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Veterinary Biologics Guideline 3.12E
Veterinary Biologics Product Review Guideline
Veterinary Biologics Section
Canadian Food Inspection Agency
2 Constellation Crescent (Floor 8),
Ottawa, Ontario K1A 0Y9
The Veterinary Biologics Section (VBS) of the Canadian Food Inspection
Agency (CFIA) is responsible for licensing veterinary biologics in Canada. This
licensing program forms an integral part of Canada's National Animal Health
Program, which strives to help protect the health of food producing animals,
domestic pets, and the Canadian public by preventing the introduction and
spread of certain important animal diseases.
To meet the requirements for licensure, veterinary biologics must be shown
to be pure, potent, safe, and effective when used in the target species
according to the manufacturer's label recommendations. In addition, the
licensing submission must also contain supporting data demonstrating that the
product can be manufactured and used without adversely affecting animal health,
human health, food safety, or the environment.
The following notes are intended to serve as a guide for reviewing licensing
submissions to evaluate compliance with the requirements of the Health of
Animals Act and Regulations. These notes are primarily designed for use by
VBS reviewers, however
manufacturers may find the notes useful in preparing new product licensing
submissions. Additional information is provided in the following legislation,
guidelines and cost recovery fee schedule:
-
Licensing Requirements for Veterinary Biologics in
Canada guideline.
-
Health of Animals Act and Regulations.
-
Summary of Requirements and Guidelines for Veterinary
Biologics in Canada.
-
Guidelines for the Regulation of Veterinary Biologics
Produced by Biotechnology.
-
Public Health Agency of Canada Laboratory Biosafety Guidelines.
-
Canadian Food Inspection Agency Containment Standards for Veterinary Facilities.
-
Canadian Council on Animal Care Guide to the Care and Use of
Experimental Animals.
-
Canadian Agri-Food Research Council Recommended Codes of
Practice for the Care and Handling of Farm Animals (series includes
guidelines for dairy cattle, beef cattle, swine, poultry, and fur bearing
animals).
-
Summary of Fees and Services Related to Veterinary
Biologics (on the reverse side of the Application for Services form
CFIA 4720).
It is the responsibility of the prospective licensee to furnish appropriate
data to demonstrate that each product meets the purity, potency, safety, and
efficacy requirements for licensure, and prepare an in-depth environmental
assessment where appropriate.
A risk-based approach is used to evaluate the safety of a product in the
target species, as well as safety for non-target species, humans, and the
environment. The environmental assessment documents are evaluated by VBS reviewers, as part of the
licensing submission.
1. Company and product information
Importer(s):
________________________________________________________________
Manufacturer:
_____________________________________________________________
Assigned Name:
__________________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
Trade Name:
_______________________________________________________________
Species: __________________________________________
VBS File Number:
____________ / ____________ / ____________
USDA
Product Code: ____________________
2. Product Components
List components under the appropriate heading.
| |
Conventional |
Recombinant DNA |
| Inactivated |
Live |
Inactivated |
Live |
| Vaccine Viruses |
. |
. |
. |
. |
| Bacteria |
. |
. |
. |
. |
| Other |
. |
. |
. |
. |
| Antiserum |
Conventional Antibody |
Monoclonal Antibody |
| Diagnostic Kit |
Conventional Antigen / Antibody |
rDNA Antigen / Monoclonal
Antibody |
| Colostrum |
. |
. |
| Other |
. |
. |
3. Reviewer Idendification and Summary Comments
Reviewer(s):
______________________________________________________________
Reviewer summary comments (List additional notes and comments under item
22):
_________________________________________________________________________
Licensure:
Veterinary Biologics Product Licence
Permit to Import Veterinary Biologics - Single Entry ( ) Temporary (
) Annual ( )
Database:
File number entered: ________________________ Licenced:
___________________
Cost recovery fee payment: _______________________________________________
4. Application For Services (CFIA 4720)
Effective April 10, 1996, the Veterinary Biologics Section began charging
fees to recover some of the costs for veterinary biologics regulatory services.
The fee schedule includes charges for review and approval of licensing
applications, as well as review and approval of production outlines and
labelling, inspection of manufacturing facilities, and issuance of import
permits (see Summary of Fees and Services Related to Veterinary Biologics, on
the reverse side of the Application for Services). New product
licensing submissions must be accompanied by the appropriate fees, as specified
in the fee schedule.
5. Veterinary Biologics Establishment Licence (CFIA 1589)
All veterinary biologics must be produced in a licensed establishment.
Canadian manufacturers require Veterinary Biologics Establishment Licence
(CFIA 1589).
American manufacturers require USDA-APHIS Veterinary
Biological Establishment License. Other foreign manufacturers should
submit equivalent document issued by licensing agency.
6. Veterinary Biologics Product Licence (CFIA 4602)
Required only for imported products. Imported products must be licensed for
use in the country of origin. American manufacturers must submit copy of
USDA-APHIS Veterinary
Biological Product License. Other foreign manufacturers should submit
equivalent document issued by licensing agency.
7. Veterinary Biologics Information Form (CFIA 1503)
Designates Canadian importer(s).
8. Application For Permit To Import Veterinary Biologics Into
Canada (CFIA
1493)
Applies to foreign manufacturers only.
9. Rationale and Justification For Use of Product in Canada.
Narrative discussion and supporting data to confirm rationale and
justification for use of product to prevent or control diseases which occur in
Canada. May include information from veterinary literature, diagnostic
laboratories, epidemiologic surveys, or veterinary practitioners' case
reports
10. Production Outline
The approved production outline serves as an agreement between the
manufacturer and the licensing agency on acceptable production and testing
methods. It is used to document all production and testing methods.
The recommended format is explained in VBS Guidelines for Preparation of
Production Outlines, Special Outlines, and Summary of Changes for Veterinary
Biologics. The section headings are listed on the following pages.
Describe test methods and specifications for acceptable serials (ie. minimum
acceptable titer at release and expiry date), or refer to a special outline for
detailed descriptions.
Indicate date of production outline on each page.
Each page must be signed by manufacturer's regulatory liaison or other
personnel responsible for quality assurance.
Clearly indicate whether production outline is for full production, bulk
vaccine for further manufacture, or filling and labelling.
Canadian manufacturers should submit three (3) copies of the production
outline. One (1) stamped approved copy will be returned to manufacturer, one
(1) stamped copy will be forwarded to Biologics Evaluation Laboratory, and one
(1) stamped copy retained in Veterinary Biologics Section files. American
manufacturers should submit two (2) copies of the production outline if the
product will not be tested in Canada, and three (3) copies if it will be tested
in Canada.
Production outline date:
Other production outlines cited:
Manufacturing processes (describe production activities, and indicate
facilities to be used):
Complete production
Preparation of bulk for further manufacture
Blending, filling and labelling
Filling and labelling
Labelling
Recommended format for Production Outline (For additional information, refer
to VBS Guidelines
for Preparation of Production Outlines, Special Outlines, and Summary of
Changes for Veterinary Biologics).
| I. |
|
Composition of the Product (genus, species, serotype,
source of isolates, proportions) |
| II. |
|
Cultures (culture media, methods, passages, times,
inactivation, in process quality assurance) |
| III. |
|
Harvest (techniques, specifications for acceptable
harvest, handling of discarded material) |
| IV. |
|
Preparation of the Product (method of inactivation,
concentration, purification, standardization of antigens, adjuvants,
preservatives, filling methods, lyophilization, amount of antigenic material
per dose, tests for inactivation). |
| V. |
|
Testing (purity, safety, potency tests for finished
product) |
|
|
For products requiring serial release, review and approve the form
Manufacturer's Serial Release Test Report to VBS (VBFM05.02) in consultation
with the Biologics Evaluation Laboratory (BEL) and the serial release designate
for VBS. |
|
A. |
Purity Tests to verify inactivation (freedom from residual
live vaccine organisms) and absence of contaminants. |
|
B. |
Safety Tests in target species or representative
laboratory species to verify that each production serial is safe for
administration in animals. |
|
C. |
Potency Tests conducted in vivo or in
vitro to verify that potency of each production serial is equivalent to
that of the reference serial which was used to demonstrate immunogenicity in
the target species. |
|
D. |
Other Quality control tests to verify that each production
serial meets specifications for moisture, residual formaldehyde, etc. |
| VI. |
|
Post Preparatory Steps (Container sizes, label
recommendations (claim), dose, route, precautions, expiry date). All label
claims must be supported by efficacy/safety data. Specific claims require
specific data. |
11. Special Outlines
Special outlines should be used to describe standard reagents or procedures
which are used in more than one product.
List titles for all special outlines cited in production outline.
Format for special outlines is explained in VBS Guidelines for Preparation of
Production Outlines, Special Outlines, and Summary of Changes for Veterinary
Biologics.
12. Master Cell Stock certification/characterization.
| A. |
Purity |
|
Confirmation of species of origin.
Freedom from contamination (bacteria, viruses, fungi, and mycoplasma) based on
cytopathic effects, fluorescent antibody screening, etc. |
| B. |
Safety |
|
Karyology to verify chromosome number
Tumorigenicity |
13. Master Seed (Virus, Bacteria)
identification/certification/characterization to verify purity and safety of
master seed.
| A. |
Purity (a)
Confirmation of organism identity (based on morphology, cytopathic
effects, fluorescent antibody screening, biochemical properties, antigens,
restriction enzyme analysis, DNA sequence, etc.) |
|
Purity (b)
Freedom from contamination (bacteria, viruses, fungi, and
mycoplasma) based on culture, cytopathic effects, fluorescent antibody
screening, etc.) |
| B. |
Safety |
|
Incapable of reverting to virulence
Serial passage in target species
Preliminary data on safety margin in case of overdose |
14. Summary Test Data For Pre-Licensing Serials
Verify uniformity, and serial-to-serial consistency of production
serials.
Demonstrate capability of producing serials to meet production outline
specifications.
For new products, require data from 3 pre-licensing serials.
For combination of previously licensed products, require data from 2
serials, as well as noninterference data
15. Research and testing data to verify purity, potency, efficacy,
and safety of final product.
| A. |
|
Purity |
|
|
Demonstrate satisfactory inactivation of vaccine strains in final
product.
Demonstrate freedom from extraneous infectious agents (ie. bacteria, fungi, virus, mycoplasma). |
| B. |
|
Potency |
|
|
Development and validation of standardized assays for quantitation of
immunogenic substances. |
| C. |
|
Efficacy |
|
|
Efficacy data must support the manufacturer's label claims.
Data from vaccination-challenge studies must demonstrate that a veterinary
biological product which has been manufactured according to the production
outline potency specifications is efficacious in the target animal species when
used according to label recommendations.
Efficacy should be evaluated using a prototype vaccine (reference serial)
which has been formulated to meet the minimum acceptable potency, as specified
in the production outline. The potency of this serial must not be greater
than the minimum production outline potency specifications.
The serial used for efficacy studies may be used as a reference for serial
release potency tests. If so, potency test validation studies should be
conducted concurrently with efficacy study.
See VBS guidelines
for additional information (eg., Summary of Requirements and Guidelines for
Veterinary Biologics in Canada and Guide for Reporting Laboratory and
Efficacy Trials).
|
| D. |
|
Safety |
|
(i) |
Safety for target species
Safe in target species when used as directed
Systemic reactions, anaphylaxis
Local reactions
Tests for residual virulence or revision to virulence (back-passage studies
for live attenuated vaccines)
Safety margin in case of overdose
|
|
(ii) |
Safety for non-target species (see also summary of
environmental assessment requirements listed in section 15(D)(iv). |
|
(iii) |
Other safety considerations (special consultation as
applicable)
Human safety - consult Health Canada
Fisheries impact assessment - consult Fisheries & Oceans Canada
Environmental assessment - consult Environment Canada (see below) |
|
|
Applications for approval to conduct field safety tests
must contain the following information, which is used to evaluate safety in the
target species, as well as other safety considerations (i.e., human safety, food safety, and environmental
impact).
- General description of the product and
recommendations for use.
- Production outline describing the manufacturing and
testing methods.
- Serial release test results to demonstrate purity,
potency, and safety for each serial of experimental vaccine to be used in the
study.
- Supporting data (safety, efficacy) from preliminary
laboratory research and controlled experiments using a prototype vaccine in
containment facilities.
- Draft experimental protocol, describing the methods and
procedures for evaluating the products, and for maintaining records of the
quantity of experimental product prepared, shipped, and used. The protocol
should also describe methods of biological or physical control.
- A tentative list of the names and addresses of the proposed recipients
(collaborating investigators) and quantity of experimental
product which is to be shipped to each individual.
- Copies of experimental product labels or label sketches
with the statement "Notice! For Experimental Use Only - Not For Sale"
or equivalent.
|
|
(iv) |
Environmental Assessment |
|
|
The environmental assessment requirements depend on the potential risk
associated with manufacturing or use of a product.
Products containing live micro-organisms which have been genetically
modified by introduction of DNA from different organisms or different
strains of the same organism would be considered high risk, and would be
subjected to an in-depth environmental assessment prior to field use or
licensure.
Products derived from deletion mutants would be considered slightly lower
risk, but would be subjected to a similar environmental assessment process.
Inactivated products and conventional modified live vaccines for indigenous
diseases would generally be considered low risk and would not require an
in-depth environmental assessment.
Refer to the Canadian Environmental Assessment Act and Regulations,
as well as supplementary information in the VBS Guidelines for the Regulation
of Veterinary Biologics Produced by Biotechnology.
Includes an assessment of environmental impact of manufacturing, field
trials, and commercial use
Scientific experts and regulatory officials in other departments (i.e., Health Canada, Environment Canada) may
be consulted as required.
The following headings list categories of information which should be
included in an environmental assessment. Additional information may also be
required, depending on the nature of the product, manufacturing methods,
intended uses, and potential environmental effects.
I. Introduction
II. Purpose and need for proposed action
III. Alternatives
IV. Molecular and biological characteristics of
parental and recombinant organisms
V. Human safety
VI. Animal safety
VII. Affected environment
VIII. Environmental consequences
IX. Mitigative measures
X. Monitoring
XI. Consultation and coordination with other
agencies, organizations, and persons
XII. Conclusion and summary
XIII. References
XIV. Appendices
|
16. Non-interference Studies
17. Bluetongue Virus Exclusion Test
18. Stability Data To Support Expiration Date
19. Labelling
Draft Copies
Final
Upon completion of the licensing requirements, and receipt and approval of
satisfactory draft labels which require no further revisions, VBS can proceed with issuance of a
Veterinary Biologics Product Licence or Permit To Import
Veterinary Biologics, on the understanding that samples of mounted final
labels will be submitted as soon as possible for approval and filing.
Draft labels may be submitted as computer generated black and white sample
labels. For products sold in multiple container sizes with identical label
text, it is acceptable to submit one set of sample labels from the smallest
container size for approval, provided the other larger labels are otherwise
identical (identical text, formatting and graphics, except for increased white
space and/or enlarged typeface on the larger labels).
VBS requires that
manufacturers submit samples of each finished label for approval and filing. If
applicants wish to receive stamped copies of final approved labels for their
records, they should submit at least two copies of each label component, so
that one copy can be retained in VBS files and the other copies
returned to the firm.
Beside mounting the actual labels onto an 8½ x 11 page, it is also
acceptable to submit colour laser printer copies as samples of finished final
labelling. The colour copies must be the actual size and the same colours as
will appear on the final label.
20. Consultation/notification for National Animal Health Program
Director, Animal Health Division
Program Planning & Coordination
International Trade
Disease Control
Veterinary Biologics & Biotechnology
Regional Animal Health Program Managers
21. Miscellaneous Supplemental Data
Draft advertising
22. Supplemental reviewer notes and comments
|
