Suzanne Farid PhD CEng FIChemEReader (Associate Professor) Co-Director EPSRC Centre for Innovative ManufacturingUCL Biochemical [email protected]
ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013
UCL Decisional Tools Research
Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production
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Engineering Doctorate Project:Evaluating The Potential of Continuous Processes for Monoclonal Antibodies: Economic, Environmental and Operational Feasibility
UCL-Pfizer Collaboration (2008-2013)
UCL academic collaborators included: Daniel Bracewell(ex-)Pfizer collaborators included: Glen Bolton, Jon Coffman
Funding: UK EPSRC, Pfizer
Acknowledgements
James PollockUCL
Suzanne FaridUCL
Sa HoPfizer
3
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
Bioprocess Decisional Tools – DomainBiotech Drug Development Cycle
Farid, 2012, In Biopharmaceutical Production Technology, pp717-74
4
Scope of UCL Decisional ToolsTypical 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?
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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
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
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
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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
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Fed-batch versus perfusion culture (New build)
Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
Commercial products using perfusion cell culture technologies
10Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
LEVELCONTROL
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSELDIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
LEVELCONTROL
LEVELCONTROL
OFF
ON
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSELDIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
LEVELCONTROL
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSELDIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
LEVELCONTROL
LEVELCONTROL
OFF
ON
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSELDIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
SPIN FILTER
LIQUID LEVEL
Spin-filter Perfusion
PRO:
CON:
InvestmentDSP consumable cost
Equipment failure rateUSP 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 densitiesFailure rates
LEVELCONTROL
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSEL DIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
LEVELCONTROL
LEVELCONTROL
OFF
ON
OFF
ON
AIRINLET
EXHAUST
ADDITIONPUMP
FLUIDINLET
VALVE
QUICK CONNECT
FILTRATE PUMP
FILTRATE
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
PROCESS VESSEL DIAPHRAGM
ATFPUMP
STANDFILTER
LIQUID LEVEL
Fed-batch versus perfusion culture (New build)Scenario trade-offs: FB v SPIN v ATF
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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 FB SPIN ATF Variable FB SPIN ATF
Reactor type SS/SUB SS SUB
Cell culture time (days) 12 60 60
Max VCD (106 cells/ml) 10 15 50
Max bioreactor vol. (L) 20,000 2000 1500
Max perf. rate (vv/day) – 1 1.5
Process yield 65% 68% 69%
Annual # batches 22 5 5
Product conc. (g/L) 2 – 10 20% FB 45% FB
Productivity (mg/L/day) 170-850 2 x FB 6.5 x FB
Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
Fed-batch versus perfusion culture (New build)Key assumptions
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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.
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Process event p(Failure) ConsequenceFed-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 inactivation 20 % 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
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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
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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
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1. FB = ATF2. SPIN
1. ATF2. FB3. SPIN
1. FB2. ATF3. 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
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Continuous chrom: clinical & commercial (Retrofit)
Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27
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
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Technology Evaluation
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Load
FT
WashLoad
FT
1 ml scale-downevaluation
3C-PCC systemvalidation
Discrete event simulation tool
Mass balance, scale-up & scheduling equations
Continuous chrom: clinical & commercial (Retrofit)
1919
3C-PCC
CV = 3 x 1 mL
Titre = 2 g/L
tres = 6.6 mins
tSwitch = 200 mins
trampup = 330 mins
trampdown = 300 mins
ramp-up ramp-downSwitch time
Continuous chrom: clinical & commercial (Retrofit)Example Chromatogram
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Acidic Designated BasicCycle (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 %
HMW Designated LMWCycle (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
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Continuous chrom: clinical & commercial (Retrofit)Product Quality (Elution peak)
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Technology Evaluation
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Load
FT
WashLoad
FT
1 ml scale-downevaluation
3C-PCC systemvalidation
Discrete event simulation tool
Mass balance, scale-up & scheduling equations
Continuous chrom: clinical & commercial (Retrofit)
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Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
PA(1 cycle)
PA (2 cycle)
PA (2 cycle) AEX VRF UFDF
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, Biochem Eng J, 69, 144-1542. 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
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Standard 3C-PCC
5 cycles 17 cycles
31.4L 3 x 4.9L = 14.7L
$ 250K resin $ 118K resin
53% reduction in resin volume40% reduction in buffer volumex2.3 increase in man-hours
Load WashLoad
Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L)
24 hour shift8 hour shift
Continuous chrom: clinical & commercial (Retrofit)Results: Economic Impact – Protein A
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PA costsOther Costs
1 x 4kg 4 x 10kg 20 x 10kg
Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27
Continuous chrom: clinical & commercial (Retrofit)Results: Impact of scale on direct costs
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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 (45-1800L/hr) + 0.5m column4C-PCC (15-600L/hr) + 4 x 0.3m columns
x3.3 Investment
~25 PIII batchesor
~ 8 PoC batches
x4 Investment
~8 PoC batches
Continuous chrom: clinical & commercial (Retrofit)Results: Impact of development phase on retrofitting investment
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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
Integrated continuous processes (New build)Results: Impact of development phase and company size on optimal
Strategies USP Capture PolishingBase case Fed-batch Batch BatchFB-CB Fed-batch Continuous BatchATF-CB ATF perfusion Continuous BatchFB-CC Fed-batch Continuous ContinuousATF-CC ATF perfusion Continuous Continuous
Continuous USP+ Continuous Capture + Continuous Polishing
Batch USP + Continuous Capture+ Batch Polishing
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SummaryProcess 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
Suzanne Farid PhD CEng FIChemEReader (Associate Professor) Co-Director EPSRC Centre for Innovative ManufacturingUCL Biochemical [email protected]
ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013
UCL Decisional Tools Research
Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production
31
Backup
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: 17-27
Continuous chrom: clinical & commercial (Retrofit)
33
Load
FT
Load FT Wash
40 g/L 65 g/L
FT
Load FTWash/ Elution
LoadWash/ Elution
Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27
3 Column Periodic Counter Current ChromatographyContinuous chrom: clinical & commercial (Retrofit)
34
-40%
e-factor (kg/ kg of protein) STD 3C-PCC Difference
Water 5900 5250 -11%Consumable 24.5 13.7 -44%
Proof-of-concept (Phase I & II) ~ 4kg DS for the average mAb (2.5g/L)
STD3C-PCC
Pollock, Bolton, Coffman, Ho, Bracewell, Farid, 2013, J Chrom A, 1284: 17-27
Continuous chrom: clinical & commercial (Retrofit)Results: Environmental Impact
35
Large FB + Cont Chrom
FB + Cont Chrom
FB + Cont Chrom
FB + Cont Chrom
Medium ATF + Cont
Chrom ATF + Cont
Chrom ATF + Cont
Chrom FB + Cont
Chrom
Small ATF + Cont
Chrom ATF + Cont
Chrom ATF + Cont
Chrom FB + Cont
Chrom
Pre-clinical PoC PIII Commercial
Com
pany
Siz
e
Manufacturing Scale
Integrated continuous processes (New build)Results: Impact of development phase and company size on optimal
Strategies USP CaptureBase case Fed-batch BatchFB-CB Fed-batch ContinuousATF-CB ATF perfusion ContinuousFB-CC Fed-batch ContinuousATF-CC ATF perfusion Continuous
Continuous USP+ Continuous Capture
Batch USP + Continuous Capture
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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 capacityInsignificant loss < 15 cycles
37
Commercial Manufacture Feasibility (3C-PCC @ 5g/L)
37
Batch 11 – surpasses harvest hold time
Batch 6 – surpasses pool vessel volume
Increasing cycle number Increasing cycle number
16 3822 16 3819