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  1. Industry TSE clearance studies for plasma-derived Factor VIII (pdFVIII) Thomas R. Kreil, Ph.D. Chair, PPTA Pathogen Safety Steering Committee FDA TSE Advisory Committee December 15, 2006 www.pptaglobal.org

  2. Plasma derived therapies Manufacturing sites in Spain, USA Plasma derived therapies Manufacturing site in Germany Plasma derived therapies Manufacturing sites in Austria, France, Sweden Plasma derived therapies Manufacturing site in Italy Regional Member: Europe Plasma derived therapies Recombinant therapies Manufacturing sites in USA, Germany, Switzerland Plasma derived therapies Manufacturing sites in USA PPTA Fractionators: Members Plasma derived therapies Recombinant therapies Manufacturing sites in USA, Austria, Switzerland, Italy

  3. Plasma-derived FVIII, pdFVIII Separation of cryoprecipitate: centrifugation • “cryosupernatant” FIX, PCC, C1INH • Cohn products • immunoglobulins • alpha-1-AT • albumin • “cryoprecipitate” FVIII preparations: • FVIII • FVIII + vWF Increasing temperature: slow thawing up to 2°C

  4. Clearance Studies: Principles INPUT, 1 prions(viruses) DOWN - SCALE OUTPUT, 2 Manufacturing plant Pathogen Safety Lab • Reduction factor, RF = log (V1xT1) / (V2xT2)

  5. Down Scale: Validation • Intermediate from production or pilot scale • Product parameters • Protein concentration, activity • Impurity profile • Process parameters • Temperature, time (stirring, incubation), ppt.-agent conc. • Pressure, flow, volume per filter area • pH, conductivity, ionic strength • Linear flow rate, resin contact time  full EQUIVALENCE between production & lab scale

  6. Investigational Prion Clearance Studies • Choice of spiking agent • Preparation of spike material • Brain homogenate • Partially-purified prion preparations • homogenized • detergent-treated • sonicated • etc. • Choice of assay for prion quantification • In vivo: animal bio-assay • In vitro: Western blot, CDI  many sources of VARIATION

  7. Prion Quantification: Controlled • Quality control for critical reagents • Good laboratory practices • not necessarily certified by national authorities • Standard Operating Procedures (SOP)s for • Preparation of spiking material • Assay performance • Acceptance criteria for assay results • Internal controls • Positive / Negative / Interference  assay SUITABILITY

  8. Prion Clearance Studies • Validated downscale • Controlled prion spike materials • Controlled prion assays • Further standardization would • Inhibit process-specific investigations(depends on expert input) • Prevent novel approaches • Discourage application of improved understanding  even virus studies are not fully standardized …

  9. Company-specific Data • Different manufacturing processes • Not necessarily all steps investigated • Detailed data for US-licensed products have been shared with the FDA • Research still ongoing …

  10. Company A TOTAL REDUCTION: 8.1 log10ID50  Product is licensed in the USA

  11. Company B * Preliminary results  Product is licensed in the USA

  12. Company C  Product is not licensed in the USA

  13. Company C  Product is not licensed in the USA

  14. Company DUPDATED Dec 14, 2006 TOTAL REDUCTION: 6.4 // 7.9 log10  Product is licensed in the USA

  15. Company EUPDATED Dec 14, 2006 TOTAL REDUCTION: 3.9 - 4.0 log10 (partial process)  Product is licensed in the USA

  16. Company F  Product is not licensed in the USA

  17. Summary / 1 • Plasma-derived FVIII products • Manufacturing processes remove prions • Reduction factors depend on • Specific manufacturing process • Number of steps investigated • Experimental design

  18. Summary / 2 • Safety margin • Level of risk: unknown, but likely low • No evidence for transmission by pdFVIII products ,or any other plasma product • High level of pharmacovigilance • Exposure: low, and getting lower • Reduction by all pdFVIII manufacturing processes • Quantification of reduction vs. unknown / low level of risk: an open equation at this point …

  19. Low, and getting lower … • vCJD epidemic in the UK  Andrews, UK HPA ( July 18, 2006)

  20. FDA questions  TSE AC / 1 • FDA questionsBased on available scientific knowledge, pls discuss whether a minimum TSE agent reduction factor, demonstrated using an exogenous (spiking) model in scaled-down manufacturing experiments, would enhance safety of the products. • PPTA responseThe plasma-protein associated vCJD risk is considered very low, although not exactly known yet, and thus any level of reduction is re-assuring.

  21. FDA questions  TSE AC / 2a • FDA questions… what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:a) Labelingthat would differentiate the lower TSE clearance products from the higher TSE clearance products. • PPTA responsePrion reduction factors are derived by different investigational approaches. Labeling, in our opinion, would thus provide information that cannot be meaningfully assessed out of context.Also, it might suggest a safety differential, which in light of the remaining uncertainties we feel cannot be substantiated.

  22. FDA questions  TSE AC / 2b • FDA questions… what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:b) Recommending addition of clearance stepsto the manufacturing method. • PPTA responseThe introduction of additional clearance steps would likely require clinical testing to confirm safety & efficacy product characteristics, with unsubstantiated benefit to the patients involved. Also, production yields would be negatively affected.

  23. FDA questions  TSE AC / 2c • FDA questions… what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:c) Performance of TSE clearance experiments using endogenous infectivity models. • PPTA response • Using (low-titered) endogenous infectivity limits demonstrable prion reduction to levels lower than those already shown for pd FVIII. • Animal and human plasma are different (significantly).  We thus believe that such experiments would result in immense animal consumption and effort, without changing product safety.

  24. Standardization: Useful ? • Advances in Science • “..high blood infectivity in transgenic mice..”, PrP w/o GPI-anchor • No pathology upon i.c. scrapie inoculation • Prion infectivity in blood: up to > 10E7 ID50/ml • Prion accumulation in the heart, cardiac amyloidosis (?!?) • “ … sensitivity of new diagnostic kits … • … effectiveness of methods for removal” • M.J. Trifilo et al., Science [2006] 313: 94 Results  MAY depend on model

  25. Standardization: Useful ? • Advances in Science REALLY ? • “..high blood infectivity in transgenic mice..” • GPI-anchorless PrP • not the patho-physiologically relevant form • truncated PrPSC physicochemically dissimilar, thus behaviour is likely different, also • natural PrPsc is hydrophobic, i.e. poorly soluble,whereas this GPI-deficient molecule is relatively soluble • M.J. Trifilo et al., Science [2006] 313: 94 Results  MAY depend on model

  26. Of mice and men … • Mouse vs human plasma has: • 420% Factor X • 270% Factor VII • 250% Factor VIII • 250% fibrinogen • 150% Factor IX • 120% Factor XI • 80% prothrombin • 75% Factor XII • Behringwerke, unpublished

  27. Different animals and men … • Animal vs human plasma: • Karges et al., Drug Research [1994] 44: 793

  28. Different animals and men … • Animal vs human plasma: • Karges et al., Drug Research [1994] 44: 793

  29. FDA questions  TSE AC / 2d • FDA questions… what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:d) Any other actions ? • PPTA responseMember companies remain committed to further investigate prions and their reduction by the plasma product manufacturing processes. We believe that open exchange of data benefit all stakeholders, and wish for continued dialogue with the agency & advisors. Given remaining uncertainties and increasingly reassuring epidemiological information, we feel that for now further actions are not justified.

  30. Conclusion • The unsubstantiated level of prion risk for pdFVIII is not a rational basis for any additional measures. • Minimum TSE reduction factors versus an unquantified, but considered very low, level of risk is not necessary. • Quantitative prion reduction labeling including a threshold would not provide meaningful safety information. • Introduction of additional manufacturing steps may adversely impact clinical product safety, and lower yield, and would require patient exposure with unclear benefits. • Endogenous prion reduction studies would not change the prion safety profile of a product. • Industry committed to research & dialogue

  31. PPTA Partners