Transcript Operational & Economic Evaluation of Integrated Continuous

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
[email protected]
ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013
Acknowledgements
Engineering Doctorate Project:
Evaluating The Potential of Continuous Processes for Monoclonal
Antibodies: Economic, Environmental and Operational Feasibility
UCL-Pfizer Collaboration (2008-2013)
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
Bioprocess Decisional Tools – Domain
Biotech Drug Development Cycle
Decisions
Uncertainties
Portfolio selection?
Process design?
Clinical (e.g. doses, transition probabilities)
Capacity Sourcing?
Build single / multi-product facility?
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, pp717-74
3
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
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







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


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)
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
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 (Pollock et al, 2013a)
 Continuous chromatography (Pollock et al, 2013b)
 Integrated continuous processing (Pollock 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


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)
Prediction of suboptimal facility fit upon tech transfer (Stonier et al, 2013; Yang et al, 2013)
Creating suitable data visualization methods

For each of aboveFarid,
examples
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)
 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)
 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): 206–219
8
Fed-batch versus perfusion culture (New build)
Commercial products using perfusion cell culture technologies
Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
9
Fed-batch versus perfusion culture (New build)
Scenario trade-offs: FB v SPIN v ATF
ATF Perfusion
Spin-filter Perfusion
LEVEL
CONTROL
LEVEL
CONTROL
LEVEL
CONTROL
QUICK CONNECT
QUICK CONNECT
FLUID
INLET
FLUID
INLET
FLUID
INLET
QUICK CONNECT
ADDITION
PUMP
ADDITION
PUMP
VALVE
ADDITION
PUMP
VALVE
VALVE
FILTRATE PUMP
FILTRATE PUMP
FILTRATE PUMP
FILTRATE
LIQUID
LEVEL LIQUID
LEVEL
SPIN LIQUID
LEVEL
FILTER
PROCESS VESSEL
PROCESS VESSEL
0.2 MICRON
HOLLOW FIBRE FILTER CASSETTE
FILTRATE
FILTRATE
HOUSING
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
HOUSING
CONTROLLER
DIAPHRAGM
DIAPHRAGM
HOUSING
LIQUID
LEVEL
ON
OFF
ATF
PUMP
ATF
STAND
PUMP
0.2 MICRON HOLLOW FIBRE FILTER CASSETTE
CONTROLLER
ON
PROCESS VESSEL
EXHAUST
AIR
EXHAUST
INLET
AIR
INLET
CONTROLLER
EXHAUST
DIAPHRAGM
AIR
INLET
OFF
ON
FILTER
FILTER
STAND
OFF
ATF
PUMP
FILTER
STAND
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): 206–219
10
Fed-batch versus perfusion culture (New build)
Key assumptions
Suites
Cell
Culture
Suite
FB
SPIN
ATF
Seed #1
Seed #1
Seed #1
Reactor type
Seed #2
Seed #2
Seed #2
CC
CC
CC
Cent
DF
DF
Variable
FB
SPIN
ATF
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
65%
68%
69%
22
5
5
2 – 10
20% FB
45% FB
170-850
2 x FB
6.5 x FB
Process yield
UF
Annual # batches
Product conc. (g/L)
DSP
Suite
Viral
Secure
Suite
ProA
ProA
ProA
VI
VI
VI
Pool
Pool
CEX
CEX
CEX
UFDF
UFDF
UFDF
VRF
VRF
VRF
AEX
AEX
AEX
UFDF
UFDF
UFDF
Productivity (mg/L/day)
Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
11
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): 206–219
12
Fed-batch versus perfusion culture (New build)
Uncertainties and failure rates
Process event
p(Failure)
Consequence
Fed-batch culture contamination
1%
Spin-filter culture contamination
6%
Spin-filter filter failure
4%
ATF culture contamination
6%
ATF filter failure
2%
In process filtration failure – general
5%
4 hour delay & 2% yield loss
20 %
4 hour delay & 2% yield loss
In process filtration failure– post viral inactivation
Batch loss
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
Pollock, Ho & Farid, 2013, Biotech Bioeng, 110(1): 206–219
13
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
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: 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): 206–219
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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: 17-27
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Continuous chrom: clinical & commercial (Retrofit)
Technology Evaluation
1 ml scale-down
evaluation
3C-PCC system
validation
Load
Discrete event
simulation tool
Wash
Load
mAb Breakthrough
100%
80%
60%
40%
100 cm/hr (14.3 mins)
230 cm/hr (6.6 mins)
300 cm/hr (5 mins)
20%
500 cm/hr (3 mins)
0%
0
FT
50
100
Challenge Load (mg/ml)
FT
18
150
Mass balance,
scale-up &
scheduling
equations
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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
19
19
Continuous chrom: clinical & commercial (Retrofit)
Product Quality (Elution peak)
CEX - HPLC
Cycle (100 cycles)
Batch (3 cycles)
3C-PCC (6 runs)
Acidic
19.3 %
Designated
75.0 %
Basic
5.7 %
18.4 %
18.3 %
74.7 %
75.8 %
6.8 %
5.9 %
HMW
0.7 %
Designated
97.6 %
LMW
1.7 %
1.0 %
0.4 %
96.9 %
98.0 %
2.1 %
1.6 %
SEC - HPLC
Cycle (100 cycles)
Batch (3 Cycles)
3C-PCC (6 runs)
20
20
Continuous chrom: clinical & commercial (Retrofit)
Technology Evaluation
1 ml scale-down
evaluation
3C-PCC system
validation
Load
Discrete event
simulation tool
Wash
Load
mAb Breakthrough
100%
80%
60%
40%
100 cm/hr (14.3 mins)
230 cm/hr (6.6 mins)
300 cm/hr (5 mins)
20%
500 cm/hr (3 mins)
0%
0
FT
50
100
Challenge Load (mg/ml)
FT
21
150
Mass balance,
scale-up &
scheduling
equations
21
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
Day 1
PA
(1 cycle)
Day 2
Day 3
PA
(2 cycle)
PA
(2 cycle)
Day 4
AEX
Day 5
VRF
Day 6
UFDF
Protein A resin costs
~ 60% Direct manufacturing costs
~ $250k per molecule
1. Simaria, Turner & Farid, 2012, Biochem Eng 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
22
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
24 hour shift
53% reduction in resin volume
40% reduction in buffer volume
x2.3 increase in man-hours
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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
24
Continuous chrom: clinical & commercial (Retrofit)
Results: Impact of development phase on retrofitting investment
PoC
(1 x 4kg)
PIII &
Commercial
(4 x 10kg)
STD: ÄKTA process (15-600L/hr)
+ 0.4m column
x4 Investment
4C-PCC (15-600L/hr)
+ 4 x 0.2m columns
~8 PoC batches
STD: ÄKTA process (45-1800L/hr)
+ 0.5m column
x3.3 Investment
4C-PCC (15-600L/hr)
+ 4 x 0.3m columns
~25 PIII batches
or
~ 8 PoC batches
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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
Integrated continuous processes (New build)
Results: Impact of development phase and company size on optimal
Strategies
USP
Capture
Polishing
Base case
FB-CB
ATF-CB
FB-CC
ATF-CC
Fed-batch
Fed-batch
ATF perfusion
Fed-batch
ATF perfusion
Batch
Continuous
Continuous
Continuous
Continuous
Batch
Batch
Batch
Continuous
Continuous
Continuous
USP
+
Continuous
Capture
+
Continuous
Polishing
Batch
USP
+
Continuous
Capture
+
Batch
Polishing
27
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
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
[email protected]
ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013
Backup
31
Continuous chrom: clinical & commercial (Retrofit)
3 Column Periodic Counter Current Chromatography
Load
Load
FT
Wash/
Elution
Load
FT
Wash/
Elution
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
Load
40 g/L
Wash/
Elution
Load
Load
Wash/
Elution
FT
Load
FT
65 g/L
Wash
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%
e-factor
(kg/ kg of protein)
STD
3C-PCC
Difference
Water
5900
5250
-11%
Consumable
24.5
13.7
-44%
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
Company Size
Large
Medium
Small
Strategies
USP
Capture
Base case
FB-CB
ATF-CB
FB-CC
ATF-CC
Fed-batch
Fed-batch
ATF perfusion
Fed-batch
ATF perfusion
Batch
Continuous
Continuous
Continuous
Continuous
FB + Cont
Chrom
FB + Cont
Chrom
Batch
FB + Cont
USP FB + Cont
Chrom+
Chrom
Continuous
Capture
ATF + Cont ATF + Cont ATF + Cont
Chrom
Chrom
Chrom
Continuous
USP
+ + Cont ATF + Cont ATF + Cont
ATF
Continuous
Chrom
Chrom
Chrom
Capture
Pre-clinical
PoC
PIII
FB + Cont
Chrom
FB + Cont
Chrom
Commercial
Manufacturing Scale
35
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
Commercial Manufacture Feasibility (3C-PCC
@ 5g/L)
Increasing cycle number
16
22
Increasing cycle number
38
16
Batch 11 – surpasses harvest hold
time
19
38
Batch 6 – surpasses pool vessel
volume
37
37