Cell Therapy Catapult
Manufacturing Solutions for cell-based ATMPs

Quality and Manufacturing Solutions for Advanced Thera...
2

•  Process Development team and capabilities
•  Process Development equipment
•  How to develop a manufacturing strateg...
CTC Capabilities: Process Development

3

Process Development
Resourcing

•  10 FTE expanding to 15 FTE by April 2014

Cap...
Process Development Capability
Primary Recovery

Akta TFF
SciLog TFF

15 FTE

Rocking platform

Cubian XC

1.7M budget
201...
Starting material and IPC Analysis

Cubian XC

Peregrine

5

xCelligence MP
Cell separation, concentration, wash and
formulation
Sepax II

Smart Max

6
Cell expansion

7

Rocking Motion
Platform

Disposable
Stirred Platform

Quantum® Hollow Fibre
Primary Recovery

8

SciLog
TFF

GE Akta
Crossflow

KSep
Filling Lines

L1
Automated
Filling Line

9

M1 Manual
Filling Line
Developing a Manufacturing Strategy
What does the product need to do?

Generate Target Product Profile
(TPP)

(Start with ...
Think about what data needs to be generated
Input-Output (IPO) Diagram

Inputs

Fixed Factors - constants

PROCESS
(Cell H...
Use TPP requirements to design experiments:
Experimental Planning

Experimental
Objective

Screening

Optimisation

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

Time in culture
Vessel Type
Detachment Agent
Hold Time...
Key Process Parameters
determined by Risk Assessment

14

Ishikawa e.g. cell harvest step
Machine

Measurement
Environment...
Interactive map of critical parameters and their
limits following experimentation
• Operating Space

C = critical

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

16
Researchers

Industry

Cell Therapy
Catapult
NHS

Investment

 
Cell Therapy Catapult
NIHR Biomedical Research Centre, 16t...
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Cell Therapy Catapult Manufacturing Solutions for cell-based ATMPs. A presentation by Head of Process Development, Sarah Callens Nov 2013

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

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

  1. 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. 2 •  Process Development team and capabilities •  Process Development equipment •  How to develop a manufacturing strategy
  3. 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. 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. 5. Starting material and IPC Analysis Cubian XC Peregrine 5 xCelligence MP
  6. 6. Cell separation, concentration, wash and formulation Sepax II Smart Max 6
  7. 7. Cell expansion 7 Rocking Motion Platform Disposable Stirred Platform Quantum® Hollow Fibre
  8. 8. Primary Recovery 8 SciLog TFF GE Akta Crossflow KSep
  9. 9. Filling Lines L1 Automated Filling Line 9 M1 Manual Filling Line
  10. 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. 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. 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. 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. 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. 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. 16. Select manufacturing strategy that will meet requirements of TPP and output of CPP 16
  17. 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

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