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Veterinary Biologics Guideline 3.32E: Guideline for minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics

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I. Introduction

The production of veterinary biologics (VB) involves the use of many materials of animal origin (MAO). These MAO present a possible risk of iatrogenic transmission of transmissible spongiform encephalopathy (TSE) prions and other disease agents to animals.

Manufacturers of VB are expected to understand the risks associated with each MAO they use. When selecting a new MAO, consideration should be given to its animal sources, testing performed to verify freedom from contamination, treatments applied to reduce the risk of contamination by viable disease agents, and the end use of the VB products containing the MAO. Manufacturers should define a quality standard for each MAO based on these attributes/parameters, and verify that each incoming lot of the MAO meets the quality standard. As an example, a quality standard for fetal bovine serum could include the criteria: must come from countries A or B; must be tested for X, Y and Z; and must be irradiated at ## kGy before acceptance for use in production.

The purpose of this guideline is to describe the information that must be provided to the Canadian Centre for Veterinary Biologics (CCVB) about the MAO used in the production of veterinary biologics licensed in Canada. This includes products manufactured in Canada for domestic use and/or for export, as well as products manufactured elsewhere which are imported into/ licensed for use in Canada. The requirements are being updated. Manufacturers will have until December 31, 2021 to comply with this version of Guideline 3.32.

Previously the CCVB has required manufacturers to identify the suppliers of each MAO and provide documentation from each supplier about the MAO. With this revision, emphasis is being shifted to the manufacturer describing its quality standard for each MAO. This will allow companies the freedom to source the MAO from another supplier, provided the quality standard continues to be upheld. Submission of Certificates of Analysis and Origin to the CCVB will no longer be required (unless specifically requested by the reviewer).

II. Legal Authority

The Health of Animals Regulations:

Section 120.3 (1) Subject to subsection (2), no person shall release a veterinary biologic unless the person

(a) submits an application for a permit for the proposed release to the Minister, accompanied by sufficient information, including the information referred to in section 120.4, to enable the Minister to determine whether the proposed release is

(i) unlikely to result in the introduction into Canada or the spread within Canada of any vector, disease or toxic substance, and

(ii) unlikely to pose a risk of harm to the environment or to human or animal health; and

(b) is issued a permit for the proposed release under section 160.

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 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.

Section 126.
Subject to section 127, every applicant for a product licence shall include with his application the material and information referred to in subsection 122(1).

Section 130.
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. Required Information

The information and documents described below must be provided to the CCVB for all veterinary biologics licensed in Canada, including products manufactured in Canada for domestic use and/or for export, as well as products manufactured elsewhere which are imported into/ licensed for use in Canada.

III. A. MAO Statement in Outline of Production

Section II of each product's Outline of Production (OP) must include a general statement about the MAO used. Below is an example of suitable text.

Materials of animal origin used in the preparation of this product are sourced from countries categorized as negligible or controlled risk for bovine spongiform encephalopathy. Measures are in place to minimize the risk of the materials of animal origin contaminating the final product with an infectious animal disease agent. Refer to Special Outline No. space for specific information.

Manufacturers should consult the CCVB about the suitability of alternative text. In general the OP statements required by the USDA-Center for Veterinary Biologics (CVB) are acceptable.

III. B. Special Outline on MAO

Manufacturers must prepare a Special Outline (SO) to describe the key attributes of each of their MAO. The SO should cover all MAO used during production, including the production of any working seed and working cell stocks (refer to section III.D. below about master seeds and master cell stocks).

The MAO SO does not have to follow the formatting convention described in Veterinary Biologics Guideline 3.7: Guideline for Preparation of Production Outlines, Special Outlines, and Summary of Changes for Veterinary Biologics. Instead the MAO SO should be prepared as an Excel spreadsheet, workbook or equivalent, and submitted to the CCVB in an electronic, searchable format. The SO need only consist of a table, or series of tables, with manufacturer identification and document version information.

The table below illustrates the minimum required MAO information, which is: material, species of origin, tissue type, country of origin, risk mitigating treatments, testing, and target animal species. It is not mandatory to follow the format of the example below precisely.

Example of an MAO SO

Special Outline No. space : Materials of animal origin used during production

Table 1: Material of Animal Origin
Material Species Table Note 1 Tissue type Table Note 2 Country of origin of source animals Table Note 3 Risk mitigating treatments Table Note 4 Testing Table Note 5 Target animal species Table Note 6
Fetal bovine serum Bovine Blood Mexico Irradiated at ≥25kGy; 0.2µm filtered cytopathic effect, hemagglutinin activation, bovine viral diarrhea virus, reovirus, rabies virus, bluetongue virus, bovine respiratory syncytial virus, bovine adenovirus, bovine parvovirus Avian, Porcine
Bovine
Porcine trypsin Porcine Pancreas USA, Canada pH <2 during processing for ≥12 hrs;
0.2µm filtered; irradiated at ≥25kGy
cytopathic effect, hemagglutinin activation, porcine parvovirus, Seneca virus A, sterility Avian, Porcine, Bovine, Canine, Feline
Porcine trypsin Porcine Pancreas Australia, NZ pH <2 during processing for ≥12 hrs;
0.2µm filtered; irradiated at ≥25kGy
cytopathic effect, hemagglutinin activation, porcine parvovirus, Seneca virus A, sterility Avian, Porcine, Bovine, Canine, Feline
Cooked meat medium Bovine Skeletal Muscle USA, Canada Only used in media autoclaved at ≥121°C for ≥20 min None Bovine
PPLO Broth Bovine Heart, Pancreas, Skin, Stomach Canada Used exclusively in media for bacterial cultures subsequently inactivated with formaldehyde None Bovine
LB Agar Bovine Milk Australia, NZ Heating at ≥100°C for 30 sec during processing None Porcine
LB Agar Porcine Pancreas Canada, USA Heating at ≥100°C for 30 sec during processing None Porcine

Table Notes

Table Note 1

The species column should preferably facilitate filtering based on the species, to allow for easy identification of MAO potentially affected by a changing disease situation in a given country. As such, rows may need to be duplicated to link an MAO to each species from which it originates.

Return to table note 1  referrer

Table Note 2

Ensure that it is evident which tissue type goes with which species. When ruminant tissues are used, preference should be given to using MAO prepared exclusively from tissue types recognised as being of low or no risk of containing TSE agents. The use of Specified Risk Material (SRM) at any stage in the production of veterinary biologics is unacceptable.

Return to table note 2  referrer

Table Note 3

Bovine MAO used in the production of veterinary biologics should be 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). The status of a 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. In addition to evaluating the risks associated with the countries of origin of the source animals, manufacturers should consider the risks associated with the country in which an MAO is processed.

Return to table note 3  referrer

Table Note 4

Identify any treatments that reduce the risk of the MAO contaminating the final product with an infectious disease agent. Such treatments may occur during the manufacturing of the MAO (e.g., prolonged processing at low pH), on the final MAO itself (e.g., irradiation, filtration, heat treatments), or on the media or solutions prepared from the MAO (e.g., highlight if an MAO is only used in media which are steam sterilized before use). Also highlight if the MAO is used exclusively in the production of antigens which undergo a subsequent inactivation treatment of the type likely to also inactivate contaminating bacterial or viral pathogens.

Return to table note 4  referrer

Table Note 5

Identify the testing performed on each lot of the MAO to verify freedom from contamination. Include both testing by the MAO supplier and any testing done upon receipt.

Return to table note 5  referrer

Table Note 6

Provide the target species in which the final product will be used. Risks associated with MAO sourced from the same species as the target species are higher than those associated with MAO sourced from other species. This is because the infectious agents potentially contaminating the MAO are more likely to be of the type capable of infecting the target species.

Note: Although manufacturers are not required to list in the MAO table each veterinary biologic product in which a particular MAO is used, manufacturers must be able to accurately and rapidly identify all products in which a particular MAO is used, and provide this information to the CCVB upon request.

Return to table note 6  referrer

Manufacturers are no longer required to identify the supplier of each MAO nor submit supplier certificates as supporting data. That said, in certain cases, the CCVB may ask for supporting documentation on a particular MAO, such as a TSE certificate of suitability issued by the European Directorate for the Quality of Medicine (EDQM), a supplier's TSE policy statement, a Certificate of Analysis or a Certificate of Origin.

Manufacturers must verify that each incoming lot of an MAO meets the parameters defined in the MAO SO table filed with the CCVB. They should also be continuously re-evaluating the risks associated with each MAO in light of changing disease situations in source countries.

i) Procedure for filing the MAO SO with the CCVB.

The information contained in the MAO SO must be maintained up-to-date by manufacturers. Canadian manufacturers must update their MAO SO with the CCVB prior to use of an MAO that does not match one of the parameter sets identified in their MAO SO table (see note below about grace period for adding MAO for newly licensed products). Foreign manufacturers must conduct an annual review of the MAO SO to verify that the information remains accurate, and submit any necessary updates to the MAO SO at that time. If no updates are required, manufactures should notify the CCVB of this by letter or email.

Note

New product licensing applications must include a list of all MAO used in the production of the product and an indication as to whether the MAO are already included in the company's filed MAO SO. For any new MAO not already in the MAO SO, all the information required for the MAO SO table must be provided in the licensing application. It is not a requirement to update the MAO SO prior to submitting a new product licensing application. The MAO SO can instead be updated upon the licensing of a new product or at the next annual review (i.e., no longer than one year after licensing).

As previously mentioned, the MAO SO should be prepared as an Excel spreadsheet, workbook or equivalent, and submitted to the CCVB in an electronic, searchable format.

A separate worksheet tab (or equivalent) in the file should serve as the identification page and include the following information:

All fields of this page should be completed by the manufacturer at the time of submission to the CCVB, with the exception of the "Filed by CCVB on" and "CCVB Reviewer" fields. These last two fields will be completed by the CCVB at the time of review and filing of the MAO SO. After filing, the CCVB will return a stamped copy of this identification page alone to notify companies of the filing of the identified version of the MAO SO.

Example of identification page

Special Outline #1: Materials of Animal Origin

Version: January 1, 2019

Veterinary Vaccine Company Inc.

VB Estab. Lic. No. 101

Ottawa, Ontario A1B 2C3

Submitted to CCVB: January 15, 2019

Filed by CCVB on: space

CCVB Reviewer: space

III. C. Declaration of Compliance

A Declaration of Compliance (See Appendix I) is required for each product confirming that the manufacturer has examined all the MAO used in the preparation of the product and has concluded that the MAO used present a negligible risk of transmitting an infectious disease to target animals via the final product. A Declaration of Compliance must be included in the licensing application for a new product. The CCVB may additionally ask companies to update their Declarations of Compliance from time to time. The Declaration of Compliance must be signed by a designated officer of the manufacturer.

III. D. MAO used in the production of master seeds and cell stocks

In addition to the MAO used during the production of a product, manufacturers and the CCVB must evaluate the risks associated with all MAO used to prepare the seeds and cells stocks serving as starting material for product manufacturing. Consequently, new product licensing applications must include information (details on source, identification methods, genetic sequencing if applicable, preparation, media, extraneous agents testing, etc.) on all master seeds and master cell stocks. This information does not need to be included in the MAO SO, but does need to be kept on file with the manufacturer and at the CCVB as part of each product file. Should the manufacturer wish to create and submit a Master Seed/ Master Cell reference table similar to the one described in Table 1 above, the CCVB would accept the submission, but it is not a requirement at this time.

Note

Master seed and master cells established prior to 1986 – If some of the required MAO information is unavailable for master seeds and master cells established prior to the first recognized case of BSE in the United Kingdom in November 1986, the manufacturer must assess the risk and evaluate the significance of the missing information in relation to the potential risk of introducing TSE infection. 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.

IV. Controls at the manufacturing facility

Manufacturers must implement suitable quality assurance programs and material traceability systems for the MAO used on-site. Each incoming lot of an MAO should be qualified before use. Manufacturers should establish a quality standard for each MAO (consistent with the information provided in the MAO SO) and document that incoming lots were checked to ensure the quality standard was met. Certificates of Analysis and related supplier documentation must be retained. Batch production records must allow one to identify which lots of each MAO were used in the manufacturing of the batch. If bovine serum, for instance, of a different quality standard is stored on-site for the Quality Control (QC) department, there must be a system in place to ensure this inventory of bovine serum cannot accidentally be used in veterinary biologic manufacturing. These quality assurance programs and material traceability systems will be evaluated during facility inspections.

V. Considerations for in vitro veterinary biologics

In vitro veterinary biologics, such as diagnostic test kits, are naturally much lower risk products, as a function of their end use. Nonetheless, manufacturers of in vitro products must still complete the MAO requirements identified in this guideline, including the MAO SO table. In the risk mitigating treatments column, highlight that use is in an in vitro diagnostic product.

Appendix I

Below is sample text for a Declaration of Compliance. The Declaration of Compliance must be printed on company letterhead and signed by a designated officer (e.g., head of regulatory affairs or quality assurance) of the manufacturer.

Declaration of Compliance

Name of the manufacturer: space

Assigned name of the product: space

Trade name of the product: space

Target species: space

CCVB product file number (if applicable): space

USDA product code (if applicable): space

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 (CCVB) of the Canadian Food Inspection Agency. We have examined all the materials of animal origin (MAO) used in the preparation of this product for their animal sources, including species, tissue type and country of origin, as well as for their pathogen inactivating treatments and purity testing requirements. The above product does not contain any Specified Risk Material and all bovine MAO originate from countries categorized as controlled or negligible risk for bovine spongiform encephalopathy. Furthermore, our assessment has concluded that the MAO used in the preparation of the above product present a negligible risk of transmitting an infectious disease to target animals via the final product. The CCVB will be notified should any of the statements in this declaration fail to remain true in the future.

Name: space Signature: space

Title: space Date: space

Specified Risk Material

Specified Risk Material means 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, but does not include material from a country of origin, or a part of a country of origin, that is designated under section 7 of the Health of Animals Regulations as posing a negligible risk for Bovine Spongiform Encephalopathy.

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