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Suzanne Farid PhD CEng FIChemE Reader (Associate Professor)

UCL Decisional Tools Research Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production. Suzanne Farid PhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing

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Suzanne Farid PhD CEng FIChemE Reader (Associate Professor)

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  1. UCL Decisional Tools Research Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production Suzanne FaridPhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering s.farid@ucl.ac.uk ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013

  2. Acknowledgements Engineering Doctorate Project:Evaluating The Potential of Continuous Processes for Monoclonal Antibodies: Economic, Environmental and Operational FeasibilityUCL-Pfizer Collaboration (2008-2013)UCL academic collaborators included: Daniel Bracewell(ex-)Pfizer collaborators included: Glen Bolton, Jon Coffman Funding: UK EPSRC, Pfizer James Pollock UCL Suzanne Farid UCL Sa Ho Pfizer

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

  4. Scope of UCL Decisional Tools

  5. Scope of UCL Decisional Tools • 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 • Farid, 2012, In Biopharmaceutical Production Technology, pp717-74

  6. Scope of UCL Decisional Tools • 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 • Farid, 2012, In Biopharmaceutical Production Technology, pp717-74

  7. Scope of UCL Decisional Tools • 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) • Scenario: New build for commercial mAbprodn • 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 mAbprodn • 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 mAbprodn • Impact of hybrid batch/continuous USP and DSP combinations • Impact of development phase, company size and portfolio size

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

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

  10. ATF Perfusion Steady state cell densities Failure rates LIQUID LEVEL SPIN FILTER Fed-batch versus perfusion culture (New build) Scenario trade-offs: FB v SPIN v ATF Spin-filter Perfusion PRO: Investment DSP consumable cost CON: 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 • Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219

  11. Cell Culture Suite ProA ProA ProA VI VI VI CEX Pool Pool DSP Suite UFDF CEX CEX VRF UFDF UFDF AEX VRF VRF Seed #1 Seed #1 Seed #1 UFDF AEX AEX Seed #2 Seed #2 Seed #2 Viral Secure Suite UFDF UFDF CC CC CC Cent DF DF UF Fed-batch versus perfusion culture (New build) Key assumptions FB SPIN ATF Suites • Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219

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

  13. Fed-batch versus perfusion culture (New build) Uncertainties and failure rates • Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219

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

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

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

  17. Continuous chrom: clinical & commercial (Retrofit) • Continuous chromatography (Pollock et al, 2013b) • Scenario: Retrofit for clinical / commercial mAbprodn • Impact of scale and development phase on cost • Retrofit costs across development phases • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

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

  19. Continuous chrom: clinical & commercial (Retrofit) Example Chromatogram ramp-up Switch time ramp-down 3C-PCC CV = 3 x 1 mL Titre = 2 g/L tres = 6.6 mins tSwitch = 200 mins trampup = 330 mins trampdown = 300 mins

  20. Continuous chrom: clinical & commercial (Retrofit) Product Quality (Elution peak) CEX - HPLC SEC - HPLC

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

  22. Continuous chrom: clinical & commercial (Retrofit) Early phase DS manufacture challenges Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb 1,2 1800L (wv) Fed-batch @ 2.5g/L Protein A resin costs ~ 60% Direct manufacturing costs ~ $250k per molecule • 1. Simaria, Turner & Farid, 2012, BiochemEng J, 69, 144-154 • 2. Bernstein, D. F.; Hamrell, M. R. Drug Inf. J. 2000, 34, 909–917. • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

  23. Continuous chrom: clinical & commercial (Retrofit) Results: Economic Impact – Protein A Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L) Standard 3C-PCC Load Wash Load 31.4L 3 x 4.9L = 14.7L 5 cycles 17 cycles $ 250K resin $ 118K resin 24 hour shift 8 hour shift 53% reduction in resin volume 40% reduction in buffer volume x2.3 increase in man-hours

  24. Continuous chrom: clinical & commercial (Retrofit) Results: Impact of scale on direct costs PA costs Other Costs 1 x 4kg 4 x 10kg 20 x 10kg • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

  25. Continuous chrom: clinical & commercial (Retrofit) Results: Impact of development phase on retrofitting investment STD: ÄKTA process (15-600L/hr) + 0.4m column x4 Investment ~8 PoC batches PoC (1 x 4kg) 4C-PCC (15-600L/hr) + 4 x 0.2m columns STD: ÄKTA process (45-1800L/hr) + 0.5m column x3.3 Investment ~25 PIII batches or ~ 8 PoC batches PIII & Commercial (4 x 10kg) 4C-PCC (15-600L/hr) + 4 x 0.3m columns

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

  27. Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal Batch USP + Continuous Capture + Batch Polishing Continuous USP + Continuous Capture + Continuous Polishing

  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. UCL Decisional Tools Research Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production Suzanne FaridPhD CEng FIChemE Reader (Associate Professor) Co-Director EPSRC Centre for Innovative Manufacturing UCL Biochemical Engineering s.farid@ucl.ac.uk ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013

  30. Backup

  31. Continuous chrom: clinical & commercial (Retrofit) 3 Column Periodic Counter Current Chromatography Wash/ Elution Load Load Load Wash/ Elution FT FT FT • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

  32. Continuous chrom: clinical & commercial (Retrofit) 3 Column Periodic Counter Current Chromatography Wash/ Elution Load 65 g/L Load 40 g/L Wash/ Elution Load Load Wash FT FT FT FT • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

  33. Continuous chrom: clinical & commercial (Retrofit) Results: Environmental Impact Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L) STD 3C-PCC -40% • Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27

  34. Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal Batch USP + Continuous Capture Continuous USP + Continuous Capture

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

  36. Commercial Manufacture Feasibility (3C-PCC @ 5g/L) Increasing cycle number Increasing cycle number 16 22 38 16 19 38 Batch 11 – surpasses harvest hold time Batch 6 – surpasses pool vessel volume

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