Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing...

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

3

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

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


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?

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

13

Payers have a common aim: to achieve the greatest health care value for the money they spend

14

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

15

Value-based pricing relies on the quantification of the added-value that a new technology delivers over SOC


16

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

19


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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?

13

22

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

24

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

26

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

30

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


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Theme 3 Build robustness into supply chains •  Closed systems for manufacturing •  Automation

Integrated Supply Chain Model Transduced T Cell

32

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


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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


Industry

Cell Therapy Catapult

Investment

Researchers

NHS

Autologous and Allogeneic Cell Therapy Industrialisation – Overcoming Clinical Manufacturing...

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