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TSE Task Force Prion reduction evaluation in the manufacturing of plasma protein therapies. Dr. Henry Baron, Chair, PPTA TSE Task Force FDA TSE Advisory Committee The Hilton Hotel, Silver Spring 14 October 2004. FVIII / vWF Products. Study Parameters

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TSE Task Force Prion reduction evaluation in the manufacturing of plasma protein therapies

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Tse task force prion reduction evaluation in the manufacturing of plasma protein therapies l.jpg

TSE Task ForcePrion reduction evaluation in the manufacturing of plasma protein therapies

Dr. Henry Baron,

Chair, PPTA TSE Task Force

FDA TSE Advisory Committee

The Hilton Hotel, Silver Spring

14 October 2004


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FVIII / vWF Products

Study Parameters

  • Prion strain: 263K hamster adapted Scrapie

    • Spike preparations:

      • Microsomes

      • Purified PrPSc

      • Detergent solubilized brain homogenate

      • 10 % brain homogenate

    • Prion detection / quantification method: CDI; Western blot, bioassay

    • 2 - 3 independent runs/spike preparation


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FVIII / vWF Products

Results

  • Product A: Consecutive salt precipitation (Preliminary data on Prion Reduction Factor):

    • Microsomes: 2.5 log10 /3.2 log10 /2.5 log10[mean: 2.7 log10]

    • Purified PrPSc: 2.9 log10 /3.3 log10 /2.8 log10[mean: 3.0 log10]

  • Product B: 3 % PEG precipitation (Published data on Prion Reduction Factor):

    • 2.2 log10 infectivity

    • 3.0 log10 PrPRES by Western blot

  • Product C: (Heparin-affinity purified): 3.5 % PEG precipitation (Preliminary data on Prion Reduction Factor):

    • Microsomes: 3.5 log10/3.5 log10

    • Detergent solubilised BH: 4.2 log10/4.2 log10


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MAb purified F VIII

  • Prion strain: 263K hamster adapted Scrapie

    • Spike preparations:

      • Brain homogenate (Mab affinity step)

      • SD treated and filtered brain homogenate (DEAE step)

    • Prion detection / quantification method: Hamster bioassay

  • Manufacturing stage studied: MAb affinity chromatography and DEAE Sephadex

    • 2 independent runs/spike preparation

  • Result (Prion Reduction Factor):

    • MAb affinity chromatography: 4.1 log10

    • DEAE Sephadex: 3.5 log10


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FIX Products

Study Parameters

  • Prion strain: 263K hamster adapted Scrapie

    • Spike preparations:

      • Microsomes

      • Purified PrPSc

      • Detergent solubilized brain homogenate

    • Prion detection / quantification method: CDI; Western Blot

    • 2 independent runs/spike preparation


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FIX Products

Results

  • Product A: Manufacturing stage studied: Planova filters in series

    • 35N

    • 15N

    • Result for detergent solubilized brain homogenate (Prion Reduction Factor):≥4.1 log10 mean


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FIX Products

  • Product B: Manufacturing stage studied: Nanofiltration (YM 100)

    • Result (Preliminary data on Prion Reduction Factor):

      • Microsomes:  3.3 log10 /  3.7 log10 [mean:  3.5 log10]

      • Purified PrPSc:  3.6 log10 /  3.6 log10 / [mean:  3.6 log10]

  • Product C: Manufacturing stage studied: Salt precipitation

    • Result (Preliminary data on Prion Reduction Factor):

      • Microsomes:  3.8 log10 /  3.6 log10 [mean:  3.7 log10]

      • Purified PrPSc:  2.9 log10 /  3.1 log10 / [mean:  3.0 log10]


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IGIV

Prion Clearance by Coupled vs Independent Steps

a Bioassay n = 1, confirmed by Western blot measurement of PrPRES, n =3

b Spiked once at the beginning of coupled steps consisting Cryo, Frac. 1, and Frac. III separation

c Spiked at the beginning of each independent step

d Not determined by bioassay, the number is derived from the coupled study. Western blot consistently

shown ~1 log clearance

Conclusion:

Prion infectivity reduction can be additive for these steps


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Single Steps vs. Combination of Steps

Immunglobulin Production

LRFLRF combined steps

Depth filtration 1 4.5

7.2

Depth filtration 2 2.8

Sum7.3

Brain homogenate spiked to intermediates

Prion reduction factor determinded by infectivity

Gregori et al. 2004


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Risk of vCJD Donors in the UK Donor Population

  • To date, 15 blood donors diagnosed with vCJD, of which 9 contributed to ~20 pools used to manufacture plasma protein therapies

  • Thus from 1980-1998 *, the incidence of vCJD donors amongst the donor population was:

    • 15 / (1,907,000 # x 18 years) =

    • 0.44 vCJD donors per million donors per year

      * Based on the time period of potential exposure to BSE until when UK plasma was no longer used for manufacture

      # In 1997 the yearly number of UK donors was 1,907,000

      (DNV vCJD risk assessment; 1999)


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BSE Exposure: EU vs. UK

i.e. ~100-fold lower EU vs UK vCJD exposure

* All UK vCJD infected donors contributed prior to the introduction of active testing for BSE.


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Active vs. Passive Detection of BSE (EU excluding UK)

~4-fold increase in BSE detection due to active testing

From: Report on the Monitoring and Testing of Ruminants for the Presence of Transmissible Spongiform Encephalopathy (TSE) in the EU in 2003, including the results of the survey of Prion Protein Genotypes in Sheep Breeds (EU report)


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Conclusions

  • Comparability of data from different PPTA member companies using different investigative approaches gives confidence that current systems are working to ensure efficient prion removal, even though prions have never been shown to exist in human plasma.

  • These efforts made by PPTA member companies represent enormous investments in applying the precautionary principle and providing reassurance on the safety of plasma products.

  • Balanced approaches are necessary to ensure both safety and availability of life-saving plasma protein therapies


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