Veterinary Biologics Guideline 3.32E
Guideline for Minimising the Risk of Introducing Transmissible Spongiform Encephalopathy Agents through Veterinary Biologics
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Table of Contents
- I. Introduction
- II. Legal Authority
- III. General Guidance
- IV. Required Information
- Outline of Production
- Special Outline
- TSE Certificate of Suitability
- Certificate of Analysis and Inventory Record
- Declaration of Compliance
- V. Veterinary Biologics Manufactured in the United States and imported into Canada
- VI. Veterinary Biologics Manufactured in Countries other than Canada and the USA
- VII. Master Seed and Master Cells Established prior to 1986
- VIII. Veterinary Biologics for Investigational or Emergency Use
- Appendix I
The Canadian Centre for Veterinary Biologics of the Canadian Food Inspection Agency (CFIA-CCVB) has prepared this guideline to provide information on requirements for minimising the introduction of transmissible spongiform encephalopathy (TSE) agents into veterinary biologics. This guideline consolidates CCVB Memorandum 2002-01 dated January 14, 2002, CCVB Memorandum 2002-04 dated October 1, 2002 and CCVB Memorandum 2003-01 dated December 31, 2003. No major changes have been made to the existing requirements. The manufacturers and importers of veterinary biologics are required to follow this guideline, and regard the above memoranda as archived regulatory documents. The manufacturers are responsible for preparing and providing all of the information required by this guideline.
An abnormal isoform of a normal cellular glycoprotein (PrP) referred to as a prion has been associated with the development of clinical TSE diseases. These abnormal isoforms are referred to as PrPRes in the case of bovine spongiform encephalopathy (BSE) and PrPSc in the case of scrapie. BSE, commonly known as "mad cow disease" is of particular interest to human health because consumption of meat products from cattle infected with PrPRes or iatrogenic administration of products contaminated with PrPRes have been considered as potential causes of variant Creutzfeldt-Jakob Disease (vCJD) in humans.
The production of veterinary biologics involves the use of many materials of animal origin (MAO). These MAO present a risk of iatrogenic transmission of TSE to animals. Manufacturers of veterinary biologics must document in their Outline of Production (OP) or Special Outline (SO) the measures they have implemented to minimise the risk of introducing such agents into their products.
II. Legal Authority
The Health of Animals Act and Health of Animals Regulations, Part XI provide authority to CFIA-CCVB for licensing and regulating veterinary biologics in Canada.
Health of Animals ActFootnote 1
Section 64. (1)
The Governor in Council may make regulations for the purpose of protecting human and animal health through the control or elimination of diseases and toxic substances and generally for carrying out the purposes and provisions of this Act, including regulations
prohibiting or regulating the importation, preparation, manufacturing, preserving, packing, labelling, storing, testing, transportation, sale, conditions of sale, advertising for sale, use and disposal of veterinary biologics and regulating their purity, potency, efficacy and safety.
Health of Animals RegulationsFootnote 2
Section 120.4 (1)
The accompanying information that is required to be provided by a person to the Minister pursuant to paragraph 120.3(1)(a) includes the following:
Section 120.4 (1)(g)
the proposed measures to mitigate any risk of harm to the environment or to human or animal health; and
Section 120.4 (1)(h)
any other information in respect of the veterinary biologic that is relevant to identifying any risk of harm to the environment or to human or animal health.
Section 121. (1)
No person shall import a veterinary biologic into Canada unless he does so under and in accordance with a permit issued by the Minister.
Section 122. (1)
Subject to subsection (2), every applicant for a permit to import a veterinary biologic into Canada shall include with his application
Section 122. (1)(h)
any information the Minister may require in order to determine, in the course of assessing the safety of the veterinary biologic, whether the introduction of the veterinary biologic into the environment could result in the spread within Canada of a vector, disease or toxic substance that would have a harmful effect on human or animal health.
No person shall sell a veterinary biologic or any diluent to be used therewith if the veterinary biologic or diluent has been prepared, manufactured, preserved, packed, labelled or tested otherwise than in the manner described in the product outline.
III. General Guidance
The risk of transmission of TSE through veterinary biologics can be greatly reduced by controlling a number of parameters. For this purpose, manufacturers of veterinary biologics must address the following:
Country of Origin
Verification that all MAO used in the production of veterinary biologics are derived from animals originating from countries recognized as having a controlled or negligible risk of BSE as categorized by the World Organisation for Animal Health (OIE). Geographical distribution of countries that reported confirmed cases of BSE to the OIE can be viewed at http://www.oie.int/eng/info/en_esb.htmFootnote 3 and the recognition of the BSE status of OIE member countries can be viewed at http://www.oie.int/eng/info/en_statesb.htm?e1d6#ResoFootnote 4. Note that the status of the country with regards to other significant animal diseases must also be evaluated before considering the country as acceptable as a source of MAO for veterinary biologics.
Species of Animal
Wherever possible, avoidance of the use of ruminant tissues and tissues from animals in which natural TSE infection occurs in the production of veterinary biologics. Note that ruminants are more susceptible to TSE infection than other animals and the risk of transmission is greatest when animals are exposed to TSE agents derived from the same species.
Confirmation that the tissue or other substances used are recognised as being of low or no risk of containing TSE agents.
Assurance that measures are taken to prevent cross- contamination of low risk materials by high risk materials and, where relevant, the method used in the preparation of MAO has been validated for inactivation of TSE agents (e.g. alkaline process used for the preparation of gelatin).
The potential risk associated with a given veterinary biologic will be considered in light of specific circumstances and available scientific knowledge. In general, risk assessments will be based on the combination of factors including:
- BSE risk categorization of the country where the source animal originated;
- Susceptibility of target animal species to TSE infection;
- Animal tissue used;
- Susceptibility of source animal species to TSE infection;
- Manufacturing process, quality assurance programs and material traceability system adopted by the manufacturer;
- Mode of administration of the veterinary biologics;
- Other factors such as age of the source animal, slaughtering method and the possibility of cross-contamination with materials defined as Specified Risk Material (SRM).
While selecting the tissue to be used in manufacturing veterinary biologics, the infectivity category of the tissue should be taken into account. SRM is defined in the Health of Animal RegulationsFootnote 2 Section 6.1 as:
- the skull, brain, trigeminal ganglia, eyes, tonsils, spinal cord and dorsal root ganglia of cattle aged 30 months or older; and
- the distal ileum of cattle of all ages.
Use of SRM at any stage in the production of veterinary biologics is not acceptable. Further information about risk categories of tissue and fluids can be found in the World Health Organization (WHO) Guidance on Transmissible Spongiform Encephalopathies in Relation to Biological and Pharmaceutical ProductsFootnote 5.
Additional consideration must be taken when assessing the risk of veterinary biologics intended for administration into food-producing animals. There is a risk of amplification of the TSE agent in ruminants that is transmissible to humans. Manufacturers must, therefore, perform a risk assessment and provide justification for using MAO in veterinary biologics intended for use in such animals taking into account the following factors:
- Where possible, manufacturers should use materials obtained from non-ruminants for products intended for administration into food-producing animals. If it is not possible, a justification should be provided for using materials of ruminant origin;
- Manufacturers must demonstrate that preventive measures and quality systems are in place to ensure that cross-contamination of MAO with SRM has not taken place.
IV. Required Information
As a measure to minimise the risk of introducing TSE infection via veterinary biologics, CFIA-CCVB requires that the following information and documents be provided for all veterinary biologics manufactured in and imported into Canada for all purposes, including emergency, experimental or restricted use, as well as for export to other countries.
A. Outline of Production
A general statement about the MAO should be included under Section II.C of the OP.
Note: An example of a general statement that should be included under Section II.C of the OP: "Ingredients of animal origin used in the preparation of this product will be procured from sources considered to be safe from animal TSE infection or contamination. Refer to Special Outline No. for specific information on country of origin, species and tissue of origin, supplier source, and supporting documents."
B. Special Outline
For each product intended for manufacturing or importation into Canada, the following information must be submitted in an SO format:
- A list of all MAO used in the preparation of a veterinary biologic and cited in the OP and, where applicable, in all referenced OPs and SOs;
- A separate list of all MAO that have been in contact with any vaccine constituents during the development of the final product (i.e., MAO used in the development of master seeds or master cells);
- For each item in IV.B.1. and IV.B.2. above, indicate the country of origin, animal species and tissue of origin, and supplier's name and address.
The same SO may include the information on all MAO used in the preparation of all veterinary biologics of a manufacturer. This way, the same SO can be referenced in all related OPs and any amendment to SO can also be made without affecting an already approved OP. Each MAO should cross reference all applicable master seeds, master cells or final products. A copy of Certificate of Analysis and Certificate of Origin for each MAO and a copy of the supplier's MAO policy statement (indicating the supplier's actions with regard to minimizing the risk of contamination of their products by animal TSE agents) must be appended to the SO.
C. TSE Certificate of Suitability
For each MAO identified by the manufacturer in the SO, the manufacturer must submit either:
- A copy of the supplier's TSE policy statement for each supplier identified in IV.B.3 above, indicating the supplier's actions with regard to minimizing the risk of contamination of their products by animal TSE agents (i.e., verification of the country of origin, animal species, health status of source animals, and type of the tissue and validated process used in preparation of MAO, and company's quality control, self-inspection and vendor audit programs for overall quality assurance);
- A valid TSE certificate of suitability (CEP) issued by the European Directorate for the Quality of Medicine (EDQM), to the supplier identified in IV.B.3. above for each MAO used in the preparation of the veterinary biologic. Since the CEP is valid for a period of five years only, the manufacturer must update each certificate as it expires.
D. Certificate of Analysis and Inventory Record
A copy of Certificate of Analysis for each lot of MAO and an accurate inventory of all MAO used in the production and testing of veterinary biologics must be maintained by the manufacturer at the site and made available to CFIA inspector when requested.
E. Declaration of Compliance
A Declaration of Compliance (See Appendix I) signed by a designated officer of the manufacturer confirming that all MAO used in the development or production of this product have originated from sources considered to be safe from animal TSE infection or contamination.
V. Veterinary Biologics Manufactured in the United States and imported into Canada
The statement regarding the ingredients of animal origin included under Section II.C. of the OP as required by the United States Department of Agriculture (USDA), Veterinary Services Memorandum No. 800.206 is considered as equivalent for USDA licensed products to the statement mentioned in Section IV.A. above. A copy of the USDA approved OP and the additional supporting documents as listed under items IV.B - IV.E will be required for each veterinary biologic intended for distribution and use in Canada.
VI. Veterinary Biologics Manufactured in Countries other than Canada and the USA
Manufacturers must prepare and provide the information stated in Section IV, and the required documents may be submitted to CFIA-CCVB via the Canadian importer. The Declaration of Compliance and other required documents must be signed by a designated officer of the manufacturer (i.e. head of the regulatory affairs or quality assurance) and not by the Canadian importer. The Canadian importers are requested to communicate this documentation requirement to their manufacturers and coordinate the submission of required documents to CFIA.
VII. Master Seed and Master Cells Established prior to 1986
If some of the information stated in Section IV above is not available for old master seeds and master cells established prior to the first recognized case of BSE in the United Kingdom in November 1986, the manufacturer must conduct a risk assessment and evaluate the significance of the missing information in relation to potential risk of introducing TSE infection. The factors such as country of origin, species and tissue of origin, and target species for the final product should be considered when conducting the risk assessment. A risk assessment in lieu of the missing information may be considered by CFIA-CCVB for old master seeds and master cells, but not for the working seeds and working cells produced after November 1986.
VIII. Veterinary Biologics for Investigational or Emergency Use
When applying for a permit to import veterinary biologics or a permit to release veterinary biologics for investigational or emergency use, the manufacturer must provide supporting documents as described under Section IV of this guideline. Each application will be evaluated on a case-by-case basis.
A sample text of the Declaration of Compliance
A Declaration of Compliance, printed on company letterhead and signed by a designated officer (i.e., head of regulatory affairs or quality assurance) of the manufacturer should be submitted to the Canadian Centre for Veterinary Biologics of the Canadian Food Inspection Agency.
Declaration of Compliance
Name of the manufacturer:
Assigned name of the product:
Trade name of the product:
CCVB product file number and
USDA product code (if applicable):
This is to confirm that the above veterinary biologic has been prepared and tested in accordance with the Outline of Production, and associated Outlines or Special Outlines filed with the Canadian Centre for Veterinary Biologics of the Canadian Food Inspection Agency. We have examined all the materials of animal origin used in the preparation of this product for their country of origin, species of animal, tissue used, supplier's source and supporting documents. The above product does not contain any Specified Risk Material originating from a country not considered to be free from bovine spongiform encephalopathy. All materials of animal origin used in the above product originated from sources considered to be safe from animal transmissible spongiform encephalopathy infection or contamination.
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