Cell Therapy Catapult Manufacturing Solutions for cell-based ATMPs. A presentation by Head of Process Development, Sarah Callens. Nov 2013

1. 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/
Catapult is a Technology Strategy Board programme

2. 2
• Process Development team and capabilities
• Process Development equipment
• How to develop a manufacturing strategy

3. CTC Capabilities: Process Development
3
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.

4. Process Development Capability
Primary Recovery
Akta TFF
SciLog TFF
15 FTE
Rocking platform
Cubian XC
1.7M budget
2013
Vi-CELL
Stirred platform
Automated
Quantum®
Fill Finish
Manual
Peregrine
In Process Control
Cell Expansion
KSep

5. Starting material and IPC Analysis
Cubian XC
Peregrine
5
xCelligence MP

6. Cell separation, concentration, wash and
formulation
Sepax II
Smart Max
6

7. Cell expansion
7
Rocking Motion
Platform
Disposable
Stirred Platform
Quantum® Hollow Fibre

8. Primary Recovery
8
SciLog
TFF
GE Akta
Crossflow
KSep

9. Filling Lines
L1
Automated
Filling Line
9
M1 Manual
Filling Line

10. Developing a Manufacturing Strategy
What does the product need to do?
Generate Target Product Profile
(TPP)
(Start with clinical need)
• Composition and dose
• Cell types, forumulation etc
• Function (may include handling
properties or physical
characteristics
• Immunomodulatory, targeting,
angiogenic, porosity, tensile
strength, surgical
implementation
• How much, how often, at what
cost
• Expiry and cold chain, facility
constraints
• Business Aspects
• Logistics
10

11. Think about what data needs to be generated
Input-Output (IPO) Diagram
Inputs
Fixed Factors - constants
PROCESS
(Cell Harvest Step )
Environmental – outside of control
Outputs

12. Use TPP requirements to design experiments:
Experimental Planning
Experimental
Objective
Screening
Optimisation
Many factors
Few levels
Fewer factors
More levels
Objective
Assessment
Scale-up/
TechTransfer
Data
Fit for purpose?
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

13. DoE Process: From Screening to Optimisation
e.g. cell harvest step
Time in culture
Vessel Type
Detachment Agent
Hold Time
Buffer Wash
Surface Type
Screening
Hold Time
Centrifugation
Parameters
Optimisation
Wash Method
Feed frequency
Wash Method
Centrifugation
Parameters
Choose
factor
ranges
Determination
of relevant
factors
Adjust factor
ranges
accordingly
Determination
of optimal
settings

14. Key Process Parameters
determined by Risk Assessment
14
Ishikawa e.g. cell harvest step
Machine
Measurement
Environment
CO2
Flow rate
C
C % CO2
Temp of
cells N
Time
X
Laminar
flow
C
C
Ambient
temp N
Media warming
(time@temp) C
Detachment
Final vol wash
of cells C
buffer
X Hold time
N Room temp
C DPBS
Vessel type
X (diffusion)
Confluence
Setting
Surface type
X
Detachment
Agent conc.
Vol of detach.
agent X
X
5% CO2 C
X
Media C
Change
method
Sampling
Material
Location
Amount
C
C
Methods
Microscope C
Setting
Daily Temp
Monitoring C
Calibration of
pipettes C
Inc door
open time
Temp of
inc. C
% CO2
PROBLEM
STATEMENT
N
Cell Yield at
70%
Confluency
Final cell wash
method (# of X
washes)
Feed X
frequency
Handling
Validation of
confluency C
Detachment
time X
Rinse of surface
after detachment X
Recovery N
process
Sample
mixing C
People
C
Different
C
operators
Time C
served
C = Constant
N = Noise
X = Experimental

15. Interactive map of critical parameters and their
limits following experimentation
• Operating Space
C = critical
• Acceptable space/Design space
NC = non-critical
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
5E3/CM2
CONTROL: 3-4 days
ACCEPTABLE: 6 Days
C
3 DAYS
NC
0.06ml/cm2
NC
CONTROL-NEAT
ACCEPTABLE- 1:2
NC
18-37 C
C
CONTROL- min 40min
ACCEPTABLE – max 120min
NC
0.06ml/cm2
C
2%
NC
Up to 180min

16. Select manufacturing strategy that will meet
requirements of TPP and output of CPP
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17. Researchers
Industry
Cell Therapy
Catapult
NHS
Investment
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
Catapult is a Technology Strategy Board programme