VB-GL-3.2: Regulation of biotechnology-derived veterinary biologics

On this page

• 1. Introduction
  • 1.1 Legal authority
• 2. Definitions
• 3. General guidance
• 4. Biotechnology-derived veterinary biologics
• 5. Licensing of biotechnology-derived veterinary biologics
• 6. Environmental release of an unlicensed veterinary biologic
  • 6.1 Field trials
  • 6.2 Emergency use
• 7. Environmental assessment

1. Introduction

The purpose of this document is to inform veterinary biologics (VB) researchers, manufacturers and Canadian importers of the requirements for VB derived from biotechnology.

The Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA) is responsible for regulating the manufacturing, testing, importation and use of VB in Canada, including VB produced using modern techniques of biotechnology.

1.1 Legal authority

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

2. Definitions

Confined release

means a release of a veterinary biologic outside of containment where physical, chemical, operational or biological controls, or any combination thereof, are employed to restrict the exit or dispersal of the organism, or material from the organism, beyond a specified area.

Containment

means a condition under which the movement of an organism is limited by 1 or more of the following mechanisms:

• a set of standard practices that are generally used in microbiological laboratories
• special procedures, equipment and laboratory installations that provide physical and other barriers, which are applied in various degrees according to the estimated biohazard
• biological barriers that limit either the infectivity of a vector or vehicle (plasmid or virus) for specific hosts, or its dissemination and survival in the environment

Containment ensures that there is no release of an organism, or material from the organism, from a research facility to the environment.

Environment

refers to the components of the earth and includes the following:

• air, land, and water
• all layers of the atmosphere
• all organic and inorganic matter and living organisms
• the interacting natural systems that include these components

Release of a veterinary biologic

refers to any discharge or emission of a veterinary biologic into the environment.

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, 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

Veterinary biologics include vaccines, bacterins, bacterin-toxoids, autogenous vaccines, colostrum, antibody products, immunomodulators, allergenic extracts, and test kits for the diagnosis of infectious diseases in animals, whether produced by modern techniques of biotechnology, or by conventional methods.

3. General guidance

Biotechnology-derived VB are licensed based on the same 4 principles as conventionally produced VB: purity, potency, safety, and efficacy. VB products are inherently variable. A live genetically modified organism's characteristics add uncertainty about its properties, from recombination variance to infectivity, pathogenicity, and virulence. The specific studies that are required to demonstrate each of these fundamental principles will depend on the product, its intended use, and the associated risks.

It is important to demonstrate that the genes or genetic sequences that are added, mutated, or deleted do not confer changes that compromise the safety characteristics of the vaccine organism. A genetically manipulated microorganism might not always exhibit the expected characteristics under basic conditions. Well-designed laboratory studies and contained animal trials should reveal any unplanned outcomes. Precautions must be taken to ensure that the genetic manipulations do not impart increased virulence, pathogenicity, or survival advantages in these organisms, beyond those found in natural or wild-type forms. The genetic modifications must not impart undesirable new or increased adhesive or invasive factors, colonization properties, different survival within the host, oncogenic properties, or other deleterious effects. Data submitted should confirm the absence of these traits.

Prior to the "release" into the environment of a live genetically modified VB, the researcher, manufacturer, or importer is required to provide detailed information about the origin and nature of the novel biotechnology-derived VB, in addition to the information required of conventional VB. The environmental release of a VB is usually associated with the licensing of a VB, but it might also be related to a research trial under confined field conditions, or the emergency use of an unlicensed VB.

To conform to Canada's environmental protection legislation, the Canadian Environmental Protection Act (CEPA 1999) and New Substances Notification Regulations, as well as the Health of Animals Regulations, before any novel VB may be released from laboratory containment into the environment, the CCVB must assess all potential animal and human health, and environmental aspects of the proposed release. For products of biotechnology, the CCVB prepares an environmental assessment (EA), a document that summarizes the molecular and biological characteristics of the product, and its target and non-target animal safety, human safety, environmental considerations, and risk-mitigating measures for its use.

4. Biotechnology-derived veterinary biologics

Examples of biotechnology-derived VB may include but not be limited to the following:

• inactivated, genetically engineered viral vaccines
• bacterins produced from genetically engineered bacteria
• viral or bacterial protein subunit vaccines purified from recombinant organisms or expression systems
• plasmid deoxyribonucleic acid (DNA) vaccines that are non-replicating in eukaryotic cells
• vaccines using a live viral vector to carry foreign genes encoding antigens and/or immune stimulants
• vaccines containing live organisms modified by gene mutation or deletion
• vaccines containing live organisms modified by gene insertion or mutation with the introduction of foreign DNA
• ribonucleic acid (RNA) vaccines and RNA platform-based prescription products
• monoclonal antibody or hybridoma products used prophylactically, therapeutically, or as components of diagnostic kits

Note: novel VB produced by co-culturing organisms, serial passage using selective culture conditions to promote mutagenesis, or other less direct methods of genetic manipulation, may be regulated in a similar manner as biotechnology-derived veterinary biologics produced by direct, intentional genetic manipulation.

5. Licensing of biotechnology-derived veterinary biologics

The assurance of safety for any VB requires that the product does not harm animal or human health, and does not adversely affect the environment. The rigorous review of the methods used in the production and testing of the VB, including the construction of any recombinant organisms, and the preparation of the EA constitutes part of the supplemental safety assessment for biotechnology-derived VB.

The CCVB requires the following information as a prerequisite to consider an application for a biotechnology-derived VB product:

• information about the parental and donor organisms
  • origin and isolation history for each organism
  • molecular and biological properties of each organism
  • pathogenicity
  • host range
  • tissue tropism
  • natural environmental distribution
• genetic modification procedures used to construct the altered organism
  • description of any intermediate cloning vectors
  • screening techniques for identification
  • sequencing data for the recombinant organism
  • sequence alignment (percent identity) with parental and donor sequences
  • sequencing primers for constructs
  • construction primer information
• description of any selectable markers and antibiotic resistance genes in the construct
• information and data about the genetically engineered organism
  • genotypic characterization
  • phenotypic characterization
  • in vitro and in vivo data to demonstrate genetic and phenotypic stability
  • purity data for the master seed
  • information on its virulence traits, replication competency, infectivity, tissue tropism, and other factors affecting pathogenicity
  • information on the fate of the construct when administered to the target animal by the intended route
  • ability of the organism to replicate in and be shed by the target animal
  • non-reversion to virulence studies examining the effect of multiple back-passages in the target animal species
  • ability of the recombinant construct to spread from vaccinated animals to other animals and organisms
  • ability of the organism to affect non-target species
  • ability of the recombinant construct to maintain itself in target and non-target populations
  • safety of the recombinant organism in target and non-target animal species
  • immunogenicity and/or vaccination-challenge studies demonstrating efficacy
  • potential for horizontal gene transfer or recombination
  • survivability of the shed organism or spilt vaccine in the environment
  • data validating the proposed potency test
• considerations and mitigative actions with respect to human safety during manufacturing, testing, and handling of the recombinant organism
• considerations and mitigative actions with respect to environmental safety during use of the recombinant organism

The specific data requirements will depend on the nature of the product, its intended use, and the associated risks. The release of live biotechnology-derived VB increases the risks when compared to inactivated biotechnology-derived organisms, plasmid DNA or purified recombinant protein-based vaccines. The CCVB requires more extensive documentation regarding the origin and nature of live products when evaluating requests for authorization for their release into the environment.

6. Environmental release of an unlicensed veterinary biologic

The CCVB evaluates requests to release unlicensed VB in Canada for restricted use in field studies and emergency situations.

6.1 Field trials

Most VB developed in Canada will need to be tested outside of the contained laboratory in a confined field trial. CCVB approval is required for product testing studies that involve the release of an unlicensed or experimental VB from laboratory physical containment. The manufacturer should provide the CCVB with a product licensing submission before proceeding to a stage where approval for a limited field trial outside the controlled containment facilities is sought. The licensing submission will include data from laboratory research and development studies, and from controlled experiments performed in containment. This data should fully characterize the recombinant organism and demonstrate its safety in target and proximal non-target animal species.

Refer to VB-GL-3.29: Safety requirements for veterinary biologics for field safety trial design for VB product licensing.

Following receipt of an application for permission to conduct a field trial in confinement, the CCVB will evaluate the proposed release activity and undertake a comprehensive review of the potential environmental effects and risks to human and animal health. The CCVB prepares an EA summarizing the characteristics of the biotechnology-derived organism, and its target and non-target animal safety, human safety, and environmental considerations. Any risk-mitigating measures are described in the EA. Prior to authorizing the field trial, the CCVB may require additional quality control tests on the product to be performed by a laboratory acceptable to CCVB. The CCVB will also review and provide comments on the study protocol.

If the proposed field trial protocol is approved, CCVB issues the manufacturer or researcher a Permit to release veterinary biologics.

Occasionally, VB produced in a foreign country may undergo field testing in Canada. In this scenario, the CCVB will evaluate the proposed confined release and approve the study protocol before allowing the importation of the test product. A CFIA inspector may monitor the study to verify compliance and ensure that permit conditions are being met.

Confined field trials are to be conducted under quarantine conditions acceptable to the CCVB, where there is adequate evidence of biological and/or physical control of the genetically engineered organism. Facilities shall be maintained and operated in an appropriate manner to prevent the dissemination of the unlicensed VB or animals that were exposed to the product. Test animals receiving any unlicensed, experimental VB must not enter the food or feed chain without prior permission from the CCVB.

6.2 Emergency use

Under certain circumstances (for example, if there is an outbreak of a disease in Canada for which there is no effective licensed VB available), the CCVB may consider an application for the release of an unlicensed biotechnology-derived VB for emergency use. In these situations, the CCVB will require information listed in section 5, together with data demonstrating its purity, potency and safety, in order to fully evaluate the proposed release and prepare an EA. In addition, the CCVB may request data supporting the efficacy of the veterinary biologic in order to be confident in its risk-benefit analysis. If the emergency use of the unlicensed veterinary biologic is approved, the CCVB will issue a Permit to release veterinary biologics and/or a Permit to import veterinary biologics, as applicable, with any necessary conditions and restrictions listed on the permit(s).

7. Environmental assessment

The environmental assessment contains information on the molecular and biological characteristics of the biotechnology-derived organism, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures. The manufacturer must submit all relevant data to aid the CCVB reviewer in preparing the EA. The CCVB reviewer will also independently research any potential safety issues, and may consult other federal and provincial government departments with expertise in areas of concern. For instance, potential human health and safety risks may be assessed in collaboration with Health Canada and the Public Health Agency of Canada. An EA must be completed before the CCVB will authorize the release of a novel organism into the Canadian environment.

The scheduling of the Health of Animals Act and Health of Animals Regulations under Schedule 4 of the Canadian Environmental Protection Act, 1999 (CEPA 1999) exempts new biotechnology-derived VB regulated by the CCVB from additional notification and assessment under the CEPA 1999. This scheduling is recognition that the environmental assessment authorities within the Health of Animals Act and Health of Animals Regulations provide an adequate level of regulatory control. Consequently, the CCVB is fully responsible for the environmental, human health and animal health assessment of a novel VB product.

After the CCVB has completed the draft EA for a biotechnology-derived VB, the manufacturer is provided a copy of the document and given the opportunity to identify any confidential business information. A publicly available bilingual version of the EA, which omits this confidential business information, is subsequently posted on the CFIA website, where it is accessible to the general public.

The public versions of previously completed EAs.