Suzanne Farid PhD CEng FIChemE

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 s.farid_at_ucl.ac.uk ECI Integrated
Continuous Biomanufacturing, Barcelona, Spain,
20-24 October 2013
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Engineering Doctorate ProjectEvaluating 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
Acknowledgements
James Pollock UCL
Suzanne Farid UCL
Sa Ho Pfizer
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Bioprocess Decisional Tools Domain
Biotech Drug Development Cycle
Farid, 2012, In Biopharmaceutical Production
Technology, pp717-74
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?
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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

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

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 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) 206219
9
Fed-batch versus perfusion culture (New build)
Commercial products using perfusion cell culture
technologies
Pollock, Ho Farid, 2013, Biotech Bioeng,
110(1) 206219
10
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) 206219
11
Fed-batch versus perfusion culture (New build)
Key assumptions
FB
SPIN
ATF
Suites
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) 206219
12
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) 206219
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 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) 206219
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) 206219
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) 206219
16
Fed-batch versus perfusion culture (New build)
Results Reconciling operational and economic
benefits

• FB ATF
• SPIN

1. ATF
2. FB
3. SPIN

1. FB
2. ATF
3. SPIN

Economic benefits dominate
Operational benefits dominate
- fed-batch, -- spin-filter, ATF
Pollock, Ho Farid, 2013, Biotech Bioeng,
110(1) 206219
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 17-27
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Technology Evaluation
Continuous chrom clinical commercial
(Retrofit)
1 ml scale-down evaluation
3C-PCC system validation
Discrete event simulation tool
Mass balance, scale-up scheduling equations
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Example Chromatogram
Continuous chrom clinical commercial
(Retrofit)
3C-PCC CV 3 x 1 mL Titre 2 g/L tres 6.6
mins tSwitch 200 mins trampup 330
mins trampdown 300 mins
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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
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Technology Evaluation
Continuous chrom clinical commercial
(Retrofit)
1 ml scale-down evaluation
3C-PCC system validation
Discrete event simulation tool
Mass balance, scale-up scheduling equations
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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 _at_ 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, 144-154 2. Bernstein, D. F. Hamrell, M. R.
Drug Inf. J. 2000, 34, 909917.
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
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
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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
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
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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
• batch process sequence
• continuous batch process sequence
• continuous process sequence

Pollock, Ho Farid, submitted
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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
Batch USP Continuous Capture Batch
Polishing
Continuous USP Continuous Capture
Continuous Polishing
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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

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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 s.farid_at_ucl.ac.uk ECI Integrated
Continuous Biomanufacturing, Barcelona, Spain,
20-24 October 2013
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Backup
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3 Column Periodic Counter Current Chromatography
Continuous chrom clinical commercial (Retrofit)
Load
FT
Pollock, Bolton, Coffman, Ho, Bracewell, Farid,
2013, J Chrom A, 1284 17-27
33
Continuous chrom clinical commercial (Retrofit)
3 Column Periodic Counter Current Chromatography
Wash/ Elution
Load
65 g/L
Load
40 g/L
FT
FT
Pollock, Bolton, Coffman, Ho, Bracewell, Farid,
2013, J Chrom A, 1284 17-27
34
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
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
Batch USP Continuous Capture
Continuous 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

19 loss in capacity
12 loss in capacity
30 loss in capacity
Insignificant loss lt 15 cycles
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Commercial Manufacture Feasibility (3C-PCC _at_ 5g/L)
Increasing cycle number
Increasing cycle number
16
38
22
16
38
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Batch 11 surpasses harvest hold time
Batch 6 surpasses pool vessel volume
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Establishing Optimal Switch Time
Protein lost
All Protein retained
Maximum protein challenge
Actual FT challenge
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Impact of Resin Life Span
Loss in DBC vs. cycle number
FT protein vs. cycle number
Batch 20 loss
After 100 cycles unbound protein in FT
100 BT 40 loss