TSE Advisory Committee European Industrial example of BSE risk management policy for implantable collagen of bovine orig

1. TSE Advisory CommitteeEuropean Industrial example of BSE risk management policy for implantable collagen of bovine origin

2. SYMATESE Biomateriaux Bovine collagen is present in many implantable devices : Hemostats, Vascular Grafts and Injectable Collagen • French manufacturer of collagen for European medical device industry, ISO 9001 Compliance • 15 Years of experience with implantable/injectable bovine collagen products

3. European BackgroundMad Cow Disease appeared in France at beginning of 1991 • Regulation and guidance was issued to handle the risk of transmitting BSE/TSE via medical devices • European standard EN 12442: animal tissue and their derivatives utilized in the manufacture of medical devices • Part 1: risk analysis • Part 2: control on sourcing, collection and handling • Part 3: validation of the elimination and or inactivation of viruses and transmissible agents • Chapter 5.2.8 in European Pharmacopoeias • Reduction of the risk of transmitting agents responsible for spongiform encephalopathy via medical products • Consideration of BSE risk for approval of devices including animal products (French committee for microbiological safety)

4. European approach to Risk Management • BSE risk management policy relies on three different aspects: • Risk analysis • Sourcing conditions • Choice of tissue • Control of animal sourcing • Processing conditions • inactivation • Validation of inactivation process • As bovine collagen manufacturer, SYMATESE has always complied with “state of the art” BSE risk control

5. Sourcing conditions For SYMATESE • Use of calf hides: • Infectivity never detected • WHO, European Pharmacopoeia classification • Selection of animals less than 6 months old • Infectivity and prions never detected in animals of less than 6 months • Calves fed with milk diet only • Slaughtering in approved facilities • Control of slaughtering conditions to avoid possibility of cross contamination with tissues of higher infectivity • Killing without intracranial penetration • Removal of skin before opening of the carcass Before April 2001 French sourcing After April 2001, sourcing change to U.S.

6. Collagen processing • Complete traceability from raw material to patient • Processing steps include conditions known to reduce or inactivate BSE/TSE contamination • 16 hours 0.15N soda treatment on hides • 1N soda treatment on dermis • 1N soda treatment on collagen suspension • Process validation from 1993 to 1997 according to European guidelines • Use of a murine C506M3 strain • 5.3 log or infectivity reduction for a part of the process only including 1N soda treatment on suspension

7. Cleaning operations • Batch to batch cleaning includes • Initial cleaning • NaOH treatment 0.1N for 16 hours or 0.5N for 1 hour • Rinsing • Prior to sourcing change: cleaning of equipment using WHO, and French Health Ministry recommendation for re-usable medical devices • 1N NaOH treatment, 1 hour on equipment • Validation of cleaning efficiency to remove proteins

8. Summary Compliance with EU standards and use of scientifically based BSE inactivation methods allow registration and sale of SYMATESE implantable collagen in Europe • Contact information : b.herbage@symatese.com