" Approved Products – the Right Choice"

Prepared by Melanie Hoare, Syndel International Inc.

From a presentation at Aquaculture Association of Canada June 1998

This review of the current state of approval processes related to aquaculture was prepared as an overview of the Canadian situation and does not represent the status in any other jurisdiction. The comments were accurate at the time they were delivered and are subject to ongoing changes.

Commonly asked questions:

• What products are currently registered in Canada for use with fish?
• What are the economics of approved product development?
• Who is involved in the registration process?
• What is the impact of Canadian regulations on product availability?
• What manufacturing requirements must a registered product meet or exceed?
• What is HACCP and what are the implications in Canada?

Introduction

Registered products for use with food fish in Canada must pass some of the most stringent and comprehensive requirements in the world. They are thoroughly regulated, from raw ingredients used for production to the condition of the final consumer product. Consumers value these regulations: we believe that they provide us with a guarantee of safety, of a standard of quality to which we are all entitled as consumers. They also act as a quality standard for exporters to use to their advantage, as Canadian regulations are viewed in the global marketplace as some of the most rigorous in the world.

By using registered and approved products, we close doors to criticism and promote success in our own industry.

Compliance with Canadian drug regulations has an effect on the number of drugs available for aquaculture use in Canada and on the cost of providing approved drugs to aquaculturalists. High costs and long delays for government review, combined with limited Canadian markets, have discouraged drug development and approval. While drug regulations are in place to ensure product safety and quality, much of the cost of compliance can be attributed to cost-recovery fees paid to government agencies and not to actual drug development and production costs.

What products are currently registered in Canada for use with fish?

There are several classes of products currently approved in Canada. Examples of registered pharmaceuticals include two anaesthetics, four antibiotics and a formalin treatment. Registered feed additives include pigments, preservatives, nutrient supplements or antioxidants. Vaccines for many common diseases of salmon have been approved for sale in Canada and are classed under biologicals. Several pesticides are currently under review.

What are the economics of approved product development?

Approval is a thorough, stringent and resource consuming process. From discovery to approval, the food animal drug development process can take up to twenty years and total costs can exceed $250M. These costs must be recovered by the manufacturer. Many other costs don’t even have anything to do with the development and production of the product. For example, it costs Syndel $6750 minimum annually for an Establishment License to handle drugs. This fee has nothing to do with manufacturing or approvals; it is just a license to do business. For each lot of drugs, already manufactured to GMP requirements and thoroughly tested, Syndel must do final analytical testing, costing approximately $1000 per lot and taking about 4 weeks. This means the lot must be held for 4 weeks before any sales can happen. The overall cost to Syndel of drug regulatory requirements is in excess of $100 000 per year for the few approved drugs we handle. The work consumes more than one full time position. This figure does not even include any of the costs of drug manufacturing, sales or distribution.

These costs must be considered in light of the small market for fish health products in Canada. Fish products make up a very small portion of the $350M annual animal health products market in Canada. By comparison, Canadian human pharmaceuticals are worth an annual $5B. For perspective, the US animal drug industry is worth $2B and their human pharmaceutical industry is worth at least $61B.

In light of these concerns with regulatory issues and profitability, we are very fortunate that we have so many products available, even though we know what we have is not nearly enough.

Who is involved in the registration process?

Product registration is a diverse and lengthy process. For different products, the process is regulated by several different government bodies, each with its own mandate, including departments of Health Canada such as HPB (Health Protection Bureau), BVD (Bureau of Veterinary Drugs), PMRA (Pest Management Regulatory Authority), and departments of Agriculture Canada (AgCan) such as VBBS (Veterinary Biologics and Biotechnology Section) and the CFIA (Canadian Food Inspection Agency).

For drugs, approvals or Notices of Compliance in Canada actually specify an approved label stipulating animal species, disease or condition, dose, delivery method and drug. These approvals are handled by BVD, an agency made up of a diverse group, including vets, senior research scientists, toxicologists and epidemiologists. This agency covers many areas of the regulatory process for vet pharmaceuticals and feed additives including human food safety, animal safety, animal efficacy and manufacturing.

What is the impact of Canadian regulations on product availability?

BVD is one of the federal agencies, like PMRA and VBBS, that has implemented a cost recovery system. Payment of fees totalling thousands of dollars is required at each stage of the review process. For example, review of applications for preliminary trials under Experimental Studies Certificates cost $960 for each new trial. The BVD cost recovery program is the most expensive in the world relative to the size of the market.

Recent changes in the GMP regulations have imposed new fees for inspections and licensing of all establishments that manufacture and sell drugs in Canada. These new costs are so large that many existing products are being withdrawn by veterinary drug manufacturers because the fees make them unprofitable. These regulations were also intended to apply to all human products including herbal medications, but successful lobbying by interest groups eliminated controls on herbal products. Veterinary drugs are now more highly regulated and costly to produce than many human medications.

BVD reviews show some important information. For example from 1995 to 1997, the number of new drug submissions has steadily decreased. The proportion that take over 6 months to review has steadily increased. Predictions for the future in Canada suggest small and medium sized manufacturers will be disadvantaged and submission numbers will dramatically decline. New drug submission numbers will continue to decline and there will be fewer submissions for additional indications.

VBBS, involved in the regulation of biologicals such as vaccines, did a review in 1997. This submission review update revealed that of the 40 total new drug submissions, only 3 were licensed. So far, the VBBS cost recovery program has recovered at least $300 000 in fees from manufacturers for approvals, since the implementation of the program in 1996.

Canadians demand stringent regulations for health and food safety, and this has earned our markets international respect. It is unfortunate that the expense of implementing these same regulations is prohibitive to our own manufacturers and producers. These increased costs and our small market size combine with government cost recovery and reorganisation to make new products and approvals even more challenging for us.

In addition to the government agencies, and of course the applicant, who may be a distributor or a manufacturer, there may also be one or more private agencies involved as facilitators in the approval process, such as Salmon Health or the Canadian Animal Health Institute. Salmon Health, part of the Canadian Aquaculture Industry Alliance, is a national fish health advocacy organization representing Canadian salmon producers, fish health suppliers and other public agencies, that facilitates the approval process in return for royalties from sales of registered products. The Canadian Animal Health Institute is a trade association representing the manufacturers and distributors of pharmaceuticals, biologicals, feed additives and pesticides used in vet medicine and livestock agriculture.

What kinds of manufacturing requirements must a registered product meet or exceed?

Registered products have to meet with a large number of conditions, set out by many different organisations depending on their nature. Manufacturing must meet current GMP (Good Manufacturing Practices).

What is GMP?

GMP is a world recognized standard assuring quality and safety of pharmaceutical and food products. All approved pharmaceuticals must be manufactured to meet these standards. GMP assures that the premises and equipment involved in production are suitable for the purpose and personnel are properly trained. It ensures that sanitary concerns are addressed. Moreover, all materials used in production must meet predefined quality standards and actual manufacturing processes are tightly controlled. Throughout the manufacturing process, quality control is defined and products are fully tested to ensure that they meet these quality standards. These quality standards include all packaging and labelling of products. All of these details are documented in advance and each batch must meet these standards.

How is GMP implemented?

All materials used are of the highest quality. Whenever available, pharmaceutical or food grade materials are used. Raw materials are obtained from reputable sources and are tested to ensure that they meet the specifications. Products are manufactured and packaged under tightly controlled conditions that are documented to ensure that products are of the highest quality. The responsibility for administering and monitoring GMP rests with Health Canada and other government agencies.

Why GMP?

GMP provides a record of all steps of manufacturing, ensuring standardized quality and safety, and management of risks associated with manufacturing.

Most chemical products are available in various levels of purity and quality. The higher the purity and the quality, the more expensive the chemical is. Approved GMP products are often of increased purity. As a rule of thumb, if a 90% pure material costs $10, then 99% pure costs $100 and 99.9% pure costs $1000. While low quality or purity product may be used safely and effectively, there may be instances where impurities will cause distress or mortalities to animal populations. Aquaculturalists have discovered that using slightly less expensive, lower quality products can be quite expensive in the loss of their final product.

What is HACCP and what are the implications in Canada?

Hazard Assessment Critical Control Points (HACCP) is the new food inspection system employed by the US Food and Drug Administration (FDA) based on principles of managing risk by controlling processing at critical points. FDA is now using HACCP as the basis for its seafood safety system. HACCP is intended to be more proactive and efficient than traditional systems of inspections of manufacturing conditions and random sampling of final products. Seafood importers and processors must now employ a HACCP program covering products entering the US. Processors must work with farmers to ensure compliance.

Drugs used in aquaculture are one of the potential "hazards" identified in the HACCP process. HACCP is a new program and the issues surrounding use of drugs and prevention of drug residues are complicated and, in many cases, are still unclear. The approach in Canada has been to involve the farmers, veterinarians, industry associations, processors and government in the development, application and monitoring of the program.

US importers of Canadian farm salmon must verify that the fish from Canada have been processed following HACCP. There are two ways for the American importer to verify compliance:

1. Obtain product from a country with which the US has a HACCP-based agreement covering equivalency of inspections programs, or
2. Implement a verification procedure including product specifications for safety and affirmative steps to ensure HACCP compliance, such as:

• obtaining processor’s HACCP and sanitation records
• obtaining third party certification that product is processed according to requirements
• inspecting facilities to ensure product is processed to meet requirements
• obtaining a copy of processor’s HACCP and a guarantee that it is being followed
• end-product testing and obtaining a guarantee that the plan is being followed

 In Canada, an approach that meets the needs of the Canadian industry and government has been developed. The Canadian industry is implementing a program for drug use based on the HACCP model that involves an industry-run program, with regulators agreeing that their legal responsibilities are covered. The program provides detailed drug use action plans for producers, verification procedures and corrective actions.

The elements of the program include:

• Meeting the regulatory requirements of both the US and Canada
• Fish handling, tracking and reporting procedures that guarantee that harvested fish have undergone the prescribed withdrawal period after treatment and meet the drug residue limits. This will involve the producers, veterinarians and processors.
• An agency that oversees compliance with the program using independent contractors or producer associations.
• Accreditiation of the program by regulators.
• Involvement of Canadian and US agencies in negotiations to establish the program.

Canada has its own Fish Inspection Act, enforced by the CFIA. The main requirements cover the issues of QMP and accountability. All federally registered facilities are subject to audits conducted by the CFIA whose inspectors determine compliance with the Fish Inspection Regulations. The CFIA has revamped its QMP to include all seven HACCP principles.

Salmon Health is developing the Healthy Salmon Program based on a HACCP model. Some of the potential guidelines in the HSP program may request only the use of therapeutants with DIN or PCP numbers and label instructions for use in aquaculture. It may request purchasing medicated feed only from CFIA inspected and approved feed mills. It will probably require proof of appropriate prescriptions, ESCs or EDRs. As a seller of market fish, the processor could cite the presence of an HSP certificate as part of a good supplier quality assurance program. You could potentially lose that quality assurance by not using registered and approved products. By choosing the approved product, both the government and the manufacturer have accountability. Fish culturists need to effectively manage the health of their stock to be internationally competitive. However, they must ensure that their products are compliant with all regulations before they are put to market. Therapeutant residues in excess of accepted tolerances can represent food product adulteration – a significant international regulatory issue. The confidence needed to ensure safe consistent, wholesome product can only be achieved by the registered compound process.

Conclusions

1. There are many compelling reasons to buy approved products.
2. Approved products carry the assurance of extensive testing for safety and effectiveness
3. Use of approved products provides the comfort of products manufactured under closely monitored quality control and manufacturing processes
4. Proceeds from sales of registered products go to support the development of new products and to support the groups that facilitate aquaculture product approvals for the sake of the industry.
5. Consumer support for approved products encourages suppliers to bring new products to our industry. Farmers constantly search for new or different or better tools for success, but if they don’t support the presently registered products, there is no incentive to development new ones.
6. There is increasing customer and public awareness and concern regarding use of therapeutants and compounds on our fish that can only be responded to effectively with the documented figures, methods and information that accompany registered products. The use of approved products helps to ensure that fish produced in Canada are raised in a humane manner and are safe for consumption. Perceptions and misconceptions caused by use of illegal or alternative products are bad business for everyone.
7. If our fish exports are not HACCP compliant, we jeopardize our relationship with the US, our major trading partner, possibly easing the way for non-tariff trade barriers. Compliance with drug regulations preserves access to international markets. In this globally competitive market, we cannot afford to be careless.

Make the right choice and use registered and approved products.