suzanne farid phd ceng ficheme reader (associate professor) co-director epsrc centre for innovative...

Suzanne Farid PhD CEng FIChemE

Reader (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

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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

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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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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



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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



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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)


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


HOUSING

CONTROLLER


ATFPUMP

STANDFILTER

LIQUID LEVEL

LEVELCONTROL

OFF

ON

AIRINLET

EXHAUST

ADDITIONPUMP

FLUIDINLET

VALVE

QUICK CONNECT

FILTRATE PUMP

FILTRATE


HOUSING

CONTROLLER


ATFPUMP

STANDFILTER

LIQUID LEVEL

LEVELCONTROL

LEVELCONTROL

OFF

ON

OFF

ON

AIRINLET

EXHAUST

ADDITIONPUMP

FLUIDINLET

VALVE

QUICK CONNECT

FILTRATE PUMP

FILTRATE


HOUSING

CONTROLLER


ATFPUMP

STANDFILTER

LIQUID LEVEL

SPIN FILTER

LIQUID LEVEL

Spin-filter Perfusion

PRO:

CON:

Investment

DSP consumable cost

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

ATF Perfusion

Steady state cell densities

Failure rates

LEVELCONTROL

OFF

ON

AIRINLET

EXHAUST

ADDITIONPUMP

FLUIDINLET

VALVE

QUICK CONNECT

FILTRATE PUMP

FILTRATE


HOUSING

CONTROLLER


ATFPUMP

STANDFILTER

LIQUID LEVEL

LEVELCONTROL

LEVELCONTROL

OFF

ON

OFF

ON

AIRINLET

EXHAUST

ADDITIONPUMP

FLUIDINLET

VALVE

QUICK CONNECT

FILTRATE PUMP

FILTRATE


HOUSING

CONTROLLER


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


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


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) 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


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


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


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


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


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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


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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


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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


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

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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 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 FIChemE

Reader (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

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3 Column Periodic Counter Current Chromatography

Load

FT

Wash/ Elution

Load

FT

Load FT Wash/ Elution



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Load

FT

Load FT Wash

40 g/L 65 g/L

FT

Load FTWash/ Elution

LoadWash/ Elution


3 Column Periodic Counter Current ChromatographyContinuous chrom: clinical & commercial (Retrofit)

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-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


Continuous chrom: clinical & commercial (Retrofit)Results: Environmental Impact

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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 Capture

Base 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

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19% loss in capacity

12% loss in capacity

30% loss in capacityInsignificant loss < 15 cycles

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Commercial Manufacture Feasibility (3C-PCC @ 5g/L)

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Batch 11 – surpasses harvest hold time

Batch 6 – surpasses pool vessel volume

Increasing cycle number Increasing cycle number

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suzanne farid phd ceng ficheme reader (associate professor) co-director epsrc centre for innovative...

Documents

siganporia et

yang et

allmendinger et

facilities farid et

perfusion systems pollock

perfusion systems lim

high titres stonier

tech transfer stonier