Veterinary Biologics Guideline 4.5E
Licensing Requirements for Veterinary Biologics in Canada
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The authority for regulating veterinary biologics in Canada is provided by the Health of Animals Act and Regulations. This legislation authorizes the federal Minister of Agriculture and Agri-Food to prescribe regulations for the manufacture, importation and sale of veterinary biologics in Canada. The Canadian Centre for Veterinary Biologics (CCVB) of the Terrestrial Animal Health Division, Animal Health Directorate, Canadian Food Inspection Agency has been delegated with the responsibility for regulating the manufacture, testing, importation, distribution and sale (including export certification) of veterinary biologics.
The veterinary biologics registration program involves review and approval of facility documents, product manufacturing and testing data, as well as inspection of facilities and finished product testing. It forms an integral part of Canada's National Animal Health Program, which is intended to help protect the health of food producing animals, domestic pets, and of the public, by preventing the introduction and spread of foreign animal diseases into Canada. The licensing requirements are described in the regulations and in guidelines which are available from the Canadian Centre for Veterinary Biologics (1, 2).
Veterinary biologics are evaluated on a case-by-case basis, and are licensed 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 environment. Other federal departments, such as Health Canada or the Department of Fisheries and Oceans are consulted during the risk and environmental assessments, when human health issues or national fish health concerns are involved.
In many respects, the Canadian licensing requirements are similar to the United States Department of Agriculture requirements for veterinary biologics. Documents prepared by using the United States Code of Federal Regulations (9 CFR) protocols and test procedures or equivalent, are accepted by the CCVB for review and licensing purposes.
Manufacturers and researchers intending to license experimental vaccines are encouraged to consult with the CCVB early in the product development process, so that the research data and quality assurance documentation are consistent with Canadian regulatory requirements, as specified in the Health of Animals Act and Regulations.
In addition to conforming with the Health of Animals Act and Regulations, all research and development projects must meet the standards and requirements for laboratory biosafety and animal care described in the current edition of the Health Canada Laboratory Biosafety Guidelines (4), and the Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals (5).
Recently, regulations have been implemented to recover fees for some of the veterinary biologics regulatory services including issuance of permits, licences and inspection of facilities. The cost recovery schedule for veterinary biologics is outlined in the Health of Animals Act and Regulations and the Canadian Food Inspection Agency Fees Notice, Part 11 - Services Related to Veterinary Biologics (Items 40-50) Service standards (response times) have been established for these regulatory services, and are available from CCVB.
Definitions for Veterinary Biologics
Veterinary biologic means (a) any helminth, protozoa or micro-organism, (b) any substance or mixture of substances derived from animals, helminths, protozoa or micro-organisms, or (c) any 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, abnormal physical state, or the symptoms thereof, in animals. These veterinary biological products include vaccines, bacterins, bacterin-toxoids and diagnostics kits.
Production outline means a detailed description of (a) the process followed in preparing a veterinary biologic and any diluent, (b) the tests used to establish the purity, safety, potency, and efficacy of a veterinary biologic, and the results of all such tests and (c) 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.
Classification of Veterinary Biologics based on risk
Veterinary biologics can be broadly classified into the following two classes, depending on the safety aspects and biological characteristics, as in Table 1. This table broadly divides biologics based on qualitative risk assessment, and helps in the selective application of criteria for further evaluation.
Class I (low risk)
Inactivated viral / bacterial vaccines (conventional or rDNA).
Inactivated viral / bacterial vaccines (conventional or rDNA).
Viral / bacterial subunit vaccines (conventional or rDNA).
Cytokines and monoclonal antibody (hybridoma) products.
Modified live conventional vaccines.
Gene deleted recombinant DNA vaccines (inactivated or live)
Class II (high risk)
Vaccines using a live vector to carry recombinant derived foreign genes.
Vaccines containing live organisms modified by insertion of foreign DNA.
The non-viable (non-replicative) products in Class I pose relatively little risk to the environment. Live products in Class I include organisms resulting from deletions or single base changes and, in these cases, supplemental data is needed to establish environmental safety. These products are subjected to the same licensing process as used for the live products of Class II.
Class II includes products containing live micro-organisms which have been genetically modified by introduction of DNA from different organisms or different strains of the same organism. This class consists of products using live vectors to carry one or more foreign genes that code for immunizing antigens and are capable of infecting and immunizing host animals.
Stages in the development, field testing, and licensing of Veterinary Biologics
The movement of veterinary biologics from contained laboratory research, to a fully licensed product for distribution and sale, can be accomplished in four stages:
Stage 1. Preliminary laboratory research must be done under appropriate containment conditions, depending on the product, and must comply with the Health Canada Laboratory Biosafety Guidelines (4) and Canadian Council on Animal Care Guide to the Use and Care of Experimental Animals (5).
Stage 2. Controlled experiments using a prototype vaccine in target and non-target species, under appropriate laboratory containment conditions. The same laboratory containment requirements as in stage 1 would apply.
Stage 3. Limited field trial using target species under confined conditions. A request for approval to conduct studies in conventional domestic animals under field conditions would require a complete licensing submission on the product, including safety data from stage 1 and stage 2 experiments.
Prior to authorization of field use of certain new products such as modified live veterinary biologics and those derived from recombinant DNA technology, 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. Information to be provided by the proponent is outlined in Appendix 1. Evaluation will be on a case-by-case basis.
For regulatory purposes, confinement is a condition under which the movement of experimental animals is confined within a designated outdoor environmental zone of control with designated borders or limits. Before authorizing the field trial, CCVB may request the Biologics Evaluation Laboratory of Canadian Food Inspection Agency, to conduct confirmatory tests on the product. The field trial facilities may also be inspected by CCVB to monitor compliance.
Stage 4. Licensure The final stage involves submission and approval of complete licensing dossier including field trial results, in support of a licensing application. The proponent must submit all necessary information including test results of the limited field trial as described for stage 3. The supporting data must demonstrate that the product is pure, potent, safe, and efficacious.
Overview of the licensing requirements and process
A. Veterinary Biologics Establishment Licence
Veterinary biologics licensed for sale in Canada must be manufactured at a facility that has been inspected and approved by CCVB. On approval of the facility, a Veterinary Biologics Establishment Licence is issued. This facility, production records and other related documents are inspected periodically to monitor compliance with the regulations.
B. 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). On development of a prototype vaccine, the manufacturer's regulatory personnel compile the product licensing dossier which includes the production outline, labelling, and supporting data, as explained below.
i) Production outline
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, and includes the following information:
(I) micro-organism(s), source, isolation and passage history, strains present and proportion of each strain; (II) culture conditions, composition of media and storage conditions; (III) technique for harvesting of the micro-organism; (IV) description of assembly of serial; (V) finished product tests and testing criteria for purity, potency, safety and efficacy; (VI) label recommendations (use, route of administration and dosage) and precaution statements. A confidentiality statement to protect business information is also provided.
Labels must contain information to show the assigned or scientific name, trade name, expiry date, serial number, route of administration, dosage, recommendations for use, precautions and the establishment number of the firm.
iii) Supporting documentation and data
Data must be provided to demonstrate (a) purity; (b) potency; (c) safety; and (d) efficacy. The label recommendations must be based on 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. Environmental safety must be demonstrated before the use of live viral, bacterial or live recombinant micro-organisms, that are to be tested outside of containment. Information requirements, as stipulated in Appendix 1, must be provided by the manufacturer to allow CCVB to make a determination and prepare an environmental assessment. This information is similar to that of the Summary Information Formats as required by the United States Department of Agriculture (6).
C. Serial Release Testing and Quality Assurance Monitoring
On satisfactory review of the product dossier by CCVB, samples from pre-licensing serials are requested of the manufacturer, along with the serial release test results, tested according to the production outline. These samples undergo confirmatory testing at the Biologics Evaluation Laboratory (BEL). Upon fulfilment of the licensing requirements, the manufacturer is then issued a Veterinary Biologics Product Licence for that particular product. The pre-licensing serials may then be released by CCVB, for sale by the manufacturer. For future release of serials of the vaccine, serial release test results are submitted by the manufacturer to CCVB and samples to the BEL, for random confirmatory testing. This process serves as a means of government monitoring of the licensed product.
D. Post-licensure Surveillance and Compliance Monitoring
Post-licensure compliance monitoring is done through the reporting and investigations of suspected adverse reactions and other consumer complaints, as well as review and approval of advertising material. The Health of Animals Regulations require manufacturers to notify 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 (e.g., suspected vaccine induced illness or mortalities in vaccinated animals). Guidelines for reporting suspected adverse reactions are available from CCVB.
E. Importation of Veterinary Biologics
Canada is free of a number of economically important animal and fish diseases. The potential of introducing such diseases into the Canadian animal and fish populations through veterinary vaccines, is significant and is evaluated in the licensing process. Importation of a biological product into Canada requires that the importer obtain a Permit to Import Veterinary Biologics. The Canadian Centre for Veterinary Biologics issues permits for (a) research, and (b) commercial distribution and sale of veterinary biologics. A veterinary biologic produced in a foreign country must be licensed in that country prior to importation into Canada.
Appendix 1. Information to be provided by the manufacturer for environmental assessment and approval for field testing of veterinary biologics derived by recombinant DNA technology.
Background: provide information on problem / action. Proposed action: objectives, location and experimental protocol; Experimental design should include, number of animals, description of the animals, dosage and route of administration, total amount of test material, method of disposing waste and decontamination of the test site.
- Molecular and biological characteristics of parental and recombinant organisms
Identification of source and strain of parental organism; Source, description, and function of foreign genetic material; Method of accomplishing genetic modification; Genetic stability, phenotypic stability, potential for recombination; Host range/specificity, tissue tropism and shed/spread capabilities; Comparison of the modified organism to parental properties; Route of administration/transmission.
- Human safety
Previous safe use; Probability and possible outcomes of human exposure; Pathogenicity of parent micro-organisms in man; Effect of gene manipulation on pathogenicity, in man; Risk associated with widespread use of the vaccine.
- Animal safety
Previous safe use; Fate of the vaccine in target and non-target species; Potential for shed and / or spread from vaccinates to contact target and non-target animals; Non-reversion to virulence demonstration through back-passage studies in animals; Effect of overdose in target and potential non-target species; Relative safety when compared to conventional vaccines; Extent of the host range and the degree of mobility of the vector.
- Affected environment
Identify site and size of site, including relevant geographical and environmental information; Ecological concerns; Extent of release into the environment; Persistence of the vector in the environment / cumulative impacts; Extent of exposure to non-target species; Behaviour of parent microorganisms and vector in non-target species; Potential of vector to infect non vertebrate organisms; Physical and chemical factors which could affect survival, reproduction and dispersal of the vector.
- Environmental consequences
Discuss problems / benefits / potential hazards; Compare benefits and problems of the experimental vaccine with licensed products.
- Mitigative measures
Discuss worker safety; Handling of vaccine; Handling vaccinated or exposed animals.
Discuss general / specific monitoring methods to determine exposure to target and non-target species.
- Conclusions and summary
List all references cited or relied upon; include personal communications.
Tables, figures, maps of the field trial area and other reports.
- Summary of Requirements and Guidelines for Veterinary Biologics in Canada. Canadian Centre for Veterinary Biologics (1995).
- Gifford, G.A. (1992). Licensing requirements for fish vaccines in Canada. Bull. Aquacul. Assoc. Canada. 92-1, 61-63.
- Silva, S.V.P.S., Samagh, B.S., Morley, R.S. (1995). Risk analysis for veterinary biologicals released into the environment. Rev. Sci. Tech. Off. Int. Epiz. 14(4), 1043-1059.
- Public Health Agency's of Canada (PHAC) Laboratory Biosafety Guidelines.
- Guide to the Care and Use of Experimental Animals: Volumes I and II (1993). Canadian Council on Animal Care. 1000-151 Slater Street, Ottawa, Ontario, Canada K1P 5H3.
- Gay, C.J., Roth, H.J. Confirming the safety characteristics of recombinant vectors used in veterinary medicine: A regulatory perspective, in Brown F (ed): Recombinant Vectors in Vaccine Development. Dev Biol Stand. Basel, Karger, 1994, vol 82, pp 93-105.
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