Veterinary Biologics Guideline 3.11E
Guideline for Inspection of Veterinary Biologics Manufacturers and Importers

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Table of Contents

I. Overview

A. Inspection Objectives

Primary Objectives

The primary objective of facility inspections is to assure that veterinary biologics manufacturers and Canadian importers meet the requirements of the Health of Animals Act and Regulations with respect to the production or importation of veterinary biologics for use within Canada and export to other countries.

Specifically, inspections are intended to assess whether manufacturers and importers 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.

Secondary Objectives

  1. To become familiar with the corporate structure, organization of the company and key personnel and note any changes that have occurred since the last inspection.
  2. To become familiar with the physical facilities, equipment, record keeping, production and quality assurance methods and note any changes that have occurred since the last inspection.
  3. To note whether or not the company is employing generally accepted good manufacturing practices and state of the art technology.
  4. To utilize the opportunity presented by a visit to the company to engage in a two-way dialogue to discuss any problems and provide the manufacturer with information regarding Canadian regulatory requirements and other pertinent information.

B. Inspection Procedures

The time devoted to an inspection may vary from one-half to three days depending upon the size of the company. Canadian manufacturers are inspected annually. Canadian importers and manufacturers located outside Canada are inspected on a three to four year cycle. Visits to research facilities and discussions of research and development programs are at the discretion of the manufacturer. Inspection findings are reinforced by organizational charts, blueprints and legends pertaining to facilities and equipment, and résumés of key personnel.

Typical inspections would include the following activities:

  1. Introduction of inspector(s)
  2. Brief meeting with management and key personnel to explain objectives of inspection
  3. Examination of licenses and permits
  4. Tour of facilities with manufacturer's regulatory liaison
  5. Wrap-up meeting to review findings and discuss action items

An inspection report should be prepared and filed shortly after the conclusion of the inspection. The manufacturer should be provided with a copy of the Inspection Report. The Inspection Report should include a summary of major changes since the last inspection including corporate structure, ownership, personnel, facility changes, equipment changes, product line changes, and a summary of the key findings and action items.

Renewal of licences and import permits is dependent on compliance with Health of Animals Act and Regulations, and conditions specified on the licences and permits.

Canadian Centre for Veterinary Biologics (CCVB) will monitor compliance by periodically conducting onsite inspections. Manufacturers and importers should periodically conduct internal inspections as part of an ongoing total quality management program.

II. Pertinent Legislation and Guidelines

The Health of Animals Act and Regulations state that the Governor in Council may make such regulations and orders as to him seem necessary for any of the following purposes, that is to say for: regulating i) the importation, preparation, manufacturing, preserving, packing, labelling, storing, testing, transportation and disposal of any veterinary biologics, and ii) the sale, advertising for sale and conditions of sale of any veterinary biologics.

The following are excerpts from the Health of Animals Regulations pertaining to veterinary biologics These excerpts are provided for use as a reference for inspectors. The full text of the Health of Animals Act and Regulations is available on the Internet.

Part XI. 121.(1)

No person shall import a veterinary biologic into Canada unless he does so under and, in accordance with, a permit issued by the Minister.

Part XI. 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 license issued by the Minister.

Part XI. 124.

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

Part XI. 128.(1)

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

  1. 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;
  2. the area immediately adjacent to the establishment is clean and protected from incursion of animals
  3. animal wastes, effluents from processing or testing, contaminated matter and dead animals are decontaminated before being removed or discharged from the establishment;
  4. 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
  5. the establishment has drainage, plumbing and sewerage that are (i) adequate to handle all wastes, and (ii) equipped with traps and vents;
  6. 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;
  7. 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;
  8. rooms 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;
  9. means are provided for warning of any failure of power or equipment or any change in the required temperature;
  10. 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 microorganisms therefrom;
  11. animals being used in a testing program or for any special purposed are segregated from all animals not being used in such program or for such purpose;
  12. a separate room is provided for animals being examined or tested (i) ante mortem, and (ii) post mortem; and
  13. every person employed therein is qualified to perform the task assigned to him.

III. Preparing Inspection Notes and Reports

A. Inspection Guideline and Background Information

The inspection guideline including the background information (Appendix A) is to be used by the inspector as a reference for clarifying the inspection objectives and facility requirements when preparing inspection notes and inspection reports.

The completed INSPECTION REPORT and INSPECTION NOTES should be signed by the inspector(s) and forwarded to the manufacturer/importer as soon as possible after the inspection, under a covering letter signed by the National Manager. A copy of the INSPECTION REPORT, INSPECTION NOTES and INSPECTION WORKSHEET (if used) will be retained in the Canadian Centre for Veterinary Biologics (CCVB) manufacturer/importer file.

B. Inspection Worksheet - (Appendix B)

During an inspection, inspectors can use the INSPECTION WORKSHEET as a reference when targeting key inspection areas. If the worksheet is used to supplement notes taken during an inspection, then it should be viewed as containing Confidential Business Information and should be protected at all times and only made available to Canadian Centre for Veterinary Biologics (CCVB) staff. The worksheet would ordinarily be retained in CCVB manufacturer/importer files, and used to prepare INSPECTION NOTES and INSPECTION REPORTS.

C. Inspection Notes - (Appendix C)

Inspection notes are prepared from information gathered by an inspector(s) during an inspection visit of the importer/manufacturer's facility. Because the notes are likely to contain Confidential Business Information, they should be protected at all times and only made available to CCVB staff and the respective importer/manufacturer.

Inspectors should prepare their INSPECTION NOTES using the above template.

D. Inspection Report - (Appendix D)

Detailed comments and information gathered in the INSPECTION NOTES are used to prepare a brief INSPECTION REPORT which summarizes the findings and assessments of the inspected facility. When applicable, the INSPECTION REPORT should indicate that further information is recorded in the INSPECTION NOTES. Because the report is likely to contain Confidential Business Information, it should be protected at all times and only made available to CCVB staff and the respective importer/manufacturer.

Inspectors should prepare their INSPECTION REPORT using the above template.

IV. References

Health of Animals Act
Health of Animals Regulations
Public Health Agency of Canada's Laboratory Bio-safety Guidelines
Agriculture and Agri-Food Canada Containment Standards for Veterinary Facilities
Canadian Council on Animal Care Guide for the Care and Use of Experimental Animals
National Farm Animal Care Council's Recommended Codes of Practice for the Care and Handling of Farm Animals

V. Appendix A - Background Information for Preparing Inspection Notes/Reports

A. Company Profile

  1. Company Name
    Note full company name as it appears on licences and permits.
  2. Veterinary Biologics Establishment Licence
    Canadian manufacturers and importers are assigned a unique establishment number which appears on a Veterinary Biologics Establishment Licence. Foreign manufacturers are assigned an establishment number by the country where facility is located. Foreign manufacturers must be licenced to manufacture and distribute veterinary biologics in the country where facility is located. Imported products must be licenced for use in the country of origin. Locate the establishment licence and record the number, the date of issuance, and the date of expiry.
  3. Mailing Address
    Note mailing address where regulatory affairs liaison can be contacted. May be either corporate headquarters or production facility address.
  4. Location of Facility
    Indicate street, city, province.
  5. Inspector(s)
    Indicate name of inspectors conducting inspection and preparing report.
  6. Inspection Date
    Indicate dates when inspection was conducted.
  7. Purpose of Inspection
  8. Previous Inspection(s)
    Note dates of previous inspections by CCVB. Also indicate dates of recent inspections by USDA-APHIS or internal auditors.
  9. Personnel Contacted
    List names of key contacts during inspection. Secondary contacts can be listed under 'Personnel' section of report.
  10. Manufacturing & Importing Activities at the Facility
    Indicates a company's involvement in manufacturing or importing activities by placing a checkmark beside Man or Imp. Provide 'snapshot' information about the size of facility and range of production activities.
Vaccine Conventional
inactivated
Conventional
live
Recombinant DNA
inactivated
Recombinant DNA
live
Bacterial Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( )
Viral Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( )
Fungal Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( )
Mycoplasma Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( )
Protozoa Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( ) Man ( ) Imp ( )
Diagnostic Kit Man ( ) Imp ( ) Man ( ) Imp ( )
Colostrum Man ( ) Imp ( )
Plasma, Serum Man ( ) Imp ( )

Vaccine fractions on premises:

Other products and activities (feeds, drugs, pesticides, autogenous vaccines, diagnostic laboratory services, etc.):

B. Major changes since last inspection

  • 11. Recent Changes at the Facility
    List major changes (corporate, personnel, facilities, equipment, products) which might influence the manufacturer's production capability.
  • 11.1 Corporate Changes
  • 11.2 Personnel Changes
  • 11.3 Facility Changes
  • 11.4 Equipment Changes
  • 11.5 Product Changes

C. Summary Observations and Comments

12. Inspection Findings and Assessment

List major observations and comments for each key component of manufacturing facility.

Examine personnel, facilities, equipment, documents & records, and operations for each key area listed in headings 12.6 to 12.13 below:

  • 12.1 Licences and Permits
  • 12.2 Personnel
  • 12.3 Facilities
  • 12.4 Equipment
  • 12.5 Sanitation and Maintenance
  • 12.6 Pre-licensing Research & Development
  • 12.7 Seeds & Cells
  • 12.8 Production
  • 12.9 Final Production (filling and labelling)
  • 12.10 Labels
  • 12.11 Quality Assurance / Quality Control Testing
  • 12.12 Animals
  • 12.13 Distribution, Marketing, and Technical Service

12.1 Licences and Permits

Objective(s)
To confirm accuracy of licences and permits, and verify that manufacturer is operating in accordance with the Health of Animals Act and Regulations, and conditions specified in current licences and permits.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 123 & 124.

Background Information and General Inspection Guidelines
The Canadian Centre for Veterinary Biologics issues establishment licences, product licences and import permits to regulate the manufacturing, importation, distribution, and sale of veterinary biologics in Canada. CCVB also regulates importation of infectious agents, serum, and material of animal/microbial origin for use in research and diagnostic laboratories.

Veterinary biologics manufacturers would ordinarily be issued some, or all, of the following permits or licences.

Veterinary Biologics Establishment Licence
Veterinary Biologics Product Licence(s)
Permit To Import Veterinary Biologics Into Canada
Permit To Import Biologics Blood and Serum
Permit(s) To Import Animal Pathogens

The Veterinary Biologics Establishment Licence and the Permit(s) To Import Veterinary Biologics Into Canada are issued for « licensed » products which are intended for commercial distribution and sale in Canada.

Manufacturers who produce autogenous vaccines are issued a licence to manufacture autogenous veterinary biologics in facilities separate from those used for preparing licensed products. Autogenous veterinary biologics are intended for limited distribution or specialty applications where licensed biologics are not available.

The Permit To Import Biologics, Blood, and Serum and the Permit To Import Animal Pathogens are issued for importation of laboratory reagents, cultures, and other research material which are not used for prevention or diagnosis of disease in animals.

Renewal of licences and import permits is dependent on compliance with Health of Animals Act and Regulations, and conditions specified on the licences and permits. CCVB will monitor compliance by periodically conducting onsite inspections. Manufacturers and importers should periodically conduct internal inspections as part of an ongoing total quality management program.

Copies of the manufacturer's current licences and permits should be attached to the inspection notes, and checked for accuracy against the manufacturer' s copy of the licence or permit. Examine all veterinary biologics licences and permits. Also examine other federal, provincial, municipal licenses, permits, and documents. Evaluate compliance with conditions on permits for importation of licensed products or organisms for research and evaluation. Materials imported under research permits must be kept separate from facilities where licensed products are manufactured, tested, or stored.

12.1

a) Veterinary Biologics Establishment Licence

Authorizes production of registered products or autogenous vaccines.

Registered products must be produced in licensed establishment; using appropriate control measures to ensure isolation of commercial products from facilities used for research, diagnostic, quality assurance testing, and autogenous vaccine production.

Verify name of regulatory liaison. Prefer to have one regulatory liaison, and one alternate regulatory liaison in case regulatory liaison is unavailable.

Verify company name, address, telephone, facsimile, regulatory contact(s), issue date, expiry date. Establishment license address should note location of each licensed manufacturing facility, which may be different from manufacturer's headquarters mailing address. If more than one manufacturing facility is used, then each site should have an establishment license.

Discuss difference in requirements for establishment licences for production of conventional registered products versus autogenous vaccines.

Establishments used for production of commercial products must be separated from facility for autogenous products. If a manufacturer producers both registered products and autogenous vaccines, personnel, facilities, equipment, reagents, and products must be kept separate.

Manufacturer must maintain a log of all infectious agents in inventory for production of autogenous vaccines, noting source of isolate, identity of culture, date of accession, name, address, species.

Manufacturer must maintain a production outline for all autogenous veterinary biologics, and must conduct appropriate quality assurance tests to verify safety, but production outlines are not submitted for approval, and samples are not submitted to BEL for confirmatory testing.

Renewal of licences and import permits is dependent on compliance with Health of Animals Act and Regulations, and conditions specified on licences and permits. CCVB may audit compliance by conducting inspection or requesting that manufacturer/importer file an interim inspection report based on an internal evaluation conducted by company representatives.

See sample veterinary Biologics Establishment Licence

12.1

b) Veterinary Biologics Product Licence

Licence issued for each veterinary biologic manufactured in Canadian establishment.

Verify accuracy of product assigned names, trade names, CCVB file numbers.

Note products with special conditions restricting use.

Verify that all products are currently in production. Recommend deleting inactive products.

See sample Veterinary Biologics Product Licence.

12.1

c) Permit To Import Veterinary Biologics Into Canada

For importation of veterinary biologics for commercial distribution or investigational use.

Verify accuracy of company name, address, telephone, facsimile, regulatory contacts.

Verify accuracy of product assigned names, trade names, CCVB file numbers, USDA-APHIS codes.

Verify that all products are currently being imported. Recommend deleting inactive products.

All imported veterinary biologics must be registered for use in country of origin.

See sample Permit To Import Veterinary Biologics Into Canada.

12.1

d) Permit To Import Biologics, Blood, and Serum

For importation of research materials, diagnostic reagents, or culture media which are not used for the prevention or diagnosis of disease in animals.

Intended for importation of non-infectious material of animal or microbial origin.

Verify accuracy of company name, address, telephone, facsimile, regulatory contacts.

Verify that potentially hazardous research materials are kept separate from manufacturing seeds and media.

Verify that all materials of animal origin used in the production of veterinary biologics originate from sources considered to be safe from animal transmissible spongiform encephalopathy infection or contamination.

Verify compliance with import permit conditions.

Note country of origin of imported veterinary biologics. Importation of injectable products is generally limited to the United States, Australia, New Zealand.

See sample Permit To Import Biologics, Blood, and Serum.

12.1

e) Permit To Import Animal Pathogens

For importation of bacteria, viruses, fungi, etc.

Infectious material imported under Permit To Import Animal Pathogens must be kept separate from licensed premises.

Verify accuracy of company name, address, telephone, facsimile, regulatory contacts.

Verify compliance with import permit conditions.

See sample Permit To Import Animal Pathogens.

12.2 Personnel

Objective(s)
To verify that all key positions (management, production, filling, quality assurance, distribution, animal care, technical service) are staffed by personnel with appropriate training and authority to ensure operation of establishment in accordance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 128 (1) (m).

Background Information and General Inspection Guidelines
Review organization chart and job descriptions, and personnel profiles to evaluate reporting relationships and responsibilities of all key personnel. Meet personnel, preferably in their work area. Verify that the facility is adequately staffed, and that there are no vacancies in key positions. Identify person responsible for maintaining updated organization charts and curriculum vitae for key personnel. Verify that all personnel are qualified for their duties, and are adequately trained and supervised. Note responsibility, signing authority, delegation of authority, in-process controls, validation procedures. Note employee health conditions that may affect product. Note general attitude of personnel toward productivity, total quality management, humane animal care, and laboratory biosafety.

Review the firm's organization chart to verify that the following areas are appropriately staffed.
Regulatory Affairs Liaison
Management/Admin
Pre-licensing Research & Development
Seeds & Cells
Production
Final Production
Labels
Quality Assurance / Quality Control Testing
Animals
Storage, Distribution
Marketing
Technical Service

Obtain a copy of the updated organization chart showing key positions and reporting relationships.

Note responsibility, signing authority, lines of communication and reporting relationships, especially relationship between personnel responsible for research, production, quality assurance testing, animal care, marketing, and technical service.

Note names and job titles of staff in key areas. Job titles should accurately reflect duties and responsibilities. Note education and training all key personnel. Manufacturer must maintain a file of job descriptions and curriculum vitae for key areas:

Production must be clearly separate from quality assurance.

Note vacancies, new appointments, and personnel changes in key areas.

Verify that there is an adequate number of employees on staff.

Identify designated regulatory affairs liaison and alternate to serve as contact with CCVB for new product submissions, labelling, advertising, production outline revisions, adverse reactions, and serial release. Serial release contact may be different from main regulatory affairs liaison.

Record name, job title, address, telephone, fax.

12.3 Facilities

Objective(s)
To verify that facilities are suitable for the intended purpose and in compliance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 128 (1) (a-m).

Inspection
Examine facilities and compare with documents (plot plans, blueprints, legends) to ensure that facilities are appropriate for production of veterinary biologics. Arrangement and construction of facilities. Verify facilities conform with plot plan, blueprint, legends. Traffic flow. Adequacy of space lights, heating, cooling, ventilation, hot/cold water, drainage. Separation of production facility from diagnostic, research activities. Isolation of product. Prevention of cross contamination. Washable surfaces in areas where cleaning & disinfection required. All rooms numbered. Laboratory biosafety. All essential facilities operational.

Examine facilities and corresponding documents (plot plans, blueprints, legends) for all key areas. Verify accuracy of plot plans, blueprints, plot plan legends, and blueprint legends. Note new construction, renovations. Special use areas must be separate from vaccine production facility (e.g. diagnostic clinic, research laboratory, pharmaceutical manufacturing, animal quarantine).

Plot Plan
A « Plot Plan » is a scale drawing of the premises. The plot plan should be entitled « Plot Plan » and indicate the company name, address, date, and name of person who prepared the plot plan. The plot plan should indicate the location of each building and other structure on the property, and show the location of boundaries and identifying adjacent properties. 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 should be provided. The plot plan drawing may be submitted in the original architect's large scale format, or reduced to fit on 8.5 x 11 paper.

Company Name

Page 1

October 5, 1997

Establishment Licence Number

 

Supercedes May 2, 1996

Prepared by:

Approved by:

Blue Prints
A « blue print » is a scale drawing of the building, showing the floor plan and location of key equipment.

Blue prints and plot plans should be accompanied by legends describing the construction and use of the facility. Each room must be identified by a unique number which should be posted over the entrance into the room. All stationary equipment used in production, testing, or storage of veterinary biologics must be uniquely numbered, and indicated on the blue print. For each room, the blue print legend should describe the physical construction of the room, and indicate the function, construction, fractions, cleaning and disinfection. These plot plans should show the location of the facilities on the property, and indicate the location of all outdoor structures such as access roads, perimeter fences, buildings, parking areas, loading docks, and animal holding pens.

Plot Plan Legend
Street Address, City, Province

Briefly describe the premises (dimensions, perimeter fences, roadways, parking areas, number of buildings, ground cover and adjacent property.

Building 1
Description:
(Briefly describe each building by providing information about dimensions, building type, construction materials, water supply, drainage, ventilation, heating, cooling, and lighting.)

Use:
(Briefly describe main use for each building, as well as all other uses.)

Building 2
Description:
Use:

Building 3
Description:
Use:

Blue Print Legends
The « blue print legend » lists the function or use of each room within the facility. It describes the function, product components used in each room. It also identifies the equipment, and clean-up procedures. The legends would provide a list of rooms and for each room the functions, fractions, equipment, clean-up procedures.

Summary of Changes
Date / Page / Section / Description of Changes
Oct 9/97 - Added examples of format and information for blue print, plot plans, and legends

Regulatory Affairs Liaison
Verify that regulatory affairs liaison and other office staff have access to appropriate office space and secure records storage.

Management/Administration
Verify that management and administration facilities provide staff with appropriate office space and secure records storage.

Pre-licensing Research & Development
Verify that research facilities are separate from production facility. Research protocols must comply with Public Health Agency of Canada Laboratory Bio-safety Guidelines (PHAC) and CCAC Guide to the Care and Use of Experimental Animals.

Seeds & Cells
Secure storage
Adequate records

Production / Final Production (General comments also apply to other areas)
Media storage, preparation
Cultivation, harvest, processing
Walk through all key areas (e.g. seeds & cells, fermentors, filling, labelling, animal rooms, storing & testing)
Smooth, impermeable (painted) surfaces to facilitate cleaning.
Sloped window ledges to avoid dust.
Adequate space
Traffic flow (personnel, equipment, product)
Positive identification of all in-process material
Verify that latest version of plot plans, blue prints, and legends are on file at CCVB
Note recent renovations
Research facilities must be separate from production areas
Note upgraded equipment, maintenance and renovations.
Check to ensure that facilities are maintained and upgraded.
Note traffic flow, warning signs, restrictions, double doors with airlocks, security doors
Change rooms, wash rooms
Hot water, soap, towels available
Ensure that room use is as indicated on legend.
Verify that construction allows proper sanitation.
Verify that facility has adequate space, light, water, drains, ventilation.
Floor layout should provide adequate isolation/protection for each product (controlled air movement, physical separation, double doors, cleanable surfaces).
Note traffic patterns, restrictions posted, understood, and obeyed.
Adequate washrooms, changing rooms separated from production area.
Adequate soap, hot water, towels.
Verify accuracy of plot plans, blue prints, legends
Check for new equipment, undocumented renovations
Determine location of production facilities versus research, animal facilities.
Note room traffic, temperatures.

Labels
Adequate space
Secure storage

Quality Assurance / Quality Control Testing
Public Health Agency of Canada Laboratory Bio-safety Guidelines

Animals
CCAC Guidelines for the Care and Use of Experimental Animals

Storage, Distribution
Marketing
Technical Service

12.4 Equipment

Objective(s)
To verify that all equipment is functional, suitable for the intended purpose, and in compliance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 128 (1) (a-m).

Inspection
Verify equipment installed conforms with blueprint, legends. Review maintenance and validation records. Examine records for automatically controlled equipment. Examine operating logs. All equipment must be uniquely identified. Laboratory bio-safety.
Verify accuracy of plot plans, blue prints, legends.
Verify that all essential equipment is operational.
Responsibility, signing authority, in-process controls, validation
Verify that equipment is monitored regularly.
Note dates of servicing for laminar flow hoods, autoclaves, etc.
Note manual versus automatic controls.
Review records for equipment checks (freezers, laminar flow hoods, incubators).
Equipment accurately and uniquely identified.
Equipment located according to blueprint & legends.
Automatically controlled equipment (autoclaves & dry heat sterilizers).
Observe equipment in operation.
Examine maintenance, service, calibration, and repair logs.

Regulatory Affairs Liaison
Documents
Plot plans, blueprints, legends.
Equipment maintenance protocols, validation procedures, operation logs.
Computer, fax, phone.
Correspondence, records (paper and electronic).

Management/Administration
Computer, fax, phone.
Correspondence, records (paper and electronic).

Pre-licensing Research & Development

Seeds & Cells
Liquid nitrogen tanks, freezers (-70ºC, -20ºC), refrigerators.
Incubators, warm rooms.
Laminar flow hoods, bio-safety cabinets, centrifuge, water bath, pipettes, vacuum lines.

Production
Media Storage, preparation, cultivation, harvest, processing.
Incubators, warm rooms, roller bottles, micro-carrier systems, culture vessels, fomenters.

Final Production
Filling, labelling, sampling.

Labels
Quality Assurance Testing
Animals
Storage, Distribution
Marketing
Technical Service

12.5 Sanitation and Maintenance

Objective(s)
To verify that compliance with the Health of Animals Act and Regulations, and staff are using appropriate sanitation, bio-containment, and maintenance practices in order to minimize the likelihood of contamination of product, accidental exposure of personnel, or contamination of the environment.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 128 (1) (a-m).

Inspection
Verify that sanitation protocols are established and followed as described in legends and production outlines. Outside drainage, debris removal. Vermin control. Appropriate disposal of biological wastes. Sewage. No unnecessary material in coolers, production areas, etc. Protective laboratory clothing. Laboratory bio-safety.

Review sanitation and maintenance documents
Plot plans, blueprints, legends
Building maintenance protocols, sanitation procedures, sanitation logs
Responsibility for cleaning, sanitation, maintenance, vermin control
Management, Administration Areas
Interior and exterior property
Offices, meeting rooms, etc.

Pre-licensing Research & Development
Seeds & Cells
Production
Final Production
Labels
Quality Assurance Testing
Animals
Vermin control especially important in production and animal areas.

Storage, Distribution
Marketing
Technical Service
Personnel
Facilities
Clean inside and outside

Equipment
Documents & Records
Health of Animals Act and Regulations
Public Health Agency of Canada Laboratory Bio-safety Guidelines
Canadian Council on Animal Care Guidelines To The Care And Use Of Experimental Animals
Cleaning & disinfection logs
Manuals (Health of Animals Act and Regulations, Public Health Agency of Canada Laboratory Bio-safety Guidelines, Guidelines To The Care And Use Of Experimental Animals) Sewage disposal regulations (federal, provincial, municipal).

Operations
Bio-safety
Sanitation

Sewage, infectious waste disposal
Appropriate containment, separate from production facility.
Responsibility, signing authority, in-process controls, validation.
Check sanitation records, verify with legends and production outline.
Each room should have a sanitation log.
Adequate drainage indoors floor drains, outdoor gravel, grass, slopes.
Outside cleanliness and drainage.
Disposal of wastes
Sanitation logs
Animal litter, animal wastes tissues, culture fluids.
Protective clothing for personnel.
Premises must be clean, neat.
No unnecessary material in fermentor rooms, warm rooms, coolers, freezers, warehouse.
Unsanitary practices must not be tolerated.
garbage, dirt, dust, clutter
floor drains cleaned regularly
tidy coolers, freezers
employee hygiene

Institutional bio-safety committee

12.6 Pre-licensing Research & Development

Objective(s)
To verify the acceptability of research done in support of product registration. To verify that research is done in accordance with the Health of Animals Act and Regulations, the Public Health Agency of Canada Laboratory Bio-safety Guidelines and the Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals.

Pertinent Regulations and Guidelines
Health of Animals Act and Regulations Part XI. 135 (1).
Canadian Council on Animal Care Guidelines To The Care And Use Of Experimental Animals.
Public Health Agency of Canada Laboratory Bio-safety Guidelines

Inspection
Verify appropriate separation of research and production (facilities, equipment, personnel, supplies). Laboratory bio-safety. Review bio-safety policies and examine institutional bio-safety committee (IBC) minutes. Verify IBC representation from appropriate staff and appropriate attention to occupational health and safety, biotechnology, and animal welfare. Disposal of experimental animals. Laboratory studies. Field trial records; compliance with restrictions.

a) Personnel

Responsibility, signing authority, in-process controls, validation

Verify that firm has an institutional bio-safety committee with appropriate representation, training, and authority to establish bio-safety policy and ensure all concerns addressed.

Verify that employees are 1) aware of bio-safety and humane care guidelines and 2) conform with the guidelines.

b) Facilities

Research must be separate from production and serial release testing.

c) Equipment

d) Documents & Records

Health of Animals Act and Regulations
Public Health Agency of Canada Laboratory Bio-safety Guidelines
Canadian Council on Animal Care Guidelines To The Care And Use Of Experimental Animals
Codes of Practice
Research organisms should be listed on legends, or legend should refer to an inventory log.
Verify that field trial records conform with conditions on import permits and letters authorizing studies.

e) Operations

Routine product testing should be separated as much as possible from research and diagnostic work. Verify separation of people, supplies, equipment which could contaminate product.

Verify the acceptability of research done in support of product registration. To verify that research is done in accordance with guidelines for bio-safety and humane animal care. Verify that animal experiments are done under appropriate veterinary supervision, and in compliance with Health Canada & CCAC guidelines.

Inventory of experimental labels, and accurate records documenting use of investigational products.
Upcoming new product submissions.
Verify control of personnel movement from research to production
Production testing should not be done in research facility
Field trial records should comply with restrictions
Humane care and euthanasia of experimental animals
Disposal of contaminated tissues

12.7 Seeds & Cells

Objective(s)
To verify the source and passage history of cell lines, media, and seed cultures used to prepare veterinary biologics. To verify that procedures are in compliance with the Health of Animals Act and Regulations and conform to the approved production outline.

Pertinent Regulations
Health of Animals Act and Regulations.

Inspection
Trace back from finished product to acquisition of seeds. Identification of master seeds, working seeds, production seeds. Seed storage, records. Working seeds and production seeds must be stored in licensed facility. Laboratory bio-safety. Immunogenicity test records for seed. Repeat immunogenicity. Signing authority, validation.

a) Personnel

Signing authority, in-process controls, validation

b) Facilities

Note storage facilities and records for cell lines, media, seeds

c) Equipment

Compliance with Public Health Agency of Canada Laboratory Bio-safety Guidelines

d) Documents & Records

Certificates of analysis for media, reagents
Production Outlines
Special Outlines

e) Operations

Tissue culture cell lines and primary cells tested for freedom from contaminants.
Source animals for primary cells tested for freedom from contaminants.
Health status of flocks supplying embryonated eggs for virus cultivation.
Ingredients of animal origin (serum, albumin, trypsin) heat sterilized or tested to verify freedom from contaminants.
Fetal calf serum must be of Canadian origin.
Ensure that accurate records are kept and that all material is accurately identified throughout all stages of production. Complete record of all microorganisms used.
Trace back one or more serials from production serial to master seed (verify documentation and physical location of material).
Verify that cell lines, media, and seed cultures corresponds to production outline.
Hazardous organisms must be handled safely & separately from others.
Note source of tissue culture cell lines.
Ingredients of animal origin must be heat sterilized or tested to verify freedom from contaminants.
Note source of serum, trypsin, albumen.
Manufacturers must use Canadian origin serum.

12.8 Production
(cultivation, harvest, processing, assembly of serials)

Objective(s)
To ensure compliance with the Health of Animals Act and Regulations, and the approved production outline.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 135. (1).

Inspection
Trace back from finished product to acquisition of seeds. System for assigning consecutive lot numbers and serial numbers to ensure unique identification of each ingredient. Annual production outline reviews. Compliance of production and testing methods with production outline. Identification of in-process material. Sterile procedures. Laboratory bio-safety. Signing authority, validation. Records.

a) Personnel

Signing authority, in-process controls, validation

b) Facilities

Note storage facilities and records for cell lines, culture media, and virus/bacteria seeds

c) Equipment

d) Documents & Records

Production Outline
Accurate, up-to-date production outlines and special outlines must be filed for each registered product. Production outlines must be reviewed annually by a committee of regulatory, QA, and production staff. All revisions must be submitted to CCVB for approval and filing.

Review production outlines, verify dates conform with those on file at CCVB.
Special Outlines
Batch Records

e) Operations

Cultivation, harvesting, batching
All procedures must conform with the approved production outline
In-process material must adequately identified
Approved (up-to-date) production outline must be available for use by production supervisors and staff. Review annually.
Media preparation area
Examine reprocessing records
Note method for assigning lot numbers and serial numbers

12.9 Final Production (filling, labelling)

Objective(s)
To ensure compliance with the Health of Animals Act and Regulations and the approved production outline. To confirm that finished product is held in quarantine until released for sale.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 132 (1).

Inspection
Filling records, fill checks. Separation of serials during filling. Elapsed time at room temperature during filling, labelling. Lyophilization procedures and records. Aseptic technique during filling. Disposal of unsatisfactory product. Label samples attached to serial record. Laboratory bio-safety. Signing authority, validation.

a) Personnel

Signing authority, in-process controls, validation
Designated samplers

b) Facilities

c) Equipment

d) Documents & Records

Production outlines, special outlines, batch records.
Filling records, fill check procedures.
Documentation of losses
Lyophilization/freezing records; note times, temperatures.
Labels attached to serial records.
Signs, stickers for identification of unlabelled vials.
Serial number allocations (consecutive).

e) Operations

Quality assurance sample collection
Random collection
Tamper resistant storage
Signatures
Training for sample collectors
Links with quality assurance laboratory.
Proper mixing during fill
Fill checks
Vial, label, package uniformity
Filled vials, packages correct
Only one product filled/labelled/packaged at a time
Minimize time out of cooler
Quality assurance sampling

12.10 Labels

Objective(s)
To verify that all labelling is in accordance with the Health of Animals Act and Regulations, and conforms with production outlines and approved sample labels.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 132, 133, 134, 135.

Inspection
Signing authority, validation. Serial numbers, expiration dates. Secure storage, inventory log for approved labels. Compare label stocks with approved labels. Label security during labelling.

a) Personnel

Responsibility, signing authority, in-process controls, validation
Accountability for accuracy of labelling.

b) Facilities

Secure storage for labels.
Draft labels stored separately from approved labels.

c) Equipment

Labelling equipment
Date, serial number stamping
In-house label printing equipment

d) Documents & Records

Master label, label inventory, procedure for assigning labels.
Samples of all approved container labels, cartons, and package inserts.
Label inventory correct.

e) Operations

Procedure for assigning serial numbers and expiry dates.
New label approval notification.
Compare production labels with samples (color, legibility).
Labels stored securely, log of labels.
Checks for imprinted serial numbers & expiration dates.
Label lists.

12.11 Quality Assurance / Quality Control Testing

Objective(s)
To ensure that products are of uniformly high quality and conform with the Health of Animals Act and Regulations and that tests are conducted in accordance with the approved production outline and special outlines.

Pertinent Regulations
Health of Animals Act and Regulations Part XI 135 (1).

Inspection
Verify that serial release testing methods conform with production outline and special outlines. Sampling. Appropriate laboratory practices, controls. Laboratory bio-safety. Animal care. Extension of expiry date. How to do for importers. Not for product sold.

a) Personnel

Responsibility, signing authority, in-process controls, validation.

b) Facilities

Organisms listed in blueprint legends.

c) Equipment

Automatic equipment validation
Laminar flow hoods, bio-safety cabinets inspections
Equipment logs (daily temperature)

d) Documents & Records

Production Outline, special outlines, serial release forms.
Examine records for unsatisfactory serials.
Examine potency and sterility testing records.

e) Operations

Total quality management
Third party validation, accreditation, proficiency testing (ISO 9000, etc.)
Audit test results and reports
All tests reported? Retests valid?
Verify that testing procedures are in compliance.
Proper techniques, recording?
Growth promotion tests 9 CFR 113.25 (b) must include two organisms and more than one dilution.
Dilution of preservatives test 9 CFR 113.25 (d)
Any tests Biologics Evaluation Laboratory cannot run?
Media sterility test

12.12 Animals

Inspection Objective(s)
To ensure that animals used for biologics production, testing, and research are handled humanely.

Pertinent Regulations and Guidelines
Health of Animals Act and Regulations

Canadian Council on Animal Care Guide to the Care and Use Of Experimental Animals.

Agriculture and Agri-Food Canada Recommended Codes of Practice for the Care and Handling of Farm Animals

Public Health Agency of Canada Laboratory Bio-safety Guidelines

Objectives
To ensure that animals used for biologics production, testing, and research are provided with an appropriate environment, feed, veterinary care, and treated humanely to conform with the Health of Animals Act and Regulations, animal care guidelines, and Public Health Agency of Canada Laboratory Bio-safety Guidelines.

a) Personnel

Responsibility, signing authority, in-process controls, validation
Animal care staff
Veterinary supervision for all treatments and medication
A veterinarian should be in charge of animal care. Not necessarily always on duty, veterinary care must be available when necessary.

b) Facilities

Animal environment (temperature, humidity, air filtration, ventilation)
Feed, water, light, bedding

c) Equipment

d) Documents & Records

Health of Animals Act and Regulations
Canadian Council on Animal Care Guide to the Care and Use Of Experimental Animals
Public Health Agency of Canada Laboratory Bio-safety Guidelines
Codes of Practice for farm animal husbandry
Animal procurement, usage, euthanasia, necropsy, disposal records

e) Operations

Euthanasia procedures, necropsy facilities
Disposal
Subject to inspection by Canadian Council on Animal Care and/or provincial authorities

12.13 Distribution, Marketing, and Technical Service

Objective(s)
To verify that the establishment's product storage and distribution practices are in accordance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 129 (1-2).

Inspection
Signing authority, validation. Serial numbers, expiration dates. Secure storage, inventory log. Cooler space. Transportation to distributors. Separation of pre-release and post-release product to prevent inadvertent distribution of unreleased product. Positive identification of unlabelled product. Security for inventory of unreleased product. Handling and disposal of returned product. Serial release procedures. Sample storage. Disposal of outdated inventory.

a) Personnel

Responsibility, signing authority, validation

b) Facilities

Physical control system for pre-release and post-release serials
Quarantine area sufficient
Reserve sample storage
All items destroyed as reported
General appearance of premises
Cooler space adequate

c) Equipment

d) Documents & Records

Inventory records
Records (receiving, pre-release quarantine, shipping, inventory, quality assurance, returns, disposal)

e) Operations

Distribution Records
How are estimates and actual inventories reconciled?
Are distribution records adequate for inventory control, recalls.
Could a total stop sale or recall be carried out by the firm if necessary?
Recall of product
Serial number shown on invoice
Procedure for investigation of complaints
Transported under refrigeration
Method of reconciling estimates to actual sales doses
To ensure that the distribution system and records are appropriate for inventory control and tracing sales and tracking system would enable a product recall if required.
Capability for stop sale or recall product to user level.
Adherence to license restrictions (e.g.. rabies vaccines to be sold to veterinarians only)

Inventory control
Methods to prevent inadvertent distribution of unreleased serials
Review the firm's stop sale policy to be sure that is in accordance with CCVB requirements.

Review documentation of any recent product recalls or stop sale to determine if actions taken were appropriate and in accordance with CCVB policy and guidelines.

Disposal of outdated product
Extension of dating records
No unsold product returned to inventory
Method of reconciling estimates to actual doses

Product Recalls
Evaluate the physical system of control and identification on pre- and post-release serials.
The serial tracking system should prevent inadvertent distribution of unreleased serials.
Watch for signs of premature shipment of serials before actual release date.

Product Storage and Inventory Records
Check to see if cooler space is adequate for licensed products at the normal level of production.
Check system for handling returned goods on premises.
Check records for returned goods.

Imported product
Ports of entry used
Average/maximum time in transit

Labels
Storage quarantined and released products identified
Packaging and labelling areas
Refrigerated storage
Unused labels

Outdated biologics shipping

Return policy
Returned goods handling, storage to ensure they are not returned to inventory.

Documentation of serial release
Computer database and hard copy of distribution records

Objective(s)
To verify that the establishment's marketing and advertising practices are in accordance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 129 (1-2).

Inspection
Verify procedures for preparation and submission of advertising material.

f) Personnel

Responsibility for preparing promotional material, submission of draft advertisements, release of approved advertisements for publication or distribution. Signing authority for submission of draft advertising and authorization of publication/distribution after CCVB approval.

g) Facilities

Office location, space (onsite versus remote location)

h) Equipment

Office furniture, equipment, computer database, desktop publishing

i) Documents & Records

Storage of draft versus approved advertisements

j) Operations

Review process for preparation and submission of advertising material.
Links with research staff for data.
Verification of draft advertising with research staff and approval through regulatory liaison.

Objective(s)
To verify that the establishment's technical service practices are in accordance with the Health of Animals Act and Regulations.

Pertinent Regulations
Health of Animals Act and Regulations Part XI. 129 (1-2).

Inspection
Product complaint logs. Adverse reaction reports. Review CCVB requirements for reporting adverse reactions. Verify that appropriate technical support is provided. Adverse reactions must be investigated and reported to CCVB within 15 days.

k) Personnel

Responsibility, signing authority for adverse reaction investigations.
Reporting relationships, mechanism for relaying consumer complaints.
Veterinary consultation available

l) Facilities

Office space, records storage

m) Equipment

Telephone number for adverse reaction complaints
Telephone answering system.
Computer database or manual records for recording adverse reactions.

n) Documents & Records

CCVB adverse reaction reporting forms.
Adverse reaction logs.

o) Operations

Review the firm's stop sale policy to be sure that is in accordance with CCVB requirements.

Review documentation of any recent product recalls or stop sale to determine if actions taken were appropriate and in accordance with CCVB policy and guidelines.

Adherence to licence restrictions.
Protocol for recording complaints and initiating investigations. Follow-up.
Capability for stop sale/recall to user level.
Sales representatives should advise customers about the procedure for reporting adverse reactions, and provide copies of CCVB adverse reaction reporting form, which may be supplemented by company forms.
Standard policy for handling complaints, call-backs.
Review recent on-farm investigations.

D. Assessment

13. Overall Assessment

The inspector's overall evaluation of facility's compliance with Health of Animals Act and Regulations. Place checkmark ( ) beside the appropriate assessment (Satisfactory, Unsatisfactory, or Other) and sub-heading.

SATISFACTORY Facility in compliance with Health of Animals Act and Regulations.

No significant deficiencies noted.

No significant deficiencies noted. A few minor operational deficiencies observed in non-critical areas which do not affect safety or product quality, but will require ongoing attention to ensure continued compliance.

No significant deficiencies noted. Minor operational deficiencies in non-critical areas which do not affect safety or product quality, but will require immediate correction to ensure continued compliance.

UNSATISFACTORY Facility not in compliance with Health of Animals Act and Regulations.

Product Quality Significant deficiencies noted in critical areas which could potentially affect product quality (purity, potency, safety, efficacy) and will require immediate correction to ensure compliance.

Laboratory Bio-safety. Significant deficiencies in compliance with Public Health Agency of Canada Laboratory Bio-safety Guidelines.

Public Health Agency of Canada Laboratory Bio-safety Guidelines.

Agriculture and Agri-Food Canada Containment Standards for Veterinary Facilities.

Animal Care Significant deficiencies in compliance with animal care guidelines.

Guide for the Care and Use of Experimental Animals

Recommended Codes of Practice for the Care and Handling of Farm Animals

Environment Significant deficiencies in compliance with regulations under the Health of Animals Act, or other federal or provincial legislation.

Other Describe other reasons why facility is not in compliance with the Health of Animals Act and Regulations.

OTHER Compliance status not assessed. Explain reasons.


Inspector Signature: space

Name, Organization, Date: space

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