New technologies in biopharmaceutical processes BioTech Vaccines Plasma

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1 New technologies in biopharmaceutical processes BioTech Vaccines Plasma Dominik Arnold

2 Challenges in Down Stream Processing Higher. Titers >4 g/l Yield > 90% Protein concentration >200 g/l Throughput > 24 h Process flexibility multipurpose Utilization > 3 batches/week Qualification / Validation ICH Qxx Automation GAMP 4/Part 11 Standardisation Platforms

3 Upstream Processing Media Filtration Exhaust Cell Harvest and Product Separation Buffer Filter Liquid Prefilter Aeration Sterilizing-grade Liquid Filter Air Sterilizing-grade Prefilter Air Filter Bioreactor Air Prefilter Sterilizing-grade Air Filter Depth Filtration Tangential Flow Filtration Centrifuge Downstream Processing and Purification Buffer Filter Buffer Filter Buffer Filter Buffer Filter Polishing Chromatography Sterilizing-grade Liquid Filter Sterilizing-grade Liquid Filtration Formulation and Filling Concentration Diafiltration Capture Chromatography Concentration Diafiltration Purification Chromatography Concentration Diafiltration Virus Removal Filtration

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5 Subprocesses in Down Stream Processing (DSP) Harvest/ Separation Capturing/ Concentration Purification/ Polishing Filtration Clarification Concentration Purification Virus Filtration Separation Capturing Polishing Sterile Filtration

6 Harvest/ Separation Clarification Separation Picture courtesy of Biocon

7 Alternative Harvest Schemes Fermenter Pre-Separation Depth-filtration Clarification Volume, Concentration, Price

8 Alternative Harvest Schemes - Small scale - Low solid load / cell density - Low viscosity - Low investment cost - All scale - All solid load / cell density - Medium viscosity - Medium investment cost - All scale - All solid load / cell density - High viscosity - High investment cost

9 Project example separation and clarification End-user Eng. company Design URS Basic engineering Layout utilities Manufactu ring Installation / Commissi oning Supervisio n Supervisio n Software implementat ion Overall facility Pall Detail engineering FS Mech/ electrical manuf&ass embly Skid Qualificati PQ Joint OQ DQ, IQ, on joint OQ Well defined process allow complex SCADA implementation Early definition of requirements allows process and operator optimized solution Engineering company insures layout and utility fit to purpose

10 Capturing/ Concentration Concentration Capturing Picture courtesy of Lonza

11 Chromatography Process Pump Column UV mv Buffer Process ph Waste Product Detector Stationary Phase Speed Capturing Mobile Phase Selectivity

12 Capturing Capacity, Yield and Resolution Column chromatography Sorbent packing (no channelling, no fine) Identical flow distribution (no preferential flow) Process control (Automation, Instrumentation) Good flow distribution, minimal pressure drop, reliable packing

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14 Project example In-line buffer dilution Reduce buffer storage for chromatography process In-line buffer mixing reduce buffer storage size by up to 20 times Reduce clean room size Reduce preparation time Simplify chromatography process system Possibility to include single use technologies due to reduced volumes Close coordination with engineering company engineering buffer management and WFI supply

15 Capturing/ Concentration Concentration Capturing Picture courtesy of GSK Bio

16 Typical Tangential Flow Process (TFF) Filtrate Diafiltation Recirculation Vessel Filtration Device Pump Feed Retentate Control Valve Filtrate/Permeate Cross Flow (CFF) Feed Retentate Transmembrane Pressure Filtrate/Permeate Filtrate Flux

17 Critical Parameter in TFF MEMBRANE CONTROLLED REGION GEL LAYER CONTROLLED REGION Filtrate Flux Rate OPTIMAL Cross Flow CF3 (Δ P 3 ) CF2 (Δ P 2 ) CF1 (Δ P 1 ) CF = CROSS FLOW VELOCITY CF 3 > CF 2 > CF 1 Transmembrane Pressure Cross Flow Membrane area, Pressure, Heat intake, Piping, Pump size

18 Disposable Technologies Flexibility and short start up time Low fix cost High variable cost Engineering Concept Standardised Technologies Standard Hardware/ Software Proven Process limitations Customised Technologies Customised Challenges specifications and qualification/validation

19 Level 1 Manual Control Automation Level 2 Setpoint Control Level 3 Sequence Control Intervention, Flexibility, Reliability, Documentation

20 Project example Concentration Product loss, yield High protein concentration (200 g/l) Ensure low protein adsorption on membrane Right pump selection to ensure process consistency at variable viscosity (up to 150 cp) Jacketed tank to maintain temperature Tank in tank design to achieve highest possible concentration Improved pipe design to ensure complete product recovery Optimized tank design to avaoid aggregation and foaming problems

21 Purification/ Polishing Purification Polishing Picture courtesy of Biogen Idec

22 Challenges in Polishing Speed Membrane Chromatography Removal of, DNA / RNA, Endotoxins,Plasmids Minimal fix cost Sterile process conditions Less consumable (buffer/cip) Polishing Speed, Selectivity, Purity

23 Filtration Virus Filtration Sterile Filtration Picture courtesy of Lonza

24 Challenges in Filtration Bioburden vers Sterility Bioburden control Sterile filter Prefiltration steps Column protection Buffer prior chromo Diafiltration - High throughput - Reduced validation - Less filter testing - Smaller sizing Before storage Sterile media End of DSP Filling - Sterility - Integrity testing - Low adsorption

25 Disposable Technologies Cleanable Disposable

26 Pro s and Con s of Disposable Systems Pro s Low installation cost Low cleaning costs and validation No assembly/maintenance costs Small footprints Minimize cross contamination Minimize operator exposure Con s Limitations on scale Limited automation Running cost Limited equipment and instrumentation Limited process pressure

27 Comparison Conventional SS versus Disposable Investment costs % lower Less and smaller equipment, smaller footprint, less utilities, shorter project time Utility costs % lower No steam, No CIP, less WFI/PW Running costs 5-30 % higher More consumables, less automation > higher labour cost Process time % lower Lower preparation cost (SIP and CIP) Business decision Scale, batches/a, new/existing plant

28 Conclusion batch size titer utilization buffer/utility consumption documentation CIP SIP purity product loss/ yield level of automation foot print fix vs running cost