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Suzanne Farid PhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering

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Presentation on theme: "Suzanne Farid PhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering"— Presentation transcript:

1 Suzanne Farid PhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, October 2013 UCL Decisional Tools Research Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production

2 2 Engineering Doctorate Project: Evaluating The Potential of Continuous Processes for Monoclonal Antibodies: Economic, Environmental and Operational Feasibility UCL-Pfizer Collaboration ( ) UCL academic collaborators included: Daniel Bracewell (ex-)Pfizer collaborators included: Glen Bolton, Jon Coffman Funding: UK EPSRC, Pfizer Acknowledgements James Pollock UCL Suzanne Farid UCL Sa Ho Pfizer

3 3 Bioprocess Decisional Tools – Domain Biotech Drug Development Cycle Farid, 2012, In Biopharmaceutical Production Technology, pp717-74

4 4 Scope of UCL Decisional Tools Typical questions addressed: Process synthesis & facility design  Which manufacturing strategy is the most cost-effective?  How do the rankings of manufacturing strategies change with scale? Or from clinical to commercial production?  Key economic drivers? Economies of scale?  Probability of failing to meet cost/demand targets? Robustness? Portfolio management & capacity planning  Portfolio selection - Which candidate therapies to select?  Capacity sourcing - In-house v CMO production?  Impact of company size and phase transition probabilities on choices?

5 5  Systems approach to valuing biotech / cell therapy investment opportunities  Process synthesis and facility design  Capacity planning  Portfolio management Challenges:  Capturing process robustness under uncertainty & reconciling conflicting outputs  Fed-batch versus perfusion systems (Lim et al, 2005 & 2006; Pollock et al, 2013a)  Continuous chromatography (Pollock et al, 2013b)  Integrated continuous processing (Pollock et al, submitted)  Stainless steel versus single-use facilities (Farid et al, 2001, 2005a &b)  Facility limits at high titres (Stonier et al, 2009, 2012)  Single-use components for allogeneic cell therapies (Simaria et al, 2013)  Adopting efficient methods to search large decision spaces  Portfolio management & capacity planning (Rajapakse et al, 2006; George & Farid, 2008a,b)  Multi-site long term production planning (Lakhdar et al, 2007; Siganporia et al, 2012)  Chromatography sequence and sizing optimisation in multiproduct facilities (Simaria et al, 2012; Allmendinger et al, 2012)  Integrating stochastic simulation with advanced multivariate analysis  Prediction of suboptimal facility fit upon tech transfer (Stonier et al, 2013; Yang et al, 2013)  Creating suitable data visualization methods  For each of above examples Scope of UCL Decisional Tools Farid, 2012, In Biopharmaceutical Production Technology, pp717-74

6 6  Systems approach to valuing biotech / cell therapy investment opportunities  Process synthesis and facility design  Capacity planning  Portfolio management Challenges:  Capturing process robustness under uncertainty & reconciling conflicting outputs  Fed-batch versus perfusion systems (Pollock et al, 2013a)  Continuous chromatography (Pollock et al, 2013b)  Integrated continuous processing (Pollock et al, submitted)  Stainless steel versus single-use facilities (Farid et al, 2001, 2005a &b)  Facility limits at high titres (Stonier et al, 2009, 2012)  Single-use components for allogeneic cell therapies (Simaria et al, submitted)  Adopting efficient methods to search large decision spaces  Portfolio management & capacity planning (Rajapakse et al, 2006; George & Farid, 2008a,b)  Multi-site long term production planning (Lakhdar et al, 2007; Siganporia et al, 2012)  Chromatography sequence and sizing optimisation in multiproduct facilities (Simaria et al, 2012)  Integrating stochastic simulation with advanced multivariate analysis  Prediction of suboptimal facility fit upon tech transfer (Stonier et al, 2013; Yang et al, 2013)  Creating suitable data visualization methods  For each of above examples Scope of UCL Decisional Tools Farid, 2012, In Biopharmaceutical Production Technology, pp717-74

7 7  Systems approach to valuing biotech / cell therapy investment opportunities  Process synthesis and facility design  Capacity planning  Portfolio management Challenges:  Capturing process robustness under uncertainty & reconciling conflicting outputs Scope of UCL Decisional Tools  Fed-batch versus perfusion systems (Pollock et al, 2013a)  Scenario: New build for commercial mAb prodn  Impact of scale on cost  Impact of titre variability and failures rates on robustness  Continuous chromatography (Pollock et al, 2013b)  Scenario: Retrofit for clinical / commercial mAb prodn  Impact of scale and development phase on cost  Retrofit costs across development phases  Integrated continuous processing (Pollock et al, submitted)  Scenario: New build for clinical / commercial mAb prodn  Impact of hybrid batch/continuous USP and DSP combinations  Impact of development phase, company size and portfolio size

8 8 Fed-batch versus perfusion culture (New build) Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219  Fed-batch versus perfusion systems (Pollock et al, 2013a)  Scenario: New build for commercial mAb prodn  Impact of scale on cost  Impact of titre variability and failures rates on robustness

9 9 Fed-batch versus perfusion culture (New build) Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Commercial products using perfusion cell culture technologies

10 10 Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 SPIN FILTER LIQUID LEVEL Spin-filter Perfusion PRO: CON: Investment DSP consumable cost Equipment failure rate USP consumable cost Scale limitations Validation burden  Compare the cost-effectiveness and robustness of fed-batch and perfusion cell culture strategies across a range of titres and production scales for new build ATF Perfusion Steady state cell densities Failure rates Fed-batch versus perfusion culture (New build) Scenario trade-offs: FB v SPIN v ATF

11 11 Cell Culture Suite DSP Suite Viral Secure Suite Seed #1 Seed #2 CC Cent DF UF ProA VI CEX UFDF VRF AEX UFDF Seed #1 Seed #2 CC DF Seed #1 Seed #2 CC ProA VI CEX UFDF VRF AEX UFDF Pool ProA VI CEX UFDF VRF AEX UFDF Pool Suites FBSPINATF VariableFBSPINATF Reactor typeSS/SUBSSSUB Cell culture time (days)1260 Max VCD (10 6 cells/ml) Max bioreactor vol. (L)20, Max perf. rate (vv/day)–11.5 Process yield65%68%69% Annual # batches2255 Product conc. (g/L)2 – 1020% FB45% FB Productivity (mg/L/day) x FB6.5 x FB Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Key assumptions

12 12 Comparison of the cost of goods per gram for an equivalent fed-batch titre of 5 g/L Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Results: Impact of scale on COG = Indirect = Material = Labour Critical cell density difference for ATF to compete with FB - x3 fold.

13 13 Process eventp(Failure)Consequence Fed-batch culture contamination 1 %Batch loss Spin-filter culture contamination 6 % Batch loss & discard two pooled perfusate volumes Spin-filter filter failure 4 % Batch loss & no pooled volumes are discarded ATF culture contamination 6 % Batch loss & discard two pooled perfusate volumes ATF filter failure 2 % Replace filter & discard next 24 hours of perfusate In process filtration failure – general 5 %4 hour delay & 2% yield loss In process filtration failure– post viral inactivation20 %4 hour delay & 2% yield loss Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Uncertainties and failure rates

14 14 Annual throughput and COG distributions under uncertainty 500kg demand, 5g/L titre Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Results: Impact of variability on robustness

15 15 Annual throughput and COG distributions under uncertainty 500kg demand, 5g/L titre Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Results: Impact of variability on robustness

16 16 1.FB = ATF 2.SPIN 1.ATF 2.FB 3.SPIN 1.FB 2.ATF 3.SPIN Economic benefits dominate Operational benefits dominate Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219 Fed-batch versus perfusion culture (New build) Results: Reconciling operational and economic benefits ─ fed-batch, -- spin-filter, ··· ATF

17 17 Continuous chrom: clinical & commercial (Retrofit) Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284:  Continuous chromatography (Pollock et al, 2013b)  Scenario: Retrofit for clinical / commercial mAb prodn  Impact of scale and development phase on cost  Retrofit costs across development phases

18 18 Technology Evaluation 18 Load FT WashLoad FT 1 ml scale-down evaluation 3C-PCC system validation Discrete event simulation tool Mass balance, scale-up & scheduling equations Continuous chrom: clinical & commercial (Retrofit)

19 19 3C-PCC CV = 3 x 1 mL Titre = 2 g/L t res = 6.6 mins t Switch = 200 mins t rampup = 330 mins t rampdown = 300 mins ramp-upramp-downSwitch time Continuous chrom: clinical & commercial (Retrofit) Example Chromatogram

20 20 AcidicDesignatedBasic Cycle (100 cycles) 19.3 %75.0 %5.7 % Batch (3 cycles) 18.4 %74.7 %6.8 % 3C-PCC (6 runs) 18.3 %75.8 %5.9 % HMWDesignatedLMW Cycle (100 cycles) 0.7 %97.6 %1.7 % Batch (3 Cycles) 1.0 %96.9 %2.1 % 3C-PCC (6 runs) 0.4 %98.0 %1.6 % CEX - HPLC SEC - HPLC 20 Continuous chrom: clinical & commercial (Retrofit) Product Quality (Elution peak)

21 21 Technology Evaluation 21 Load FT WashLoad FT 1 ml scale-down evaluation 3C-PCC system validation Discrete event simulation tool Mass balance, scale-up & scheduling equations Continuous chrom: clinical & commercial (Retrofit)

22 22 Day 1Day 2Day 3Day 4Day 5Day 6 PA (1 cycle) PA (2 cycle) PA (2 cycle) AEXVRFUFDF Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb 1,2 1800L (wv) 2.5g/L Protein A resin costs ~ 60% Direct manufacturing costs ~ $250k per molecule 1. Simaria, Turner & Farid, 2012, Biochem Eng J, 69, Bernstein, D. F.; Hamrell, M. R. Drug Inf. J. 2000, 34, 909–917. Continuous chrom: clinical & commercial (Retrofit) Early phase DS manufacture challenges Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

23 23 Standard3C-PCC 5 cycles17 cycles 31.4L3 x 4.9L = 14.7L $ 250K resin$ 118K resin 53% reduction in resin volume 40% reduction in buffer volume x2.3 increase in man-hours Load Wash Load Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L) 24 hour shift 8 hour shift Continuous chrom: clinical & commercial (Retrofit) Results: Economic Impact – Protein A

24 24 PA costs Other Costs 1 x 4kg 4 x 10kg20 x 10kg Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: Continuous chrom: clinical & commercial (Retrofit) Results: Impact of scale on direct costs

25 25 PoC (1 x 4kg) PIII & Commercial (4 x 10kg) STD: ÄKTA process (15-600L/hr) + 0.4m column 4C-PCC (15-600L/hr) + 4 x 0.2m columns STD: ÄKTA process ( L/hr) + 0.5m column 4C-PCC (15-600L/hr) + 4 x 0.3m columns x3.3 Investment ~25 PIII batches or ~ 8 PoC batches x4 Investment ~8 PoC batches Continuous chrom: clinical & commercial (Retrofit) Results: Impact of development phase on retrofitting investment

26 26 Integrated continuous processes (New build) Scenarios: Alternative integrated USP and DSP flowsheets DSP scheduling a)batch process sequence b)continuous + batch process sequence c)continuous process sequence Pollock, Ho & Farid, submitted  Integrated continuous processing (Pollock et al, submitted)  Scenario: New build for clinical / commercial mAb prodn  Impact of hybrid batch/continuous USP and DSP combinations  Impact of development phase, company size and portfolio size

27 27 Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal StrategiesUSPCapturePolishing Base caseFed-batchBatch FB-CBFed-batchContinuousBatch ATF-CBATF perfusionContinuousBatch FB-CCFed-batchContinuous ATF-CCATF perfusionContinuous Continuous USP + Continuous Capture + Continuous Polishing Batch USP + Continuous Capture + Batch Polishing

28 28 Summary Process economics case study insights: Fed-batch versus perfusion culture for new build –Economic competitiveness of perfusion depends on cell density increase achievable and failure rate Continuous chromatography retrofit –Continuous capture can offer more significant savings in early-stage clinical manufacture than late-stage Integrated continuous processes for new build –Integrated continuous processes offer savings for smaller portfolio sizes and early phase processes –Hybrid processes (Batch USP, Continuous Chrom) can be more economical for larger / late phase portfolios

29

30 Suzanne Farid PhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, October 2013 UCL Decisional Tools Research Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production

31 31 Backup

32 32 3 Column Periodic Counter Current Chromatography Load FT Wash/ Elution Load FT Load FT Wash/ Elution Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: Continuous chrom: clinical & commercial (Retrofit)

33 33 Load FT Load FT Wash 40 g/L 65 g/L FT Load FT Wash/ Elution Load Wash/ Elution Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: Column Periodic Counter Current Chromatography Continuous chrom: clinical & commercial (Retrofit)

34 34 -40% e-factor (kg/ kg of protein) STD3C-PCCDifference Water % Consumable % Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L) STD 3C-PCC Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: Continuous chrom: clinical & commercial (Retrofit) Results: Environmental Impact

35 35 Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal StrategiesUSPCapture Base caseFed-batchBatch FB-CBFed-batchContinuous ATF-CBATF perfusionContinuous FB-CCFed-batchContinuous ATF-CCATF perfusionContinuous Continuous USP + Continuous Capture Batch USP + Continuous Capture

36 36 Impact of Resin Life Span ( MabSelect x100 cycles ) Standard cycling study (40mg/ml) Column regeneration (NaOH) 100% breakthrough cycling study –x2.2 the load volume vs. standard 36 19% loss in capacity 12% loss in capacity 30% loss in capacity Insignificant loss < 15 cycles

37 37 Commercial Manufacture Feasibility 5g/L) 37 Batch 11 – surpasses harvest hold time Batch 6 – surpasses pool vessel volume Increasing cycle number

38 38 Establishing Optimal Switch Time 38 Maximum protein challenge Actual FT challenge Protein lostAll Protein retained

39 39

40 40 Impact of Resin Life Span 40 Batch ~20% loss 100% BT ~40% loss Loss in DBC vs. cycle numberFT protein vs. cycle number After 100 cycles unbound protein in FT


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