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Veterinary Biologics Guideline 3.22E

Guidelines for the Submission, Testing and Reporting of Biological Samples

PREFACE

This document provides a general description of the sample handling procedures followed by the Biologics Evaluation Laboratory (BEL), plus guidelines and requirements for manufacturers of veterinary biologics who submit biological samples to the BEL for quality assurance monitoring. These are outlined in the following sections:

This document supersedes all other previously issued BEL directives/documents on these subjects. It is intended to apply to all biological samples sent for laboratory analysis to the BEL or its designate laboratory facility. Exceptions to these guidelines/policies may exist for special investigation cases.

I. GENERAL REQUIREMENTS FOR MANUFACTURERS SUBMITTING BIOLOGICAL SAMPLES FOR LABORATORY TESTING

Samples of all serials of veterinary biologicals produced and or sold by Canadian manufacturers must be submitted to the BEL for testing before these products can be released for sale. No samples of products imported into Canada are to be submitted unless specifically requested.

In order to avoid unnecessary delay in releasing the test results, the samples of each product to be marketed should be submitted to BEL when final container filling is completed. The requirements for the number of vials or containers to be submitted for each serial are listed in III. Criteria and Frequency for the Testing of Biological Samples Other than Master Seeds - BEL SampleRequirements. Each container or vial will have a label and/or insert carrying at minimum the information outlined below. Labelling requirements for final products are covered in greater detail in the Health of Animals Regulations, Part XI, the Guidelines for Labelling of Veterinary Biologics, and the Guidelines for Labels on Veterinary Biologics Containers of 20 mL or Less.

1. Scientific (proper) name of the product
2. Product tradename
3. Lot/serial number
4. Expiry date (if available).
5. Volume and number of doses
6. Name of the manufacturer
7. Reconstitution directions
8. Date submitted

Each submission will be sent in the approved product carton, accompanied by the insert and the recommended diluent where applicable. The product should be shipped in a manner that ensures it remains at the recommended storage temperature in transit.

All manufacturers' test results for each serial are to be forwarded to the Veterinary Biologics Section (VBS) for approval and release of the serial (using form, Manufacturer's Serial Release Test Report to VBS ).

All samples are to be forwarded to the following address:

Biologics Evaluation Laboratory
The Canadian Food Inspection Agency
3851 Fallowfield Road
P.O. Box 11300, Station H
Nepean, Ontario K2H 8P9
Canada

II. BEL PROCEDURES FOR SAMPLE RECEIPT, TESTING AND REPORTING

A. Samples Tested at the BEL Centre of Expertise

1. Packages containing samples from manufacturers are received at Central Receiving area (3851 Fallowfield Road, Nepean) and are recorded and numbered.

2. The receiving technician immediately delivers the samples to the BEL technical staff. If the BEL contact is not available, the samples are refrigerated at Central Receiving until BEL staff is contacted and retrieves them.

3. Individual samples are inspected and deemed to be in either satisfactory or unsatisfactory condition upon arrival. Replacement samples may be requested for those arriving in unsatisfactory condition.

4. The samples are recorded in the BEL's database using a unique sample number and accompanied by the appropriate tombstone information.

5. The manufacturer or sender of the samples and the Veterinary Biologics Section (VBS) are notified of receipt of the samples (using BEL form BE971020, attached).

6. Steps 1-5 are completed within five working days (usually 2 or 3 days).

7. The decision to test and the type of testing to be done is decided in accordance with the criteria described in Sections III and IV.

8. If the serial is tested, upon completion of the test, the results (e.g. results would include the BEL's titer in potency testing or the presence or absence of growth in sterility tests or Mycoplasma tests with concomitant interpretation of whether the product has passed or failed the test) and the authority to release the serial will be sent to the manufacturer within 35 working days from the receipt of the samples. Because of the length of time of time required for certain purity tests such as Mycoplasma or adventitious viruses, 45 working days will be required. This assumes that the manufacturer's test results have also been received by VBS. Should the tests conducted yield suspicious, equivocal or results interpreted as failure, the manufacturer will be notified and the tests may be repeated.

9. The officer in charge of serial release at VBS is responsible for reporting test results to manufacturers.

B. Samples Tested at an External Lab Facility

1. Sample Handling - Samples sent directly to an external testing facility

1. The VBS will inform the BEL and the testing facility that a sample(s) will arrive for testing.

2. Within two working days of sample receipt, the testing facility will provide to the BEL by Fax (using BEL Form BE971021, attached):

   a)	The date and condition of the samples when received.
   b)	The sample(s) manufacturer, product tradename, lot#, expiry date.
   c)	For each lot#, the number of vials and the volumes received.
   d)	Anticipated test completion date(s).
   e)	Copies of the supporting documents that accompany the sample shipment

3. Upon receipt of the above information, the BEL will assign a BEL Sample Tracking Number(s) and inform the testing facility.

4. BEL will also advise the manufacturer (using BEL Form BE971020) that the samples were received by the testing facility.

2. Reporting - Test results received from the external testing facility
The external lab facility will submit the test results (referencing the BEL lab number) to the BEL. The BEL will submit a test report to VBS.

III. CRITERIA AND FREQUENCY FOR THE TESTING OF BIOLOGICAL SAMPLES OTHER THAN MASTER SEEDS

A. The term "test", unless specifically stated otherwise, generally refers to tests for purity, potency and/or safety. Testing of a product or serial can be one or any combination of tests on that product or serial.

1. The first three serials of any product shall be tested (includes licensed and prelicensed).

2. Subsequent serials shall be tested at the rate of approximately twenty percent of the total number of serials of any given product received (based on previous numbers received). A product will be tested at least once in a 12 month period when there are fewer than five submissions during the same period.

3. Products that have a history of problems (e.g. contamination, adverse reactions), originate from a new manufacturer, have had recent problems, have been produced according to modifications or changes in Production Outlines, or for other appropriate reasons, may be tested more frequently.

4. The testing frequency will also be influenced by a number of factors including resource availability and the fact that the BEL only has retrospective knowledge of the number of serials of any given product that are produced annually which forms the basis for its projected estimate of the number of serials of any given product it will receive in the subsequent year.

5. Other considerations include:

   a.	Vial Size
   	Serials of a product comprising more than 1 vial size are tested as follows: For Sterility and/or Mycoplasma, all vial sizes are tested in one testing session as a representative of that serial. For Potency and/or Safety one vial size may be representative of that serial. Failure in any test for any vial size may be considered failure of the serial i.e. all vial sizes.
   b.	Subserials
   	Subserials will be considered as separate serials for testing purposes, for all categories of testing, i.e. Purity, Potency, Safety. All subserials of any given product, when received concurrently, will not be released until the results of any tested subserials are known. If failure occurs in one or more subserials of a product, all subserials may be in question.

IV. POLICIES AND REQUIREMENTS FOR THE VERIFICATION TESTING OF MASTER SEEDS

A. Master Seed Bacteria

1. All working seed stocks or master seed stocks if they are used as working stock shall be tested.

2. For frozen cultures a minimum of 2 vials containing at least 1 mL per vial is required. For lyophilized cultures at least 2 vials are required (Note: For genetically modified/engineered bacteria an additional vial is required).

3. Testing shall be carried out for identity and characterization and to verify the absence of extraneous viable bacteria and fungi.

B. Information Required from Manufacturer for Master Seed Bacteria

Prior to the BEL's receipt of master seed bacteria the following information should be provided to the BEL:

1. Genus, species and additional taxonomic data (e.g. serotype if available, description of genetic modification if applicable).

2. Origin and history

3. Conditions for storage (e.g. media, temperature, lyophilized, frozen etc.)

4. Conditions for propagation (e.g. media, temperature, CO₂, aeration etc.)

5. Results of any characterization and identity testing (e.g. morphological characteristics, temperature range of growth, speciation by biochemical testing, serotyping etc.)

C. Master or Working Seed Cell Banks

1. All working seed banks or master seed banks if these are used as working stock, of each cell line or primary cells ("normal" mammalian cells only) used in the manufacture of biologicals shall be tested.

2. Samples of each production lot derived from master or working seed banks as described above shall be tested at 5 passages beyond the maximum allowable passage as defined in the Outline of Production. Passaging of cells is to be carried out by the manufacturer and may also be passaged by the BEL.

3. Testing of the above master and/or working seeds and production lots shall be for sterility, including Mycoplasma, adventitious agents, species verification.

D. Cells - sent frozen on dry ice

1. If the manufacturer has separate master and working cell stocks, BEL requires a minimum of 2 vials with a minimum total volume of 2 mL of master stock and a minimum of 4 vials with a minimum total volume of 4 mL of working stock.

2. If master and working cell stocks are one and the same, a minimum of 6 vials with a minimum total volume of 6 mL are required.

E. Information Required from Manufacturers for Master Seed Cell Lines

Prior to the BEL's receipt of master seed cell lines the following information should be provided to the BEL:

1. History

   a.	identification (name and species of cell line)
   b.	origin of cell line
   c.	source of cell line
   d.	passage history of cells
   e.	maximum cell passage allowable for vaccine production lot

2. Growth Conditions

   a.	normal split ratio
   b.	growth medium
   c.	temperature, CO2, humidity requirements
   d.	maintenance medium

3. Freezing Conditions

   a.	freeze medium
   b.	cell density recommended
   c.	conditions (liquid or vapour phase)

4. Results of any QC testing done

F. Master or Working Seed Virus Stocks

1. All working seed stocks or master seed stocks, if these are used as working stock (including genetically modified/engineered viruses) used in the manufacture of biologicals shall be tested.

2. Samples of each virus from the maximum allowable passage level for vaccine production (as defined in the outline of production) shall be tested. Passaging of virus is to be carried out by the manufacturer and may be passaged by the BEL.

3. Testing of the above virus samples shall be for sterility, including Mycoplasma, adventitious agents and virus verification (including genetic analysis where necessary).

G. Virus - sent frozen on dry ice

1. If the manufacturer has separate master and working virus seeds, a minimum of 2 vials with a minimum total volume of 2 mL of the former and a minimum of 4 vials with a minimum total volume of 4 mL of the latter would be required.

2. If master seed and working virus seeds are one and the same, a minimum of 6 vials with a minimum total volume of 6 mL would be required.

3. A minimum of 2 vials with a minimum total volume of 2 mL of neutralizing antiserum to master seed virus (if virus was totally neutralized in a maximum 1:1 ratio with antiserum) would also be required.

NOTE: For genetically modified viruses, one mL extra for all categories.

If, at any time, a manufacturer intends to put into use a new master or working stock of either cells or virus, the new stock(s) should be resubmitted to BEL (as above) for testing.

H. Information Required from Manufacturers for Master Seed Virus

Prior to the BEL's receipt of master seed virus the following information should be provided to the BEL:

1. History
   

   a.	name (family, genus) of virus
   b.	origin of virus
   c.	source of virus
   d.	passage history
   e.	maximum virus passage allowable for vaccine production lot
   f.	titer of master seed

2. Growth Conditions
   

   a.	cell line(s) generally used
   b.	medium, incubation temperature
   c.	moi, adsorption time, usual time of harvest
   d.	expected titer range

3. Storage Conditions
   

   a.	temperature
   b.	condition (liquid or lyophilized)
   c.	stability

4. Results of any QC testing done

V. APPENDIX

The following forms constitute part of this guideline and are appended.

Form BE971020

Report for Receipt of Biologics Samples

T=will be tested; NT=will not be tested; ECDT=estimated completion date of test

_______________    ________________
Leader, BEL C of E    date y/m/d

(BEL Form: BE971020 replaces BE970627)

Form BE971021

Report for Receipt of Biologics Samples

# = number of containers; Vol=volume in each container; BEL#=tracking number assigned by BEL; ECDT=estimated completion date of test

_________________    ________________
for Lab Testing Facility    date y/m/d

(BEL Form: BE971021 replaces BE970628)