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VB-GL-3.34: Requirements for veterinary biologics facilities

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  1. Introduction
  2. General requirements
  3. Manufacturing areas
  4. Quality control testing laboratories
  5. Storage areas
  6. Labelling and packaging areas
  7. Equipment and utilities
  8. Personnel
  9. Sanitation and hygiene
  10. Facility documents
  11. Requirements for establishment licence or registration
  12. Contract manufacturing and testing
  13. Post-licensing changes to facility and equipment
  14. Self-inspection
  15. Facility inspection by the CFIA
  16. Decommissioning of the facility and equipment
  17. References
  18. Annex – Glossary and terminology

1. Introduction

The Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA) is responsible for licensing veterinary biologics (VB) manufacturing and testing establishments in Canada, and for registering foreign VB establishment intending to manufacture and licence veterinary biologics products for use and distribution in Canada. All VB intended for manufacturing, distribution and use in Canada, or for export from Canada to other countries, must be manufactured in facilities approved by the CCVB. The approval of a new VB establishment involves a review of the facility, personnel, manufacturing and quality control (QC) and quality assurance (QA) documents. A pre-licensing inspection is required for approval of a new VB establishment in Canada. A VB manufactured in another country and intended for importation into Canada should be manufactured in an establishment licensed and inspected by the competent regulatory authorities of the exporting country. VB establishments located in foreign countries must be acceptable to the CCVB and may also be inspected by the CCVB.

Once all requirements are met, the CCVB will issue a Canadian veterinary biologic establishment licence to a Canadian manufacturing or testing facility, and a veterinary biologic establishment registration to a foreign manufacturing facility.

The purpose of this guideline is to provide information to VB manufacturers regarding the establishment and facility requirements for manufacturing, testing, preservation, packaging, labelling and storage of VB. Due to the significant differences in production processes, nature of the final products, and routes or methods of use of a diverse range of VB, the information provided in this document should be considered in general terms only. For specific requirements, manufacturers are encouraged to contact the CFIA-CCVB at the early stage of their planning, and especially in the conceptual stage of the design process for a new facility or a facility to be renovated.

This guideline also provides guidance to Canadian VB testing facilities and may be used by Canadian commercial VB importers for information on storage requirements for VB.

Legal authority

The Canadian Health of Animals Act (Section 64.[1][s]) and the Health of Animals Regulations (Part XI - Veterinary Biologics) confer the legislative authority to regulate manufacturing, testing, packaging, labelling, import, export, storage, transport, sale and disposal of VB.

2. General requirements

3. Manufacturing areas

4. Quality control testing laboratories

5. Storage areas

6. Labelling and packaging areas

7. Equipment and utilities

8. Personnel

Refer to VB-GL-3.28: Requirements for personnel involved in the manufacturing, testing, and importation of veterinary biologics

9. Sanitation and hygiene

10. Facility documents

The following information should be included in the facility document file in sufficient detail:

11. Requirements for establishment licence or registration

The approval of a new Canadian VB manufacturing facility involves a review of the facility documents, manufacturing and testing protocols, the type of organism handled, the type of product manufactured, personnel qualification, quality control procedures, and proper equipment and utilities for the intended purpose. Issuance of a Canadian veterinary biologics establishment licence (Can. Vet. Bio. Est. Lic.) is considered in conjunction with a VB product licence. A stand-alone Can. Vet. Bio. Est. Lic. for manufacturing will not be issued without a concurrently issued VB product licence. For additional information on new product licensing submission procedures, please refer to VB-GL-3.1: Preparation of new product licensing (registration) submissions for veterinary biologics.

When the facility documents as listed under Section 10. Facility documents above and the documents for a new product submission as listed in VB-GL-3.1 are ready, manufacturers should submit all the documents together to the CCVB along with a cover letter and applicable licensing fee.

Any VB manufacturing facility located outside of Canada must be approved and regulated by the competent regulatory authorities of the respective country(ies) before the facility documents are submitted to the CCVB. VB manufacturers in foreign countries are required to submit a copy of facility documents listed above, in the form of a site master file or similar, when making a new product submission with the CCVB. An updated copy of facility documents must be submitted to the CCVB whenever there is a major change in facility, equipment and/or process that could potentially impact the purity, potency, safety and/or efficacy of the VB. Commencing in 2023, the CFIA-CCVB will issue a Canadian veterinary biologics establishment registration to approved manufacturing facilities located outside of Canada.

Facility and personnel information should be prepared as PDF, JPG, JPEG or PNG files for submission by a file hosting service or by email (email attachments not to exceed 18 Mb) to CCVB applications. Facility documentation requirements, as specified above, and personnel documentation for new establishments should be compiled and submitted under the following section headings:

  1. Cover letter introducing the establishment, its activities and facilities, and identifying the regulatory contacts
  2. Establishment licence or registration from regulatory authority of the exporting country (foreign companies only)
  3. Blueprint and plot plan with legends, HVAC, biocontainment, process and product flow and all supporting information
  4. Site master file or equivalent
  5. Quality assurance and quality control policies and procedures
  6. List of all VB and non-VB products manufactured within the establishment
  7. List of all microorganisms stored within the establishment
  8. Organization chart for key personnel

12. Contract manufacturing and testing

The licence holder of a VB product may outsource certain VB manufacturing and testing steps (such as the production of bulk antigens, particular manufacturing steps that require specialized facility, equipment or expertise, in vitro or in vivo QC testing of in-process and final product samples, quarantine storage and distribution, export, etc.) under contact to a third party facility (contract facility) that is acceptable to the CCVB. The contract facility must meet all the licensing requirements relevant to specified VB activities and agree to comply with all the technical and regulatory requirements as specified in the Canadian Health of Animals Act and regulations, and as described in the manufacturing and testing protocols filed by the product licence holder.

The contract facility for manufacturing and/or testing may submit an application for a Can. Vet. Bio. Est. Licence to the CCVB as described below and undergo a pre-licensing inspection of all relevant sites. Refer to Section 15. Facility inspection by the CFIA for details on facility inspection. Upon satisfactory completion of the licensing process, the contract facility will be authorized by the CCVB to perform the specified manufacturing and testing activities under contract from the product licence holder. Depending on the specific VB activities allowed, a Vet. Bio. Est. Lic. will be issued for either VB manufacturing or VB testing, or for both. The Vet. Bio. Est. Lic. must be renewed annually by submitting a renewal application with applicable documents and fees.

In order for the contract facility to maintain the Vet. Bio. Est. Lic. in subsequent years, all documents filed with the CCVB must be kept current and the facility must continue to stay in compliance with regards to the specified technical and regulatory requirements.

Approval of contract manufacturing or testing of additional products from the same or other product licence holders will require an additional review by the CCVB to ensure that the new or additional products can be safely manufactured or tested at the same contract facility without adversely affecting the quality and safety of the previously approved product(s).

A third party contract facility responsible for solely for the provision of quarantine storage, distribution and logistics support, export services, and/or quality assurance services is not eligible for a Can. Vet. Bio. Est. Lic.

The CCVB does not issue veterinary biologics establishment registrations to contract manufacturing facilities located outside of Canada. Any VB contract manufacturing facility located outside of Canada must be approved and regulated by the competent regulatory authorities of the respective country(ies) before the facility documents are submitted to the CCVB. VB contract manufacturers in foreign countries are required to provide a copy of facility documents, listed above, in the form of  a site master file or similar, when the contracting foreign manufacturing establishment initiates a new VB product submission with the CCVB. An updated copy of the contract manufacturing facility documents must be submitted to the CCVB whenever there is a major change in facility, equipment and/or process that could potentially impact the purity, potency, safety and/or efficacy of the VB.

Information required for the approval of a third party contract facility

Third party contract facility information should be prepared as PDF, JPG, JPEG or PNG files for submission by file hosting service or sent by email (email attachments not to exceed 18 Mb) to CCVB Applications

For those contract facilities that are only interested in offering limited in vitro and/or in vivo QC testing to licensed manufacturers in Canada, an option for listing the contract testing facilities on manufacturer's Vet. Bio. Est. Lic. may be considered. In such a case, the contract testing facility will be considered as an extension of the manufacturer's Vet. Bio. Est. Lic., therefore, will be regulated through the licence holder provided that the contract facility meets all the technical requirements related to specified VB activities. A separate Vet. Bio. Est. Lic. is not issued to a contract testing facility that is regulated through the licensed holder. Contact the CFIA-CCVB for the specific requirements for limited in vitro and/or in vivo contract testing for VB in Canada.

13. Post-licensing changes to facility and equipment

The Canadian VB establishment licence holder is required to review and update the facility, manufacturing and testing documents filed with the CCVB on a regular basis. All significant changes to facility, equipment and processes that potentially impact the purity, potency, safety and efficacy of the VB must be submitted to the CCVB in advance for review and approval prior to the implementation.

Major renovations or additions of new structures to an existing building should be initiated only after consultation with the CCVB. Repair, maintenance, renovations or new constructions should not adversely impact the ongoing manufacturing and testing activities. A risk assessment should be conducted to identify any risks posed by the renovation or new construction and the appropriate measures to be implemented to minimize the potential impact to purity, potency, safety and efficacy of the VB.

Significant changes to or replacement of critical equipment and utilities will require requalification prior to their use in the manufacturing and testing of approved VB.

Companies holding a VB establishment registration are required to update the facility, manufacturing and testing documents filed with the CCVB once approved by the regulatory authority in the country of manufacturing.

14. Self-inspection

Self-inspection is an important part of the QA program. Self-inspection should be conducted to monitor the implementation and compliance with the technical standards and regulatory requirements, and to identify necessary corrective and preventative measures.

Self-inspection should be conducted in an independent and systematic manner by competent individual(s) within the company or by external experts at an appropriate interval. All aspects of VB operations, such as facility, equipment, personnel, documentation, manufacturing, QC, distribution, complaints and recall should be audited. A review of the policies, operating procedures and practices should also be conducted.

Detailed records of self-inspection should be maintained and reports should be prepared to identify all deficiencies, deviations and non-compliance observed, and the corrective and preventative measures to be implemented.

A follow-up review of the implementation and enforcement of the corrective and preventative measures should be conducted.

15. Facility inspection by the CFIA

Purpose of inspection

The purpose of the VB facility inspection by the CFIA is to assure that veterinary biologics establishments meet the requirements of the Health of Animals Act and regulations with respect to the production and testing of veterinary biologics for distribution and use within Canada and for export to other countries. Specifically, inspections are intended to assess whether establishments are in compliance with veterinary biologics licensing requirements, and are conforming with the conditions specified on licences and permits issued under the authority of the Health of Animals Act and regulations.

Types of inspection

Pre-licensing inspection: A pre-licensing inspection is conducted prior to the approval of a new facility to verify that the facility, personnel, equipment, materials, and processes meet the licensing requirements and the establishment is capable of manufacturing VB to the quality standards appropriate to their intended use.

Regular inspection: The regular on-site inspection of a licensed facility is conducted to verify establishment's ongoing compliance with the Health of Animals Act and regulations, and the Production Outline filed with the CCVB with regards to the manufacturing, testing, packaging, labelling, import, export, storage, transport, sale and/or disposal of the VB.

Follow-up inspection: A follow-up inspection is conducted to verify if the corrective and preventative actions (CAPA) to address the significant deficiencies identified during the previous inspection have been completed and are satisfactory. The need for a follow-up inspection is determined on a case-by-case basis based on the seriousness and complexity of the required CAPA and the establishment's compliance history. Normally, a documentary evidence of an establishment's actions to address the deficiencies may be acceptable to avoid an on-site follow-up inspection.

Scheduling and frequency of inspection

A pre-licensing inspection is conducted on a mutually agreed upon date after consultation with the establishment. Regular or follow-up inspection may be conducted with or without prior notification to the establishment. If a prior notification is provided, the date of the inspection will be mutually agreed upon and scheduled during periods of manufacturing, testing, packaging and labelling of the VB. A risk-based approach is used to determine the inspection frequency of a particular facility.

Domestic VB manufacturing and testing facilities are typically inspected annually.

Manufacturing facilities located in the United States which are licensed and inspected by the United States Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS) Center for Veterinary Biologics (CVB), may not be routinely subjected to comprehensive in-depth inspections by the CFIA-CCVB. However, facilities producing veterinary biologics for reportable or other monitored diseases, or autogenous vaccines or products for export only with minimal USDA-CVB regulatory oversight, may be subjected to periodic on-site inspections to verify compliance with Canadian veterinary biologics regulations and permit conditions, and to ensure that the regulated manufacturer is aware of and conforming to Canadian regulatory requirements, as documented in the product licensing data and reports filed with the CCVB.

Manufacturing facilities located in countries other than the USA, which are licensed and inspected on a regular basis by their regulatory authorities, are inspected by the CFIA-CCVB approximately every 4 years, as determined by the CCVB. More frequent inspections of foreign facilities may be necessary if there are major changes in the facilities or the products, or if there are major non-compliances.

Scope and length of the inspection

The scope and length of the inspection depends on the purpose and type of inspection, the size and complexity of the facility, activities, and the compliance history of the establishment.

An in-depth facility inspection typically includes an introductory meeting, a tour of the facility, and a verification of:

A wrap-up meeting is conducted at the end of the inspection to summarize the inspection findings and to discuss the company's plan for addressing the identified deficiencies. Following the inspection, a written inspection report, outlining the inspection findings, action items and recommendations, is provided to the company.

Depending on the size of the facility, the volume and the number of products manufactured, and the number of participating inspectors; the length of an on-site facility inspection may vary from 1 to 5 days.

For additional information, refer to VB-GL-3.11: Inspection of veterinary biologics manufacturers and importers.

16. Decommissioning of the facility and equipment

When a VB facility is no longer in operation or is in the process of shutting down, it should be properly decommissioned to ensure that the buildings and all associated equipment, utilities, and furniture are free from all physical, chemical, biological or radioactive hazards. Decommissioning is a process to ensure that the facility and its associated infrastructure are rendered safe and comply with the environmental health and safety requirements for its new use, repair, renovation, or demolition.

The same decommissioning principles apply to an individual piece of equipment used in the production and testing of VB. The equipment should be properly cleaned and decontaminated by using a validated method before its removal from the premises for transfer to another facility, calibration, maintenance, repair or disposal.

The decommissioning should comply with all applicable federal, provincial and local health, safety and environmental requirements.

The decommissioning of a VB facility requires a risk assessment to identify all potential risks and to develop a detailed "decommissioning plan". The decommissioning plan should identify the individual(s) responsible for supervising and carrying out the decommissioning activities, and should include a list of all buildings, areas, equipment, and utilities requiring cleaning and decontamination. When possible, the company's biosafety officer and environmental health and safety officer should be consulted and included in the decommissioning team. The CCVB should be notified of the company's decommissioning plan in advance, and will proceed to amend or revoke the VB establishment licence or VB establishment registration permission accordingly.

A detailed protocol should be prepared to describe the procedures used for cleaning and decontamination. A separate decommissioning tag should be prepared and applied to each building, area, and each piece of equipment, utilities and furniture. The decommissioning tag should show the name/ID of the area or equipment, and should identify the decommissioning status (decontamination complete or pending) and the date of decontamination. A complete and accurate record of decommissioning should be maintained.

17. References

  1. The Canadian Health of Animals Act (Refer to Section 64.[1][s])
  2. TheHealth of Animals Regulations (Refer to Part XI - Veterinary Biologics, Sections 123 - 130)
  3. Canadian Biosafety Standard (CBS), Biosafety and BioSecurity, Public Health Agency of Canada
  4. Containment Standards for Facilities Handling Aquatic Animal Pathogens, Office of Biohazard Containment and Safety, Canadian Food Inspection Agency
  5. ISO 14644-1: Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness. International Organization for Standardization (ISO)
  6. ISO 14644-2: Cleanrooms and associated controlled environments – Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration. International Organization for Standardization (ISO)
  7. Guide to Good Manufacturing Practice for Medicinal Products  Part 1 and Annexes, Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-Operation Scheme (PIC/S), Geneva, Switzerland
  8. Primary Containment for Biohazard: Selection, Installation and Use of Biological Safety Cabinets, Second Edition , Centre for Disease Control and Prevention and National Institute of Health
  9. Canadian Biosafety Handbook, Second Edition, Public Health Agency of Canada
  10. Federally reportable diseases , Canadian Food Inspection Agency
  11. Guidelines for Canadian Drinking Water Quality - Summary Tables, Health Canada (2022)

18. Annex – Glossary and terminology

Airlock
A small room with interlocking doors, constructed to maintain air pressure control between adjoining rooms that generally have different air cleanliness standards. The intent of an airlock for an aseptic process area is to prevent ingress of particulate matter and microorganism contamination from a lesser controlled area. In a VB facility, airlocks are critical separation barriers between areas of different environmental air cleanliness classifications and between containment and non-containment areas.
Aseptic technique
The manipulation of sterile materials in such a way as to minimize the risk of microbiological contamination from the environment.
Biohazard
A biological agent, such as an infectious microorganism, toxin or prion, that poses a threat to the health of humans, animals or the environment.
Biosafety
Methods or processes that are implemented to prevent unintentional exposure to infectious materials and toxins, or their accidental release.
Biological safety cabinet (BSC)
A primary containment device that provides protection for personnel, the environment, and the product, when working with biological materials.
Changeover
The program by which a processing area is cleared of supplies and components used in the manufacturing of a previous product and then prepared for the production of a new product. This often includes parts changeover and/or special cleaning and decontamination to eliminate cross-contamination.
Classified area
An area with airborne viable and non-viable particle contamination controlled within pre-set limits. For a VB manufacturing facility, a classified area implies ongoing environmental monitoring.
Cleanroom
A specially constructed space that is environmentally controlled with respect to airborne particulates and microbial agents, temperature, humidity, air pressure, airflow pattern, air motion and lighting. A cleanroom is intended to minimize the introduction, generation and retention of particles inside the room.
Closed system
A processing system that utilizes holding/transfer equipment in which the products, materials and critical components are not exposed to the environment external to the holding/transfer equipment.
Containment
The action of confining a biological agent or other entity within a defined space.
Controlled area
An area constructed and operated in such a manner that some attempt is made to control the introduction of potential contamination and the consequences of accidental release of living organisms.
Critical area
A critical area is one in which the sterilized product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility. This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. To maintain product sterility, it is essential that the environment in which aseptic operations (for example, equipment setup, filling) are conducted be controlled and maintained at an appropriate quality.
Critical activity
An activity that if not properly controlled may cause significant variation in the quality of the finished product.
Cross-contamination
The process by which bacteria or other microorganisms are unintentionally transferred from one substance or object to another, with harmful effect.
Decontamination
To make safe by eliminating poisonous or otherwise harmful substances, such as microorganisms, noxious chemicals or radioactive materials.
Downstream process
The downstream process involves processing the materials collected during the upstream stage into a finished product.
Environmental monitoring program
Defined documented program which describes the routine particulate and microbiological monitoring of the processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded.
HEPA filter
High efficiency particulate air filter.
HVAC
Heating, ventilation, air conditioning.
Laminar flow
An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector.
Personal protective equipment (PPE)
Specialized clothing or equipment worn by employees for protection against health and safety hazards. PPE may include, but is not limited to, lab coats, gowns, full-body suits, gloves, protective footwear, safety glasses, safety goggles, masks and respirators.
Primary containment
A system of containment which prevents the escape of a substance into the immediate working environment. It involves the use of closed containers or safety biological cabinets, along with secure operating procedures.
Secondary containment
A system of containment which prevents the escape of a substance (including a biological agent) into the external environment or into other working areas. It involves the use of rooms with a specially designed air handling system and airlocks, the sterilization of materials prior to disposal and the use of secure operating procedures. In many cases, it will add to the effectiveness of primary containment.
Directional airflow
An airflow moving towards a specific  direction, either inward or outward, in a robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.
Upstream process
Refers to all the activities needed to gather the materials required to create a product.
Validation
A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result that meets predetermined acceptance criteria.
Verification
A process to evaluate a product, service, or system, for compliance with a regulation, requirement, specification, or imposed condition.
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