Clinical and Commercial Facility Design for Continuous

Report
Facility Drivers for Housing
Start-to-Finish Continuous
Bioprocessing
.
Disruptive changes in scale &
operational expectations
vs.
traditional batch operations
Bradley E Kosiba, PhD, CPIP
BK Collaborative, LLC
ECI Integrated Continuous Biomanufacturing
Clinical and Commercial Facility Design for Continuous
Biomanufacturing
October 23, 2013
Scope of Disruption
• Facility Drivers
• Process Scale
• Process Duration
• Process Integration
• Points of Disruption
• Process Development
• Clinical Production
• Manufacturing
• A Few Technology Gaps
• Miniaturization of Biotech
Scale
Compare to 13,000L Fed Batch BioRx
• Production Bioreactor Harvests
• 3 X 13,000L fed batch per week = 1 X 3,700L Perfusion @1.5V/day
At similar titers this leads to…
• Seeds per Quarter (3 months)
• 36 batch vs. 1 perfusion
• Downstream piping flows (approx.)
• Batch – 50 LPM transfer/250 LPM UF retentate
• Continuous – 5 LPM harvest, 0.5 LPM polishing, 0.05 LPM final DS
• Tank volume for Unit Operations (UOs)
• Batch: 1,000 – 20,000L Process Tanks.…….. 200L final DS (3/week)
• Continuous: 20 – 500L Surge Tanks…………. 200L final DS (3/week)
Integration
The Slippery Slope to Continuous BioProcessing
• Demise of “hold and test” steps
• Directly replace offline with PAT
• Rise of QbD
• Increases predictability
• Reduce offline confirmation testing
• Move to mini-batch chrom
• Limit column size
• Upgrade to continuous mini-batch operation
• Combine UOs for efficiency
• Pairing flow-through chrom with next batch step
• Full automation reduces human error
• Automate transitions between unit ops/cleaning/prep
Duration
• Perfusion duration to 3 months (or more?)
• Fully integrated downstream = same duration
• Equipment Sanitation
• Minibatch processes allow periodic cleaning
• Challenge: maintain sanitation of remaining flow paths
• Equipment/Sensor/Separation Media Durability
• Change out/recalibration needed?
• SU disposables capable of 3+ month duration?
• Product/Batch Uniformity
• Steady state perfusion supports glycosylation uniformity
• Downstream process uniformity eliminates final batch mix?
Scope of Disruption
• Facility Drivers
• Process Scale
• Process Duration
• Process Integration
• Points of Disruption
• Process Development
• Clinical Production
• Manufacturing
• A Few Technology Gaps
• Miniaturization of Biotech
Process Development
• Scale
• Scaled down continuous UO availability?
• 50L BioRx = 0.5 - 50 ml/min downstream
• Integration
• Automation of Lab-scale Integrated Continuous Processes
• User friendly
• Whole process
• Multi vendor UO tolerant?
• Duration
• Steady State Development Platform Benefits
• Iterative automated DOE design space mapping over long runs
• Final Drug Substance (DS) or Product (DP) quality readout
• And Challenges
• Sanitation of small, non-GMP flow paths
• Maintaining continuous buffer supplies
Clinical Production
• Scale
• Clinical batches made at full manufacturing “scale” (not duration)
• Duration
• Clinical Batches from multiple short duration runs
• Clinical Batches collected sequentially from one long duration run
• Combinations
• Integration
• Requires full, integrated process & automation program
• Stable Steady-State processes
• Could facilitate clinical experience at non-center point conditions
• Planned excursions within design space during clinical runs
• Collect “batches” under different parameter regimes
Commercial Production
• Scale
• 1x 3,700 L culture vs. 3x 13,000L cultures
• 0.05 – 5 LPM vs. 50 – 250 LPM
• Integration
• Full automation of Continuous process
• Automated transitions between process, cleaning and prep cycles
• No holds or stops between Unit Operations
• Duration
• Process Validation
• Relevant experience from continuous clean utility systems (WFI, CS, CAP)
• Relies heavily on robust QbD package to gain confidence before PV runs
• Lack of routine human intervention reduces uncertainty
• True Risk-based batch sizing
• vs. Risk + Capital cost based sizing
Scope of Disruption
• Facility Drivers
• Process Scale
• Process Duration
• Process Integration
• Points of Disruption
• Process Development
• Clinical Production
• Manufacturing
• A Few Technology Gaps
• Miniaturization of Biotech
Technology Gaps
Continuous single-pass buffer exchange (GMP)
• Multi-stage UF/dilution
• brute force engineering
• Multi-stage 1-pass UF concentration exists in food industry
• Countercurrent 1-pass UF
• Similar to renal dialysis
• Probably multi-stage pumping
• Continuous Size Exclusion Chromatography desalting
•
•
•
•
Simple Vo vs. Vi separation
Uses current multi-column technology
Dilutes product (requires 1-pass UF concentration for final DS)
Available today
Technology Gaps
Properly Scaled Unit Operations
•
•
•
•
Current sizing equal to batch sized UO’s
Integrated Continuous BioProcessing at smaller scale!
Even further scale-down for bench-scale development
Sanitation at smaller scale for long runs a challenge!
• Disposable fluid paths may help non-minibatch UO’s
The Miniaturization of Biotech
• Early Biotech
• 100’s L BioRx and Downstream process
• Tanks 10’s - 100’s L
• 1 – 5 LPM
• Current Biotech
• 6 X 10,000+ L BioRx and Downstream processes
• Tanks 10,000’s L
• 50 – 250 LPM
• Miniature Integrated Continuous Bioprocess
• 1-2 X 1,000’s L BioRx
• Tanks 10’s – 100’s L
• 0.05 – 5 LPM
Summary
• Scale, Integration, Duration
• Process Development, Clinical Production, Commercial Prod’n
• Technology Gaps
• Miniaturization of Biotech (Facilities)
Acknowledgements
• Rick Lawless, Associate Director, NCSU BTEC
• NCSU Chem Engineering CBioP Senior Project Team 2012-13

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