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Driving Value in the Evolution Toward Continuous Monoclonal Antibody Processing
This document discusses the evolution toward continuous monoclonal antibody (mAb) manufacturing using next generation processing technologies. It describes how intensified upstream processes like perfused seed trains and high cell density fed-batch can reduce process times and increase titers. Flow through polishing is also examined as having the potential to reduce buffer volumes by 80-90% and decrease polishing process times by 70%, thereby lowering costs of goods sold by 5-10% according to process modeling. The document advocates for an evolutionary approach combining intensification, connection, and flexibility to deliver higher speed, lower costs and risks in mAb production.
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Driving Value in the Evolution Toward Continuous Monoclonal Antibody Processing
- 1. Merck KGaA Darmstadt, Germany MichaelPhillips, Habib Horry, Michael Felo Driving Value in the Evolution Toward Continuous Mab Processing
- 2. The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. 2
- 3. Table of Contents DrivingValue in the Evolution Toward Continuous Mab Processing 3
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- 5. BPOG Technology RoadMap A Major Shift in Business Drivers Market Growth Cost Pressure Uncertainty New Product Classes Business Drivers Flexibility Reduce product change- over time by 90% Speed Reduce new facility build times by 70%. Compress production lead time by 80% Cost 90% reduction in cost to manufacture and CAPEX Quality 10X transformation in mfg. robustness and reliability Process Analytics 5 Next Generation Processing https://www.biophorum.com/category/resources/tech nology-roadmapping-resources/introduction/
- 6. Market Research Drivers forAdoption of Next Generation Processing Technologies Cost Control / CoGs Reduction 90% Facility Flexibility 93% Multiple Molecule Pipeline 77% Multi-Use Product Facilities 73% 6
- 7. Market Research The ManyDefinitions of Next Generation Processing Process Intensification for existing bottleneck Process Compression Continuous Processing New greenfield facility leveraging single-use Industry definitions of Next Generation Processing Light Asset Facility ?? 7
- 8. 8 Any technology, expendable,service, or system which significantly changes the existing monoclonal antibody manufacturing template to deliver: Speed Flexibility Quality Cost Next Generation Processing
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- 10. 10 Factory of theFuture Evolutionary Journey Across Many Disciplines Timeline Today Near-term Mid-term End state Process Batch Intensified Connected Continuous Format Stainless Hybrid Single Use SU/Closed Controls Process Monitoring Unit operation control Integrated process control Holistic process control Analytics QC Manufacturing At-line In-line/real-time Software Unit Operation Control Systems Connectivity Paperless Facility Process Simulation
- 11. Focus Areas: (1) CellCulture Media For Intensified Processes (2) Integrated Perfusion Bioreactor (3) Protein A for Intensified Capture (4) In-Line Viral Inactivation (5) Flow Through Polishing Toolbox (6) Single-Pass UF/DF 2018 2018-2020+ 11
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- 14. MCB 200 vial NN-1 or x x SeedTrainInoc. Train Production MWCB 200 vial BatchBatch Intensified Seed Intensified Production • Fed-batch • Conventional Perfusion 1. High Cell Density Process Intermediates 2. Perfused Seed Train 1. High Seed Fed-Batch 2. Concentrated Fed-Batch 3. Ultra High VCD Fed-Batch 4. Steady State Perfusion 5. Dynamic Perfusion Intensified Upstream Several Opportunities for Intensified Upstream Processing 14
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- 16. Intensified Upstream Intensified ProductionProcesses – Single Harvest N-1 N Typical Processing Values Conventional Fed-Batch 14 – 21 days VCD: 10 – 30 .106 Titer: 1 X Concentrated Fed-Batch 14 – 21 days VCD: 100 – 200 .106 Titer: 3 – 6 X Ultra High VCD Fed-Batch 14 – 21 days VCD: 50 – 150 .106 Titer: 2 – 4 X High Seed Fed-Batch 9 – 16 days VCD: 10 – 30 .106 Titer: 1 – 1.3 X Perfusion Batch Batch Batch Fed-Batch Fed-Batch Fed-Batch Perfusion Perfusion X X High Seed Concentrated; Ultra High VCD Conventional 16
- 17. Intensified Upstream Intensified ProductionProcesses – Continuous Harvest N-1 N Typical Processing Values Conventional Perfusion 30+ days VCD: 30 – 50 .106 VCD Controlled High Density Perfusion 30+ days VCD: 50 – 100+ .106 VCD Controlled Dynamic Perfusion 14 – 21 days VCD: 100 – 200 .106 No VCD Control Perfusion Perfusion Perfusion Batch Batch Batch Conventional High Density Dynamic 17
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- 19. Intensified Upstream Intensified SeedTrain Batch x 1-2 mL 10 - 30 .106 VC/mL N-1 or x Batch MCB/MWCB Inoculum Train Seed Train Production CRD Perfusion CRD 50-100 .106 VC/mL or or 4.5mL 50-500 mL bag CRD CRD N CRD (2) High Cell Density Process Intermediates (1) Perfused Seed Train 19
- 20. Intensified Seed Train PerfusedSeed Train 14 days 10 days Conventional Fed-Batch (~ 0.2 .106 VC/mL) High Seed Fed-Batch (~ 5 .106 VC/mL) Conventional (Batch N-1) 3 days3 days3 days3 days or 5 days Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) Compressed Seed Train: facility utilization and reduced footprint High Seed: increased manufacturing capacity, facility utilization 8 days or 3 days3 days3 days 10 days or 3 days3 days3 days3 days 5 days8 days or 3 days3 days3 days 20
- 21. Intensified Seed Train HighCell Density Process Intermediate Batch x 1-2 mL 10 - 30 .106 VC/mL N-1 or x Batch MCB/MWCB Inoculum Train Seed Train Production 50-100 .106 VC/mL or or 4.5 mL 50-500 mL bagCRD CRD N CRD High Cell Density Process Intermediate CRD Perfusion CRD 21
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- 23. 23 What is Biosolve®Software? • Excel-based process model from BioPharm Services • Limited Calculates process economics • Database of industry averages with the option for user- specific information Benefits of Process Modeling 1. Focus on the “holistic process” 2. Side-by-side evaluation of alternatives 3. Can run “what if”, sensitivity analyses 4. Clear communication of value Unique Intensified Operation Modules of Process Modeling 1. Perfusion seed train and production options 2. Continuous chromatography 3. Flow through polishing 4. Single-pass TFF Biosolve® Software The Benefits of Process Modeling (Value Modeling)
- 24. Upstream Value Modeling Intensified(High) Seed Train 14 days 10 days Conventional Fed-Batch (~ 0.2 .106 VC/mL) High Seed Fed-Batch (~ 5 .106 VC/mL) Conventional (Batch N-1) 3 days3 days3 days3 days or 5 days High Seed (N-1 Perfusion) High Seed: increased manufacturing capacity, facility utilization 10 days or 3 days3 days3 days3 days 60-300 mL 1-2 L 10 L 50-200 L 1600- 2000 L 24
- 25. Upstream Value Modeling Assumptions Conventional Train N-2 (Batch) N-1 (Fed-Batch) Production (Fed-Batch) HarvestProduct Titer Reactor Volume 200 L 500 L 2000 L 5 g/L Duration 3 Days 5 Days 14 Days - High Seed Train N-2 (Seed) N-1 (Perfusion) Production (Fed-Batch) Harvest Product Titer Reactor Volume 50 L Batch 200 L (2 VVD) 2000 L Fed-batch 5 g/L Duration 3 Days 10 Days 10 Days - • Value modeling focus on upstream only (all other processes held constant) • Seed train bioreactor volumes differ based on feed-in ratios • High seed train scenario duration 1 day longer than base-case • Production bioreactor run is 4 days shorter or N-2 Seed N-1 Seed Production Centrifugation Depth Filtration Full DSP 25
- 26. Upstream Value Modeling Comparisonwith High Seed Train Scenario 11.5% COGS reduction with High Seed Train Scenario • N-2 reactor through depth filters COGS Contribution Lower COGS with High Seed Train despite higher media costs Bioreactor: 2k L fed-batch Titer: 5 g/L Mab 26
- 27. Upstream Value Modeling Impacton Plant Throughput • High Seed Train Scenario provides: • Shorter time in production bioreactor • Increased batches per year • Additional production bioreactors deliver further increase in capacity High Seed: increased manufacturing capacity, facility utilization Bioreactor: 2k L fed-batch Titer: 5 g/L Mab 27
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- 30. Toolbox Approach Flow ThroughPolishing Leached Protein A Aggregates Virus Host Cell DNA Host Cell Protein Others? (Fragments, Charge Variants) Chemistries Matrices Devices 30
- 31. 3 1 Flow Through Polishing ExistingToolbox ▪ Eshmuno® CP-FT resin Flow through aggregate removal at high loading 5 – 10X buffer reduction Easy implementation ▪ NatriFlo® HD-Q AEX membrane Impurity clearance at high loading High velocity operation (~1 sec RT) ▪ Millistak+® Pod CR depth filter Activated carbon media Binding: van der Waals interactions Size-based selectivity Impurity (MW) Capacity Insulin 60 g/L Methotrexate 75 g/L Pluronic® F68 surfactant 75 g/L Antifoam C > 16 g/L 31
- 32. Low pH VI Pool Virus Filter Pool CarbonDepth Filter + FT-AEX FT-CEX + Virus Filtration In-line pH Low pH VI Pool Depth Filter Pool CEX Pool AEX Pool Virus Filter Pool pH Adjust & Dilution Depth Filter Bind & Elute CEX FT-AEX Virus Filtration Traditional Batch Polishing Flow Through Polishing 32 Batch vs. Integrated Implementation of Flow Through Technology Robust Performance with Significant Footprint Reduction Robust Purification across 8 Molecules - High product yield (83 – 91%) - Aggregates: < 1% - Fragments: up to 1 LRV - HCP clearance: < 10 ppm Significant Facility Footprint Reduction - Lower media and buffer requirements - Eliminate intermediate hold tanks - Single-skid operation
- 33. 33 Value Modeling What ValueDoes FT Polishing Deliver? Bioreactor Clarification Affinity Chromatography Virus Inactivation CEX Bind and Elute Flow Through AEX Viral Clearance Final Filtration Concentration & Diafiltration Traditional Batch (Baseline) Depth Filtration Four polishing steps run continuously without intermediate hold steps • Lower buffer volume • Higher loading on chromatography media and virus filter • Smaller facility footprint for systems, columns, and tanks Bioreactor Clarification Affinity Chromatography Virus Inactivation Final Filtration Concentration & Diafiltration Flow Through Polishing Activated Carbon Flow Through CEX Flow Through AEX Viral Clearance Bioreactor: 2k L fed-batch Titer: 5 g/L Mab
- 34. Assumption Activated Carbon AEX FTCEX FT Virus Filtration Technology Millistak+® Carbon Filter Eshmuno® Q resin Eshmuno® CP-FT resin Viresolve® Pro filter Yield 93% 95% 95% 98% Capacity 1500 g/m2 3000 g/L 1000 g/L 5000 g/m2 # Re-uses Single use 150 150 Single use # Buffers 1 5 4 0 Activated Carbon Flow Through CEX Flow Through AEX Viral Clearance Value Modeling 34
- 35. 35 Baseline Scenario vs.Flow Through Polishing • Most significant savings capital, consumables, and labor • Buffer reduction due primarily from switching CEX to flow through mode 10% COGS reduction 47% Buffer reduction 43% COGS reduction 87% Buffer reduction Polishing alone… Total process… Value Modeling Bioreactor: 2k L fed-batch Titer: 5 g/L Mab
- 36. COGS Reduction withVarying Titers and Scales Value Modeling 36 • Varying product titer and bioreactor volume • Comparison made between batch and flow through polishing processes Benefits increase with increasing titer & independent of bioreactor scale
- 37. 37 Value Modeling –Baseline vs. FT Polishing Impact on buffer volumes & facility footprint CEX Bind and Elute Flow Through AEX Virus Filter Depth Filtration Activated Carbon Flow Through CEX Flow Through AEX Virus Filter Bioreactor: 2k L fed-batch Titer: 5 g/L Mab
- 38. 38 Value Modeling –Baseline vs. FT Polishing Impact on buffer volumes & facility footprint CEX Bind and Elute Flow Through AEX Virus Filter Depth Filtration Activated Carbon Flow Through CEX Flow Through AEX Virus Filter X X X X Bioreactor: 2k L fed-batch Titer: 5 g/L Mab
- 39. 39 Process Time DecreasesCan Drive Output Value Modeling Bioreactor: 2k L fed-batch Titer: 5 g/L Mab Time Savings • 72% decrease in polishing process time • 24% decrease in overall DSP process time • Replace B/E CEX contributes most to decrease Decreased Process Time More Batches / Year 12.4 hours 3.5 hours
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- 42. Summary Through the useof process modeling significant improvements identified with Flow Through Polishing: • COGS reduction 5-10% • Footprint reduction through reduced buffer volumes and hold tanks • 72% reduction in processing time with flow through polishing There is an evolution happening in bioprocessing • Step change in business drivers • Intensification and Connection • Increased Flexibility & Speed, Decreased Risk & Cost Perfusion operations in seed train and production bioreactor can: • Shorten overall process time • Increase product titer • Enable continuous processing with constant harvest 42
- 43. Michael.Felo@emdmillipore.comHabib.Horry@emdgroup.com Michael.Phillips@emdmillipore.com Michael FeloHabib Horry MichaelPhillips The vibrant M, Eshmuno, Millistak+, Viresolve, and NatriFlo are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2018 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.