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Single Use technologies in Downstream processing and Fill-Finish
Niels Guldager
Senior consultant, Process and Technology
Single use technologies in Biomanufacturing processesISPE DACH Conference, Marseille, May 26-26th, 2011
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Presentation outline
Single Use Technologies in Downstream Processing and Fill-Finish
• Purpose: Overview presentation - highlight technical/process/plant floor aspects
• Background and perspective
• SU in Downstream processes
• SU in Fill-Finish
• Case: Compounding
Disclaimer:
Overview only partial, - not comprehensive
Examples selected for illustrative purpose
360° survey always recommended
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Close to 1,700 colleagues at more than 25locations in 12 countries around the world.
NNE Pharmaplan: Where we are
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Industry trends
• One example: 900 Medicines and Vaccines against Cancer in testing
• 200+ are Monoclonal Antibody-based (mAb)
• Towards personalized medicine
• More specialized therapies
• More specific (smaller) patient populations
• Orphan drugs
• Biosimilars
• - other factors…
• Smaller campaigns
• Multiproduct facilities
• More frequent product changeovers PhRMA 2011 Report
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Generalized Biomanufacturing Bulk process flow
Bulk Filtration Freezer
• Basis: MAb production process
Isolate product Bulk formulationVirus clearance, orthogonal methods
Remove impurities, reduce volume, change buffers
Day Days
Physical-chemical processes
Virus inactivation
Virus filtration
Generate biomass Remove biomass
Weeks Day
Biological processes Physical-chemical
Generate product
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Centrifugation
• CARR Unifuge
• Disc bowl operation – discharge etc. – integrated with pump/skid
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Depth filtration
• Cell removal
• Elimination of cleaning housing, aerosols generation
• Significant solid waste contribution
• Membrane can also have secondary purification effect (HCP, DNA…)
3M Purification PALL Sartorius Stedim Merck Millipore
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Column chromatography
• GE Healthcare – also including disposable fluid path• Prepacked• Campaign use (not one-time use)
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Membrane chromatography
• Flow through polishing (HCP, DNA, Viruses)
• Membrane bound ligands for improved mass transfer area
• No packing, large throughput, buffer and time savings
Sartorius-Stedim PALL Merck Millipore Natrix
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UF/DF TFF
• Buffer exchange, volume reduction
• Shear
• Pressures
• Flowrates, tube diameters
JM SeparationsMilliporeSciLog
Novasep
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Virus reduction filtration
• Timing
• Pressure monitoring
• Flushes
• Integrity testing
Sartorius-Stedim Millipore
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Freeze-thaw
• Controlled rate – cryopreservation prevention
• Bag protection
Sartorius-Stedim Celsius Bag freeze-thaw system
Advanced Scientific Sartorius-Stedim
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Generalized Biomanufacturing Bulk process flow
Bulk Filtration Freezer
• Basis: MAb production process
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Generalized Biomanufacturing Fill-finish flow
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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SU in Fill-Finish: Potentially a good match
• Volumes and flow rates in general relatively low• Heat and mass transfer demands in general moderate• Concern more: Repeatability, accuracy, physical stress
• Container/closure, filters already characterized, leachables/extractrables not ”new”• Risk high – everything critical• Durations relatively short• Protein concentrations high
Bosch PreVas single use filling assembly
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Compounding - mixing
HycloneATMI ATMI Xcellerex
• Mixing technology – vibrating, paddle, agitator, levitating impeller
• Circular or rectangular
• Several designs to avoid/reduce particle generation
• Ability to move impeller really slow
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Compounding - mixing
Merck Millipore Sartorius-Stedim Hynetics
• Large range of volumes
• Mobile or stationary
• Visual process
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Powder transfer
• Transfer and rinse from pre-weighed bag
• Very controlled operation
• Very low dust generation to surroundings
Hyclone
ATMI
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Example: Compounding large scale
CHALLENGE
• Washing and sterilizing tanks
• Physically moving stainless steel tanks around
• Many tanks in clean, dirty, operation states – housekeeping effort
• Maintenance
Example mobile tank (IAI Biopharma)
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Example: Compounding large scale
SINGLE USE TECHNOLOGY ALTERNATIVE
• Single use mixing systems – bag plus powder bags
• Floor scale
POTENTIAL IMPROVEMENTS
• Fast setup
• Improved ergonomics
• Faster compounding operation
Sartorius-Stedim
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Generalized Biomanufacturing Fill-finish flow
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Single use filling
Now available from all well known filling machine suppliers
• Eliminate washing, sterilization• Fast setup
Bosch
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From Compounding to Filling
• Single use sterile filtration manifold - connect through wall
Millipore
Bosch
Recommended reference:
[1] Miriam Monge, Andrew Sinclair: End-to-End Deployment of Single-Use Technology in Aseptic Filling of Vaccines at GSK, BioPharm International, Feb 1, 2010, Vol 23, Issue 2
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Single use filling flow path
• Enabling formulation-to-filling single use flow path
From Groninger
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Generalized Biomanufacturing Fill-finish flow
• Novel pre-washed, pre-sterilized container technologies
• To reduce need for support functions and simpliy operations
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Reducing support operations
Pre-filled syringes – NEST technology
• Nest arrives with syringes pre-sterilized, gamma-irradiated
• Outside surface sterilized before entry to filling machine (VHP, E-beam…)
• System also potentially useful for introducing assemblies etc.
• Reducing need for wash and sterilization tunnel
Bausch and Strobel Becton Dickinson
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Reducing support operations
Pre-sterilized, closed vial system
• Vial and stopper integrated, closed system
• Filling by penetration of seal
• Re-seal by laser beam
• Stopper in place through entire operation
• Eliminating cleaning and sterilization
Aseptic Technologies, Crystal system
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Sequence optimization
Lyophilization cap system
• Perhaps more optimal sequence – cap in place before lyophilization
• Cap clicks in place by place tray pressure
• Simplifies operations after freeze drying
Lyoseal, Biocorp, biocorp.fr
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Presentation message
• Large potential for single use technology
• Industry trends support introduction of single use technology in fill-finish
• Risk management central for successful introduction
PDA Technical report on SU, due 2011
Single Use Technologies in Biomanufacturing Processes, ISPE DACH/France – May 26-27, Marseille, FranceNiels Guldager, Senior Consultant Bioprocess and Technology, [email protected]
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Thank you for your attention!
• Now with single use technology chapter!!!
ISPE Biopharm development and manufacturing baseline guide
ISPE Baseline Guide Bioproces…Due 2011
• -
• -
• -
• Regulatory
• Qualification
• Process
• Support systems
• Facility
• Scale-up, tech transfer
• Single Use technology
Biopharm processdevelopment and manufacturing