1. WEST NILE VIRUS FDA Blood Product Advisory Committee Meeting 13 to 14 March 2003 Dominique Pifat, Ph.D. Bayer Biological Products on behalf of PPTA Viral Safety Working Group

2. Draft Flaviviridae Pestiviruses Bovine viral diarrhea virus Classical swine fever virus Border disease virus Flaviviruses Tick-borne encephalitis viruses St. Louis encephalitis Dengue viruses Yellow Fever virus West Nile Virus Hepaciviruses Hepatitis C Virus

3. Draft TRANSMISSION THROUGH BLOOD PRODUCTS FDA response: October 3, 2002 Information about West Nile Virus and Blood Safety FDA response: October 25, 2002 Guidance for Industry: Recommendations for the Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Known or Suspected West Nile Virus Infection „FDA has reviewed the viral reduction processes in place for all plasma derivatives. The methods in place have been validated to inactivate flaviviruses related to WNV.“

4. Draft Enveloped viruses with a broad range of physical characteristics have been shown to be similarly susceptible to inactivation methods Similar Susceptibilities Different enveloped viruses are very susceptible to a number of different inactivation methods

5. Draft FDA WORKSHOP November 4 & 5, 2002 OUTCOMES „The WNV data presented support the FDA‘s conclusion, in that WNV does not behave differently than other flaviviruses.“ The data presented at the November FDA workshop confirm that: „ The concept of using a range of physicochemically diverse model viruses for the validation of virus reduction steps has also been verified, in that the behaviour of a virus of interest, i.e. WNV, has been adequately predicted !“

6. Draft Progress since November 2002 At the FDA workshop PPTA announced that member companies would commitment to perform verification studies with West Nile Virus Since then, PPTA member companies have generated additional supportive data on the inactivation of West Nile Virus in a variety of processes and using a number of inactivation and removal methods.

7. Draft Pasteurization

8. Draft Detection limit Detection Limit WNV Pasteurisation Inactivates Viruses (heat treatment/stabilised aqueous solution/60°C)

9. Draft Detection limit Detection Limit WNV Pasteurisation Inactivates Viruses (heat treatment/stabilised aqueous solution/60°C)

10. Draft Detection limit Detection Limit WNV Pasteurisation Inactivates Viruses (heat treatment/stabilised aqueous solution/60°C)

11. Draft Detection limit Detection Limit WNV Pasteurisation Inactivates Viruses (heat treatment/stabilised aqueous solution/60°C)

12. Draft WNVBVDV  5.9 log 10 reduction (setpoint)  6.2 log 10 reduction (half conc.)  6.1 log 10 reduction Inactivation of WNV & BVDV during 60°C Pasteurization of HPPS Limit of Detection  7.3 log 10 reduction

13. Draft WNVBVDV  4.9 log 10 reduction Inactivation of WNV & BVDV during 60°C Pasteurization of Prolastin Limit of Detection  6.4 log 10 reduction 

14. Draft West Nile Virus, and relatives / „model viruses and WNV for „verification“

15. Draft Solvent Detergent

16. Draft  0.3% TNBP/1% Tween 0.15% TNBP/0.5% Tween WNVBVDV  6.0 log 10 reduction (setpoint)  6.1 log 10 reduction (half conc.) LOD (0.3% TNBP/1% Tw) LOD (0.15% TNBP/0.5% Tween) Except for the 0.5 hr samples, all WNV infectivity was at the limit of detection.  2.4 log 10 reduction (setpoint)  5.2 log 10 reduction (half conc.) Inactivation of WNV & BVDV during TNBP/Tween Treatment of Koate

17. Draft  0.3% TNBP/0.2% Cholate 0.15% TNBP/0.1% Cholate WNVBVDV  5.9 log 10 reduction (setpoint)  6.2 log 10 reduction (half conc.)  4.0 log 10 reduction (setpoint)  3.8 log 10 reduction (half conc.) Inactivation of WNV & BVDV during TNBP/Cholate Treatment of IGIV Limit of Detection 0.3% TNBP/0.2% Cholate Limit of Detection 0.15% TNBP/0.1% Cholate

18. Draft West Nile Virus, and relatives / „model viruses and WNV for „verification“

19. Draft Other Methods

20. Draft West Nile Virus, and relatives / „model viruses and WNV for „verification“

21. Draft West Nile Virus, and relatives / „model viruses“ West Nile Virus „verification“ study Asahi 15 N nanofiltration of  1 -Proteinase Inhibitor Assay: NGI, SuperQuant™ RT PCR Assay for WNV

22. Draft West Nile Virus, and relatives: model viruses and WNV for „verification“ * B Horowitz & E Ben-Hur, Ann. Med. (2000) vol. 32, p. 475

23. Draft BVDV: A RELEVANT MODEL FOR WNV BVDV closely resembles flaviviruses including WNV BVDV has been successfully used to model HCV inactivation The largest body of inactivation data exists for BVDV These data provide assurance that WNV will be inactivated during plasma - derived product manufacture Studies performed with WNV demonstrate the very effective inactivation capacity of dedicated virus inactivation steps The data presented here confirm that studies utilizing a broad spectrum of model viruses are predictive of the behavior of other enveloped viruses such as WNV. Such studies will continue to be predictive in the future Conclusions (1)

24. Draft A successful precedent for a collaboration between Regulators Academia Patient organizations Industry  to the ultimate benefit of concerned patients !! Conclusions (2)