Catapult is a Technology Strategy Board programme
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
The translational funding gap 2
Catapult
• Little evidence yet that new cell therapies can be developed, licensed and adopted successfully
• Limited investment from commercial sector
• Limited precedents for valuable exits via IPO or acquisition
• Most large corporates are observing and waiting
• Operational SME’s lack finance and breadth of resources for rapid advance
Mood is changing…….
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
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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
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Number of Staff at Cell Therapy Catapult
0
10
20
30
40
50
60
70
80
No of Staff Projected Staff
Addressing Key Sector Barriers
6
• Health Economics • Business plans • Manufacture & Supply vs Service • Reimbursement • Investment Risk
Business
• Robustness & Reliability • COGS & Scale up • Characterisation & Analytical • Comparability • GMP • CMC • Delivery
Manufacturing and
Supply Chain
• Complex Regulatory Landscape • Pre Clinical Packages • Clinical trial design • NHS partnering
Clinical And
Regulatory
Clinical Operations & Regulatory Affairs
Process Development
Business Development
Successful Path to Commercialisation 7
• Efficacy and safety hypothesis and evidence • Definition and characterisation of cellular product
• 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
Science
Clinical
Manufacturing
Business
Reg
ulat
ory
agen
cy d
ialo
gue
on
plan
s at
eac
h st
age
Transition from Discovery Science to Manufacturing Science
8
Pre-Clinical FIM Phase II-III
Manufacturing Science
Discovery Science
Cell Therapy Catapult Strategy for industrialisation of cell therapy processes
9
CONTRACT MANUFACTURING
GROW UK SECTOR
INNOVATION
SME
NHS
ACADEMIA
CT CATAPULT
NON-CLINICAL
PROCESS DEVELOPMENT
ASSAY
DEVELOPMENT
MANUFACTURING
GMP PROVING LAB
Lab - Pilot - Scale
Commercial Scale
10
Catapult GMP Proving Lab
Catapult Multi Functional Pod
Core Themes to ensure Sector success 10
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
Catapult is a Technology Strategy Board programme
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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?
For healthcare products, price, reimbursement and demand are interlinked determinants of profit
All these have to be effectively addressed to reach commercial goals…
PROFIT
PRICE
DEMAND REIMBURSEMENT
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Payers have a common aim: to achieve the greatest health care value for the money they spend
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Does it add value
over SOC?
Comparative clinical
effectiveness
Is it worth it?
Cost-effectiveness Price comparison
Should we control its use?
Restrictions
Can we afford it?
Budget impact
Is the product needed?
Unmet need
Do we need to fund it?
Political imperative
The emphasis on these elements differs across markets, most notably the use of
cost-effectiveness in decision-making
Payers are key market access decision-makers (with input from clinical and economic advisors)
Cost-based Competitor-based Value-based
What is it?
• Price is set by assumptions on costs, expected sales volumes and margins
• Price is driven by the pricing of competitor 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
Comments • Becoming obsolete;
no longer resonates with payers
• Enforced by many reimbursement systems for “undifferentiated” products
• Typical approach for differentiated products
Pricing approaches in healthcare are shifting towards value-based models
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Value-based pricing relies on the quantification of the added-value that a new technology delivers over SOC
Catapult is a Technology Strategy Board programme
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Theme 2 • Theme 2: Collaboration across industry
sectors • Common challenges already solved: • Biopharmaceutical • Common challenges already solved: • Vaccine
Significant Opportunity to Leverage knowledge from related sectors
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Synergies
Spill-over Benefits
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Established Biologics Knowledge
New Cell Therapy Knowledge
Creating Innovative Manufacturing Critical Mass
Leverage Existing Capabilities and Capacity
Re-innovate Prevent Wheel- re-invention
UK PLC
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
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Catapult is a Technology Strategy Board programme
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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
Is the Traditional Supply Chain Model Applicable?
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Allogeneic Adherent Cell Process
Expa
nd prim
ary c
ells
Isolate ce
lls from
biopsy
Bank ce
lls (if req
uired)
Revive ce
lls (if req
uired)
Expa
nd ce
llsHa
rvest, form
ulate and fill for storage/shipment
Isolate ta
rget ce
lls
Open process
Tissue biopsy Biopsy dissection
Isolate target primary cells
Enzymes
Enzymatic digestion
Primary cells Culture in T flasks Growth media
Expandedprimary cells
OR
Cell freeze bags Cryovials Bank cells
Retrieve frozen cell bag Thaw bag/vial Cells Culture in T flasks
Expandedprimary cells
Growth media
Growth media Culture in cell factoryCells Expanded Cells
Expanded Cells
Cell freeze bags Final product Bank
Isolate cells
Isolated cells Cell strainer
Enzymes
Enzymatic digestion Bank cells if required
Formulate and fill Final product Shipment
LN2
LN2
LN2
Media
Media
LN2 Media
We make complex
products !
Allogenic Cell Process
End to End Supply Chain Unites Sector 15
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AUTOLOGOUS
ALLO
GEN
EIC
HESCs
iPSCs
HSCs
CD4/8+ Tcells
M/Stroma SCs
Cell Based Medicinal Products cover a wide product area
Cancer Vaccine
TEPs
Cell-Device Combination
Gene modified cells
Cell core element Reproducible and Robust process and analytics • Identity • Purity • Potency • Efficacy
Control process variation 25
STABILITECH TECHNOLOGY Cell
expansion
Process Raw material
Analytical and Potency
In- Process Control
Cell differentiation
QbD Tools
Donated material 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?
Critical areas
Raw material variation
• Patient starting material • Process materials
• Inter- vendor • Inter-batch
• Huge impact on reproducibility • Vendor engagement
• More technology support and partnerships
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Base Lot 1
Base Lot 2
Complete Lot 1
Complete Lot 2
Amino Acid Analysis by Capillary Zone Electrophoresis
Quality by Design Toolkit – Essential for complex medicines
Link Critical Process Parameters to Critical Quality Attributes
Experimental Design Philosophy 28
Hold
Temp
Time
One Factor At a Time (OFAT): • Poor coverage of experimental space • May miss optimal solution
Design of Experiments: • Good coverage of experimental
space • High efficiency designs
Time
Hold
Temp LO
HI
LO HI LO
HI
LO
HI HI
HI
Manufacturing impact upon live cell products
Loss of intact cells % Loss of intact cells % Hold time = 5 mins Hold time = 120 mins
• Intact cell losses increase with an increase in both RCF and Spin time
• A pre-process hold stage increases cell loss
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Fluidigm Digital PCR
Roche Lightcyler
ABI QuantStudio
EpMotion robotics
QiaCube
Fortessa X20
MacsQuant
Tecan M1000
In-Cell 2200
A1R confocal
CTC Capabilities: Analytical Development Product characterisation to routine QC Have to know what cQA to measure
10 FTE £1.25M Budget
Catapult is a Technology Strategy Board programme
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Theme 3 Build robustness into supply chains • Closed systems for manufacturing • Automation
Integrated Supply Chain Model Transduced T Cell
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Cell Count Transduce (Day 4)
Activate in Culture
(Days 1-3)
Volume Reduce (Day 10)
Cell Count Cryo-
preserve (Day 10)
Storage Transport Transplant
Collection PBMC Count
Debead and Wash (Day 10)
Cell Count
Micro
Cell Expansion (Days 4-10)
Transport
Micro
Blood Count
PBMC Separation
(Day 1)
Cell Selection (Day 1)
Temperature Monitoring
Outcome Reporting
Sampling Kit
Reagents
Consumables
Test Results
Date/Time
Cytokines
Equipment
Shipper
Virus
Data Logger
Operator
Media
Patient Details
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
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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
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Stirred platform
CTC Process Development Capability Scaleable automation Enclosed not functional enclosure
15 FTE
1.7M budget
Fill Finish
Primary Recovery Ce
ll Ex
pans
ion
In Process Control
Cubian XC
Peregrine Automated Manual
Quantum®
Rocking platform
Vi-CELL
KSep SciLog TFF
Akta TFF
Catapult is a Technology Strategy Board programme
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Theme 3 Build robustness into supply chains • Increased product stability • Increased raw material stability
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
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4 – 6th March 2014
Catapult is a Technology Strategy Board programme
Industry
Cell Therapy Catapult
Investment
Researchers
NHS