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Experimental Clearance of TSE Infectivity in Plasma-derived FVIII Products. TSE Advisory Committee December 15, 2006 Dorothy Scott, M.D. Office of Blood Research and Review/CBER. 4. Risk Characterization Importance Analysis (slide from S. Anderson). -. +. Questions to the Committee.

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Experimental clearance of tse infectivity in plasma derived fviii products

Experimental Clearance of TSE Infectivity in Plasma-derived FVIII Products

TSE Advisory Committee

December 15, 2006

Dorothy Scott, M.D.

Office of Blood Research and Review/CBER


4. Risk Characterization FVIII ProductsImportance Analysis (slide from S. Anderson)

-

+


Questions to the committee
Questions to the Committee FVIII Products

1. Based on available scientific knowledge, please discuss whether a minimum TSE agent reduction factor, demonstrated using an exogenous (spiking) model in scaled-down manufacturing experiments, can be identified, that would enhance vCJD safety of the products.

a. If yes, what TSE agent reduction factor is most appropriate?

2. If the Committee identifies a minimum TSE reduction factor that would enhance vCJD safety what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:

  • Labeling that would differentiate the higher clearance products from other products;

  • Recommending addition of TSE clearance steps to the manufacturing method;

  • Performance of TSE clearance experiments using endogenous infectivity models;

  • Any other actions?


TSE Clearance Evaluation: FVIII ProductsExogenous

(“Spiking Experiment”) Model

TSE Spike Plasma

(e.g. – infected brain,

brain subfractions,

spleen) Cryoprecipitation Cryoprecipitate

(FVIII) – assay

for infectivity

Cryopoor Plasma Supernatant

Assay for infectivity


Exogenous clearance studies spiking material
Exogenous Clearance Studies – Spiking Material FVIII Products

  • “Ideal” spiking material

    • Physically/chemically replicates blood infectivity

    • Easy to prepare, widely available

    • High-titer material

  • Committee discussion 9/18/06 (What would be optimal spiking material and its preparation?)

    • Brain subfractions may be better than whole homogenate

    • Can higher titer infectivity fractions relevant to blood infectivity be generated?

      • LDL//VLDL bound fraction from plasma

      • Other purification methods (e.g. solublized homogenate)

      • “There is no pending resolution of the physical form of [blood] infectivity”

    • Spiking studies use human plasma and intermediates - highly process-relevant (animal plasma may fractionate differently)


Exogenous experiments selection of tse strains and animal model tseac discussion 9 18 06
Exogenous Experiments – Selection of TSE strains and animal model (TSEAC discussion 9/18/06)

  • Most relevant strains may be BSE/vCJD-related, but well-characterized and practical vCJD model in rodents not yet available

  • Transgenic mice (PrP-transgenic for specific TSE strain) may provide greater sensitivity/shorter incubation periods) – e.g. BSE into “bovinized” mice; scrapie into “ovinized” mice

  • Human TSE’s studied in “humanized” mice – continue to be developed


Exogenous experiments bioassay or immunoassay tseac 9 18 06
Exogenous Experiments – Bioassay or Immunoassay? (TSEAC 9/18/06)

  • Immunoassays are based on binding of PrP-TSE to an antibody

    • Rapid

    • Some examples of infectivity without detectable PrPTSE

    • Examples of PrPTSE without infectivity

    • Generally less sensitive than bioassay

  • Bioassays (in vivo)

    • Slow

    • Require large numbers of animals for infectivity titration


Exogenous experiments bioassay or immunoassay
Exogenous Experiments – Bioassay or Immunoassay? 9/18/06)

  • TSEAC discussion 9/18/06

    • Enhancement of binding assay sensitivity with PMCA* may be possible

    • Replacement of bioassay with binding assays

      • Would require very careful validation

      • Still currently important to assay infectivity

  • Tissue culture bioassay models – not fully developed for use in titrating infectivity in clearance studies, but may eventually be rapid (30 day incubation)

* protein misfolding cyclic amplification


“We are never going to have the best assay. That is the nature of science. We keep moving ahead and making things better.”

R. Colvin, TSEAC 9/18/2006


Tse agent reduction factor
TSE Agent Reduction Factor nature of science. We keep moving ahead and making things better.”

  • What is a reasonable minimum clearance that would enhance vCJD safety of pdFVIII products?

  • Viral validation analogy – how is viral safety demonstrated?

  • Information from FDA pdFVIII risk assessment – sensitivity analysis for clearance levels


Viral safety amount of clearance
Viral Safety – amount of clearance nature of science. We keep moving ahead and making things better.”

  • Experiments are similar to TSE clearance – spiking of infectious virus into plasma or intermediate, and assessing removal

  • Viremia ranges higher than blood infectivity range estimated for TSE’s

    • 4-9 Log10/ml for HCV, HIV-1, HBV

    • 7 Log 10/ml for HAV; 13 log10/ml for B19 virus

    • 2-30 i.c. IU/ml estimated for TSE’s

  • TSE infectivity estimate in plasma (based on animal models): 2-30 IU/ml x 800 ml plasma = 3.2-4.4 log10 IU total

  • Viral clearance usually at least for the maximum amount of virus expected + “margin of safety”


Viral safety amount of clearance1
Viral Safety – amount of clearance nature of science. We keep moving ahead and making things better.”

  • Margin of safety (at least 2-3 additional logs of clearance) may be prudent because –

    • Manufacturing conditions cannot be identical in every respect for every lot (critical parameters are within specified ranges)

    • Viremia range could be higher than reported

    • Virus model is not identical to field viruses (e.g., HCV cannot be studied due to lack of culture methods; similar model viruses are used to demonstrate clearance)


Impact of tse clearance on mean potential vcjd risk person year pdfviii risk assessment table 5 3 a
Impact of TSE clearance on mean potential vCJD risk/person/year (pdFVIII risk assessment table 5.3.A.)

Log10 TSE Clearance

* Available data suggests that all U.S.-licensed products are likely to

have TSE clearance of > 4 log10


Question 2
Question 2 risk/person/year (pdFVIII risk assessment table 5.3.A.)

If the Committee identifies a minimum TSE reduction factor that would enhance vCJD safety what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:

  • Labeling that would differentiate the higher clearance products from other products;

  • Recommending addition of TSE clearance steps to the manufacturing method,

  • Performance of TSE clearance experiments using endogenous infectivity models;

  • Any other actions?


Current FDA Recommendation: Labeling for risk/person/year (pdFVIII risk assessment table 5.3.A.)

Risk of CJD in Plasma Derivatives

“Because [this product] is made from human blood, it carries a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.”


Voluntary labeling based on submission of tse clearance studies
Voluntary Labeling (based on submission of TSE clearance studies)

  • In DESCRIPTION section: “Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.”

    • Characterizes study as investigational

    • Introduces the concept of models for vCJD and CJD


Voluntary labeling continued
Voluntary Labeling (continued) studies)

  • In DESCRIPTION section “Several of the individual production steps in the [product name] manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include [process][(logs)]), [process][(logs)], [etc.]. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.”

    • States that clearance was observed, with specific logs removal

    • Provides an estimation effectiveness in context of low levels of infectivity


TSE Clearance Evaluation: studies) Endogenous

Infection model

Plasma from TSE-infected animal

Cryoprecipitation Cryoprecipitate

(FVIII) – assay

for infectivity

Cryopoor Plasma Supernatant

Assay for infectivity


Endogenous tse studies relevance to blood infectivity
Endogenous TSE studies: Relevance to Blood Infectivity studies)

  • Comparison of results from endogenous and exogenous infectivity studies suggest similar reductions for some precipitations

    • Limited number of endogenous studies

  • Endogenous infectivity characteristics in plasma

    • Small size

    • Difficult to sediment (in its native form)

    • Poorly aggregated

    • May be lipid/plasma-protein associated


Endogenous tse clearance studies
Endogenous TSE Clearance Studies studies)

  • Relevance to human blood highly likely

  • Limited clearance can be demonstrated because starting infectivity is low (est. 2-30 IU/ml)

    • Large numbers of donor and assay animals may compensate for low titers

      • Recipients – volume injectible i.c. for titration: 0.02 ml mice; 0.05 ml hamsters

      • For 100 ml plasma: 5000 mice or 2000 hamsters

  • Large animal models (Scrapie, BSE)

    • Experimental logistics - herd management, limited locations, incubation time, availability

    • Scale-down logistics – dedicated pilot laboratories

  • Can studies be done using large animal plasma donor with small animal assay?

  • Animal plasma fractionation – equivalence to human plasma for studied clearance steps?


  • Questions to the committee1
    Questions to the Committee studies)

    • Based on available scientific knowledge, please discuss whether a minimum TSE agent reduction factor, demonstrated using an exogenous (spiking) model in scaled-down manufacturing experiments, would enhance vCJD safety of the products.

      a. If yes, what TSE agent reduction factor is most appropriate?

      2. If the Committee identifies a minimum TSE reduction factor that would enhance vCJD safety what actions should FDA consider in cases when a licensed pdFVIII has a lower reduction factor:

      • Labeling that would differentiate the higher clearance products from other products;

      • Recommending addition of TSE clearance steps to the manufacturing method;

      • Performance of TSE clearance experiments using endogenous infectivity models;

      • Any other actions?