Risk assessment: The Safety of Blood Products

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• Risk assessment The Safety of Blood Products
• presented by
• Dr. Thomas R. Kreil
• Baxter BioScience
• on behalf of the
• PPTA Pathogen Safety Steering Committee
• Technical meeting with FDA
• April 29, 2003

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The safety of blood products

• Risk assessment considerations
• Plasma viremia
• Infectious virus titer of positive units
• Prevalence of viremia in the population
• Resulting plasma manufacturing pool loads
• Reduction by manufacturing processes
• Further relevant features

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West Nile Virus - Viremia
Symptomatic Individuals

• 102 105 iu/ml in patients with underlying
  malignant disease
• CM Southam AE Moore, Am J Trop Med Hyg 1951
  31 724
• 2.5 x 106 c/ml 3 days after onset of
  neurological symptoms
• C Huang et al., http//www.cdc.gov/ncidod/EID/vol8
  no12/02-0532.htm
• Otherwise Healthy Donors
• 1-5 x 103 c/ml FDA BPAC briefing package, March
  13, 2003
• 2 x 105 c/ml 1 in 7,107 (out of samples 75
  targeted for risk )
• A Conrad / NGI, BPAC March 13, 2003
• ? worst case 2 x 105 PCR copies/ml

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West Nile Virus
Infectious virus titer of positive units

• Mean PCR detectable amount of virus 0.00289
  pfu/mL (0.001640 0.005099 pfu/mL)
• A Conrad / NGI, BPAC March 13, 2003 CDC WNV
  panel (Lanciotti)
• Assuming that already ONE copy is PCR
  detectable? 1 infectious virus particle per 346
  (196-610) genomes
• Viremia of max. 2x105 PCR detectable genomes,
  at only 1 infectious particle per 196 genomes
• ? worst case max. 1,020 infectious units per ml

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West Nile Virus
Prevalence of viremia in the population

• ? Modeling approach
• US average risk 0.36 per 10,000 donors
• US maximum risk 1.55 per 10,000 donors (peak
  epidemic)
• Michigan about 4 per 10,000 donors (during the
  epidemic)
• Michigan about 10 per 10,000 donors (peak
  epidemic, Sept 1)
• Detroit up to 20 per 10,000 donors (peak
  epidemic, Sept 1)
• Dr. Lyle Petersen / CDC BPAC, March 13, 2003
  http//www.fda.gov/ohrms/dockets/ac/03/transcripts
  /3940t1.htm

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West Nile Virus
Prevalence of viremia in the population

• ? Verification by testing (viremia study)
• Samples from Cleveland and Detroit i.e.
  highest risk areas
• Obtained during the first three weeks of
  September 2002 i.e. highest risk period
• model estimated risk 8.2 per 10,000 in that
  population.
• TaqMan PCR 6 / 5,761 samples positive, i.e.
  viremia prevalence
• worst case 10.4 per 10,000

Dr. Sue Stramer / ARC BPAC, March 13, 2003
http//www.fda.gov/ohrms/dockets/ac/03/transcripts
/3940t1.htm
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West Nile Virus
Resulting plasma pool loads

• Max. viremic donor prevalence 10.4 per
  10,000 ? i.e. approx. 1 per 1,000
• Max. viremia levels 1,020 infectious units /
  ml
• Dilution of viremic donations into manufacturing
  pools? maximum of 1 infectious unit per ml,
  assuming the
• highest potential load, and the
• highest prevalence
• ? WORST CASE (earthquake during a hurricane)

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West Nile Virus
Base case

• Plasma viremia 1-5 x 103 c/ml (FDA BPAC
  info)assume mean of 3,000, statistically
• Infectious virus titer of positive units 10
  units/ml1 infectious virus particle per 346
  genomes, i.e. mean of determined range
• Prevalence of viremia in the population
  2/10,000average risk throughout the U.S., during
  peak epidemic
• Resulting plasma manufacturing pool loads ?
  0.001 units/ml
• PLUS reduction by manufacturing processes !

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West Nile Virus
Resulting plasma pool loads

• WNV would be below the limit of detection for
  current virus assays
• Inconsistent with current practice for HIV, HCV
  and HBV

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West Nile Virus
Reduction by manufacturing processes

• ALL dedicated virus inactivation steps which
  have been investigated so far resulted in
• ? complete inactivation of WNV
• reduction factors ranging between gt5.5 and gt8.2
• ? very rapid inactivation kinetics of WNV
• ? verification of the fact that WNV behaves
  exactly like predicted from model virus (BVDV,
  TBEV) data !!

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West Nile Virus
Reduction by manufacturing processes ?

• Besides dedicated virus inactivation steps, other
  steps contribute to virus reduction during
  manufacturing process.
• only dedicated steps considered
• For manufacturing process, the overall virus
  reduction capacity is determined by a combination
  of virus inactivation and virus removal.
• only inactivation investigated

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West Nile Virus
Further relevant features

• Acute self-limiting infection life-long
  test-based donor deferral is only prudent
  for
  chronically-infected persons
• ? No medical benefit to the donor
• ? No public health benefit from WNV testing

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West Nile Virus

• Conclusions
• Donation loads below limit of detection for
  current test strategies
• Typical flavivirus characteristics
• Effective viral reduction by existing processes