Update on viral inactivation

1
Update on viral inactivation
Tim Carroll Director of Immunohaematology Market
Development
2
ARCBS study

• Assuring the safety of blood components
• Voluntary, non-remunerated donors
• Donor education
• Stringent donor selection criteria
• Highly sensitive laboratory screening of donated
  blood
• These measures result in an extremely low
  residual risk of transfusion-transmitted viral
  infection (TTVI)

3
Background

• Residual risk of TTVIs in Australia
• Hepatitis B 1 in 633,000 transfusions
• Hepatitis C 1 in 6,387,000 transfusions
• Human T-cell lymphotrophic virus I/II (HTLVI/II)
  1 in 6,820,000 transfusions
• HIV 1 in 9,242,000 transfusions
• Estimates current to January 2006

4
Prevalence Reduction
5
Plasma products

• To ensure the safety of CSL Bioplasmas plasma
  derivatives from blood borne pathogens
• Maintain a watching brief on emerging and
  recurrent pathogens of concern (TNVs)
• Identify, develop and introduce sensitive assays
  for the detection of pathogens in plasma
• Generate comprehensive validation data on
• the efficacy of CSLs dedicated viral
  inactivation and removal steps in the
  manufacturing process
• the ability of selected steps in the
  manufacturing process to remove viruses and/or
  putative prions

5
6
Plasma Processing - Australia
ARCBS - collection
red cells, platelets
blood
plasma
Finished product - Immunoglobulins - Albumin
- Clotting Factors
6
ARCBS - distributes product
7
Advantages of Chromatography

• Gentle process
• Higher Yield
• Higher purity
• Automation and closed system
• Facilitates extraction of additional proteins
• Viral and Endotoxin clearance

7
8
Ion Exchange Chromatography Gel Filtration
8
9
OPTIMISING QUALITY SAFETY OF PLASMA PRODUCTS
Plasma quality screening Minimize viral risk in
the initial plasma pool 1. Strict donor
exclusion criteria 2. Individual plasma
donation screening - Serology tests (HIV,
HCV, HBV) - NAT (HIV, HCV) 3. Plasma pool
screening - Serology tests (HIV, HCV, HBV)
- NAT (HIV, HCV, parvovirus B19)
9
10
OPTIMISING QUALITY SAFETY OF PLASMA PRODUCTS
VIRAL BARRIER 2 Viral load reduction
Precipitation and/or chromatography
10
11
OPTIMISING QUALITY SAFETY OF PLASMA PRODUCTS
VIRAL BARRIER 3 First viral inactivation /
removal step Pasteurisation Solvent /
Detergent Low pH (/- caprylate)
11
12
OPTIMISING QUALITY SAFETY OF PLASMA PRODUCTS
VIRAL BARRIER 4 Second viral inactivation /
removal step Dry heat Pasteurisation Low
pH Dedicated Virus filter(s)
12
13
OPTIMISING QUALITY SAFETY OF PLASMA PRODUCTS
13
14
The Big 5 for Plasma Fractionation
14
15
Pathogen SafetyIntragam-P Viral Clearance Data
HIV HAV HBV HCV B19 Cryosupernatant
- gt2 - - - Supernatant I -
gt2 - - - Delipidation/Euglobulin
- - - - gt5.5 DEAE - gt2.1
0 gt1.1 - MacroPrep HQ - -
- gt3.9 - Pasteurisation gt5.5 gt5.4
gt6.5 gt5.7 - Low pH incubation gt4.4
- gt6.2 gt2.9 - Total Reduction
gt9.9 gt11.5 gt12.7 gt13.6 gt5.5 Investigative
study
15
16
Pathogen SafetySummary of LRFs
Note all validated LRF are equal to or less
than
16
17
TSEs
CJD in the United Kingdom1994 - 2006(as at
1st September 2006 Dept. of Health, UK)
18
Guidelines and Regulatory Positions

• FDA Note for Guidance (2002)
•  Model TSE agents are removed from plasma
  products by manufacturing steps such as
  precipation, depth filtration and column
  chromatographydata suggest that the vCJD agent
  is similarly reduced by some manufacturing
  steps 
• Impact donor deferral and batch withdrawal
  policy subsequently (2003) on TSE clearance
  labeling
• WHO Guidelines (2003)
•  Experimental studies from several research
  groups have consistently shown substantial
  reduction of spiked TSE infectivity during plasma
  fractionation steps, and there is growing
  evidence that the risk from plasma derivatives is
  negligible. 
• Impact donor deferral and batch recall
  recommendations

18
19
Efficacy of CSLs Manufacturing Process(es) in
Removing Putative Prions - Publications

• Investigation of Prion Removal/Inactivation from
  Chromatographic Gel
• - Thyer J, Unal A, Middleton D, Bingham J.,
  Braun M., Uren E. and Maher D.
• Vox. Sang. in press.
• Prion Removal Capacity of Chromatographic and
  Ethanol Precipitation steps used in the
  Production of Albumin and Immunoglobulins
• - Thyer J, Unal A, Thomas P, Eaton B, Bhashyam
  R, Ortenburg J, Uren E, Middleton D,
• Selleck P and Maher D.
• Vox. Sang. in press.
• Investigation by Bioassay of the Efficacy of
  Sodium Hydroxide Treatment on the Inactivation of
  Mouse Adapted Scrapie
• - Unal, A., Thyer, J., Uren, E., Middleton, D.,
  Braun, M., Maher, D.
• Biologicals in press.

20
TSE Conclusions

• No reported cases of vCJD in recipients of plasma
  fractionated products
• Risk appears extremely small and currently
  remains theoretical
• Further precautionary measures have been taken
  based on conservative risk modelling
• restriction of plasma for Biostate to donors who
  have never visited a BSE country
• Research continues into possible additional
  process steps to increase capacity to remove
  prions should they be in the starting plasma pool

21
VIRAL INACTIVATION OF CELLULAR COMPONENTS
22
METHODS FOR REMOVAL OF PATHOGENIC VIRUSES FROM
CELLULAR COMPONENTS

• 1. Leucocyte depletion
• currently in use, requires careful validation
• benefit relates to intracellular viruses only
• 2. Light activated chemical approaches
• photodynamic inactivation
• psoralens

23
PHOTOSENSITISED VIRAL DECONTAMINATION

• More effective for plasma and platelets than for
  red cells
• Selection of specific wavelength to activate the
  dye
• Use of quenchers e.g. mannitol vitamin E
• Modifying rate at which light is delivered
• Evidence of activity against broad range of
  infectious agents
• viruses
• enveloped
• non-enveloped
• bacteria
• parasites
• malaria
• T. Cruzii
• possible avoidance of alloimmunisation

24
PHOTOCHEMICAL INACTIVATION

• Issues
• Safety profile
• psoralens are potential carcinogens
• toxic effects
• risk reduction or risk substitution?

25
INACTIVATION OF PATHOGENS PRESENT IN RED CELL
CONCENTRATES

• Technologically more challenging
• Light based approaches unlikely to be effective

26
Summary Swiss cheese model of safety

• Recognise that any system has gaps
• Put systems to catch anything getting trough a
  gap
• Donor qualification
• Donor testing
• Pooled plasma EIA
• Pooled plasma NAT
• Production process
• Dedicated viral inactivation

27
Summary

• Donor screening is still the cornerstone of viral
  safety
• EIA based screening of donor pools cost
  effective but leaves a window
• NAT screening of donor pools expensive but
  reduces the window
• Different fractionation methods have different
  safety profiles
• Viral inactivation methods vary form manufacturer
  to manufacturer and product to product
• Current systems are very reliable and effective
• Further work continues
• TSEs
• TNVs
• Cellular products

28
(No Transcript)