Veterinary Biologics Guideline 3.16E
Guideline for Registration of Immunoglobulin Supplements

Introduction

Colostrum products and other immunoglobulin supplements are classified as veterinary biologics, which are licensed by the Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency. To fulfill licensing requirements, manufacturers are required to demonstrate that their products are safe and effective when used according to the label recommendations. In addition, manufacturers must submit a detailed description of manufacturing and testing methods, as well as sample labelling. Upon fulfilment of the licensing requirements, the CCVB issues a Veterinary Biologics Product Licence for Canadian manufacturers and a Permit To Import Veterinary Biologics for imported products.

The CCVB's licensing requirements for veterinary biologics are generally similar to those of the United States Department of Agriculture, Animal and Plant Health Inspection Service, Center for Veterinary Biologics (USDA-APHIS-CVB), and data submitted to the CVB is also generally acceptable to meet our requirements. We require that products originating in the United States be manufactured in CVB licensed facilities and licensed with the CVB. The CVB issues a United States Veterinary Biologics Establishment License and a United States Veterinary Biological Product License when licensing requirements have been fulfilled. Prospective importers must submit an Application For Permit to Import Veterinary Biologics into Canada, as well as a signed Veterinary Biologics Information Form, in which the foreign manufacturer designates the applicant as an authorized importer.

General Potency and Efficacy Requirements

To fulfill the potency and efficacy requirements, colostrum supplements must be shown to contain sufficient immunoglobulin to be of substantial benefit to colostrum-deprived animals. The registration and testing requirements depend on the proposed label claim. The minimum acceptable antibody concentration would depend on the nature of the product and its intended use, however some general guidelines and benchmarks have been established, and these are discussed below.

"Nonspecific" Immunoglobulin Supplements

Products intended for use as a 'nonspecific' immunoglobulin supplement must be shown to contain a consistent quantity of immunoglobulin which is satisfactorily absorbed when the product is fed according to label directions. This would usually entail:

1. demonstrating that the product contains a standard quantity of immunoglobulins as measured by radial immunodiffusion or some other approved method and
2. demonstrating that the immunoglobulins are satisfactorily absorbed when administered to colostrum-deprived calves according to label recommendations.

"Specific" Antibody Supplements

For products with a specific disease prevention claim, the basic immunoglobulin assay and absorption data would need to be supplemented by:

1. a more specific potency test to quantitate specific antibodies and
2. challenge-protection studies to demonstrate that the antibodies confer passive resistance to experimental infection. For example, a product intended for use as an aid in preventing enteric colibacillosis in calves would require:
3. 1. a potency test to quantitate specific K99 antibodies in the product, and
   2. challenge-protection data to verify that the product confers resistance to enteric colibacillosis when used according to the label directions.

Colostrum Supplement versus Colostrum Replacement

It has been reported that 'normal' bovine colostrum typically contains at least 50 grams of immunoglobulin per liter, and 'normal' suckling calves typically consume between 100-300 grams of immunoglobulin, so that post-suckling serum immunoglobulin concentrations are usually in the range of 8-10 mg/mL, or more. Due to the difficulty in manufacturing colostrum replacements with sufficient immunoglobulin to match the levels in normal colostrum, these products are usually labelled for use as colostrum supplements, rather than colostrum replacements. Products intended for use as colostrum supplements in calves should contain at least 24 grams of total immunoglobulin per dose. Products intended for use as colostrum supplements in other species should contain comparable antibody concentrations. An optimal colostrum replacement would be required to confer much higher levels antibody levels than those which would be acceptable for a colostrum supplement.

Absorption Studies To Demonstrate Passive Transfer

For calves, serum immunoglobulin levels below 8 mg/mL would generally be considered indicative of partial failure of passive transfer of immunoglobulins, and levels below 5 mg/mL would be classified as severe failure of passive transfer. Absorption studies should, therefore, attempt to demonstrate post-feeding serum antibody levels in the range of 8 mg/mL, or higher.

Additional information on requirements for licensing of veterinary biologics are described in Veterinary Biologics Guideline 3.1 Guidance for Prepration for New Product Licencing (Registration) Submission for Veterinary Biologics. Enquiries may be directed to the Canadian Centre for Veterinary Biologics.

References

1. Blood D.C. and O.M. Radostits. Veterinary Medicine, 7th edition. London: Baillaire Tindall, 1989; 107-114.
2. Gay G.C. and T.E. Besser. Calves: Factors affecting colostral immunoglobulin absorption. Animal Nutrition and Health 1985; 29-32.
3. Olson D.P. Comparison of two methods for thawing colostrum before supplemental feeding to newborn calves. The Bovine Practitioner 1989;83-86.
4. Olson D.P., Duren E.P., et al. Clinical observations and laboratory analysis of factors that affect the survival and performance of beef cattle. The Bovine Practitioner 1989; 4-11.