review of publicly available information on tse clearance by steps used to manufacture fviii...
TRANSCRIPT
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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
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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?
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How is risk reduction by manufacturing assessed?
TSE material (brain, infectious)+ plasma or intermediate material
Scaled-down process step (laboratory simulation)
Measure leftover infectivity
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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)
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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
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Influence of starting materials and filter on PrPsc or infectivity clearance by depth filtration –
Starting Material Depth Filter Reduction Factor (log10)
Fr V (albumin) Seitz KS80 > 4.9Fr V (albumin) CUNO Delipid 1 2.3S I + III (IGIV) Millipore AP20 < 1Fr II (IGIV) Seitz K200 > 2.8(Foster et. al., Vox Sang 78: 86-95, 2000)
Fr I supernatant (IGIV, albumin) Supra P80 < 1Fr V supernatant (albumin) Supra P80 > 1.1Fr V supernatant (albumin)Prp-sc spike Supra P80 > 2.4(Vey et al, Biologicals 30:187-96, 2002)
IgG manufacture filtration 1 > 4.5filtration 2 > 2.8
(ZLB package insert, Carimune)
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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)
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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 50-1000 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
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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)
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Published and/or publicly presented TSE clearance values for FVIII
manufacturing processesManufacturing Step Clearance Reported
Cryoprecipitation 1, <1, 1, 1, 1
PEG or glycine precipitation 2.2-3.0, 1.7-3.3
Ion exchange chromatography 3.1, 3.5
Affinity purification 4.1
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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
Alphanate heparin affinityHumate-P not publicly availableKoate-DVI PEG precipitationHemofil-M Immunoaffinity, ion exchangeMonarc-M “Monoclate Immunoaffinity
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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 maximum 7-9 logs (two steps, higher clearance, if additive)
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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?