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Veterinary Biologics Guideline 3.34:
Guideline on Facility Requirements for Veterinary Biologics

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I. 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 facilities in Canada. All VB intended for manufacturing, distribution and use in Canada, or for export from Canada to other countries, must be manufactured in a facility approved by the CCVB. The approval of a new VB manufacturing facility involves a review of the facility, personnel, manufacturing and quality control (QC)/quality assurance (QA) documents. A pre-licensing inspection is required for approval of a new VB facility in Canada. A VB manufactured in another country and intended for importation into Canada should be manufactured in a facility licensed and inspected by the competent regulatory authorities of the exporting country. The facilities located in foreign countries must be acceptable to the CCVB and may also be inspected by the CCVB.

The purpose of this guideline is to provide information to VB manufacturers regarding the 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.

II. 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. This includes licensing and ongoing oversight of VB manufacturing facilities. The full text of the Health of Animals Act and the Health of Animals Regulations is available on the Department of Justice website:

Health of Animals Act

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

64 (1)(s) prohibiting or regulating the importation, exportation, preparation, manufacturing, preserving, packaging, 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;

64 (1)(s.1) respecting quality management programs, quality control programs, safety programs, preventive control plans or any other similar programs or plans to be implemented by persons who conduct any activity regulated under this Act;

Health of Animals Regulations, Part XI

Establishment Licence and Product Licence

123 No person shall prepare, manufacture, preserve, pack, label or test a veterinary biologic unless he does so under and in accordance with an establishment licence issued by the Minister.

124 No person shall manufacture a veterinary biologic unless he does so under and in accordance with a product licence issued by the Minister.

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).

127 Where the Minister has issued a product licence to a person, he may issue a product licence to such person in any subsequent year and that person is exempt from any of the requirements of subsection 122(1) as the Minister may specify.

Requirements of Operation in a Licensed Establishment

128 (1) No person shall prepare, manufacture, preserve, pack, label, store or test a veterinary biologic in a licensed establishment unless

(a) the establishment and the equipment therein is sound in construction, clean, in good repair and equipped with means to maintain it in a sanitary condition;

(b) the area immediately adjacent to the establishment is clean and protected against the incursion of animals;

(c) animal wastes, effluents from processing or testing, contaminated matter and dead animals are decontaminated before being removed or discharged from the establishment;

(d) the floors and walls of every room and area in which a veterinary biologic is prepared, manufactured, preserved or tested are of a hard finish suitable for cleaning;

(e) the establishment has drainage, plumbing and sewerage that are

(i) adequate to handle all wastes, and

(ii) equipped with suitable traps and vents;

(f) the establishment has dressing rooms, lavatories and showers that are

(i) adequate in size and equipment for the number of persons using them, and

(ii) well lighted and ventilated to the outside;

(g) eating rooms, if provided, are separate from, and do not lead directly into, any room used for preparing, manufacturing, preserving, storing, testing, packing or labelling a veterinary biologic;

(h) rooms or areas are provided, where required, that are capable of being maintained at a uniform and constant temperature within any desired range and are equipped with thermometers that provide a continuous permanent record of temperature;

(i) means are provided for warning of any failure of power or equipment or any change in the required temperature;

(j) rooms, areas and equipment are provided, where required, that are capable of being maintained free of air-borne contaminants to any desired degree and preventing the escape of micro-organisms therefrom;

(k) animals being used in a testing program or for any special purpose are segregated from all animals not being used in such program or for such purpose;

(l) a separate room is provided for animals being examined or tested

(i) ante mortem, and

(ii) post mortem; and

(m) every person employed therein is qualified to perform the task assigned to them

(2) Every holder of a licence issued under these Regulations shall without delay inform the Minister of any change or addition to the material or information furnished to the Minister for the purpose of obtaining the licence.

(3) Every person employed in a licensed establishment shall

(b) be immunized against diseases likely to be encountered therein; and

(c) wear clothing and use equipment adequate to protect him against all hazards likely to be encountered therein.

(4) Unless otherwise permitted by a veterinary inspector, no veterinary biologic shall be tested in a licensed establishment except in a separate room or building that is used exclusively for testing veterinary biologics.

(5) No diagnostic examination or procedure involving the use of

(a) a dead or diseased animal,

(b) diseased animal matter, or

(c) an unidentified culture of micro-organisms, fungi or moulds shall be conducted in a licensed establishment except in a room or area separate from and not leading into any room or area used for preparing, manufacturing, preserving, storing or testing a veterinary biologic.

(6) Unless otherwise permitted by a veterinary inspector, no research or experimentation shall be conducted in a licensed establishment except in a room or area separate from and not leading into any room or area used for preparing, manufacturing, preserving, storing or testing a veterinary biologic.

129 (1) Every holder of a product licence shall

(a) keep and make available for inspection by a veterinary inspector records with respect to the preparation, manufacture, preservation, storage, testing, sale and distribution of every veterinary biologic manufactured under the product licence and any diluent to be used therewith; and

(b) furnish the Minister with such samples of the veterinary biologic as the Minister may require from time to time.

(2) Every record referred to in paragraph (1)(a) shall be retained by the licensee for at least two years following the expiration date of the veterinary biologic to which it relates.

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.

130.1 Every veterinary biologic imported, sold, advertised or offered for sale in Canada shall be stored at a temperature between 2°C and 7°C unless otherwise stated in the product outline or the labelling.

III. General considerations

1. The facility and equipment must meet the appropriate containment requirements for the microbial agents to be handled and types of activities to be performed to protect personnel and the environment. Refer to the Canadian Biosafety Standard and the Containment Standards for Facilities Handling Aquatic Animal Pathogens for appropriate containment requirements for terrestrial animal pathogens and aquatic animal pathogens, respectively. Due to the increased risk associated with the handling of large volumes of viable microbial cultures, additional considerations and mitigation measures are required for VB manufacturing facilities as compared to research and diagnostic labs at the same biocontainment level.

2. In addition to the above biocontainment requirements for the protection of personnel and the environment, VB must be protected from environmental contamination and cross-contamination at all stages of production to ensure product safety and purity.

3. The facility and its operation should comply with all applicable federal, provincial and local health, safety and environmental requirements, including Workplace Hazardous Materials Information System (WHMIS).

4. Facility, equipment, materials, and processes used in the manufacturing of VB must be situated, designed, constructed, adapted, maintained and validated to ensure that the VB are consistently produced and controlled to the quality standards appropriate to their intended use.

5. Separate production areas with dedicated air handling systems should be used for the handling of viable spore-forming organisms that are resistant to disinfection and capable of persistence in the manufacturing environment.

6. Production of vaccines against federally reportable diseases is not allowed in Canada.

7. The production area for autogenous VB should be separate from the licensed commercial VB production areas. The facility, equipment and personnel requirements for autogenous VB are generally the same as those required for licensed commercial VB.

8. Areas for research, diagnostic and QC activities should be physically separate from the VB manufacturing areas with a separate air handling system.

9. Lockers, toilets, washrooms and lunch rooms should be of adequate size for the number of users. These rooms should not lead directly to the VB manufacturing, testing or storage areas. The location of toilets within the facility should not adversely affect, directly or indirectly, the required air cleanliness of the VB manufacturing and testing areas.

10. No microbial agents, including new microbial seeds, should be introduced into a VB manufacturing facility without the advance written approval from the CCVB.

11. Manufacturing, processing, handling or storage of unrelated or unregulated products should not be carried out in the licensed VB facility.

12. Access to the VB facility should be restricted to authorized personnel only. Visitors and contractors should be signed in with a verification of their ID, and escorted at all times.

IV. Manufacturing areas

1. The types and volume of VB to be produced, and the complexity of the manufacturing processes should be taken into consideration when developing a new facility.

2. An essential part of contamination prevention is the adequate separation of the areas of operation. A vaccine manufacturing facility should have, at the minimum, a separate area for each of the following key activities: storage of raw materials and supplies; a common area for materials and equipment preparation, such as cleaning, decontamination, sterilization; inoculum preparation; microbial culture scale up, inactivation and harvesting; blending of vaccine components; aseptic filling of blended product in final containers; labelling and packaging; and storage of quarantined and released products.

3. Cell culture-derived, egg embryo-derived and live vaccines require separate areas and processing equipment for upstream portion of manufacturing. Use of the same downstream manufacturing area (for example, filling, packaging) and equipment for the production of multiple compatible products, such as inactivated bacterial antigens or inactivated viral antigens, may be acceptable on a campaign basis, provided a thorough risk assessment has been conducted, and an appropriate "changeover" procedure, including cleaning and decontamination of the manufacturing area and equipment by a validated method, has been established.

4. Rooms and hallways within the facility should be laid out in such a way as to allow the production to take place in areas connected in a logical order, corresponding to the sequence of operations and to the required cleanliness levels.

5. Flow of personnel, raw materials, VB product, by-product and waste within the facility should be logically designed to prevent cross-contamination.

6. Rooms, airlocks and air handling system should be designed to work as secondary containment for biological materials or other hazardous substances and, should be suitable for preventing the escape of such substances into the external environment or into other working areas.

7. All rooms and work areas where VB are manufactured or stored should be kept orderly, clean and free of dirt, dust and vermin.

8. Floors, walls, and ceilings should be smooth and impervious, free from cracks and open joints, and should permit easy and effective cleaning and disinfection.

9. Drains should be of adequate size and should be equipped with suitable traps and vents. The discharge of effluent into the municipal sewer system should comply with the local requirements.

10. Lighting, temperature, humidity and ventilation should be appropriate so that they do not adversely affect, directly or indirectly, the VB during their production and storage, the proper functioning of equipment or the working environment for personnel.

11. The pipework, light fixtures, ventilation points and other utilities should be designed and positioned to avoid the creation of recesses and to facilitate cleaning. For repair and maintenance purpose, these utilities should be accessible from outside the manufacturing areas.

12. Appropriate measures should be implemented to prevent, control, clean and decontaminate accidental spills throughout the facility.

13. There should be a comprehensive preventative maintenance program to ensure that the building, equipment and utilities used in the manufacturing of VB meet performance standards and remain in a good state of repair. Major changes, repair or maintenance of the facility and equipment should not adversely affect the operation of the facility and equipment or the product quality.

14. The air handling systems should be designed, constructed and maintained to minimize the risk of cross-contamination between different manufacturing areas and any accidental escape of pathogens to the external environment.

15. The air supply into manufacturing areas should be filtered through High Efficiency Particulate Air (HEPA) filters. The nature of the activities conducted in a particular area determines the appropriate air classification/air cleanliness for that area.

The air quality in these areas should be properly controlled and monitored for the presence of airborne particulate and viable microorganisms.

16. In general, rooms where viable microbial agents are handled should be maintained under negative pressure relative to the adjacent areas to prevent the escape of infectious agents into other areas of the facility or to the exterior environment. The room where sterile materials, such as sterilized media, bulk antigens, excipients and final products are handled should be maintained at positive pressure relative to the adjacent areas to maintain product sterility and to prevent cross-contamination.

17. The use of fermenters, bioreactors and processing vessels with closed system minimizes the risk of contamination and improves production efficiency. Therefore, these types of equipment should be used for the production and processing of large volumes of microbial cultures.

18. Airlocks facilitate a better control of air cleanliness and air balance within the critical manufacturing areas. Airlocks are usually installed between the entrance of a higher classified area, such as an aseptic filling room, and an adjoining lesser classified area, such as a hallway. Airlock doors should be interlocked to prevent them from being opened simultaneously. Depending on the function of a particular manufacturing area, a separate airlock for movement of personnel (personnel airlock) and materials (material airlock) between a higher classified manufacturing area and the adjoining lesser classified area should be considered.

19. The filling of vaccines should be performed aseptically in a cleanroom specifically designed, equipped and maintained to minimize exposure of sterile materials to potential contamination hazards. There should be no sink or drain in the filling room. Air supplied to the filling room should be filtered through terminal HEPA filters. Environmental monitoring of the filling room should be performed for viable and non-viable particles. To maintain the appropriate air cleanliness and air pressure, the entry and exit of personnel should be through an airlock. All materials brought into this room should be sterilized with a double wrapping and then transferred through an airlock with appropriate surface decontamination. All personnel assigned to filling activities must be trained on cleanroom procedures.

20. Aseptic processing of small volumes of microbial cultures and sterile materials can be safely performed in Class II biosafety cabinets (BSC) or Class III biosafety cabinets (isolator/glove box) that are designed to protect personnel, the product and the environment. The BSC and isolators used for the handling of viable microorganisms should not be used for the processing of sterile materials, such as sterile media, vaccine components and final products.

21. The use of horizontal laminar flow cabinets ("clean bench") only protects the product from contamination. The air flow from the horizontal laminar flow cabinet is usually discharged toward the user; therefore, this device should not be used for handling hazardous biological or toxic materials.

The risk of contamination and cross-contamination within VB manufacturing facility can be further reduced by implementation of the following technologies and options:

V. Quality control testing laboratories

1. QC testing laboratories should be designed, constructed and operated to suit the QC activities to be performed in that space. QC laboratories should be physically separate from the VB manufacturing areas with a separate air handling system and dedicated equipment.

2. Appropriate containment standards must be followed when handling viable microbial agents.

3. There should be adequate space for the storage of laboratory supplies and samples of raw materials, in-process materials, final products and for environmental monitoring.

4. The space allotted for various in vitro QC tests, such as microbiology, molecular biology, chemistry etc., should be adequate and located in a logical order to prevent mix-ups and cross- contamination.

5. Use of a Class III BSC (isolator/glove box) or a separate cleanroom should be considered for sterility testing to avoid any risk of cross-contamination and to improve reliability and performance.

6. In vivo QC testing involving animals should be located in a separate building.

VI. Storage areas

1. Storage areas for raw materials, bulk antigens and final products should be designed, constructed and maintained to ensure appropriate storage conditions, such as temperature, humidity, ventilation and lighting.

2. Storage area for raw materials should be separate from that of antigens and finished products.

3. Storage areas should be of sufficient capacity for orderly storage of various materials and products, such as raw materials, supplies, bulk antigens, and quarantined or released serials of VB.

4. In general, the vast majority of VB are stored at a temperature range between 2°C – 8°C in walk-in coolers and refrigerators.

5. The temperature inside the walk-in coolers, refrigerators and freezers should be validated by temperature mapping, and monitored and documented at predetermined intervals. The walk-in coolers, refrigerators and freezers used for the storage of VB materials, including master seeds, bulk antigens and final products should be linked to an alarm system to alert designated personnel in the event of a temperature excursion.

6. New serials of VB should be held in quarantine until officially released by authorized personnel of the company. The inventory of new serials should be made available for sale and distribution only after they are officially released as per the established requirements.

7. There should be a separate designated and secured area for quarantined products. If stored in the same room, any rejected, recalled and returned products should be clearly identified and segregated to avoid any confusion and mix-ups.

8. Flammable, volatile and highly reactive solid and liquid chemicals should be stored under safe and secure conditions, and should be appropriately labelled.

9. Access to storage areas should be restricted to authorized personnel only.

VII. Labelling and packaging areas

1. The labelling and packaging area is usually located close to the final product storage area to minimize the time out of refrigeration for the vaccine being labelled. There should be adequate space for orderly flow of labelling and packaging activities to prevent mix-ups and confusion.

2. All inventories of labelling materials, including final container labels, carton labels and package inserts should be securely stored under lock and key at all times. Access to labelling materials must be restricted to authorized personnel.

3. A new shipment of labels should only be entered into inventory after verification by QA personnel to ensure that the labels fully comply with the approved label(s) on file. Any rejected or outdated labelling materials should be segregated from the current labels and should be properly destroyed and documented.

4. Labelling of only one serial of VB should be performed in the area at a time. Prior to starting a new labelling session, the labelling and packaging area should be carefully examined to ensure that the area is free of unnecessary and unrelated materials to avoid mix-ups and mislabelling.

5. Labelling materials should be issued for use by authorized personnel according to the approved procedure. The serial number and expiration date, either pre-printed on the label or to be printed at the time of labelling, should be verified by the QA personnel before starting the labelling session. Any unused, damaged or defective labelling materials should be properly destroyed and documented after completion of each labelling session.

6. A complete and accurate record of receipt, use and disposal of all labelling materials should be maintained.

VIII. Equipment and utilities

1. Equipment used in the manufacturing, processing, packaging and testing of VB should be of appropriate design and size, and suitably located to facilitate operations for its intended use and for its cleaning, decontamination and maintenance.

2. Each critical piece of equipment used in manufacturing, processing and testing should be clearly identified with a unique number or code, and all repairs, maintenance, validation and usage should be properly documented for verification and traceability purposes.

3. All pieces of equipment, such as fermenters, bioreactors, processing and holding vessels, mixers, sterilizers, lyophilizers, filling machines, refrigerators, freezers, incubators, BSC, fume hoods, air handling and filtration systems etc., must be qualified for installation, operation and performance for the intended use prior to being put into service, and thereafter on a predetermined interval, as per the established validation plan.

4. Measuring, weighing and control instruments should be of proper range and accuracy. These instruments should be properly calibrated at pre-defined intervals, as per the established methods.

5. Equipment, such as fermenters, bioreactors and processing equipment used in the culturing or processing of viable microbial agents and hazardous materials, should form a tight seal around all openings when in operation, and should act as primary containment.

6. All surfaces and parts of equipment and containers that come in contact with a VB or its components during manufacturing, processing and storage should be non-reactive, non-corrosive and non-toxic, and should not alter the chemical or biological characteristics of the VB or its components. The product contact surfaces of the equipment and fittings should be able to withstand the temperature, pressure and chemicals used in cleaning, decontamination and sterilization.

7. All utilities necessary for manufacturing operations, such as electricity, hot and cold water, steam, gases, compressed air, vacuum, and HVAC (Heating, Ventilation, and Air Conditioning) systems should be of adequate capacity, suitably located, and regularly maintained and validated. The water treatment system should be able to generate a reliable supply of water of an appropriate quality and should be tested at predetermined intervals.

8. The VB facility should be equipped with an emergency backup power generator that is tested for performance and reliability on a regular basis. All critical equipment and utilities used in the manufacturing, processing, testing and storage of VB and their components should be connected to emergency power in the event of a power failure.

9. Equipment and parts that are unnecessary or defective should be clearly identified and removed from production areas after proper cleaning and decontamination.

IX. Personnel

Refer to Veterinary Biologics Guideline 3.28 (Guideline for Personnel Requirements).

X. Sanitation and hygiene

1. Detailed policies and procedures on sanitation, pest control, biocontainment and maintenance should be established and implemented.

2. The exterior of the buildings should be clean; and free from debris and vermin.

3. All manufacturing, testing and storage areas should be clean, free from clutter and well-maintained.

4. There should be appropriate procedures in place for the collection, treatment and disposal of biohazardous solid and liquid waste. Biohazardous waste may be decontaminated by a validated method within the facility prior to disposal in accordance with the applicable federal, provincial and municipal requirements. Alternatively, biohazardous waste may be properly packaged for collection by an external contractor who has been authorized for the handling, transportation and disposal of biohazard and chemical waste.

5. Detailed policy and procedure on personal hygiene should be established and implemented. All personnel should be trained on good sanitation and hygiene practices, including proper gowning, de-gowning, hand washing, and sanitizing before entering and after exiting the manufacturing and testing areas.

6. Street clothes, shoes and jewelry should be removed and appropriate PPE should be donned before entering the manufacturing, testing, packaging and storage areas.

7. Cosmetic makeup, smoking, eating, drinking, chewing gums, and storage of food and drinks in the manufacturing, testing, packaging and storage areas should be prohibited. No house plants or pets, such as small ornamental fish, should be kept in the manufacturing, testing, packaging and storage areas.

8. Any illness and open skin lesions should be reported to the manager or supervisor to evaluate the risk and applicable preventative measures. Depending on the microorganisms used in production and testing, a health exam and vaccination of employees may be required before the start of employment and thereafter at a predetermined interval.

XI. Facility documents

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

1. Information about the manufacturer, its corporate structure and management

2. A list of all the sites where manufacturing, testing, packaging, storage, shipping and receiving activities are carried out

3. Information on any third party contract manufacturing, testing, packaging, storage and distribution services, if applicable

4. List of all the VB and any non-VB products, such as pharmaceuticals or natural health products, to be manufactured, handled or stored at the site

5. List of all the microbial agents and cell lines, including reference organisms used in QC testing, that will be handled or stored on the premises

6. Brief description of the policy on procurement and quality control of raw materials, including materials of animal origin, used in the manufacturing and testing of VB

7. Brief description of cold chain maintenance for VB and VB components held at the facility, and during shipment and distribution to customers

8. Brief description of the measures and practices for prevention of contamination and cross-contamination within the facility

9. Brief description of the cleaning, sanitation, pest control, effluent collection, decontamination and disposal procedures

10. Brief description of the biocontainment and biosafety program

11. List of all the critical pieces of equipment and utilities used in the manufacturing and testing of VB

12. Brief description of the HVAC systems, including the total number and location of HVAC systems, and any dedicated HVAC systems for particular rooms or areas

13. Brief description of the water systems, including water quality (purification type), and the production and storage capacity of the water systems

14. Brief description of other relevant utilities, such as steam, compressed air, gases, emergency power, effluent treatment, etc.

15. Brief description of the policies and procedures for the validation and preventative maintenance of facility, equipment and utilities (including the frequency of validation and preventative maintenance)

16. Plot Plan: A plot plan is a scaled drawing of the premises showing all buildings and boundaries of the property, and adjacent properties and roadways. The buildings should be numbered on the plot plan, and each numbered building should be assigned a descriptive name on a list beside the drawing. The scale, key dimensions, and directions (compass points) should also be provided.

17. Plot Plan Legend: Plot plan legends should identify all buildings on the premises and corresponding functions of each building, and briefly describe the construction materials used throughout the building. A separate legend may not be necessary, if the above information is already included on the plot plan.

18. Blueprint: A blueprint is a scaled drawing of the floor plan of each building. Each room and hallway should be identified by a unique number and by its corresponding function(s). The blueprint should also identify all rooms where VB or VB components are exposed to the room environment. All stationary equipment used in the production, testing, packaging or storage of VB should be uniquely numbered and identified on the blueprints. The blueprints should also indicate the building number and compass points.

19. Blueprint Legend: For each room, the blueprint legend should describe the physical construction of the room, and list the function, equipment location, microorganisms, VB or VB component(s) handled, and cleaning procedures.

Each page of plot plans, blueprints, and legends should indicate the name, address, and establishment number of the manufacturer and should be signed and dated by an authorized person of the company. All pages of the plot plan and blueprint legends, excluding the cover page, should be consecutively numbered. The plot plan and blueprint drawings may be submitted as the original architectural or engineering drawings or reduced to fit on 8.5" x 11" size paper, provided they are legible.

20. A floor plan showing the flow of personnel, equipment, raw material, intermediate product, final product and waste within the facility

21. A floor plan showing the cleanroom classification, air pressure differentials and directional airflow of various VB areas within the facility

XII. Requirements for establishment licence

The approval of a new VB manufacturing facility involves a review of the facility documents, manufacturing and testing protocols, the type of organism handled, the type of product produced, 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 product licence. A stand-alone Can. Vet. Bio. Est. Lic. will not be issued without a concurrently issued VB Product Licence. For additional information on new product licensing submission procedures, please refer to VB Guideline 3.1: Guidance for Preparation of New Product Licensing (Registration) Submissions for Veterinary Biologics.

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

The CFIA-CCVB does not issue a Can. Vet. Bio. Est. Lic. to manufacturing facilities located outside of Canada. 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 under Section XI 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.

XIII. Contract manufacturing and testing

The licence holder of a 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, and in vitro or in vivo QC testing of in-process and final product samples) 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 should 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 XVI below 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 license 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).

Information required for the approval of a third party contract facility

  1. A cover letter explaining the purpose of the application and identifying the firm's regulatory contact
  2. CFIA Form 1503 (Veterinary Biologic Information) and CFIA Form 4720 (Application for Services) with applicable fees
  3. All relevant documents listed under Section XI above
  4. Personnel information as per Veterinary Biologics Guideline 3.28 (Guideline for Personnel Requirements)
  5. A signed copy of the technical agreement between the product licence holder and the contract facility, clearly describing the roles and responsibility of each party in fulfilling the technical and regulatory requirements for the contracted activities
  6. A set of all Outlines of Production, Special Outlines, Standard Operating Procedures (SOP) that are relevant to the contracted manufacturing and/or QC testing activities
  7. A list of all relevant SOP maintained and used by the contract facility, including SOP related to biocontainment and biosafety (Biosafety Manual)
  8. A copy of relevant biocontainment certificates or licences issued by Public Health Agency of Canada (PHAC), and the CFIA Office of Biohazard Containment and Safety (OBCS)
  9. For facilities involved in in vivo QC testing – a brief description of the sourcing of test animals, acceptance criteria, general husbandry practices, and animal health management of each animal species maintained at the facility and used in in vivo QC testing

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 license 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.

XIV. Post-licensing changes to facility and equipment

The 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.

XV. 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.

XVI. Facility inspection by the CFIA

Purpose of inspection

The purpose of the VB facility inspection by the CFIA is to assure that veterinary biologics manufacturers meet the requirements of the Health of Animals Act and regulations with respect to the production of veterinary biologics for distribution and use within Canada and for export to other countries. Specifically, inspections are intended to assess whether manufacturers 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 firm 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 manufacturer'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 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 manufacturer's compliance history. Normally, a documentary evidence of manufacturer'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 manufacturer. Regular or follow-up inspection may be conducted with or without prior notification to the manufacturer. 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 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 four 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 manufacturing facility, manufacturing activities, and the compliance history of the manufacturer. An in-depth facility inspection typically includes, an introductory meeting, a tour of the facility, verification of licences and permits, personnel, facility design, equipment, sanitation and maintenance, pre-licensing research and development, seeds and cells, production records, QC testing, animals, filling, packaging, labels, distribution, marketing and technical services. A wrap-up meeting is conducted at the end of the inspection to summarize the inspection findings and to discuss the manufacturer'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 – 5 days.

For additional information, refer to VB Guideline 3.11 (Guideline for Inspection of Veterinary Biologics Manufacturers and Importers).

XVII. 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.

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.

XVIII. 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, Third 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

Annex - Glossary and terminology

Glossary and terminology

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.
A biological agent, such as an infectious microorganism, toxin or prion, that poses a threat to the health of humans, animals or the environment.
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.
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.
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.
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.
The process by which bacteria or other microorganisms are unintentionally transferred from one substance or object to another, with harmful effect.
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 Programme
Defined documented programme 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.
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.
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.
A process to evaluate a product, service, or system, for compliance with a regulation, requirement, specification, or imposed condition.
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