Review of Publicly Available Information on TSE Clearance by Steps Used to Manufacture FVIII Products TSE Advisory Committee October 31, 2005 Dorothy Scott,

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Review of Publicly Available Information on TSE Clearance by Steps Used to Manufacture FVIII Products TSE Advisory Committee October 31, 2005 Dorothy Scott, M.D. Division of Hematology/OBRR/CBER

Questions to the Committee Does the Committee agree with FDA’s proposed approach for estimating clearance of TSE’s from FVIII products by manufacturing, for use in the risk assessment model? What experimental data would enable refinement of these estimates, and allow comparisons of clearance effected by various steps in FVIII manufacture?

How is risk reduction by manufacturing assessed? TSE material (brain, infectious) + plasma or intermediate material Scaled-down process step (laboratory simulation) Measure leftover infectivity

Relevance of Clearance Studies for TSE Plasma Infectivity “Spiking” studies –Can demonstrate significant clearance levels because spike = 6-9 logs infectivity –Physical similarity to blood-borne form of TSE agents uncertain Similar behavior is some situations: e.g. convergence of clearance for EtOH precipitations with spiking vs. endogenous infectivity Questioned for filtrations that are size-dependent (e.g. nanofiltration) When characteristics of blood-borne infectivity defined, relevance of spiking preparations can be studied Endogenous infectivity studies – most relevant but cannot demonstrate high levels of clearance (starting infectivity 1-2 logs/ml)

Estimating TSE clearance in FVIII products – Methods (1) 1.Use published literature to identify clearance values from similar steps for FVIII or other products -different clearance levels often demonstrated for similar steps -Differences likely due to product/process specifics

Influence of starting materials and filter on PrP sc or infectivity clearance by depth filtration – Starting MaterialDepth FilterReduction Factor (log 10 ) Fr V (albumin)Seitz KS80 > 4.9 Fr V (albumin)CUNO Delipid S I + III (IGIV) Millipore AP20 < 1 Fr II (IGIV)Seitz K200 > 2.8 (Foster et. al., Vox Sang 78: 86-95, 2000) Fr I supernatant (IGIV, albumin)Supra P80 < 1 Fr V supernatant (albumin)Supra P80 > 1.1 Fr V supernatant (albumin)Prp-sc spikeSupra P80 > 2.4 (Vey et al, Biologicals 30:187-96, 2002) IgG manufacturefiltration 1 > 4.5 filtration 2 > 2.8 (ZLB package insert, Carimune)

Estimating TSE clearance in FVIII products – Methods (2) 2. Use product-specific studies to identify clearance values Product-specific studies -More relevant to specific products -Not available for all FVIII products -Many studies not evaluated in detail by FDA/CBER -Variations in study methods -Spiking preparation (brain preparations – variably clarified/solubleized/sonicated; microsomes, fibrils) -Assays for TSE – surrogates (Prpsc measures), or bioassay; results may differ (FDA labeling claims based on demonstration of infectivity reduction)

Plasma Derived FVIII Products “Classic Definitions” – purity defined by FVIII activity* –Intermediate purity (SA 1-10 U/mg protein) (often contain VWF) –High purity (SA U/mg protein) –Very high purity (SA: 3000 U/mg protein) Methods used in purification include cryoprecipitation, PEG precipitation, glycine precipitation, size exclusion, ion exchange, monoclonal antibody affinity chromatography, heparin affinity chromatography Potential clearance of vCJD may not correlate with classic definitions of purity *Before addition of albumin excipient

Studies of TSE clearance in FVIII Products Foster et al, Vox Sang 2000; 78:86 (Prp-tse) Lee et al, J. Virol. Meth. 2000; 84:77 (bioassay) Lee et al, Transfusion 2001; 41:449 (bioassay) Rohwer/Baxter/ARC (referenced by PPTA/H. Baron TSEAC [2/2003] Vey et al, Biologicals 2002; 30:187 (Prp-tse) Brown et al, Transfusion 1999; 39:1169 (bioassay)

Published and/or publicly presented TSE clearance values for FVIII manufacturing processes Manufacturing StepClearance Reported Cryoprecipitation1, <1, 1, 1, 1 PEG or glycine precipitation , Ion exchange chromatography3.1, 3.5 Affinity purification 4.1

Potential TSE clearance steps in manufacture of some FVIII products – Publicly available information* * References: package inserts, publications. Proprietary processes that may contribute to clearance are not listed here Alphanateheparin affinity Humate-Pnot publicly available Koate-DVIPEG precipitation Hemofil-MImmunoaffinity, ion exchange Monarc-M“ MonoclateImmunoaffinity

Risk Estimate Proposal for TSE Clearance Values Range of clearance values is suggested by available studies for different manufacturing steps Clearance ranges selected are consistent with additional data available to FDA Proposal is to run risk assessment 3 times, with three different clearance ranges: Likely minimum:2-3 logs (single step, intermediate clearance level) Midrange:4-6 logs (single step, higher clearance level, or multiple additive steps) Likely maximum7-9 logs (two steps, higher clearance, if additive)

Questions to the Committee Does the Committee agree with FDA’s proposed approach for estimating clearance of TSE’s from FVIII products by manufacturing, for use in the risk assessment model? What experimental data would enable refinement of these estimates, and allow comparisons of clearance effected by various steps in FVIII manufacture?