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A Cost Analysis and Evaluation of Perfused Seed Train Scenarios Through Process Modeling

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The document presents a cost analysis and evaluation of perfused seed train scenarios using process modeling in bioprocessing for Merck KGaA. It highlights the benefits of perfused seed trains, including reduced lead times, increased production capacity, and significant cost reductions in manufacturing. The webinar series discusses various model scenarios and the advantages of process modeling in assessing perfusion technology for intensified upstream processing.

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Merck KGaA Darmstadt, Germany Jeffrey Barna, Habib Horry A Cost Analysis and Evaluation of Perfused Seed Train Scenarios Through Process Modeling
2 The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.
Part II of the BioContinuum™ Seed Train Platform webinar series: Novel Perfusion Filter and Controller for N-1 Application  Considerations for a scalable cell retention device for perfusion applications  Case study demonstrating capabilities of novel perfusion filter and controller for intensified upstream processing Previous Webinar 3
0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
Speed Reduce new facility build times by 70%. Compress production lead time by 80%. Quality 10X robustness. 90% reduction in cost of poor quality. Flexibility Reduce product change-over time by 90%. Cost 90% reduction in cost to manufacture and CAPEX. Business Drivers Market Growth Uncertainty New Product Classes Cost Pressure Market Trends Market Trends, Business Drivers and Key Enablers to Drive Next Generation BioProcessing: Process Intensification Process Analytics Software & Automation Key Enablers Single Use 6
less footprint Less capital reduction in construction time reduction OPEX Reduction in cost of quality 90% 90% 70% 60% 90% Paradigm Shift: The Facility of the Future will require a transformation in how biologics are developed and manufactured Process Format Analytics Digital Controlled Inline Single Use Intensified Integrated Real Time Closed Connected Autonomous Predictive Sterile Continuous 7
Upstream Process Intensification for mAbs A Multitude of Strategies all based on perfusion technology Batch x 1-2ml each 10-30 x106 vc.ml-1 N-1 or x Batch N Fed Batch MCB/MWCB INOCULATION TRAIN SEED TRAIN PRODUCTION CRD Perfusion CRD 50-100 x106vc.ml-1 or or 4.5ml 50-500ml bagCRD CRD Perfusion N CRD Continuous protein harvest • Steady State Perfusion • Dynamic Perfusion Single protein harvest • High Seed Fed batch • Ultrahigh VCD Fed-Batch • Concentrated Fed-Batch Production medium Cryo Medium Perfused Seed Train Processes Can be utilized with any production method Perfusion-based Production and Harvest processes Continuous vs. single protein harvest, High cell densities, long durations Expansion medium Cell Culture Media Formulations Enabling intensified seed and production trains High Qp Low CSPR Low OUR High Shear resistance Perfusion Optimized Cell Line Maximizing protein yield and quality in perfusion operations 8
Definition Perfused Seed Train 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 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 9
0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
11 What is Biosolve®? • Excel-based process model from BioPharm Services • Calculates process economics • Database of industry averages with the option for user- specific information Benefits of Process Modeling • Focus on the “holistic process” • Side-by-side evaluation of alternatives • Can run “what if”, sensitivity analyses • Clear communication of value Unique Intensified Operation Modules of Process Modeling • Perfusion seed train and production options • Continuous chromatography • Flow through polishing • Single-pass TFF Biosolve® The Benefits of Process Modeling (Value Modeling)
Perfused Seed Train Model Assumptions 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 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) 8 days or 3 days3 days3 days 10 days or 3 days3 days3 days3 days 5 days8 days or 3 days3 days3 days 12 Models to be tested:
Perfused Seed Train Model Assumptions 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 vc/mL) Conventional (Batch N-1) 3 days 10L 3 days 100mL 3 days 30mL 5 days 60L,200L Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 13 Models to be tested: 3 days 400mL 3 days 2L 125mL 500mL 2X500mL 2X3L 20L 200L 2000L 7 days 10L 20L 3 days 10L 20L 9 days 60L,200L 200L 7 days 10L 20L 4 days 200L 200L Same as above Same as above Same as above 2000L Each model contains a traditional downstream!
Scope 14 • Constant production titer • Constant production duration • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Single Bioreactor Multiple Bioreactors (6) 14 days 4 g/L vs. 10 days 4 g/L Traditional High Seed 14 days >4 g/L
Scope 15 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors2 Seed Trains 3:1 Ratio
Scope 16 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors3 Seed Trains 2:1 Ratio
Scope 17 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors6 Seed Trains 1:1 Ratio
0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
Single Bioreactor, Constant Production Titer 19 CoG’s ($/g) 116.39 116.80 101.17 101.64 Throughput (kg/yr) 90.18 90.18 125.25 125.25 Batches/yr 18 18 25 25 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production • ~13.5% reduction in CoG’s by switching to perfused seed train • Increased throughput as well; decreased production duration increases batches/yr • Cost reduction driven by higher throughput; brings down capital High Seed Fed Batch Traditional Fed Batch
Single Bioreactor, Constant Production Duration 20 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • Traditional: 14 day production • High Seed: 14 day production • Experimental data suggests titer can increase 2-3X through high seeding production • Traditional seed train was compared to perfused N-1 seed train with varying production titers • Higher throughput drives down all costs; increased product mass per batch High Seed Fed Batch CoG’s ($/g) 116.4 101.2 120.1 90.6 75.6 64.0 57.0 Throughput (kg/yr) 90.18 125.25 90.18 135.27 180.36 225.45 270.54 Batches/yr 18 25 18 18 18 18 18
Single Bioreactor, Constant Production Duration 21 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • Traditional: 14 day production • High Seed: 14 day production Seed Train Titer Total CoG’s ($/g) % Reduction Traditional 4 g/L 116.39 pN-1 6 g/L 90.56 22% pN-1 8 g/L 75.56 35% pN-1 10 g/L 63.98 45% pN-1 12 g/L 56.99 51% High Seed Fed Batch CoG’s ($/g) 116.4 101.2 120.1 90.6 75.6 64.0 57.0 Throughput (kg/yr) 90.18 125.25 90.18 135.27 180.36 225.45 270.54 Batches/yr 18 25 18 18 18 18 18
Single Bioreactor Scenarios - Summary 22 Constant Production Titer 14 days 4 g/L vs. 10 days 4 g/L ❖ High Seed options increase batch/yr and throughput 18 –> 25 batch/yr 90 –> 125 kg/yr ❖ Drives capital CoG’s down, total CoG’s down 13.5% Constant Production Duration Traditional High Seed ❖ Greater benefit observed through keeping constant production duration ❖ Overall CoG’s reduced 22-51% ❖ Throughput increase 50-200%; proportional to titer increase ❖ No change in batches/yr Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 14 days 4 g/L vs. 14 days >4 g/L Traditional High Seed Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2)
0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
3:1 Production/Seed Train Ratio 24 Assumptions • 6 X 2000L Bioreactor • 2 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 67.38 77.25 85.46 82.80 Throughput (kg/yr) 495.99 315.63 275.55 315.63 Batches/yr 99 63 55 63 • No cost or throughput benefit for 3:1 production/seed train ratio • With 6 bioreactors, production is no longer bottleneck
3:1 Production/Seed Train Ratio 25 Assumptions • 6 X 2000L Bioreactor • 2 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production • No cost or throughput benefit for 3:1 production/seed train ratio • With 6 bioreactors, production is no longer bottleneck Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional N-1 2.64 99 Compressed Seed Fed Batch Perfused Rocker 4.12 63 Perfused Seed (pN-1) N-1 4.76 55 Perfused Seed (pN-2/pN-1) N-2 Rocker 4.12 63
2:1 Production/Seed Train Ratio 26 Assumptions • 6 X 2000L Bioreactor • 3 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 65.88 67.58 75.03 73.08 Throughput (kg/yr) 551.11 475.95 410.82 475.95 Batches/yr 110 95 82 95 • Similarly to 3:1, no cost or throughput benefit for 2:1 production/seed train ratio • Bottlenecking effect is less pronounced, due to extra seed train
2:1 Production/Seed Train Ratio 27 Assumptions • 6 X 2000L Bioreactor • 3 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional Production 2.39 110 Compressed Seed Fed Batch Perfused Rocker 2.74 95 Perfused Seed (pN-1) N-1 3.17 82 Perfused Seed (pN-2/pN-1) N-2 Rocker 2.74 95 • Similarly to 3:1, no cost or throughput benefit for 2:1 production/seed train ratio • Bottlenecking effect is less pronounced, due to extra seed train
1:1 Production/Seed Train Ratio 28 Assumptions • 6 X 2000L Bioreactor • 6 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 66.88 65.35 65.06 66.52 Throughput (kg/yr) 551.11 546.10 761.53 761.53 Batches/yr 110 109 152 152 • Negligible CoG’s differences, though significant increase in throughput for high seed fed batch • With 1:1 ratio, production becomes bottleneck again; decreased HiSeed production duration increases throughput
1:1 Production/Seed Train Ratio 29 Assumptions • 6 X 2000L Bioreactor • 6 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional Production 2.39 110 Compressed Seed Fed Batch Production 2.40 109 Perfused Seed (pN-1) Production 1.73 152 Perfused Seed (pN-2/pN-1) Production 1.73 152 • Negligible CoG’s differences, though significant increase in throughput for high seed fed batch • With 1:1 ratio, production becomes bottleneck again; decreased HiSeed production duration increases throughput
Increased Titer with High Seed Production – 3:1 P/S ratio 30 Assumptions • 3:1 P/S ratio • 6 X 2000L Bioreactor • 2 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 67.38 85.46 85.46 62.49 52.01 43.78 39.39 Throughput (kg/yr) 495.99 275.55 275.55 413.33 551.11 688.88 826.66 Batches/yr 99 55 55 55 55 55 55 High Seed Fed Batch • As seen earlier, process bottlenecks reduce batches/yr for perfused seed options at 3:1 P/S ratio • Increased titer offsets that reduction in most cases, ultimately increasing throughput • Higher throughput and product per batch drives down CoG’s
Increased Titer with High Seed Production – 2:1 P/S Ratio 31 Assumptions • 2:1 P/S ratio • 6 X 2000L Bioreactor • 3 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 65.88 75.03 75.03 54.67 45.75 38.49 34.64 Throughput (kg/yr) 551.11 410.82 410.82 616.24 821.65 1027.06 1232.57 Batches/yr 110 82 82 82 82 82 82 High Seed Fed Batch • Similar trend observed • With bottleneck effect diminishing, throughput increase is larger
Increased Titer with High Seed Production – 1:1 P/S Ratio 32 Assumptions • 1:1 P/S ratio • 6 X 2000L Bioreactor • 6 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 66.88 65.06 70.79 51.46 43.08 36.17 32.67 Throughput (kg/yr) 551.11 761.53 546.10 819.14 1092.19 1365.24 1638.29 Batches/yr 110 152 109 109 109 109 109 High Seed Fed Batch • Again, for 1:1 P/S ratio, production becomes bottleneck • Batches/yr more or less constant • Most significant increase in throughput
Increased Titer with High Seed – Summary (6 Bioreactors) 33 • When considering the potential for increased titer through high seed fed batch, virtually all scenarios offer benefits • For both CoG’s and throughput, most benefit is found at 1:1 production/seed train ratio • Decrease CoG’s 23-51% • Increase throughput 65-230% % CoG’s Reduction and % Throughout Increase calculated by comparing to Traditional 4 g/L process
Multiple Bioreactor Scenarios - Summary 34 Constant Production Titer 14 days 4 g/L vs. 10 days 4 g/L ❖ No benefit observed in 3:1 and 2:1 P/S scenarios; bottleneck issues ❖ At 1:1 P/S ratio, throughput increase due to increase batches/yr 109->152 batches/yr Constant Production Duration Traditional High Seed ❖ Overall CoG’s decrease and throughput increase at all P/S ratios ❖ For 3:1 and 2:1 P/S ratios, batches/yr is reduced, even with CoG’s and throughput benefits Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 14 days 4 g/L vs. 14 days >4 g/L Traditional High Seed Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2)
35 Implementing perfused seed trains can bring down cost of manufacturing and increase product throughput, all while keeping production bioreactor in fed batch mode Perfused seed trains allow for high seeding of production bioreactor, which has the potential for achieving higher titers, especially when incorporating a strong media platform Summary If higher titers observed: • Adding additional seed trains and production bioreactors at 1:1 ratio brings the most benefit • CoG’s reduced 24-52%, kg/yr increase 65-230% • Benefits even at 3:1 and 2:1, with additional benefit of needing less batches per year • 3:1 – CoG’s reduced 7-42%, kg/yr increase 11-67% • 2:1 - CoG’s reduced 19-49%, kg/yr increase 24-149% If higher titers are not observed: • Single bioreactor scenarios still see CoG’s reduced by 13.5% and throughput increase of 39% at shorter high seed FB duration • Adding additional seed trains and production bioreactors at 1:1 ratio increases throughput
The vibrant M and BioContinuum 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. © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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A Cost Analysis and Evaluation of Perfused Seed Train Scenarios Through Process Modeling

  • 1. Merck KGaA Darmstadt, Germany Jeffrey Barna, Habib Horry A Cost Analysis and Evaluation of Perfused Seed Train Scenarios Through Process Modeling
  • 2. 2 The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.
  • 3. Part II of the BioContinuum™ Seed Train Platform webinar series: Novel Perfusion Filter and Controller for N-1 Application  Considerations for a scalable cell retention device for perfusion applications  Case study demonstrating capabilities of novel perfusion filter and controller for intensified upstream processing Previous Webinar 3
  • 4. 0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
  • 5. 0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
  • 6. Speed Reduce new facility build times by 70%. Compress production lead time by 80%. Quality 10X robustness. 90% reduction in cost of poor quality. Flexibility Reduce product change-over time by 90%. Cost 90% reduction in cost to manufacture and CAPEX. Business Drivers Market Growth Uncertainty New Product Classes Cost Pressure Market Trends Market Trends, Business Drivers and Key Enablers to Drive Next Generation BioProcessing: Process Intensification Process Analytics Software & Automation Key Enablers Single Use 6
  • 7. less footprint Less capital reduction in construction time reduction OPEX Reduction in cost of quality 90% 90% 70% 60% 90% Paradigm Shift: The Facility of the Future will require a transformation in how biologics are developed and manufactured Process Format Analytics Digital Controlled Inline Single Use Intensified Integrated Real Time Closed Connected Autonomous Predictive Sterile Continuous 7
  • 8. Upstream Process Intensification for mAbs A Multitude of Strategies all based on perfusion technology Batch x 1-2ml each 10-30 x106 vc.ml-1 N-1 or x Batch N Fed Batch MCB/MWCB INOCULATION TRAIN SEED TRAIN PRODUCTION CRD Perfusion CRD 50-100 x106vc.ml-1 or or 4.5ml 50-500ml bagCRD CRD Perfusion N CRD Continuous protein harvest • Steady State Perfusion • Dynamic Perfusion Single protein harvest • High Seed Fed batch • Ultrahigh VCD Fed-Batch • Concentrated Fed-Batch Production medium Cryo Medium Perfused Seed Train Processes Can be utilized with any production method Perfusion-based Production and Harvest processes Continuous vs. single protein harvest, High cell densities, long durations Expansion medium Cell Culture Media Formulations Enabling intensified seed and production trains High Qp Low CSPR Low OUR High Shear resistance Perfusion Optimized Cell Line Maximizing protein yield and quality in perfusion operations 8
  • 9. Definition Perfused Seed Train 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 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 9
  • 10. 0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
  • 11. 11 What is Biosolve®? • Excel-based process model from BioPharm Services • Calculates process economics • Database of industry averages with the option for user- specific information Benefits of Process Modeling • Focus on the “holistic process” • Side-by-side evaluation of alternatives • Can run “what if”, sensitivity analyses • Clear communication of value Unique Intensified Operation Modules of Process Modeling • Perfusion seed train and production options • Continuous chromatography • Flow through polishing • Single-pass TFF Biosolve® The Benefits of Process Modeling (Value Modeling)
  • 12. Perfused Seed Train Model Assumptions 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 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) 8 days or 3 days3 days3 days 10 days or 3 days3 days3 days3 days 5 days8 days or 3 days3 days3 days 12 Models to be tested:
  • 13. Perfused Seed Train Model Assumptions 14 days 10 days Conventional Fed-Batch (~ 0.2 E6 vc/mL) High Seed Fed-Batch (~ 5 E6 vc/mL) Conventional (Batch N-1) 3 days 10L 3 days 100mL 3 days 30mL 5 days 60L,200L Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 13 Models to be tested: 3 days 400mL 3 days 2L 125mL 500mL 2X500mL 2X3L 20L 200L 2000L 7 days 10L 20L 3 days 10L 20L 9 days 60L,200L 200L 7 days 10L 20L 4 days 200L 200L Same as above Same as above Same as above 2000L Each model contains a traditional downstream!
  • 14. Scope 14 • Constant production titer • Constant production duration • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Single Bioreactor Multiple Bioreactors (6) 14 days 4 g/L vs. 10 days 4 g/L Traditional High Seed 14 days >4 g/L
  • 15. Scope 15 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors2 Seed Trains 3:1 Ratio
  • 16. Scope 16 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors3 Seed Trains 2:1 Ratio
  • 17. Scope 17 • Constant production titer, 3:1 P/S • Constant production titer, 2:1 P/S • Constant production titer, 1:1 P/S • Constant production duration, 3:1 P/S • Constant production duration, 2:1 P/S • Constant production duration, 1:1 P/S Proposed Scenarios Models: Conventional (Batch N-1), Compressed Seed Train, High Seed (pN-1), High Seed (pN-2/pN-1) Goal Gain an understanding of the potential benefits of perfused seed trains through Biosolve® Multiple Bioreactors (6) 6 Bioreactors6 Seed Trains 1:1 Ratio
  • 18. 0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
  • 19. Single Bioreactor, Constant Production Titer 19 CoG’s ($/g) 116.39 116.80 101.17 101.64 Throughput (kg/yr) 90.18 90.18 125.25 125.25 Batches/yr 18 18 25 25 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production • ~13.5% reduction in CoG’s by switching to perfused seed train • Increased throughput as well; decreased production duration increases batches/yr • Cost reduction driven by higher throughput; brings down capital High Seed Fed Batch Traditional Fed Batch
  • 20. Single Bioreactor, Constant Production Duration 20 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • Traditional: 14 day production • High Seed: 14 day production • Experimental data suggests titer can increase 2-3X through high seeding production • Traditional seed train was compared to perfused N-1 seed train with varying production titers • Higher throughput drives down all costs; increased product mass per batch High Seed Fed Batch CoG’s ($/g) 116.4 101.2 120.1 90.6 75.6 64.0 57.0 Throughput (kg/yr) 90.18 125.25 90.18 135.27 180.36 225.45 270.54 Batches/yr 18 25 18 18 18 18 18
  • 21. Single Bioreactor, Constant Production Duration 21 Assumptions • 1 X 2000L Bioreactor • 1 X Seed train • Traditional: 14 day production • High Seed: 14 day production Seed Train Titer Total CoG’s ($/g) % Reduction Traditional 4 g/L 116.39 pN-1 6 g/L 90.56 22% pN-1 8 g/L 75.56 35% pN-1 10 g/L 63.98 45% pN-1 12 g/L 56.99 51% High Seed Fed Batch CoG’s ($/g) 116.4 101.2 120.1 90.6 75.6 64.0 57.0 Throughput (kg/yr) 90.18 125.25 90.18 135.27 180.36 225.45 270.54 Batches/yr 18 25 18 18 18 18 18
  • 22. Single Bioreactor Scenarios - Summary 22 Constant Production Titer 14 days 4 g/L vs. 10 days 4 g/L ❖ High Seed options increase batch/yr and throughput 18 –> 25 batch/yr 90 –> 125 kg/yr ❖ Drives capital CoG’s down, total CoG’s down 13.5% Constant Production Duration Traditional High Seed ❖ Greater benefit observed through keeping constant production duration ❖ Overall CoG’s reduced 22-51% ❖ Throughput increase 50-200%; proportional to titer increase ❖ No change in batches/yr Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 14 days 4 g/L vs. 14 days >4 g/L Traditional High Seed Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2)
  • 23. 0 0 0Agenda Introduction to Perfused Seed Trains1 Model Assumptions and Plan2 Single Bioreactor Scenarios3 0 Multiple Bioreactor Scenarios4
  • 24. 3:1 Production/Seed Train Ratio 24 Assumptions • 6 X 2000L Bioreactor • 2 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 67.38 77.25 85.46 82.80 Throughput (kg/yr) 495.99 315.63 275.55 315.63 Batches/yr 99 63 55 63 • No cost or throughput benefit for 3:1 production/seed train ratio • With 6 bioreactors, production is no longer bottleneck
  • 25. 3:1 Production/Seed Train Ratio 25 Assumptions • 6 X 2000L Bioreactor • 2 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production • No cost or throughput benefit for 3:1 production/seed train ratio • With 6 bioreactors, production is no longer bottleneck Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional N-1 2.64 99 Compressed Seed Fed Batch Perfused Rocker 4.12 63 Perfused Seed (pN-1) N-1 4.76 55 Perfused Seed (pN-2/pN-1) N-2 Rocker 4.12 63
  • 26. 2:1 Production/Seed Train Ratio 26 Assumptions • 6 X 2000L Bioreactor • 3 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 65.88 67.58 75.03 73.08 Throughput (kg/yr) 551.11 475.95 410.82 475.95 Batches/yr 110 95 82 95 • Similarly to 3:1, no cost or throughput benefit for 2:1 production/seed train ratio • Bottlenecking effect is less pronounced, due to extra seed train
  • 27. 2:1 Production/Seed Train Ratio 27 Assumptions • 6 X 2000L Bioreactor • 3 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional Production 2.39 110 Compressed Seed Fed Batch Perfused Rocker 2.74 95 Perfused Seed (pN-1) N-1 3.17 82 Perfused Seed (pN-2/pN-1) N-2 Rocker 2.74 95 • Similarly to 3:1, no cost or throughput benefit for 2:1 production/seed train ratio • Bottlenecking effect is less pronounced, due to extra seed train
  • 28. 1:1 Production/Seed Train Ratio 28 Assumptions • 6 X 2000L Bioreactor • 6 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production CoG’s ($/g) 66.88 65.35 65.06 66.52 Throughput (kg/yr) 551.11 546.10 761.53 761.53 Batches/yr 110 109 152 152 • Negligible CoG’s differences, though significant increase in throughput for high seed fed batch • With 1:1 ratio, production becomes bottleneck again; decreased HiSeed production duration increases throughput
  • 29. 1:1 Production/Seed Train Ratio 29 Assumptions • 6 X 2000L Bioreactor • 6 X Seed train • 4 g/L titer • Traditional: 14 day production • High Seed: 10 day production Process Bottleneck Unit Op Bottleneck Time (days/batch) Batches/yr Traditional Production 2.39 110 Compressed Seed Fed Batch Production 2.40 109 Perfused Seed (pN-1) Production 1.73 152 Perfused Seed (pN-2/pN-1) Production 1.73 152 • Negligible CoG’s differences, though significant increase in throughput for high seed fed batch • With 1:1 ratio, production becomes bottleneck again; decreased HiSeed production duration increases throughput
  • 30. Increased Titer with High Seed Production – 3:1 P/S ratio 30 Assumptions • 3:1 P/S ratio • 6 X 2000L Bioreactor • 2 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 67.38 85.46 85.46 62.49 52.01 43.78 39.39 Throughput (kg/yr) 495.99 275.55 275.55 413.33 551.11 688.88 826.66 Batches/yr 99 55 55 55 55 55 55 High Seed Fed Batch • As seen earlier, process bottlenecks reduce batches/yr for perfused seed options at 3:1 P/S ratio • Increased titer offsets that reduction in most cases, ultimately increasing throughput • Higher throughput and product per batch drives down CoG’s
  • 31. Increased Titer with High Seed Production – 2:1 P/S Ratio 31 Assumptions • 2:1 P/S ratio • 6 X 2000L Bioreactor • 3 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 65.88 75.03 75.03 54.67 45.75 38.49 34.64 Throughput (kg/yr) 551.11 410.82 410.82 616.24 821.65 1027.06 1232.57 Batches/yr 110 82 82 82 82 82 82 High Seed Fed Batch • Similar trend observed • With bottleneck effect diminishing, throughput increase is larger
  • 32. Increased Titer with High Seed Production – 1:1 P/S Ratio 32 Assumptions • 1:1 P/S ratio • 6 X 2000L Bioreactor • 6 X Seed train • Traditional: 14 day production • High Seed: 14 day production CoG’s ($/g) 66.88 65.06 70.79 51.46 43.08 36.17 32.67 Throughput (kg/yr) 551.11 761.53 546.10 819.14 1092.19 1365.24 1638.29 Batches/yr 110 152 109 109 109 109 109 High Seed Fed Batch • Again, for 1:1 P/S ratio, production becomes bottleneck • Batches/yr more or less constant • Most significant increase in throughput
  • 33. Increased Titer with High Seed – Summary (6 Bioreactors) 33 • When considering the potential for increased titer through high seed fed batch, virtually all scenarios offer benefits • For both CoG’s and throughput, most benefit is found at 1:1 production/seed train ratio • Decrease CoG’s 23-51% • Increase throughput 65-230% % CoG’s Reduction and % Throughout Increase calculated by comparing to Traditional 4 g/L process
  • 34. Multiple Bioreactor Scenarios - Summary 34 Constant Production Titer 14 days 4 g/L vs. 10 days 4 g/L ❖ No benefit observed in 3:1 and 2:1 P/S scenarios; bottleneck issues ❖ At 1:1 P/S ratio, throughput increase due to increase batches/yr 109->152 batches/yr Constant Production Duration Traditional High Seed ❖ Overall CoG’s decrease and throughput increase at all P/S ratios ❖ For 3:1 and 2:1 P/S ratios, batches/yr is reduced, even with CoG’s and throughput benefits Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2) 14 days 4 g/L vs. 14 days >4 g/L Traditional High Seed Conventional (Batch N-1) Compressed Seed Train High Seed (N-1 only) High Seed (N-1 & N-2)
  • 35. 35 Implementing perfused seed trains can bring down cost of manufacturing and increase product throughput, all while keeping production bioreactor in fed batch mode Perfused seed trains allow for high seeding of production bioreactor, which has the potential for achieving higher titers, especially when incorporating a strong media platform Summary If higher titers observed: • Adding additional seed trains and production bioreactors at 1:1 ratio brings the most benefit • CoG’s reduced 24-52%, kg/yr increase 65-230% • Benefits even at 3:1 and 2:1, with additional benefit of needing less batches per year • 3:1 – CoG’s reduced 7-42%, kg/yr increase 11-67% • 2:1 - CoG’s reduced 19-49%, kg/yr increase 24-149% If higher titers are not observed: • Single bioreactor scenarios still see CoG’s reduced by 13.5% and throughput increase of 39% at shorter high seed FB duration • Adding additional seed trains and production bioreactors at 1:1 ratio increases throughput
  • 36. The vibrant M and BioContinuum 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. © 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.