Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mab Production

Transcription

1 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 UCL Biochemical Engineering ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, October 2013

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

3 Bioprocess Decisional Tools Domain Biotech Drug Development Cycle Decisions Portfolio selection? Process design? Capacity Sourcing? Build single / multi-product facility? Uncertainties Clinical (e.g. doses, transition probabilities) Technical (e.g. titres, equipment failure) Commercial (e.g. sales forecasts) Constraints Time Capacity Budget Regulatory Skilled labour Metrics Speed Ease of scale-up Cost of goods Fit to facility Robustness Farid, 2012, In Biopharmaceutical Production Technology, pp

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? 4

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, pp

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, pp

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 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 7

8 Fed-batch versus perfusion culture (New build) 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 Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1):

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

10 ON OFF Fed-batch versus perfusion culture (New build) Scenario trade-offs: FB v SPIN v ATF Spin-filter Perfusion ATF Perfusion FLUID INLET LEVEL CONTROL FLUID INLET LEVEL CONTROL QUICK CONNECT ADDITION PUMP ADDITION PUMP VALVE FILTRATE PUMP LIQUID LEVEL SPIN FILTER LIQUID LEVEL PROCESS VESSEL DIAPHRAGM FILTRATE 0.2 MICRON HOLLOW FIBRE FILTER CASSETTE HOUSING CONTROLLER EXHAUST AIR INLET ATF PUMP STAND FILTER PRO: Investment DSP consumable cost Steady state cell densities Failure rates 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):

11 Fed-batch versus perfusion culture (New build) Key assumptions Suites FB SPIN ATF Variable FB SPIN ATF Seed #1 Seed #1 Seed #1 Reactor type SS/SUB SS SUB Cell Culture Suite Seed #2 CC Cent DF Seed #2 CC DF Seed #2 CC Cell culture time (days) Max VCD (10 6 cells/ml) Max bioreactor vol. (L) 20, Max perf. rate (vv/day) Process yield 65% 68% 69% UF Annual # batches ProA ProA Product conc. (g/l) % FB 45% FB Productivity (mg/l/day) x FB 6.5 x FB DSP Suite ProA VI VI Pool VI Pool CEX CEX CEX UFDF UFDF UFDF Viral Secure Suite VRF AEX UFDF VRF AEX UFDF VRF AEX UFDF Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1):

12 Fed-batch versus perfusion culture (New build) Results: Impact of scale on COG = Indirect = Material = Labour 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):

13 Fed-batch versus perfusion culture (New build) Uncertainties and failure rates Process event p(failure) Consequence Fed-batch culture contamination 1 % Batch loss Spin-filter culture contamination 6 % Spin-filter filter failure 4 % ATF culture contamination 6 % ATF filter failure 2 % Batch loss & discard two pooled perfusate volumes Batch loss & no pooled volumes are discarded Batch loss & discard two pooled perfusate volumes 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 inactivation 20 % 4 hour delay & 2% yield loss Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1):

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):

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):

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

17 Continuous chrom: clinical & commercial (Retrofit) 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 Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284:

18 Continuous chrom: clinical & commercial (Retrofit) Technology Evaluation 1 ml scale-down evaluation 3C-PCC system validation Discrete event simulation tool Load Load Wash 100% FT mab Breakthrough 80% 60% 40% 20% 0% Challenge Load (mg/ml) FT 100 cm/hr (14.3 mins) 230 cm/hr (6.6 mins) 300 cm/hr (5 mins) 500 cm/hr (3 mins) Mass balance, scale-up & scheduling equations 18 18

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 t res = 6.6 mins t Switch = 200 mins t rampup = 330 mins t rampdown = 300 mins 19 19

20 Continuous chrom: clinical & commercial (Retrofit) Product Quality (Elution peak) CEX - HPLC Acidic Designated Basic 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 % SEC - HPLC HMW Designated LMW 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 % 20 20

21 Continuous chrom: clinical & commercial (Retrofit) Technology Evaluation 1 ml scale-down evaluation 3C-PCC system validation Discrete event simulation tool Load Load Wash 100% FT mab Breakthrough 80% 60% 40% 20% 0% Challenge Load (mg/ml) FT 100 cm/hr (14.3 mins) 230 cm/hr (6.6 mins) 300 cm/hr (5 mins) 500 cm/hr (3 mins) Mass balance, scale-up & scheduling equations 21 21

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) 2.5g/L Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 PA (1 cycle) PA (2 cycle) PA (2 cycle) AEX VRF UFDF 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, Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284:

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 Load Wash 31.4L 3 x 4.9L = 14.7L 5 cycles 17 cycles $ 250K resin $ 118K resin 8 hour shift 53% reduction in resin volume 40% reduction in buffer volume x2.3 increase in man-hours 24 hour shift 23

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:

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

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 mab prodn Impact of hybrid batch/continuous USP and DSP combinations Impact of development phase, company size and portfolio size DSP scheduling a) batch process sequence b) continuous + batch process sequence c) continuous process sequence Pollock, Ho & Farid, submitted 26

27 Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal Strategies USP Capture Polishing Base case Fed-batch Batch Batch FB-CB Fed-batch Continuous Batch ATF-CB ATF perfusion Continuous Batch FB-CC Fed-batch Continuous Continuous ATF-CC ATF perfusion Continuous Continuous Continuous USP + Continuous Capture + Continuous Polishing Batch USP + Continuous Capture + Batch Polishing 27

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 28

29

30 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 UCL Biochemical Engineering ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, October 2013

31 Backup 31

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

33 Continuous chrom: clinical & commercial (Retrofit) 3 Column Periodic Counter Current Chromatography Load Wash/ Load 40 g/l Elution 65 g/l Load FT Wash Wash/ Load FT Elution FT FT Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284:

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

35 Integrated continuous processes (New build) Results: Impact of development phase and company size on optimal Strategies USP Capture Base case Fed-batch Batch FB-CB Fed-batch Continuous ATF-CB ATF perfusion Continuous FB-CC Fed-batch Continuous ATF-CC ATF perfusion Continuous Company Size Large Medium Small FB + Cont Chrom ATF + Cont Chrom FB + Cont Chrom ATF + Cont Chrom Continuous USP ATF + + Cont ATF + Cont Continuous Chrom Chrom Capture Batch FB + Cont USP FB + Cont Chrom+ Chrom Continuous Capture ATF + Cont Chrom ATF + Cont Chrom FB + Cont Chrom FB + Cont Chrom Pre-clinical PoC PIII Commercial Manufacturing Scale 35

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

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