Although worldwide public hysteria over issues relating to bovine spongiform encephalopathy (BSE) is diminishing as the number of new cases drops, government agencies continue to put in place controls to prevent the spread of BSE and related transmissible spongiform encephalopathies (TSE) such as new variant Cretzfeldt-Jakob Disease. These controls affect the transport and use of animal derived materials in regulated manufacture.

As 1998 draws to a close the impact of Commission Decision 97/534/EC of 30 July 1997 on the prohibition of the use of material presenting risks as regards transmissible spongiform encephalopathies continues to be felt. This decision has been very controversial as it would eliminate most of the pharmaceuticals coming into the European Union as most contain gelatin. It was not implemented 1 January 1998 nor was it implemented 1 April 1998. The Commission proposed it be repealed, but the member states requested implementation be deferred to 1 January 1999. The decision places a ban on the use of 'specified risk materials' in the manufacture of pharmaceuticals and cosmetics. Specified risk materials were defined as: a) the skull, including the brain and eyes, tonsils and spinal cord of: bovine animals aged over 12 months, ovine and caprine animals which are aged over 12 months or have permanent incisor tooth erupted through the gum; b) the spleens of ovine or caprine animals.

Both a Commission Decision and a Regulation have been in draft to prevent and control TSEs while moderating a total ban on the import of products manufactured with 'specified risk materials.' Ten drafts of the Commission Decision have been introduced and rejected in 1998. It is likely that implementation of 97/534/EC will be postponed for a third time. Both the Commission Decision and the Regulation as drafted exempt medicinal products, medical devices, their starting materials, and intermediate products. They define 'specified risk materials' in terms of country of origin as well as the part of the animal from which they are obtained.

The Biotechnology working Group of the Committee for Proprietary Medicinal Products (CPMP) in the European Agency for the Evaluation of Medicinal Products revised its Note For Guidance On Minimizing The Risk Of Transmitting Animal Spongiform Encephalopathy Agents Via Medicinal Products in October 1998. Where animal derived materials, especially ruminant derived materials, must be used in manufacture, particular emphasis must be placed on the sourcing of these materials. Where bovine materials are used in manufacturing processes the source (country of origin) of the animals, the nature of the animal tissue used, and the production process must be considered. Products specifically mentioned as unlikely to be infectious include: milk and its derivatives, properly collected and processed hair and wool based products, and properly processed tallow and gelatin derivatives.

A European directive on good manufacturing practices (GM) for starting materials and the inspection of medicinal product manufacturers as well as the manufacturers of their starting materials has been proposed. A Community register of inspection reports, manufacturing authorizations, and GMP certificates is proposed.

The most important action taken by the Food and Drug Administration in recent years has been to prohibit the use of protein derived from mammalian tissues in ruminant feed. The final rule as published 5 June 1997 in the Federal Register became effective 4 August 1997. The FDA published recommendations for the use of bovine-derived materials in the manufacture of products intended for human use in December of 1993 and again in may 1996. These letters require manufacturers to maintain records of the origin of the materials used. The most recent letter states, 'We strongly recommend you take whatever steps are necessary to assureƒyou are not using materials that have come from cattle born, raised, or slaughtered in countries where BSE is known to exist.' In 1997 the FDA published a Guidance for Industry: The sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use. On 6 November 1998 the FDA issued Guidance for FDA Reviewers and Industry: Medical Devices Containing Materials Derived from Animal sources (Except for In Vitro Diagnostic Devices). Both of these documents contain good background information on BSE issues and recommendations for safe use of animal derived materials.

The United States Department of Agriculture (USDA) continues to maintain that BSE is not known to exist in the United States or Canada.

The list of countries where BSE is known to exist includes France, Great Britain (includes the Falkland Islands), Northern Ireland, the Republic of Ireland, Oman, Luxembourg, Switzerland, Portugal, Belgium, and the Netherlands. Since December 1997 (Federal Register January 6, 1998) the USDA has prohibited the import of most bovine products from Europe. The reasons for this ban were given as inadequate surveillance and inadequate important restrictions between countries in Europe.

The USDA has taken aggressive measures to prevent BSE in the United States. These measures include prevention, education, surveillance, and response. Since 1989 the Animal Plant Health Inspection Service (APHIS) has prohibited the importation of ruminants and ruminant products from countries where BSE has been diagnosed in native cattle. APHIS has an extensive education program for veterinary practitioners, lab personnel, industry personnel, and producers. APHIS has implemented the most comprehensive BSE surveillance program in the world. As of 30 November 199 7553 brains of suspect cattle have been examined for evidence of BSE. No evidence of BSE or other TSE has been detected. APHIS has drafted an emergency response plan for use in the unlikely event that BSE should be detected in North America. The USDA has submitted documentation to the European Union in support of granting the USA 'BSE-Free' status. The European Union has requested a dossier from all countries supporting their claimed BSE status. The US dossier meets the requirements of the Organisation Internationale Des Epizooties (OIE)..

Even though there has been a strong focus on BSE issues, there has been some action to control the spread of traditional adventitious viral contaminants.

The International Conference on HarmonizationÍs (ICH) Q5A Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin was published by the FDA in the Federal Register September 24, 1998. This guidance 'describes approaches fro evaluating the risk of viral contamination and the potential of the production process to remove viruses from products derived from human or animal cell lines.' The CPMP Biotechnology Working Party has revised their Note For Guidance On Virus Validation Studies: The Design, Contribution And Interpretation Of Studies Validating The Inactivation And Removal of Viruses based on this ICH harmonized document. Other regulatory efforts affect the import and export of animal derived materials. Council Directive 92/118/EEC of 17 December 1992 or 'Balai Directive' covers the animal health and public health requirements governing trade in certain products not covered by other directives. Draft commission decision of 1993, laying down the animal health requirements and veterinary certification for the import from third countries of blood products of animals not intended for human or animal consumption and amending Commission Decision 94/278/EC is the further definition of the specific annex chapter dealing with blood and blood products of animal origin from the 'Balai' Directive. It is currently in draft revision 10. It requires that blood product for pharmaceutical or technical use imported from third countries where Foot-and-Mouth Disease and/or Blue Tongue are known to exist be treated in one of three ways: Heat to 65Á for at least 3 hours or Change in pH to 5 for 3 hours or Gamma radiation at 2.5 mega rads

As action on this directive has stalled due to focus on BSE issues (it has been in draft revision 10 since 1995), individual countries have enacted legislation to prevent the spread of traditional viral agents. These countries include the United Kingdom, France, Germany, Belgium, the Netherlands.

These are just some of the current animal derived materials issues. If you have more information about issues to share please contact Greg Hanson at HyClone Laboratories, Inc. 1725 South HyClone Road, Logan, Utah 84321 or by E-Mail at greg.hanson@perstorp.com.