TSE Clearance in Plasma Derivatives - PowerPoint PPT Presentation

1 / 16
About This Presentation
Title:

TSE Clearance in Plasma Derivatives

Description:

Paradigm: Validation of Virus Removal/inactivation Includes: Scaling down process steps ... Membrane-free infectious material (e.g. fibrils) Blood and blood fractions ... – PowerPoint PPT presentation

Number of Views:294
Avg rating:3.0/5.0
Slides: 17
Provided by: FDA1
Category:

less

Transcript and Presenter's Notes

Title: TSE Clearance in Plasma Derivatives


1
TSE Clearance in Plasma Derivatives
  • TSE Advisory Committee
  • February 8, 2005
  • Dorothy Scott, M.D.
  • DH/OBRR/CBER/FDA

2
TSE Clearance Studies and Risk Assessment
  • Clearance is an important factor in overall risk
    estimation
  • Clearance by manufacturing process CAN be tested
    in scaled-down studies
  • Viral clearance studies paradigm applied

3
Paradigm Validation of Virus Removal/inactivation
Includes
  • Scaling down process steps
  • Spiking appropriate steps with high titer of
    infectious agent (actual or model)
  • Determination reduction factors for each step
  • Summing reduction factors from non-orthogonal
    processes to give a total log10 reduction value

4
Studies of Clearance of TSE Agents
  • Source of infectivity
  • Brain preparations from experimentally infected
    animals with human/animal TSE agents
  • Blood from experimentally infected animals
  • Form infectious agent
  • Brain homogenate
  • Subcellular fractions
  • Membrane-free infectious material (e.g. fibrils)
  • Blood and blood fractions
  • Alterations in form during manufacturing
    (conditioning)

5
Measures of Clearance
  • Assays to measure outcomes
  • In vivo infectivity laborious, expensive,
    long-term experiments, but considered most
    relevant and most sensitive
  • In vitro - measurements of PrPSc
  • Bridging in vivo to in vitro results scientific
    controversy exists

6
TSE Clearance Evaluation Spiking Model
TSE Spike Plasma Cryoprecipitation Cryop
recipitate (FVIII) Cryopoor
Plasma Supernatant Albumin, IGIV,
A1PI, etc.
High titer caveat
7
TSE Clearance Evaluation Endogenous
Infection model
Plasma from TSE-infected animal Cryoprecipitati
on Cryoprecipitate (FVIII) C
ryopoor Plasma Supernatant Albumin,
IGIV, A1PI, etc.
Low titer Relevance Limitations
8
TSE Clearance Studies
  • Steps studied
  • EtOH precipitation
  • PEG precipitation
  • Salt precipitation
  • Depth filtration
  • Nanofiltration
  • Column chromatography
  • Clearance relies upon
  • Partitioning (non-robust?)
  • Additiveness of steps
  • (demonstrated)
  • Appropriate scale-down
  • Relevance of model

9
TSE Clearance and Individual Manufacturing
Processes
  • Manufacturing processes are highly individual
  • Rigorous demonstrations of TSE clearance need to
    be based upon the specific manufacturing
    process

10
Specificity of Process Clearance PrPsc
(microsomal spike) by Depth Filtration
Influence of Starting Materials and Filter
Starting Material Depth Filter Reduction Factor
(log10) Fr V (albumin) Seitz KS80
4.9 Fr V (albumin) CUNO Delipid 1 2.3 S I
III (IGIV) Millipore AP20 (IGIV) Seitz K200 2.8 Foster et. al., Vox
Sang 78 86-95, 2000 Fr I supernatant (IGIV,
albumin) Supra P80 (albumin) Supra P80 1.1 Fr V supernatant
(albumin) Prp-sc spike Supra P80 2.4 Vey
et al, Biologicals 30187-96, 2002
11
OBRR Actions to Minimize Risk of TSE Agents in
Blood Products TSE Clearance
  • TSEAC (2/2003) endorsed FDA consideration of
    labeling claims for TSE clearance in plasma
    derivatives, based upon specific demonstration of
    TSE removal during manufacturing
  • TSE clearance study submissions encouraged by
    OBRR
  • Submissions received, evaluations in progress

12
FDA Requests for Submission TSE Clearance Data
  • Voluntary
  • Best current methods
  • Model selection not restricted but needs to be
    justified
  • 3 Logs clearance for non-robust steps
    considered significant
  • Science-in-evolution

13
TSE Clearance and Risk Assessment
  • TSE clearance a critical variable in risk
    assessments for vCJD
  • Clearance can be tested on a laboratory scale,
    with caveats (spike relevance, model agents,
    etc.)
  • Data can be provided for risk assessments
    specific study of product provides best
    approximation of clearance
  • Clearance studies, and advances in these study
    methods could improve precision of risk estimates

14
Published TSE Clearance Studies for Plasma
Derivatives (1)
  • Brown, P et al. The distribution of infectivity
    in blood components and plasma derivatives in
    experimental models of transmissible spongiform
    encephalopathy. Transfusion 1998 38810-6
  • Brown, P et al. Further studies of blood
    infectivity in an experimental model of
    transmissible spongiform encephalopathy, with an
    explanation of why blood components do not
    transmit CJD in humans. Transfusion 1999 39
    1169-78
  • Lee, DC et al. Monitoring plasma processing steps
    with a sensitive Western blot assay for the
    detection of prion protein. J. Virol. Meth. 2000
    84 77-89
  • Foster, PR et al. Assessment of the potential of
    plasma fractionation processes to remove
    causative agents of transmissible spongiform
    encephalopathy. Transfusion Science 2000
    2253-56
  • Foster, PR et al. Assessment of the potential of
    plasma fractionation processes to remove
    causative agents of transmissible spongiform
    encephalopathy. Vox Sanguinis 2000 7886-95
  • Lee, DC et al. A direct relationship between the
    partitioning of the pathogenic prion protein and
    transmissible spongiform encephalopathy
    infectivity during the purification of plasma
    proteins. Transfusion 2001 41 449-55

15
Published TSE Clearance Studies for Plasma
Derivatives (2)
  • Cai, K et al. Solvent-dependent precipitation of
    prion protein. Biochem Biophys. Acta 2002 1597
    28-35
  • Stenland, JS et al. Partitioning of human and
    sheep forms of the pathogenic prion protein
    during the purification of therapeutic proteins
    from human plasma. Transfusion 2002 421497-1500
  • Vey, M et al. Purity of spiking agent affects
    partitioning of prions in plasma protein
    purification. Biologicals 2002 30187-96
  • Reichl, HE et al. Studies on the removal of a
    BSE-derived agent by processes used in the
    manufacture of human immunoglobulin. Vox
    Sanguinis 2002 83137-45
  • Van Holten, RW et al. Removal of prion challenge
    from an immune globulin preparation by use of a
    size-exclusion filter. Transfusion 2002
    42973-4.
  • Van Holten RW et al. Evaluation of depth
    filtration to remove prion challenge from an
    immune globulin preparation. Vox Sang 2003
    8520-4.

16
Published TSE Clearance Studies for Plasma
Derivatives (3)
  • 13. Trejo, SR, et al. Evaluation of virus and
    prion reduction in a new intravenous
    immunoglobulin manufacturing process. Vox Sang
    2003 84176-87.
  • Burnouf T et al. Nanofiltration of single plasma
    donations feasibility study. Vox Sang 2003
    84111-119.
  • Gregori,et al. Partitioning of TSE infectivity
    during ethanol fractionation of human plasma.
    Biologicals 2004 32 1-10.
  • Foster, PR et al. Distribution of a bovine
    spongiform encephalopathy-derived agen over
    ion-exchange chromatography used in the
    preparation of concentrates of fibrinogen and
    factor VIII. Vox Sang 2004 8692-9.
Write a Comment
User Comments (0)
About PowerShow.com