engineering a blood processing facility for viral safety · engineering a blood processing facility...
TRANSCRIPT
Engineering a blood processing facility for viral safety
Presented by Cameron Roberts, Senior Engineer
7 February, 2018
Slide 2 © PharmOut 2016
Introduction
Engineering a blood processing facility for viral safety
1. What are viruses?
2. Why is viral safety important?
3. What level of risk is acceptable
4. Starting materials of human or animal origin
5. Challenges of removing viruses from biological materials
6. Inactivate and remove residual viruses during processing
7. Adhere to GMP in all production steps
8. Impact on facility and process design
9. Case study
Slide 3 © PharmOut 2016
What are viruses?
In context of manufacturing medicines from human or animal sources:
• Virus don’t replicate or metabolise outside of host cell
• Genetic structure (e.g. DNA or RNA)
• Not living organism as unable to reproduce
• Causative agent of disease
• Risk of transmission to patient
• Usually species specific
• Viruses are very small
Slide 4 © PharmOut 2016
Virus risks in human blood plasma
Virus Structure
Hepatitis A Non-enveloped single stranded RNA 28-30nm
Hepatitis B Enveloped double stranded DNA 40-45 nm
Hepatitis C Enveloped single stranded RNA 40-50 nm
HIV Enveloped single stranded RNA 80-130 nm
Slide 5 © PharmOut 2016
Challenges of removing viruses from biological materials
Generally biologicals (animal or human origin) are:
• Of limited supply hence desirable to maximise yield
• Costly to collect and test
• Variable risks over geography, population and time
• Sensitive to temperature, pH and mechanical shear
• Sterile medicines processed aseptically
To achieve viral safety it is desirable to:
• Minimise virus risks in starting material
• Achieve viral reduction without reducing product yield
• Prevent re-contamination after each viral reduction step
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Swiss Cheese Model: Blood Products
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Limitation of selection / screening
Viral safety steps not related to facility design:
• Select donors (or controlled herds)
• Screen donations - sampling and testing individuals
• Pool testing
• Manage post donation events
Limitations:
• Reliable test for know nucleic acid (NAT) or antibodies
• Window between donor infection and detectable test
• QC testing of finished product unlikely to detect low concentration of virus
So manufacturing steps are essential for viral safety
Slide 8 © PharmOut 2016
Viral safety: Inactivate and remove residual viruses during processing
Examples of inactivating and removing viruses during processing:
1. Virus inactivation
• Heat treatment: pasteurisation, lyophilisation
• Low pH incubation
• Solvent detergent
2. Virus removal
• Nano-filtration
• Chromatography
Two or more steps required
Viral clearance studies required
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Viral inactivation procedures
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Viral removal procedures
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Viral inactivation example: Pasteurisation
Bulk Pasteurisation of human albumin:
• Heat treatment
• Temperature: 60 +/- 0.5 °C
• Duration: 10-11 hours continuously
• Demonstrated safety with respect to hepatitis viruses and HIV
• Need to demonstrate process parameters
Challenges in process tank design
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Pasteurisation Process Steps
Process step Challenge
Set up Viral decontamination prior to use
Clean in Place Effective viral decontamination (sodium hydroxide concentration, time and temperature)
Steam in Place System designed for steam pressure, vacuum and temperature
Charging product Risk of unpasteurised product falling into tank after pasteurisation
Heat up phase Even temperature, mild agitation, whole tank
Pasteurisation As above 60+/-0.5°C
Cool down
Transfer Prevent re-contamination
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Pasteurisation tank design
T
T
T
Process Control
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Viral safety: Adhere to GMP in all production steps
GMP is critical to viral safety
Key Considerations:
1. Starting material is main contamination source
2. Identify process steps to reduce viral load in product
3. Multiple viral reduction steps required
4. Processing after viral reduction steps to prevent recontamination
Cross contamination technical measures (EU GMP Chapter 5)
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Process and Facility Design
Process and Facility Design considerations:
1. Dedicated process equipment (especially centrifuges, ultrafiltration and chromatography are difficult to clean)
2. Closed or single use equipment
3. Separate “safety zones” after each viral reduction step
4. Separate entrances
5. Separate air handling units
6. Separate cleaning equipment (manual, CIP, room)
7. Personnel, product, equipment and waste flow
8. Multidiscipline team
Diafiltration to Clarification
Post-Chromatography to Filling
Purification to Chromatography
Buffer Preparation
Dispensary
MAL Starting Materials
HPW, CIP etc.
MAL Packaging Materials
MAL Packaging Materials
PAL to Grade D
PAL to Grade C to Chromatography
PAL to Grade C Post Chromatography
Cell Separation
BWB transfer
Packaging Materials
Warehouse Starting Materials
Cool Room
Wash room
Storage room
Corridor
MAL Filled bags
Personnel flow
Material flow
Process flow
CNC
Interconnecting Spaces
P/T
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Architectural Layout
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Process design: P&ID development
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Layout with Process Equipment 3D
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HVAC Schematic
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Separate Air Handling Units
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Clean Room Ductwork Layout
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Conclusion
Viral safety involves:
• Selection and testing of starting materials
• Demonstrated viral reduction steps
• Cross functional design team
Viral reduction steps dictate:
• Handling of product after viral reduction
• Layout of facility
• Facility design and operation to prevent re-contamination
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Thank you.Any Questions?
Cameron Roberts
Senior Engineering