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

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Information about Industrialization of a stem cell process - How to identify the right...
Health & Medicine

Published on February 6, 2014

Author: FabienMONCAUBEIG

Source: slideshare.net

Description

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

Workshop: Industrialization of a stem cell process – How to identify the right strategy? October 21, 2013 – Bethesda, MD IBC - Cell Therapy Bioprocessing Fabien Moncaubeig Sr Application Specialist & Cell Culture Lab Associate 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 semiconductor 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 Copyright 2012 ATMI, Inc. All Rights Reserved.

Our know how Application & Development Center 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 PD for New Bioreactor development Brussels PD Services / Support implementation of our technologies Tech transfer to your facility or to your CMO Minneapolis Surface 500m² 100m² Classification Class 10,000 (ISO class 7) Non-classified Biosafety level BL-2 BL-2 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 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 Allogeneic Low # passages possible (Adult SC, chondrocytes, ...) Patient to Patient variability Multiple parallel batches Logisitc Donor reproducibility Passage limitations High # passages possible (hES, iPS,...) Targeted lot scale Downstream and formulation Copyright 2012 ATMI, Inc. All Rights Reserved.

Biological challenges to consider during process development and scale-up 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 www.solohill.com Changing production platform may require clinical trial bridging www.solohill.com 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 ofReserved. Copyright 2012 ATMI, Inc. All Rights polystyrene culture surfaces. - Zeiger AS, Hinton B, Van Vliet KJ.

Technical challenges to consider during process development and scale-up Taking everything into consideration 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 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 Copyright 2012 ATMI, Inc. All Rights Reserved.

What are the technological options for cell production 3D environment Or Or any other suitable SUB 21,000cm² Scale/unit Planar technologies 18,000cm² 25,000cm² 122,400cm² Copyright 2012 ATMI, Inc. All Rights Reserved.

Technology choice is driven by batch size and # patients Cells per lot Or Or any other suitable SUB Future technologies Allogeneics 10’s 50’s 100’s 500’s 5000’s >10000’s Patients per year Autologous Copyright 2012 ATMI, Inc. All Rights Reserved.

Technical and financial considerations regarding Downstream process scale-up 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 + - - +++ 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 * Jacob Pattasseril, Hemanthram Varadaraju, LyeTheng Lock, and Jon A. Rowley, “Downstream Technology Landscape for Large-Scale Therapeutic Cell Processing”,BPI, March 2013, Copyright 2012 ATMI, Inc. All Rights Reserved.

Now, lets compare the pros and cons of 3 different scale-up approaches using, Multilayers, Xpansion, Microcarriers Copyright 2012 ATMI, Inc. All Rights Reserved.

Technical considerations for a scale-up in multilayer systems Limited process development: Multitray systems with headspace Compact multitray  Almost no process dvt required  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 Copyright 2012 ATMI, Inc. All Rights Reserved.

Manufacturing and Business considerations for a large scale multitray process 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 50 45 40 FTE Hours required / day Process B - Hyperstack 36 Process B – Xpansion 200 35 30 25 20 15 10 5 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 0 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 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) CoGs Lower cost /batch than multitray systems Lower FTE requirements Higher Consumable cost/cm² Batch Cost distribution Xpansion Hyperstack Copyright 2012 ATMI, Inc. All Rights Reserved.

Manufacturing and Business considerations for a large scale Xpansion process Xpansion enables to decrease investment and delays requirement for new facility 2015 2014 Xpansion 200 Hyperstack 36 Clinical trial phase 3 (300 patients) 2016 FDA approval 2017 2018 2019 Commerci alization (>50,000) Early commercialization (1,000 – 25,000 patients) CMO or current facility NEW Facility building Facility running full capacity Facility running under capacity $ 3,732,885 CMO or current facility NEW Facility building under capacity Facility running full capacity $ 3,463,142 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 www.solohill.com 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 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-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 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 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 depending on therapy and company status R&D effort capacity Targeted batch size Short & long term Patient number forecast Cell production platform Process constraints Clinical phase status Copyright 2012 ATMI, Inc. All Rights Reserved.

Conclusion Pros & cons summary table for large scale allogeneic therapies Cell quality Controlled Contaminat Process Process change risk ion risk environment Max scale Required dvt (initial dvt (pH, DO, cell (#operatio expertise achievable Footprint duration process in n/cm²) observation) required TF) COGS /cm² Initial Investment required for commercial scale Multitray system (10 or 40) Compact multitray (36) Xpansion Microcarrier + SUB Hollow fiber 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 therapy : scaling-up allogeneic stem cell manufacturing from multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig Copyright 2012 ATMI, Inc. All Rights Reserved.

Case study Promethera process comparaison Phase I/II Process Aseptic process EMERGENCE P0/P1 P3/P4: 4 CS-10 P4/P5: 2 x 5 CS10 P5R: 2 x 15 CS10 Centrifugation/Filling Freezing FORMULATION 3,4x109cells May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from 27 multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig Copyright 2012 ATMI, Inc. All Rights Reserved.

Case study Promethera process comparaison Phase I/II Process Phase II/III Process EMERGENCE P0/P1 P0/P1 P3/P4: 4 CS-10 P3/P4: 1 CS10 P4/P5: 2 x 5 CS10 P4/P5: 1 XP100 P5R: 2 x 15 CS10 P5R: 5 XP200 Centrifugation/Filling Centrifugation/Filling Freezing Freezing Aseptic process EMERGENCE FORMULATION 3,4x109cells Closed process 22,1x109cells RECONSTITUTION May 2013 – Bio 2013 - ”Enabling cell therapy : scaling-up allogeneic stem cell manufacturing from 28 multi-tray stacks to Xpansion™ multiplate bioreactor” – Eric Halioua –Fabien Moncaubeig 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 Copyright 2012 ATMI, Inc. All Rights Reserved.

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