Risk assessment: The Safety of Blood Products
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Risk assessment: The Safety of Blood Products p resented b y Dr. Thomas R . Kreil Baxter BioScience o n behalf of the PPTA Pathogen Safety Steering Committee Technical meeting with FDA April 29, 2003. The safety of blood products. Risk assessment considerations Plasma viremia

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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/vol8no12/02-0532.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 >5.5 and >8.2

    •  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


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