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VB-GL-3.29: Safety requirements for veterinary biologics

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1. Introduction

The purpose of this document is to advise veterinary biologics manufacturers of the safety requirements for veterinary biologics manufactured in, or imported into, Canada.

The Canadian Centre for Veterinary Biologics (CCVB) uses a multi-step process to evaluate the safety of veterinary biologics (VB). This includes the review and approval of the manufacturing process, technical reports and test data submitted by manufacturers for master seeds, cell lines, and product serials, and post-licensure monitoring of product serial releases and adverse events. A risk-based approach is used to determine the appropriate standards, processes, tests, and laboratory and field trials to apply in evaluating the safety of a VB.

This guideline is directed primarily at Canadian manufacturers and foreign manufacturers in countries other than the United States (U.S.). The safety requirements for VB manufactured in the U.S. and licensed by the U.S. Department of Agriculture (USDA) are similar to Canadian requirements.

Information and submission requirements to license new VB can be found in VB-GL-3.1: Preparation of new product licensing (registration) submissions for veterinary biologics and references therein. Autogenous vaccines, in vitro diagnostic kits, colostrum and antibody products may have different safety requirements than those covered in this guideline. Manufacturers of these types of VB are directed to view the relevant product-specific guideline(s).

1.1 Legal authority

1.2 Definitions

Adverse event

means any observation in animals, whether or not it is considered to be product related, that is unfavourable and unintended and that occurs after any use of veterinary biologic(s)

Containment

means a condition under which the movement of an organism is limited by one 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, and/or
  • biological barriers that limit either a) the infectivity of a vector or vehicle (plasmid or virus) for specific hosts, or b) 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.

Non-target animal

is an animal belonging to a species, or to a group of animals (for example, pregnant), not intended for the final use of the veterinary biologic

Outline of Production

is a detailed description of:

  • the process followed in preparing a veterinary biologic and any diluent to be used with it
  • the methods and procedures to be employed in handling, storing, administering and testing a veterinary biologic and any diluent to be used with it, and
  • the tests used to establish the purity, safety, potency and efficacy of a veterinary biologic, and the purity and safety of any diluent to be used with it
Target animal

is an animal belonging to a species, or group of animals (for example, pregnant), intended for the final use of the veterinary biologic

2. Pre-licensing safety

2.1 General process

Progression from inception to licensure of a VB product can be accomplished in the following stages:

Preliminary research and development work will usually be conducted under the control of institutional biohazard/biosafety personnel. After the initial submission to CCVB, researchers may find additional guidance about the design and completion of controlled animal experiments by consulting the CCVB. CCVB approval is not required prior to conducting laboratory experiments in containment, provided that the vaccine is produced in house and vaccinated animals do not enter the food or feed chain. Release of a VB from laboratory physical containment to field conditions requires CCVB approval and a permit to release veterinary biologics (PRVB) (refer to Appendix 1). Information on field safety trials is provided in Appendix 2.

2.2 Master seed and cell line quality control

The manufacturer is responsible for quality control testing and certification of master seeds and/or cell lines used in the production or testing of a VB. The results of these analyses must be submitted to CCVB in support of licensure. CCVB may request verification testing through a Canadian Food Inspection Agency (CFIA)-approved laboratory. The quality control testing of master seeds and/or cell lines may include:

2.3 Reversion to virulence

For live VB, reversion to virulence studies (also known as backpassage studies) must be performed to evaluate the genetic stability of the vaccine. These studies provide assurance that the product will not revert to virulence when passaged in the target animal. In backpassage studies, a group of animals is administered an appropriate dose of the live vaccine organism via the route most likely to lead to replication and reversion. Subsequently, an attempt is made to recover the vaccine organism from these animals at the time interval and by the route (secretion or tissue) that it is most probable to recover the vaccine organism. Any recovered vaccine organism is then inoculated directly into another group of susceptible animals. After each passage, the presence and quantity of test organisms must be determined. No evidence of an increase in virulence, indicative of reversion, shall be seen with passage. The virus or microorganism isolated from the last passage must be characterized genotypically and/or phenotypically, and compared to the master seed to evaluate genetic stability and reversion to virulence.

Manufacturers are encouraged to follow the procedures outlined in the U.S. Department of Agriculture Veterinary Services Memorandum No. 800.201 and Guideline 41 of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH) entitled Target animal safety: Examination of live veterinary vaccines in target animals for absence of reversion to virulence, regarding backpassage studies.

2.4 Laboratory and target animal safety studies

Preliminary safety testing of a VB typically includes a mouse safety test and testing in the target animal, often during the initial proof-of-concept studies. Safety tests are conducted to ensure that the VB does not cause undue local or systemic reactions in animals. The VB formulation employed in these safety experiments should contain a level of antigen at or near the proposed maximum allowable antigen. Contained animals studies should also address the safety of administering an overdose (typically 10x for live and 2x for inactivated) and/or repeated single doses of the experimental product.

2.5 Shed and spread

For live VB, data are required on the mode, rate and duration of shedding, as well as the propensity of the organism to spread to contact target and non-target animal species.

2.6 Bluetongue virus exclusion testing

Manufacturers are required to conduct bluetongue virus exclusion tests on all live vaccines for use in ruminants that utilize non-irradiated bovine or other ruminant serum, or when the virus is grown on either primary bovine or other primary ruminant cells. Further information on bluetongue virus exclusion testing may be found in VB-GL-3.6: Bluetongue virus exclusion testing of veterinary biologics.

2.7 Seneca Valley virus and pseudorabies virus exclusion testing

Manufacturers are required to demonstrate the absence of Seneva Valley virus and pseudorabies virus (Aujeszky's disease) in all live porcine virus vaccines that utilize non-irradiated porcine serum or are grown on primary porcine cells. Further information on pseudorabies testing may be found in VB-GL-3.31: Pseudorabies virus exclusion testing of veterinary biologics.

2.8 Replicating avian leukosis virus testing

All embryonated eggs, chicks or chicken tissue used as ingredients in VB must be derived from unvaccinated specific pathogen free (SPF) flocks. Testing of these VB for lymphoid leukosis virus contamination must be performed in a manner acceptable to CCVB, and described in the Outline of Production (OP) or in a special outline (SO).

2.9 Materials of animal origin

In order to minimize the risk of introducing animal transmissible spongiform encephalopathy (TSE) agents or other contaminants into Canada through VB, all materials of animal origin (MAO) used in the development and production of a VB must be identified, along with the species and tissue of origin, supplier, and source country, in a SO referenced in the OP. Manufacturers of VB are responsible for ensuring that any MAO contained within their products are acquired from suppliers who can confirm that the MAO were derived from sources considered to be safe from animal TSE infection or contamination. VB must not contain any material defined as specified risk material (SRM). The manufacturer must provide a certificate from each supplier indicating the supplier's actions with respect to minimizing the risk for contamination of their product by animal TSE agents. Further information regarding MAO requirements and the Declaration of compliance may be found in VB-GL-3.32: Minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics.

2.10 Field safety trials

Field safety trials are conducted prior to licensure to demonstrate that a VB is safe for use in the target animal and does not cause unexpected adverse events and/or mortality when used as recommended by the manufacturer. The field safety trial provides a degree of confidence with respect to the rate of occurrence of adverse events, and identifies reactions that may require precautionary statements on the product label. VB (typically more than 1 pre-licensing serial) are usually tested for field safety at 3 geographically distinct locations. Enough animals must be vaccinated on each premise to be statistically relevant with the exact number depending on the product. One third of the animals tested in a field safety trial must be at the minimum age indicated for vaccination. Pre-licensing serials are not released for use in field trials without the previous submission and CCVB approval of the documentation outlined in Appendix 2. Refer to Appendix 2 for information on the reporting of field safety trial results.

To release the VB into the environment, researchers and developers must obtain a PRVB prior to conducting a field trial. This permit authorizes the use of a VB product for "investigational use only" to generate field safety data in support of a licence application. Requirements for a PRVB are listed in Appendix 1.

2.11 Environmental assessment

As a condition of the PRVB, all live vaccines derived through biotechnology, as well as products containing organisms considered novel to Canada, must have a detailed environmental assessment (EA). This document contains information on the molecular and biological characteristics of the novel vaccine, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures. Refer to VB-GL-3.2: Regulation of biotechnology-derived veterinary biologics for EA requirements and format. 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 with other federal and provincial government departments with expertise in areas of concern. The EA must be completed before CCVB can authorize the release of the organism for a field safety trial.

2.12 Consistency of production

The production of safe, pure, potent and efficacious vaccines requires quality assurance procedures to ensure the uniformity and consistency of the production process. Prior to completing licensure, the manufacturer should produce in its facilities three consecutive pre-licensing serials of completed product according to the product OP, to evaluate batch-to-batch uniformity. The size of the pre-licensing serial should normally be at least a third of the maximum size of serial that will be produced upon licensure. The manufacturer must test each of these serials for safety, purity and potency as described in the product OP.

3. Post-licensing safety

3.1 Serial release testing

The manufacturer is required to conduct all appropriate tests (including bluetongue virus exclusion, pseudorabies virus exclusion or replicating avian leukosis virus testing where appropriate) described and agreed upon in the OP prior to the release of each serial of a VB that is produced or sold in Canada. For Canadian manufacturers and foreign manufacturers from countries other than the U.S., the results from such tests must be communicated to CCVB via signed copies of a Manufacturer's serial release test report, and must be retained in the manufacturer's records for a minimum of 6 years. In addition, samples of each serial must be stored by a manufacturer for at least 6 months past the expiry date.

Manufacturers may be required to submit samples of each serial to a CFIA-approved laboratory according to VB-GL-3.22: Master seed stocks, master cell stocks and serial requirements.

3.2 Reporting suspected adverse events

The Health of Animals Regulations require every holder of a VB licence or permit (manufacturers, commercial importers, veterinarians, or diagnostic laboratories) to report, in writing, any information concerning, or any evidence of, a significant deficiency in safety, potency or efficacy of a VB within 15 days after the date on which that information or evidence is known to the holder or is generally known to the industry. Upon receipt of a suspected adverse event report by CCVB, the manufacturer is asked to investigate and prepare a report for the owner's veterinarian and the CFIA. If the problem is resolved to the satisfaction of the veterinarian/client, no further action is usually requested by CCVB. However, if the outcome is not satisfactory, CCVB may initiate regulatory action depending on the case. This may include, but is not limited to, further safety testing, temporary stop sale, product recall, or product withdrawal from the market. For more information on the responsibilities of veterinary practitioners and veterinary biologics companies for reporting and investigating suspected adverse events, refer to VB-GL-3.15: Reporting suspected adverse events to veterinary biologics.

Note: While holders of import permits are not required to report each separate suspected adverse event which has occurred in another country, they are required to report any information or suspected adverse event which may indicate a significant deficiency in the safety, potency or efficacy of a product being distributed in Canada.

4. Laboratory biosafety and animal use

The manufacturer is responsible for ensuring that the appropriate biocontainment level is used to handle any live organisms used in the development and evaluation of the VB. All aspects of the development and evaluation of a VB must meet the standards and regulations for laboratory biosafety and animal use described in the documents listed below, along with the relevant provincial legislation, and local safety and animal care authorities:

5. Special considerations for manufacturers in the United States

U.S. manufacturers, and "permittees" in the U.S. of foreign manufacturers, may apply to license in Canada a veterinary biologic product already licensed by the USDA. In this situation, CCVB will review all pertinent USDA documentation (scientific data and correspondence) and will notify the manufacturer of any additional safety requirements.

Test results for pre-licensing serials reported on the Animal and Plant Health Inspection Service Form APHIS 2008 – Veterinary biologics production and test report must be provided to CCVB.

6. Appendices

Appendix 1: Permit to release veterinary biologics

A permit to release veterinary biologics (PRVB) contains information on the nature of the veterinary biologic product, the conditions for use, and any restrictions. Where applicable, the information required by CCVB in order to issue the permit must include the following:

Upon review of the above information, CCVB will specify certain conditions for use of the unlicensed veterinary biologic. These conditions will be determined on a case-by-case basis and may include (but are not limited to):

Appendix 2: Field safety trials

General

The purpose of a field safety trial is to assess the safety of a VB in its target population under the conditions of its intended use. Field safety trials can detect adverse events of unexpected type or frequency that might indicate a need for further investigation, or warrant a precautionary statement in the labelling. Field safety trials may be monitored by the CFIA.

Approval by CCVB

All field safety trials conducted in Canada require approval from CCVB prior to their commencement. In support of a licensing application and prior to starting the field trial, investigators must submit the following documents for review by CCVB:

Field safety trial report

Part 1 – Experimental protocol

Part1 of the field safety trial report, which is submitted to CCVB for approval prior to conducting the field safety trial, must include the following information:

Field safety trial amendments

Should changes to the experimental protocol describing the field safety trial be necessary, the manufacturer must notify CCVB in writing by providing the following:

Part 2 – Results and conclusions

Part 2 of the field safety trial report, which is submitted to CCVB in support of an application for licensure, contains the following information:

Table 1: Estimates of the maximum percent of the population that could be susceptible to a particular adverse event given the number of animals that were observed in a field safety trial with no reaction, for 95% and 99% confidence levels (based on an approximation to the binomial distribution).

Number of animals tested with no reactions Maximum percent susceptible
95% (C.L.) 99% (C.L.)
100 3.0 4.6
200 1.5 2.3
300 1.0 1.5
400 0.7 1.1
500 0.6 0.9
1000 0.3 0.5
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