Catapult is a Technology Strategy Board programme

Cell Therapy Catapult Manufacturing Solutions for cell-based ATMPs

Quality and Manufacturing Solutions for Advanced Therapies Workshop Sarah Callens Head of Process Development November 2013 Sarah.callens@ct.catapult.org.uk http://ct.catapult.org.uk/ 

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•  Process Development team and capabilities

•  Process Development equipment

•  How to develop a manufacturing strategy

CTC Capabilities: Process Development

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Process Development

Resourcing •  10 FTE expanding to 15 FTE by April 2014

Capabilities •  QbD, experimental design, TPP, risk analysis, device design control, bioreactor design, automation and software design, CoG reduction

•  iPS culture, directed differentiation, decellularisation, encapsulation, large-scale cell culture, cell banking, 3D scaffold production, suspension culture, GMP production experience

•  Process development for autologous immune therapies, closed processing, large scale adherent and suspension cultures, novel process development for 2D and 3D therapies.

Stirred platform

Process Development Capability

15 FTE

1.7M budget 2013

Fill Finish

Primary Recovery C

ell E

xpan

sion

In P

rocess Control

Cubian XC

Peregrine Automated Manual

Quantum®

Rocking platform

Vi-CELL

KSep SciLog TFF

Akta TFF

Starting material and IPC Analysis 5

Cubian XC Peregrine xCelligence MP

Cell separation, concentration, wash and formulation

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Sepax II

Smart Max

Cell expansion 7

Rocking Motion Platform

Disposable Stirred Platform

Quantum® Hollow Fibre

Primary Recovery 8

SciLog TFF

GE Akta Crossflow

KSep

Filling Lines 9

L1 Automated Filling Line

M1 Manual Filling Line

Developing a Manufacturing Strategy

What does the product need to do? (Start with clinical need) •  Composition and dose

•  Function (may include handling properties or physical characteristics

•  Business Aspects

•  Logistics

Generate Target Product Profile (TPP) •  Cell types, forumulation etc

•  Immunomodulatory, targeting, angiogenic, porosity, tensile strength, surgical implementation

•  How much, how often, at what cost

•  Expiry and cold chain, facility constraints

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Think about what data needs to be generated

PROCESS (Cell Harvest Step )

Inputs Outputs

Fixed Factors - constants

Environmental – outside of control

Input-Output (IPO) Diagram

Bioprocess Development entails a progressive approach to Goal Attainment Unit Operations within a Bioprocess do not reside as stand alone operations within a Bioprocess Train The cell product and the process by which its produced cannot be separated – the product is the process Experimental Planning requires a degree of rational progression to successfully address the goal: producing a robust, efficacious and economically viable product

Use TPP requirements to design experiments: Experimental Planning

Experimental Objective

Screening Optimisation Objective Assessment

Scale-up/ TechTransfer

Many factors Few levels

Fewer factors More levels Data

Fit for purpose?

DoE Process: From Screening to Optimisation e.g. cell harvest step

Time in culture

Vessel Type

Detachment Agent

Buffer Wash

Surface Type

Hold Time

Feed frequency

Wash Method

Centrifugation Parameters

Hold Time

Centrifugation Parameters

Wash Method

Screening Optimisation

Determination of relevant

factors

Determination of optimal

settings

Adjust factor ranges

accordingly

Choose factor ranges

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PROBLEM STATEMENT Cell Yield at 70% Confluency

Environment Measurement

Machine

Material

Methods

People

Temp of inc.

% CO2

Inc door open time

Time served

Different operators

Microscope Setting

Daily Temp Monitoring

Calibration of pipettes

% CO2

Confluence Setting

Media warming (time@temp)

Temp of cells

Ambient temp

CO2

Laminar flow

Room temp

Detachment Agent conc.

DPBS Final vol wash buffer

Surface type

Vol of detach. agent

5% CO2

Hold time

Media Change method

Sampling

Amount

Location

Final cell wash method (# of washes)

Detachment time

Feed frequency

Handling

Validation of confluency

Detachment of cells

Recovery process

Sample mixing

C

C

C

C C

C

C

C C

C

C C

C C

C C

C

C

N

N

N

N N

X

X

X

X

X

X X

X

C = Constant N = Noise X = Experimental

C Flow rate Time

C

X

Vessel type (diffusion) X

Rinse of surface after detachment X

Key Process Parameters determined by Risk Assessment

Ishikawa e.g. cell harvest step

Interactive map of critical parameters and their limits following experimentation

Minimum Seeding Density Max Incubation time Feeding frequency Volume of Detachment Agent Dilution of Detachment Agent Temperature of Detachment Time of Detachment Recovery Volume Protein in Recovery Buffer Post-Detachment Holding Time

C

C

C

NC

NC

NC

C

NC

C

NC

5E3/CM2

CONTROL: 3-4 days ACCEPTABLE: 6 Days

3 DAYS

0.06ml/cm2

CONTROL-NEAT ACCEPTABLE- 1:2

18-37 C

CONTROL- min 40min ACCEPTABLE – max 120min

0.06ml/cm2

2%

Up to 180min

• Operating Space

• Acceptable space/Design space C = critical

NC = non-critical

Select manufacturing strategy that will meet requirements of TPP and output of CPP

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Catapult is a Technology Strategy Board programme

Industry

Cell Therapy Catapult

Investment

Researchers

NHS

  Cell Therapy Catapult NIHR Biomedical Research Centre, 16th Floor Tower Wing, Guy's Hospital Great Maze Pond, London, SE1 9RT DDI: +44 (0) 207 1883428  Mob: +44(0)7891 295131 chris.herbert@ct.catapult.org.uk