test Results and Quality Control of Seed Stocks, Cell Stocks and VB Serials
The manufacturer is required to submit quality control reports for the identity, purity, genetic and phenotypic stability for the master cell stocks and master seed stocks used in the production of the VB. Manufacturers holding or seeking a Canadian Veterinary Biologics Establishment Licence must obtain permission from the CCVB before introducing any new master seeds or any new cell cultures into the production area. The CCVB may request that samples of master seed and master cell stocks are submitted to a laboratory acceptable to the CCVB for confirmatory testing.
To complete licensing requirements, manufacturers must provide summary test results from three consecutive pre-licensing serials, tested according to the Section V tests of the production outline. Upon completion of all licensing requirements, the manufacturer is then issued a Canadian Veterinary Biologics Product Licence for that particular product. The pre-licensing serials may then be released by the CCVB, for sale by the manufacturer, provided that they are within the expiry date.
Once a VB is licensed, the manufacturer must submit summary test results to demonstrate serial-to-serial consistency of production serials in agreement with the OP specifications. All serials must be released by the CCVB prior to distribution and sale in Canada.
Post-licensure Compliance Monitoring
Post-licensure compliance monitoring is done through the reporting and review of suspected adverse reactions and other consumer complaints. The Health of Animals Regulations require manufacturers to notify the CCVB of cases where there is any information or any evidence of a significant deficiency in safety, potency or efficacy of a veterinary biologic, within 15 days from the date the information is known.
Importation of Veterinary Biologics
Veterinary Biologics can be imported into Canada, but only with a valid Permit to Import Veterinary Biologics. For licensed products, these are issued by the CCVB to the Canadian importer(s) designated by the product manufacturer.
For further information please contact the Canadian Centre for Veterinary Biologics.
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