Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing Hurdles Early A presentation by Chief Operating Officer, Dr Stephen Ward Nov 2013
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Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing Hurdles Early A presentation by Chief Operating Officer, Dr Stephen Ward
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Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing Hurdles Early A presentation by Chief Operating Officer, Dr Stephen Ward Nov 2013
- 1. Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing Hurdles Early Marcus Evans 11th Annual Commercial Translation of Regenerative Medicine Dr Stephen Ward, Chief Operating Officer 25th November 2013 Catapult is a Technology Strategy Board programme
- 2. The translational funding gap 2 • • • Limited precedents for valuable exits via IPO or acquisition Most large corporates are observing and waiting • Mood is changing……. Limited investment from commercial sector • Catapult Little evidence yet that new cell therapies can be developed, licensed and adopted successfully Operational SME’s lack finance and breadth of resources for rapid advance
- 3. Strategic Goals of Cell Therapy Catapult Pipeline • Increased cell therapies in UK clinical trial and clinical use Value • Investible propositions created leading to cell therapy companies that succeed and stay in the UK Attractiveness • Demonstrating that the UK is the place to do this work, with increased inward investment Goals • Build a £10bn industry 3
- 4. Cell Therapy Catapult • Facilities • 1200 sq. m on 12th floor • Capacity for 80-100 people • Open end Q1 2014 • Currently in temporary facilities in KCL 4
- 5. Number of Staff at Cell Therapy Catapult 80 70 60 50 40 30 20 10 0 No of Staff Projected Staff
- 6. Addressing Key Sector Barriers Business Manufacturing and Supply Chain Clinical And Regulatory • Health Economics • Business plans • Manufacture & Supply vs Service • Reimbursement • Investment Risk • Robustness & Reliability • COGS & Scale up • Characterisation & Analytical • Comparability • GMP • CMC • Delivery • Complex Regulatory Landscape • Pre Clinical Packages • Clinical trial design • NHS partnering Business Development Process Development Clinical Operations & Regulatory Affairs 6
- 7. Regulatory agency dialogue on plans at each stage Successful Path to Commercialisation 7 Science • • Efficacy and safety hypothesis and evidence Definition and characterisation of cellular product Clinical • • • • Patient population, unmet medical need, differentiation Safety Robust evidence of efficacy Dose and dosing regimen • • • GMP manufacturing process; release; comparability assays Supply logistics Scale-up / scale –out; Control of cost • • • Pricing and reimbursement plan Defensibility (IP, know-how…) Commercialisation partner Manufacturing Business
- 8. Transition from Discovery Science to Manufacturing Science Pre-Clinical FIM Phase II-III Manufacturing Science Discovery Science 8
- 9. Cell Therapy Catapult Strategy for industrialisation of cell therapy processes 9 CT CATAPULT INNOVATION SME NON-CLINICAL PROCESS DEVELOPMENT MANUFACTURING CONTRACT MANUFACTURING NHS ACADEMIA ASSAY DEVELOPMENT GMP PROVING LAB GROW UK SECTOR
- 10. Lab - Pilot - Scale 10 Catapult Multi Functional Pod Commercial Scale Catapult GMP Proving Lab
- 11. Core Themes to ensure Sector success Theme 1: For sector to mature we need to be driven by ‘market need’, including COGs Theme 2: Collaboration across industry sectors Theme 3: Build robustness into supply chains 10
- 12. 12 Theme 1 • • • • • Commercial driver for product Not driven by scientific interest Manufacture to a sensible price point Reimbursement strategy Ask question; will product ever be used? Catapult is a Technology Strategy Board programme
- 13. For healthcare products, price, reimbursement and demand are interlinked determinants of profit All these have to be effectively addressed to reach commercial goals… PRICE PROFIT REIMBURSEMENT 13 DEMAND
- 14. Payers have a common aim: to achieve the greatest health care value for the money they spend Payers are key market access decision-makers (with input from clinical and economic advisors) Is it worth it? Does it add value over SOC? Cost-effectiveness Price comparison Can we afford it? Budget impact Comparative clinical effectiveness Should we control its use? Restrictions Do we need to fund it? Is the product needed? Unmet need 14 Political imperative The emphasis on these elements differs across markets, most notably the use of cost-effectiveness in decision-making
- 15. Pricing approaches in healthcare are shifting towards value-based models Cost-based Competitor-based Value-based What is it? • Price is set by • Price is driven by assumptions on the pricing of costs, expected sales competitor volumes and margins products • Price is based upon therapeutic / economic value to the customer Examples • Cost-plus pricing • ROI based pricing (e.g. PPRS in UK) • Penetration pricing • Reference group pricing • Value-based pricing • Becoming obsolete; no longer resonates with payers • Enforced by many reimbursement systems for “undifferentiated” products • Typical approach for differentiated products Comments Value-based pricing relies on the quantification of the added-value that a new technology delivers over SOC 15
- 16. 16 Theme 2 • Theme 2: Collaboration across industry sectors • Common challenges already solved: • Biopharmaceutical • Common challenges already solved: • Vaccine Catapult is a Technology Strategy Board programme
- 17. Significant Opportunity to Leverage knowledge from related sectors Synergies Spill-over Benefits 17
- 18. Creating Innovative Manufacturing Critical Mass Established Biologics Knowledge Re-innovate Prevent Wheelre-invention New Cell Therapy Knowledge Leverage ExistingUK PLC Capabilities and Capacity 18
- 19. Cell Therapy Catapult cross-sector strategy • Hired development/production staff from Biopharma and Vaccine industry • Interact with High Value Manufacturing Catapult • National Biologics Manufacturing Centre • Fill finish • Formulation • Volume reduction • Centre for Process Innovation • Micro-electronic printing: stability and integrity • Supply Chain Initiative (AMSCI) • Fully integrated ‘vein to vein’ GMP platform 19
- 20. 20 Theme 3 Build robustness into supply chains • Understanding End to End Supply Chain • Controlling Variation • Raw material • In process control • Reactive processing • Closing processes • Automation • Stability Catapult is a Technology Strategy Board programme
- 21. Is the Traditional Supply Chain Model Applicable? 13
- 22. Allogenic Cell Process 22 Allogeneic Adherent C ell Process Enzymes Biopsy d issection Enzymatic digestion Isolate target cells Tissue biopsy Expand primary cells Bank cells (if required) LN2 Cell s trainer Enzymatic digestion Isolate target primary cells Bank cells if required Media Primary cells Culture in T flasks Expanded primary cells Growth media OR Expanded primary cells Cell freeze bags LN2 Cryovials LN2 Retrieve frozen cell bag Bank cells Media Thaw bag/vial Cells Growth media Culture in T flasks Media Expand cells Revive cells (if required) Isolate cells Enzymes Isolated cells Cells Harvest, formulate and fill for s torage/shipment We make complex products ! Isolate cells from biopsy Open process Growth media Cell freeze bags Culture in cell factory Final p roduct Expanded Cells Bank LN2 Expanded Cells Formulate and fill Final p roduct Shipment
- 23. End to End Supply Chain Unites Sector 15
- 24. Cell Based Medicinal Products cover a wide product area 24 HESCs ALLOGENEIC Cancer Vaccine TEPs iPSCs HSCs Gene modified cells Cell-Device Combination M/Stroma SCs CD4/8+ Tcells AUTOLOGOUS Cell core element Reproducible and Robust process and analytics • Identity • Purity • Potency • Efficacy
- 25. Control process variation 25 Critical areas Analytical and Potency Donated material QbD InProcess Control STABILIT Tools ECH TECHNOL OGY Cell differentiation Process Raw material Cell expans ion How can we be smart to untangle hugely complex processes How to identify what is important ? How do they interact? How to control the system? How to analyse success?
- 26. Raw material variation 26 Amino Acid Analysis by Capillary Zone Electrophoresis Base Lot 1 Base Lot 2 Complete Lot 1 Complete Lot 2 • Patient starting material • Process materials • Inter- vendor • Inter-batch • Huge impact on reproducibility • Vendor engagement • More technology support and partnerships
- 27. Quality by Design Toolkit – Essential for complex medicines Link Critical Process Parameters to Critical Quality Attributes
- 28. Experimental Design Philosophy 28 Design of Experiments: One Factor At a Time (OFAT): • Poor coverage of experimental space • May miss optimal solution • Good coverage of experimental space • High efficiency designs HI HI HI HI Time Time HI Temp Hold Temp LO LO LO Hold HI LO
- 29. Manufacturing impact upon live cell products Hold time = 5 mins Loss of intact cells % Hold time = 120 mins Loss of intact cells % • Intact cell losses increase with an increase in both RCF and Spin time • A pre-process hold stage increases cell loss
- 30. CTC Capabilities: Analytical Development Product characterisation to routine QC Have to know what cQA to measure In-Cell 2200 30 Fluidigm Digital PCR Roche Lightcyler A1R confocal 10 FTE £1.25M Budget ABI QuantStudio Fortessa X20 EpMotion robotics QiaCube MacsQuant Tecan M1000
- 31. 31 Theme 3 Build robustness into supply chains • Closed systems for manufacturing • Automation Catapult is a Technology Strategy Board programme
- 32. 32 Integrated Supply Chain Model Transduced T Cell Micro Collection Transport Debead and Wash (Day 10) Cell Count Volume Reduce (Day 10) Micro Cell Count PBMC Separation (Day 1) Cell Selection (Day 1) PBMC Count Cell Expansion (Days 4-10) Cell Count Transduce (Day 4) Activate in Culture (Days 1-3) Cryopreserve (Day 10) Storage Transport Transplant Blood Count Operator Equipment Virus Temperature Monitoring Media Test Results Shipper Outcome Reporting Reagents Date/Time Data Logger Patient Details Consumables Cytokines Sampling Kit
- 33. What is the current manufacturing scene • Conflicts across a diverse Industry • No clear pattern • Legacy phase III need • Often Autologous • (semi) Open processes • • High grade B clean rooms Short ambient stability • Raw material and product Scale out model • Central facility = 100 MBSCs • • • • Repetitive Automation De-centralised = 5 to 10 regional centres Ensure product consistency 33
- 34. What is the future? • Next generation need • Fully Enclosed • • Automation Isolator driven if needed • Low Grade D rooms More Allogeneic products • • • Centralised, Smaller footprint Volume reduction • Economy of scale possible • Seemless fill finish capability • Longer shelf life 34
- 35. CTC Process Development Capability Scaleable automation Enclosed not functional enclosure Primary Recovery Akta TFF SciLog TFF 15 FTE Rocking platform Cubian XC 1.7M budget Vi-CELL Stirred platform Automated Manual Quantum® Fill Finish Peregrine In Process Control Cell Expansion KSep
- 36. 36 Theme 3 Build robustness into supply chains • Increased product stability • Increased raw material stability Catapult is a Technology Strategy Board programme
- 37. Product stability • <24 hours shelf life • Severe limitation on market penetration and COGs • Longer shelf-life at +2 to 8°C • More ruggedness to manage deviations • Cryopreservation as appropriate 37
- 38. 38 4 – 6th March 2014
- 39. Researchers Industry Cell Therapy Catapult NHS Catapult is a Technology Strategy Board programme Investment