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 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 = 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 V o vs. V i 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