Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved.
Fabien Moncaubeig
Sr Applicat...
Copyright 2012 ATMI, Inc. All Rights Reserved.
ATMI Lifesciences where we come from
ATMI LIFESCIENCES
Is part of ATMI Inc,...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Our know how
ATMI approach combines both Product
development , Process deve...
Copyright 2012 ATMI, Inc. All Rights Reserved.
What we want to offer to the cell therapy
industry
Complete solution for ce...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Different scale-up and manufacturing challenges for
each segment
Autologous...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Your process = Your product
Has never been so true !
Parameters impacting p...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Mimic final scale conditions from the early
development steps
Evaluate impa...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Business challenges to consider for
process development and scale-up
Suppor...
Copyright 2012 ATMI, Inc. All Rights Reserved.
21,000cm²
What are the technological options for
cell production
Scale/unit...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technology choice is driven by batch size and # patients
50’s10’s 100’s 500...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technical and financial considerations
regarding Downstream process scale-u...
Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved.
Now, lets compare the pros an...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technical considerations for a scale-up in
multilayer systems
Limited proce...
Copyright 2012 ATMI, Inc. All Rights Reserved.
High footprint requirement
Requires high, early, investment in factory / CM...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technical considerations for a scale-up in
Xpansion
Linear scalability from...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Manufacturing and Business considerations for a large
scale Xpansion proces...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Manufacturing and Business considerations for a large
scale Xpansion proces...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technical considerations for a scale-up
with microcarriers 1/2
Very high sc...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Technical considerations for a scale-up
with microcarriers 2/2
Copyright 2012 ATMI, Inc. All Rights Reserved.
Manufacturing and Business considerations for a large
scale microcarrier-ba...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Summary of technology scale capacity and
associated R&D efforts
Ana S. Sima...
Copyright 2012 ATMI, Inc. All Rights Reserved.
A dual approach to cover short and long
term needs
Copyright 2012 ATMI, Inc. All Rights Reserved.
Conclusion
No Universal answer
Multiple factors with specific weight depend...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Conclusion
Controlled
environment
(pH, DO, cell
observation)
Contaminat
ion...
Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved.
Thank you
Copyright 2012 ATMI, Inc. All Rights Reserved.
Case study Promethera introduction
May 2013 – Bio 2013 - ”Enabling cell the...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Case study Promethera process
comparaison
May 2013 – Bio 2013 - ”Enabling c...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Case study Promethera process
comparaison
May 2013 – Bio 2013 - ”Enabling c...
Copyright 2012 ATMI, Inc. All Rights Reserved.
Case study Promethera – cost
comparaison
May 2013 – Bio 2013 - ”Enabling ce...
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Industrialization of a stem cell process - How to identify the right Strategy - IBC Oct 2013

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This presentation reviewed the current strategies and their associated benefits and challenges to scale up the production of adherent stem cells.

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Industrialization of a stem cell process - How to identify the right Strategy - IBC Oct 2013

  1. 1. Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved. Fabien Moncaubeig Sr Application Specialist & Cell Culture Lab Associate Workshop: Industrialization of a stem cell process – How to identify the right strategy? October 21, 2013 – Bethesda, MD IBC - Cell Therapy Bioprocessing
  2. 2. Copyright 2012 ATMI, Inc. All Rights Reserved. ATMI Lifesciences where we come from ATMI LIFESCIENCES Is part of ATMI Inc, a global company market leader in efficient process solutions for the semi- conductor and lifesciences industry ATMI support leading company in the GMP manufacturing of vaccines, Mabs and protein production since 10 years ATMI is expert in clean manufacturing and supply of integrated technologies for cell culture ATMI leverage is core competency in cell culture to develop innovative technologies and efficient processes
  3. 3. Copyright 2012 ATMI, Inc. All Rights Reserved. Our know how ATMI approach combines both Product development , Process development & optimization ATMI has two Applications & Development centers: Fully equipped cell culture clean rooms. 45 experienced team including Engineers & Bioengineers Tech transfer to your facility or to your CMO PD Services / Support implementation of our technologies PD for New Bioreactor development Application & Development Center Brussels Minneapolis Surface 500m² 100m² Classification Class 10,000 (ISO class 7) Non-classified Biosafety level BL-2 BL-2
  4. 4. Copyright 2012 ATMI, Inc. All Rights Reserved. What we want to offer to the cell therapy industry Complete solution for cell based product manufacturing Offer a full solution for cell growth and harvest, based on the best technologies availables Leverage our expertise in cell culture and cell therapy process development to streamline industrialization of cell therapy products Optimize and enable high volume manufacturing of cell based therapy Develop the future solutions
  5. 5. Copyright 2012 ATMI, Inc. All Rights Reserved. Different scale-up and manufacturing challenges for each segment Autologous Low dose. cells per patient < 108 High dose. cells per patient > 108 Low # passages possible (Adult SC, chondrocytes, ...) High # passages possible (hES, iPS,...) Allogeneic Patient to Patient variability Multiple parallel batches Logisitc Donor reproducibility Passage limitations Targeted lot scale Downstream and formulation
  6. 6. Copyright 2012 ATMI, Inc. All Rights Reserved. Your process = Your product Has never been so true ! Parameters impacting product (cell) quality: Shear stress 1 2D VS 3D growth 2 Growth Surface Material 3 Changing production platform may require clinical trial bridging 1: Biotechnol Bioeng. 2007 Feb 15;96(3):584-95. - Effects of shear stress on 3-D human mesenchymal stem cell construct development in a perfusion bioreactor system: Experiments and hydrodynamic modeling. - Zhao F, Chella R, Ma T. 2: Tissue Eng Part A. 2009 Jul;15(7):1763-73. doi: 10.1089/ten.tea.2008.0306. - Phenotype and gene expression of human mesenchymal stem cells in alginate scaffolds. - Duggal S, Frønsdal KB, Szöke K, Shahdadfar A, Melvik JE, Brinchmann JE. 3: Acta Biomater. 2013 Feb 26. pii: S1742-7061(13)00105-0. doi: 10.1016/j.actbio.2013.02.035. - Why the dish makes a difference: Quantitative comparison of polystyrene culture surfaces. - Zeiger AS, Hinton B, Van Vliet KJ. Biological challenges to consider during process development and scale-up www.solohill.com www.solohill.com
  7. 7. Copyright 2012 ATMI, Inc. All Rights Reserved. Mimic final scale conditions from the early development steps Evaluate impact of any process change Increasing cell culture scale implies streamlining and optimizing all related operations : Media preparation Fluid handling Harvest Concentration Rinsing Freezing Filling Increase scale implies indroducing and validating new technologies Technical challenges to consider during process development and scale-up Taking everything into consideration
  8. 8. Copyright 2012 ATMI, Inc. All Rights Reserved. Business challenges to consider for process development and scale-up Supporting product lifecycle Accelerate time to market, reduce development time and ressources Mitigating risk for market approval, minimize changement Supporting commercilization ramp up, offer flexible production Offer an affordable product, implement a cost effective manufacturing
  9. 9. Copyright 2012 ATMI, Inc. All Rights Reserved. 21,000cm² What are the technological options for cell production Scale/unit Or Or any other suitable SUB 3D environment Planar technologies 122,400cm²18,000cm² 25,000cm²
  10. 10. Copyright 2012 ATMI, Inc. All Rights Reserved. Technology choice is driven by batch size and # patients 50’s10’s 100’s 500’s 5000’s >10000’s Cells per lot Patients per year Allogeneics Or Or any other suitable SUB Future technologies Autologous
  11. 11. Copyright 2012 ATMI, Inc. All Rights Reserved. Technical and financial considerations regarding Downstream process scale-up Choice will be led by Harvest volumes to process Time constraint Concentration factor and final targeted volume For large volumes, combination of these technologies may be required 100L  Unifuge 1700LATMI or Centrifuge bags  <135ml Fluidized bed (i.e:Ksep) Large scale centrifuge (i.e:Unifuge) Small scale centrifuge (i.e:ATMI) Tangential Flow Filtration Flow rate (ml/min) 400 – 9600 3000 500 20 - 12,500 Hold-up volume (ml) 100 - 1600 1700 135 100’s-1000’s Disposable cost ($) 2000-2500*(Ksep 400) 3000 950 1500-3500$* Process dvt effort + - - +++ * Jacob Pattasseril, Hemanthram Varadaraju, LyeTheng Lock, and Jon A. Rowley, “Downstream Technology Landscape for Large-Scale Therapeutic Cell Processing”,BPI, March 2013,
  12. 12. Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved. Now, lets compare the pros and cons of 3 different scale-up approaches using, Multilayers, Xpansion, Microcarriers
  13. 13. Copyright 2012 ATMI, Inc. All Rights Reserved. Technical considerations for a scale-up in multilayer systems Limited process development: Multitray systems with headspace  Almost no process dvt required Compact multitray  Additional optimization of fluid transfer and harvest protocol required Scale-up strategy = Scale-out: Max scale/unit = 25,440 cm² (Cell Factory 40) Increase number of units Linear increase of footprint (incubators) Implementation of automated manipulator system can reduce FTE need Cell observation can be challenging in the largest scale units (>36 trays) Cm²/volumetric footprint
  14. 14. Copyright 2012 ATMI, Inc. All Rights Reserved. High footprint requirement Requires high, early, investment in factory / CMO High FTE cost per batch Uneven FTE needs High number of operations = high failure rate Manufacturing and Business considerations for a large scale multitray process 0 5 10 15 20 25 30 35 40 45 50 1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 191 201 211 221 231 241 251 261 271 281 291 301 311 321 331 FTE Hours required / day Process B - Hyperstack 36 Process B – Xpansion 200
  15. 15. Copyright 2012 ATMI, Inc. All Rights Reserved. Technical considerations for a scale-up in Xpansion Linear scalability from 10 (6,120cm²) to 200 plates (122,400cm²) Scale-up by maintaining linear speed constant Controlled environment: pH, DO, Temperature monitoring & control Cell observation Process development required to : Optimize process parameters Harvest protocol
  16. 16. Copyright 2012 ATMI, Inc. All Rights Reserved. Manufacturing and Business considerations for a large scale Xpansion process Minimize footprint compared to multilayer 4 Xpansion 200 fits in 1 incubator (42.5 x 34.5 x 87 inches) Lower cost /batch than multitray systems Lower FTE requirements Higher Consumable cost/cm² Batch Cost distribution Hyperstack CoGs Xpansion
  17. 17. Copyright 2012 ATMI, Inc. All Rights Reserved. Manufacturing and Business considerations for a large scale Xpansion process Clinical trial phase 3 (300 patients) FDA approval Early commercialization (1,000 – 25,000 patients) Commerci alization (>50,000) 2014 2015 2016 2017 2018 2019 NEW Facility building $ 3,732,885 Facility running under capacity Facility running full capacity CMO or current facility NEW Facility building under capacity Facility running full capacity $ 3,463,142 CMO or current facility Hyperstack36Xpansion200 Xpansion enables to decrease investment and delays requirement for new facility
  18. 18. Copyright 2012 ATMI, Inc. All Rights Reserved. Technical considerations for a scale-up with microcarriers 1/2 Very high scale lot size achievable: 6g cytodex1/L x 500L = 1,320m² Developing a microcarrier process is challenging, requiring time and high expertise level : Process development challenges: Identify scalable cell attachment and growth mixing conditions Develop scalable harvest protocol (timings) Maximize cells/ml (carrier density) Develop a seeding train with bead to bead transfer Microcarrier key selection criteria to consider: Density, cm²/g, g/L achievable, coating Impact on : mixing requirements, cells/ml Bioreactor challenge: Low shear while maintaining mixing capacity Keep aggregates in suspension/movement www.solohill.com
  19. 19. Copyright 2012 ATMI, Inc. All Rights Reserved. Technical considerations for a scale-up with microcarriers 2/2
  20. 20. Copyright 2012 ATMI, Inc. All Rights Reserved. Manufacturing and Business considerations for a large scale microcarrier-based process Process development substantially longer and risky Could delay phase III or early commercialization Low footprint compared to any planar system Limited Facility size requirement Easy future capacity increase Dramatically lower CoGs
  21. 21. Copyright 2012 ATMI, Inc. All Rights Reserved. Summary of technology scale capacity and associated R&D efforts Ana S. Simaria, Sally Hassan, Hemanthram Varadaraju, Jon Rowley, Kim Warren, Philip Vanek, Suzanne S. Farid, Allogeneic cell therapy bioprocess economics and optimization: Single-use cell expansion technologies, Biotechnologie & Bioengineering, released online on August 16th, 2013
  22. 22. Copyright 2012 ATMI, Inc. All Rights Reserved. A dual approach to cover short and long term needs
  23. 23. Copyright 2012 ATMI, Inc. All Rights Reserved. Conclusion No Universal answer Multiple factors with specific weight depending on therapy and company status R&D effort capacity Targeted batch size Short & long term Patient number forecast Clinical phase status Process constraints Cell production platform
  24. 24. Copyright 2012 ATMI, Inc. All Rights Reserved. Conclusion Controlled environment (pH, DO, cell observation) Contaminat ion risk (#operatio n/cm²) Process dvt expertise required Process dvt duration Cell quality change risk (initial process in TF) Max scale achievable Required Footprint COGS /cm² Initial Investment required for commercial scale Multitray system (10 or 40) Compact multitray (36) Xpansion Microcarrier + SUB Hollow fiber Pros & cons summary table for large scale allogeneic therapies
  25. 25. Copyright 2012 ATMI, Inc. All Rights Reserved.Copyright 2012 ATMI, Inc. All Rights Reserved. Thank you
  26. 26. Copyright 2012 ATMI, Inc. All Rights Reserved. Case study Promethera introduction May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig
  27. 27. Copyright 2012 ATMI, Inc. All Rights Reserved. Case study Promethera process comparaison May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig 27 EMERGENCE P0/P1 P3/P4: 4 CS-10 Phase I/II Process Aseptic process P4/P5: 2 x 5 CS10 P5R: 2 x 15 CS10 Centrifugation/Filling Freezing FORMULATION 3,4x109cells
  28. 28. Copyright 2012 ATMI, Inc. All Rights Reserved. Case study Promethera process comparaison May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig 28 EMERGENCE P0/P1 P3/P4: 4 CS-10 P0/P1 P3/P4: 1 CS10 Phase I/II Process Phase II/III Process P4/P5: 1 XP100 Aseptic process P4/P5: 2 x 5 CS10 P5R: 2 x 15 CS10 Centrifugation/Filling Freezing FORMULATION Centrifugation/Filling Freezing RECONSTITUTION 3,4x109cells Closed process 22,1x109cells P5R: 5 XP200 EMERGENCE
  29. 29. Copyright 2012 ATMI, Inc. All Rights Reserved. Case study Promethera – cost comparaison May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig

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