VB-GL-3.13: Autogenous veterinary biologics

1. Introduction
- 1.1 Legal authority
2. General guidance
3. Production of autogenous VB
4. Additional information
5. Appendices
- Appendix 1: Sample copy of manufacturer's serial release test report (MSRTR) for an autogenous veterinary biologic
- Appendix 2: Example of autogenous veterinary biologics summary information

1. Introduction

The purpose of this guideline is to provide information regarding the requirements for manufacturing, importation and distribution (including exportation) of autogenous veterinary biologics for use in terrestrial animals and farmed fish. The Canadian Centre for Veterinary Biologics (CCVB) is responsible for licensing veterinary biologics (VB), including autogenous vaccines, under the legal authority of the Health of Animals Act and the Health of Animals Regulations.

In accordance with the Health of Animals Act Section 64.(1)(s), veterinary biologics (VB) must be shown to be pure, potent, efficacious and safe. However, during an emergency, data to demonstrate potency and efficacy may be exempted under Section 131.1 (1) of the Health of Animals Regulations. Autogenous VB may be approved to meet a specific and immediate need when a disease is associated with a new pathogenic organism, when licensed commercial VB are not effective or not available to prevent or control the disease situation.

Use of infected tissue, blood, serum or faeces from sick or dead animals in healthy animals and use of bedding materials from contaminated premises to other premises is considered unacceptable from a veterinary biosecurity perspective. This practice is in violation of Health of Animals Regulations Part X Sections 112 and 113.1.

Note: This guideline uses terminology for terrestrial animals. In the case of autogenous VB for fish, the reader should substitute the terms hatchery, or fish farm, where appropriate, for the terrestrial references.

1.1 Legal authority

Health of Animals Act

Health of Animals Regulations, Part XI

2. General guidance

2.1 Basic criteria

Veterinary biologics manufacturers in Canada and the United States (U.S.) must obtain a licence and written approval from the CCVB for the production of autogenous VB
Licensed Canadian and U.S. manufacturers prepare autogenous VB for emergency use by or under the direction of a licensed veterinarian
A valid veterinarian-client-patient relationship is a prerequisite for the use of autogenous VB
Each use of an autogenous VB must be justified based on clinical and laboratory diagnosis and a veterinary prescription
Autogenous VB shall be prepared from the culture(s) of microorganism(s) isolated from the infected animals and judged to be the cause of the current infectious disease affecting the herd, flock, or an individual animal on the premises
Autogenous VB shall consist of cultures or extracts of microorganisms that are inactivated and nontoxic
Autogenous VB are to be used only in the herd or flock of origin unless justified by the attending licensed veterinarian
Autogenous VB must be considered safe for the target and non-target animals, humans, and the environment
Only the amount of autogenous VB needed for primary and booster vaccinations of the herd or flock of origin within a year shall be produced
- Any left over autogenous VB must be destroyed
Potency, efficacy and field safety of autogenous VB are not established
Due to lack of efficacy and potency data, the expiration date for the autogenous VB shall not exceed twelve months from the date of harvest
- The extension of expiration dating is not permitted
Applications for production and use of autogenous VB against certain diseases may be evaluated in consultation with other relevant authorities of the Canadian Food Inspection Agency (CFIA) and other departments and agencies
The production and use of an autogenous VB containing live microbial organisms is not permitted
The production and use of an autogenous VB containing viral and bacterial combinations is not permitted
The production of autogenous VB against the diseases that are regulated by the CFIA under its disease control or eradication program is not permitted

2.2 Roles and responsibilities of the attending veterinarian

The attending licensed veterinarian will be responsible for:

ensuring a proper veterinarian-client-patient relationship
coordinating disease diagnosis, isolation and identification of causative organism
issuing a prescription for an autogenous VB
maintaining records of prescriptions and use of autogenous VB
directing the administration of the autogenous VB
in the case of U.S. manufactured autogenous VB
- applying for an import permit
- maintaining a copy of the import permit
- complying with all conditions noted on the import permit
reporting suspected adverse reaction due to autogenous VB to the manufacturer and/or the CCVB

2.3 Roles and responsibilities of the manufacturer

The Canadian or U.S. manufacturer will be responsible for:

preparing microbial seeds for the production of autogenous VB
ensuring the purity and identity of seed materials
production, testing, packaging, labelling, storage and distribution of autogenous VB in accordance with the Health of Animals Acts and regulations, this guideline, veterinary biologics establishment licence, veterinary biologics product licence and approved Outline of Production (OP) and related special outlines (SO)
ensuring that each serial of autogenous VB has been evaluated for purity, sterility and safety prior to its use
maintaining appropriate records
retaining samples of each serial of autogenous VB for confirmatory testing when requested by the CCVB
reporting any suspected adverse reaction due to autogenous VB to the CCVB in accordance with the Health of Animals Regulations Part XI Section 135.1

3. Production of autogenous VB

3.1 Facility and personnel requirements

The facility, personnel and equipment must be suitable for manufacturing, preservation, packaging, labelling, testing, storage and distribution of autogenous VB
The facility must be inspected by a CFIA veterinary inspector and approved by the CCVB prior to production of autogenous VB
Microbial seeds used for the production of autogenous VB must not be introduced into non-autogenous VB manufacturing facilities
The autogenous VB manufacturing facility must be separated from the laboratories where diagnostic and research activities are carried out
A separate dedicated facility or area is required for the production of autogenous VB containing virus or spore-forming organisms
Each serial of autogenous VB must be prepared on a campaign basis

Refer to the following guidance for facility, personnel, and equipment requirements:

Health of Animals Regulations, Section 128
VB-GL-3.34: Requirements for veterinary biologics facilities
VB-GL-3.28: Requirements for the personnel involved in the manufacturing, testing, and importation of veterinary biologics

3.2 Data and documentation requirements for licensing autogenous VB

Canadian and U.S. autogenous VB manufacturers should refer to the following guidance for preparing an autogenous VB licensing submission:

The following documents are required for an autogenous VB licensing application:

a cover letter introducing the submission and identifying the regulatory contact
Form CFIA/ACIA 4720 – Application for Services and the financial account number of the applicant
Form CFIA/ACIA 1503 - Veterinary biologics information
a signed copy of a generic OP for the autogenous VB that require similar materials and methods for production and testing
- a separate OP will be required for each autogenous VB, if the production and testing methods differ significantly from the generic OP
a signed copy of each SO (such as test methods for sterility, safety, inactivation, residual formaldehyde, etc.)
information on materials of animal origin used for isolation of seed materials, and production and testing of autogenous VB
Declaration of compliance for materials of animal origin
a copy of a sample manufacturer's serial release test report (MSRTR) (refer to appendix 1)
- A sample copy of the MSRTR is not required from U.S. manufacturers
adjuvant safety data for autogenous VB formulated with an adjuvant
validation data for product inactivation
draft container labels and package insert

Each application is reviewed on a case-by-case basis. Additional information may be requested by the CCVB at the time of review.

Companies should contact the Pre-market Application Submissions Office (PASO) if they require information about opening a CFIA billing account or to pay by credit card.

3.3 Labelling of autogenous VB

Canadian and U.S. autogenous VB manufacturers must submit a generic label with the initial licensing application. Depending on the size of the final container, some of the information may be included in the package insert. Final container label must present information to customers in both English and French. The CCVB may allow the use of a bilingual insert as a substitute for fully bilingual container label. Refer to VB-GL-3.3: Labelling of veterinary biologics.

The labelling for autogenous VB must contain the information as listed below:

assigned name of the product (for example, for bacterial product, Autogenous bacterin followed by the name of the bacteria, or for viral product, Autogenous vaccine followed by the name of the virus and the term "Killed virus")
- A trade name is not permitted for an autogenous VB
species of animal in which the autogenous VB will be used
name and address of the attending licensed veterinarian
name, address and establishment licence number of the manufacturer
preservatives and inactivating agents used in the autogenous VB
net quantity (volume or doses) in the container
expiration date and serial number of the product
dosage, recommended route of administration, frequency of vaccination and withdrawal period
storage conditions
the label or package insert must include the following standard cautionary statements:
"For veterinary use only. For vaccination of healthy animals against disease(s) caused by ... [name(s) of the organism(s)]. Do not vaccinate within 21 days (or more depending on the type of the adjuvant used) before slaughter. An autogenous veterinary biologic is used in an emergency situation when a licensed product is not available to prevent the spread of a disease to healthy animals. Potency and efficacy of this biologic have not been established. This product has been prepared for use only by or under the direction of a licensed veterinarian."
additional cautionary statements or warnings as required

3.4 Additional requirements and restrictions for production and use of autogenous killed viral vaccines

A separate submission is required for each autogenous killed virus vaccine; this will cover all strains of a particular virus type. Each application for an autogenous killed virus vaccine is reviewed on a case-by-case basis in consideration of that virus, its known strains and variants.

In addition to the documents listed above, an application for autogenous killed virus vaccine will include:

data on cell lines and embryonated eggs
- primary cells and established cell lines used in the production of an autogenous vaccine must meet the same requirements as a fully licensed vaccine
- primary cells and established cell lines must undergo confirmatory testing by an independent laboratory as directed by the CCVB
- embryonated eggs must be obtained from an acceptable supplier of specific pathogen free (SPF) eggs
- the source of the SPF eggs must be identified in the OP
data on virus seed
- virus seed used for an autogenous killed virus vaccine must be tested for identity and purity
- an adequate number of virus seed samples must be retained by the manufacturer for independent confirmatory testing when required by the CCVB

3.5 Requirements for importation of autogenous VB from the United States

The approval of autogenous VB manufactured in the U.S. is a 3-step process.

Step 1: The U.S. manufacturer must meet the data and documentation requirements for the manufacturing facility, and materials and methods used in production and testing of autogenous VB. The U.S. manufacturing facility will be inspected by a CFIA veterinary inspector before the approval of the first autogenous VB.

In addition to the requirements listed above, U.S. manufacturers are required to submit the following materials:

copies of United States Department of Agriculture (USDA)-Center for Veterinary Biologics (CVB) approved Outline of Production and SOs
copy of the USDA-CVB approved label and package insert
a set of up-to-date facility and personnel documents
a copy of the most recent inspection report by the USDA-CVB

CCVB approval of the submitted documentation allows U.S. manufacturers to prepare autogenous VB for attending veterinarians in Canada in accordance with the specific conditions or restrictions identified at the time of the approval.

Step 2: The attending Canadian veterinarian submits the following documents to apply for a permit to import a specific serial of autogenous VB:

a completed form CFIA/ACIA 4720 - Application for services with the appropriate fee to import a specific autogenous VB serial, service option 3.(2), project code 1346
a completed and signed form CFIA/ACIA 5569 Veterinarian's application for an import permit for prescription platform product or autogenous veterinary biologic describing the specific disease problem, including:
- names, addresses and phone numbers of the owner and attending veterinarian
- date of the disease outbreak
- animal species and number of animals affected
- tentative diagnosis
- dates of specimen collection and/or isolation of the causative agent
- rationale for use of the autogenous VB, especially in non-adjacent premises
- a copy of the laboratory report

Step 3: The U.S. manufacturer submits the following documents directly to the CCVB:

summary of test results (U.S. form APHIS 2008) for the serial of autogenous VB to be imported
a copy of the label that will be used for the serial intended for use in Canada showing:
- the name and address of the attending licensed veterinarian
- serial number
- expiration dating that shall not exceed 12 months from the date of harvest
the inactivation report for the specific serial of autogenous VB to be imported

Each request for production and importation of an autogenous VB serial from the U.S. is reviewed on a case-by-case basis. Additional information may be requested by the CCVB at the time of review. Upon approval of the application, a single entry permit to import veterinary biologics will be issued to the attending veterinarian for a specific serial of the autogenous VB. A copy of the permit must be kept on file by the attending veterinarian and a copy of the permit must accompany each shipment.

Canadian veterinarians and U.S. autogenous VB manufacturers should contact the Pre-market Application Submissions Office (PASO) if they require information about opening a CFIA billing account or to pay by credit card.

Autogenous killed virus vaccine

For a serial of an autogenous killed virus vaccine, the attending veterinarian is required to submit forms CFIA/ACIA 4720 and CFIA/ACIA 5569 to the CCVB prior to placing their order with the U.S. manufacturer. The CCVB will pre-approve the production of the serial and relay this information to both the applicant and the U.S. manufacturer. The U.S. manufacturer is required to submit the serial-specific test results, serial-specific label, and inactivation report directly to the CCVB once tests are completed, and before the CCVB will issue the import permit to the veterinarian.

3.6 Requirements for production and use of multivalent autogenous VB

Ordinarily, autogenous bacterin or autogenous killed viral vaccines shall be monovalent. However, an autogenous VB containing more than one organism may be prepared and used at the discretion of the attending licensed veterinarian.

Production and use of autogenous VB containing multiple organisms must be justified in writing. An autogenous VB shall contain only the organisms which are isolated from the same herd or flock, and are considered to be the cause of the current disease situation. Since the data to support lack of antigenic interference is not available for autogenous VB, the number of antigenic fractions contained in an autogenous VB must be minimized as much as possible. The risk of adverse reactions due to a multivalent autogenous VB must also be considered.

Separate approval is not required from the CCVB for the production of autogenous bacterin vaccine containing more than one organism. A copy of the written justification from the attending veterinarian must be maintained in the batch file and made available to a CFIA veterinary inspector when requested. The approved OP must describe the materials and methods used in production and testing of all antigens of a multivalent autogenous VB.

Pre-approval from the CCVB is required prior to production of autogenous killed viral vaccines containing more than one organism.

Autogenous VB must not be mixed with licensed products because supporting data to evaluate the impact of the autogenous product on the safety and efficacy of the licensed product is not available.

3.7 Requirements for production and use of autogenous VB in adjacent and non-adjacent premises

Autogenous VB are to be used only on the premises from which the microorganism was isolated. At the discretion of the attending licensed veterinarian, an autogenous VB may be used in adjacent premises if the animals at the adjacent premises are considered to be at risk. Only the isolate from the recent outbreak of infectious disease shall be used.

An autogenous VB may be used at non-adjacent premises only with a valid justification from the attending licensed veterinarian. The veterinarian must clearly identify the common links or sources that could potentially transmit the disease between the herd of origin and the non-adjacent premises.

Separate approval is not required from the CCVB for use of an autogenous VB in adjacent and non-adjacent herds. However, a copy of the written justification from the attending veterinarian must be maintained in the batch file and made available to a CFIA veterinary inspector when requested.

3.8 Requirements for production and use of autogenous VB beyond 36 months

Autogenous VB may be produced from the same isolate up to 36 months without additional data and justification, provided that updated information as specified in form CFIA/ACIA 5569 Information Required for Prescription Platform Product and Autogenous Veterinary Biologics is on file. The long term use of the same isolate for production and use of an autogenous VB is not considered an emergency under Section 131.1 (1) of the Health of Animals Regulations. Therefore, the use of the same isolate for production of autogenous VB beyond 36 months from the date of its first isolation must be justified. All requests for the use of an isolate beyond 36 months are reviewed by the CCVB on a case-by-case basis.

To approve the same isolate for production of autogenous VB beyond 36 months from the date of isolation and up to 60 months, the attending veterinarian(s) must submit a written request to the CCVB and provide justification for its continuous use. The justification must include but is not limited to the satisfactory performance from the previous use, information on vaccine safety, effectiveness and ongoing diagnosis/surveillance effort.

3.9 Serial release procedure for autogenous VB, including autogenous killed viral vaccines

The required quantity of representative samples from each serial must be collected for testing by the manufacturer and for retention by the manufacturer for independent confirmatory testing as directed by the CCVB.

Each serial of autogenous VB must be tested for sterility, safety, completion of inactivation, residual formaldehyde (if applicable), and any other tests as specified in the approved OP. All required tests must be completed satisfactorily and documented in the MSRTR before releasing the serial for shipment. A satisfactory serial can be released by the quality control or quality assurance supervisor of the manufacturer after verifying its compliance with the requirements.

The CCVB may require manufacturers to submit serial release documents for review, if the new serial is significantly different from the products previously produced by the manufacturer or there is a significant change in the production and/or testing process. After satisfactory review of the documents, the CCVB will authorize the manufacturer to release the serial(s).

3.10 Requirements for production of autogenous VB for export to foreign countries

A new serial of autogenous VB may be prepared by a Canadian manufacturer for export to a foreign country under the existing product licence with the conditions listed below. Requests for production of an autogenous killed virus vaccine for export to foreign countries will be reviewed on a case-by-case basis and the specific requirements will be identified during the review of the application. Written authorization from both the regulatory authority of the importing country and the CCVB must be obtained prior to initiating the production of a new serial of autogenous VB intended for export. The manufacturer will be responsible for complying with the national, provincial and local regulations of the importing country, and any conditions or restrictions specified by the regulatory authority of the importing country

The seed material imported into Canada must be in the form of pure culture and not in the form of animal tissue or body fluid
- The Canadian manufacturer importing the seed materials must contact Biohazard Containment and Safety in the CFIA or the Public Health Agency of Canada, as appropriate, for the specific requirements for import permit for animal pathogens
The seed culture must be tested to confirm the identity of the organism and purity of the culture.
The seed culture must be found to be pure prior to introduction into the autogenous VB production facility
Production of autogenous VB against animal pathogens which are not present in Canada or diseases exotic to Canada is not permitted
The materials and methods used in the production and testing of the export serial must conform to the materials and methods described in the OP for autogenous VB on file with the CCVB
The manufacturer will be required to revise the current OP and/or submit new OP and SO, if the materials and methods used in the production and testing of the export serial vary from the generic OP or SO filed with the CCVB
- The new or revised OPs and SOs must be approved by the CCVB before the production of the export serial
All materials of animal origin used in the production and testing of the export serial must conform to the requirements described in VB-GL-3.32: Minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics
The total volume or doses of the serial must be as specified in the official document issued by the regulatory authority of the importing country
Multiple serials or sub-serials from the same seed may be prepared to complete the volume or doses specified in the initial permit or official document issued by the regulatory authority of the importing country
- Similarly, additional serials or sub-serials may also be prepared from the same seed to export additional shipments if authorized by the regulatory authority of the same country through an amended or new official document
- The official document must be maintained by the manufacturer to justify the production and export of multiple serials or sub-serials
A serial or sub-serial of an autogenous VB prepared for export to one country cannot be exported to a second country without written approval from the destination country as well as from the CCVB
A new serial of an autogenous VB can be shipped only after all tests (including completion of inactivation, sterility and animal safety test) are completed satisfactorily
The label used for the autogenous VB may be prepared as per the requirements and in the language of the importing country, however, the label must clearly identify the product as an autogenous VB showing:
- the name of the organism
- target animal species
- net quantity in the container (volume or doses)
- storage conditions
- serial number
- expiration date
- name and address of the manufacturer, and
- Canadian veterinary biologics establishment number
In order to prevent any inadvertent use of the product in Canada, the label must include a statement "For use in [name of the country] only" or "Not for use in Canada" or another equivalent statement
Accurate, complete and current records of production, testing, shipping and receiving of all starting materials, bulk antigens and finished product must be maintained by the manufacturer and made available to a CFIA veterinary inspector when requested

Procedure for obtaining written approval from the CCVB for production and export of autogenous VB to foreign countries

To obtain an approval, the Canadian manufacturer must submit the following documents to the CCVB for review:

a cover letter identifying the name of the organism and number of doses/volume to be produced
a statement confirming that the production and shipment of the new serial of the autogenous veterinary biologic will conform with the required conditions
a copy of the official document (such as permit, licence, certificate or equivalent) issued by the regulatory authority of the importing country showing the name of the organism and number of doses/volume to be exported
a copy of the certified translation, if the official document is not in English or French
a copy of the laboratory report confirming purity of the culture and identity of the organism

After the receipt and satisfactory review of the above documents, the CCVB will authorize in writing the introduction of the seed into the autogenous VB production facility for production of a new serial of autogenous VB. There is no cost recovery fee associated with this service.

3.11 Record keeping

The following records for each serial of autogenous VB must be maintained by the manufacturers and made available to a CFIA veterinary inspector when requested:

signed veterinary prescription for each serial of an autogenous VB
information about the specific disease problem as provided by the attending veterinarian
microorganism isolation and laboratory test report
isolate/seed inventory record with all isolates listed by their unique identification (ID) number
accurate and complete production and testing records
inventory and distribution record for each serial
copy of the label used for each serial
records of any suspected adverse reactions
written justification from the attending veterinarian for the following circumstances:
- using the same isolate in production of a new serial of autogenous VB beyond 36 months
- preparing multivalent autogenous VB
- preparing the same autogenous VB for adjacent and non-adjacent herds

3.12 Reporting of autogenous VB production

A summary of all serials of autogenous VB produced, including unsatisfactory serials, must be reported by the manufacturers to the CCVB on a quarterly basis. Foreign manufacturers will only be required to report on those serials of autogenous VB that are manufactured for use in Canada. Quarterly reports should be submitted no later than the last day of January, April, July, and October. Summaries must include the following information:

Name, address, establishment licence number of the manufacturing facility
Product file number
Serial number
Name of the microorganism(s) and isolate number(s)
Date of serial release
Number of containers and total doses produced
Expiration date of the serial
Name and address of the farm
Name of the attending veterinarian

The summary information must be signed and dated by the authorized representative of the company. An example of the summary information to be submitted is found in Appendix 2. Other formats of summary information are also acceptable.

3.13 Restrictions on advertisement of autogenous VB

The authority for regulating the advertisement of VB is provided in the Health of Animals Regulations, Part XI Section 135. (1) and 135. (2) which require all advertised claims to be supported by data on file with the CCVB. Manufacturers of autogenous VB may advertise their services for the purpose of informing Canadian veterinarians. However, any specific autogenous VB or any claim against specific disease (including potency and efficacy) must not be advertised, due to the lack of data to support potency, field safety and efficacy.

4. Additional information

Contact the CCVB if you have additional questions or need clarification on regulations and requirements for autogenous veterinary biologics.

Guidelines and forms are available on the CCVB website.

5. Appendices

Appendix 1: Sample copy of manufacturer's serial release test report (MSRTR) for an autogenous veterinary biologic
Appendix 2: Example of autogenous veterinary biologics summary information

Appendix 1: Sample copy of manufacturer's serial release test report (MSRTR) for an autogenous veterinary biologic

Company name
Canadian veterinary biologics establishment licence number
Telephone - facsimile

Product name:

CCVB file number:
Outline of Production date:
Animal species:
Name and address of the farm:

Serial number:
Unique identification number of isolate:
Fill date:
Expiration date:
Container size (doses or mL):
Total number of containers:
Total number of doses:

Name and address of the attending veterinarian:

Test and reference	Date on test yyyy/mm/dd	Date off test yyyy/mm/dd	Test requirement^{Table Note 1}	Test results	Code:^{Table Note 2}
Purity (pre-inactivation) OP/SO reference
Sterility - bulk product OP/SO reference
Sterility - finished product OP/SO reference
Animal safety OP/SO reference
Residual formaldehyde OP/SO reference
Other tests (specify) OP/SO reference

Disposition by manufacturer

All tests completed satisfactory (yes or no):
Eligible for release (yes or no):
Destroyed (if yes, reasons for destruction):
Additional comments (if applicable):

Signature of the laboratory technician:

Date:

Signature of the QA manager: