Recent Advances In The Integration Of Single Use Bioprocessing Technologies For Cell Therapies

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Information about Recent Advances In The Integration Of Single Use Bioprocessing...
Technology

Published on February 6, 2014

Author: FabienMONCAUBEIG

Source: slideshare.net

Description

This presentation given at ISBiotech in March 2013 gives an introduction about single use technologies challenges in the field of Cell therapies, focusing on adherent cells and allogeneic therapies.

It then presents how the Xpansion bioreactor can help overcome the current technology gap for large cell production.

Case studies of Adult Liver Progenitor Cells and Mesenchymal Stem Cells amplified with this bioreactor are included in this presentation.

Recent Advances in the Integration of Single-Use Bioprocessing Technologies for Cell Therapies Fabien Moncaubeig Sr Application Specialist Cell Culture Lab Associate fmoncaubeig@atmi.com 3rd ISBiotech Annual Meeting March 11-15, 2013 - Rosslyn, Virginia, USA Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Who is ATMI LifeSciences? Single-Use Technology (SUT) Market Pro/Cons & new approaches Cell Therapy Definition The market Learning from our customers ATMI solution: Integrity® Xpansion™ Multiplate bioreactor Case studies & valude model Conclusions OUTLINE 2 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Who is ATMI LifeSciences? ATMI LifeSciences strives to be the source of BioPharm process efficiency by providing comprehensive disposable solutions (technologies & support services) Integrity® line of single-use technologies Sterilizable Packaging (NewformTM) Application & Development Center ATMI has two Applications & Development centers (US & Belgium) : Integrity® Liquid and Powder Vessels Fully equipped clean rooms. BL2 and BL3 GMPgrade suites, Class 10,000 (ISO7) environment Integrity® Mixing Systems 45 experienced team including Engineers & Bioengineers Integrity® Bioreactors PD for New Bioreactor development PD Services / Support implementation of our technologies Tech transfer to your facility or to your CMO Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Who is ATMI LifeSciences? ATMI LifeSciences strives to be the source of BioPharm process efficiency by providing comprehensive disposable solutions that maximize product yield and integrity. ATMI LifeSciences added-value Product designs: Innovative and effective solutions ATMI hardware & disposable components designed for full integration Quality: Integrity® TK8 “One-Film” is best of breed & reduces validation costs Class 5 vessel manufacturing facilities reduce particle load Industry’s most stringent & sensitive integrity testing reduces contamination risk Supply chain security Vertical integration of clean film extrusion Duplicate facilities & experienced global supply chain Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Single-Use Technology Market The single-use technology market is currently booming with estimated growth of 330% over the last 5 years WE KNOW THAT Growth Estimate Biotherapeutics/Upstream +107% Total SUT market +330% Upstream Single-Use Bioprocessing Systems - Ronald A. Rader, Eric S. Langer BioProcess International, Vol. 10, No. 2, February 2012, pp. 12–19 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Single-Use Value Proposition WE KNOW THAT SUT claims Decrease capital, labor & operating costs Flexibility in design and ease of integration Eliminate cleaning and sterilization Decrease build-out time and time to market Reduce risk of cross-contamination and microbial contamination Supply chain security IPTonline © 2004 The Pharmaceutical Technology Journal Beyond the bioreactor: exploiting the full potential of Single-Use Technology Paul Chapman and Mani Krishnan (Millipore) Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

What is really driving/limitating SUT adoption ? Drivers of SUT adoption $$$ Limitating factors to SUT adoption Limited Scale Limit CAPEX Equivalent or lower COGS Flexibility Same room can welcome different scales or technologies CMO = early adopter Disposable customization= Fast response to change Increased capacity Jan 15, 2013 (Vol. 33, No. 2) - Single-Use Systems Entice Multiple Users Angelo DePalma, Ph.D. Current limitations of bags/bioreactor volumes = 2000 to 3000 L Supplyer-dependence Supply chain security Double sourcing Outsourced Quality Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

SUT Pros & Cons led to hybrid/new approaches Fully single-use facilities are mostly considered at R&D & clinical scales. When increasing scales, manufacturers tend to implement hybrid solutions. SUT R&D + clinical production Small scale production (<1000L) The application of disposable single use equipment, and it’s impact on biopharma plant design – Andy Rayner – PM Group Large scale production / Dedicated facility Stainless Steel Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell therapy - Definition “Deployment of various stem cell classes for the explicit use in the restoration of a given physiological function in vivo that has been damaged by disease or injury processes”* Cell therapy Allogeneic Immunotherapy Stem cells as a tool for drug discovery Autologous * Nov 1, 2012 (Vol. 32, No. 19) - Cellular Therapy Wave Finally Cresting - Lee Buckler, J.D., Enal Razvi, Ph.D. Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell Therapy Market The cell therapy market is emerging and reached $550 Million revenue in 2012. Vaccines Revenue MAbs Cell therapy Gene therapy $550 Million in revenue in 2012* Mainly from orthopedic and skin applications Market maturity 10 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved. * Nov 1, 2012 (Vol. 32, No. 19) - Cellular Therapy Wave Finally Cresting - Lee Buckler, J.D., Enal Razvi, Ph.D.

Cell Therapy Market Cell therapies can be autologous (the donor is the patient) or allogeneic (multiple patients/donor). With many applications, this makes it a complex market with many different business models. AUTOLOGOUS ALLOGENEIC Service oriented SME business model Product oriented Big Pharma business model Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell Therapy Market Cell therapy constraints have different weights than in the Biopharma industry making the SUTs adopted from the beginning. Cell therapy constraints: Sterile process (no final filtration) Limited investment capacity (SME VS Big pharma) Autologous therapies: High risk of cross contamination Process variability due to donor variety BIOPHARMA Large Scale limitation Supplier dependence Stainless Steel CELL THERAPY Flexibility CAPEX Cross contamination risk SUT Hybrid approach (SS + SUT) Large Scale limitation Supplier dependence Stainless Steel Flexibility CAPEX Cross contamination risk SUT Full Single-Use approach Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell Therapy Market Current processes are already “single use” but scalable cell amplification tools are missing Cell Preparation, Isolation Initial sample Cell concentration and formulation Cell expansion Multiple passages of Amplification Primary cell culture Detachment Washing Cryopreservation solution Harvest Washing Media Cell harvest Media Final container for treatment Concentration device Waste Rinsing Waste Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell Therapy Market Current processes are already “single use” but scalable cell amplification tools are missing Cell Preparation, Isolation Initial sample Cell concentration and formulation Cell expansion Multiple passages of Amplification Primary cell culture Cryopreservation solution Detachment Washing Harvest Washing Media Cell harvest Media Final container for treatment Concentration device Waste Rinsing Waste No technology gap SUT available Large Scale technology gap (Single use or not) Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell Therapy Market Reason why there is a technology gap for stem cell production is related to the nature of the cells Your process = Your product Has never been so true ! Stem Cells growth conditions are more stringent than immortalized cell lines. Additional parameters impacting product (cell) quality: Shear stress 1 2D VS 3D growth 2 Growth Surface Material 3 Need for a new type of bioreactor 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: Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved. Quantitative comparison of polystyrene culture surfaces. - Zeiger AS, Hinton B, Van Vliet KJ.

Learning from our Customers Back in 2009, ATMI LifeSciences was approached to develop a bioreactor solution to enable the scale-up of their processes. ATMI customer requests “I want a compact bioreactor that enables to replace 20 CS10” in a fully closed system with a controlled process (pH, DO, Temp.) enabling cell confluence monitoring and keeping the same microenvironment for cell growth Very low shear stress Same contact material 2D surface Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI solution: Integrity® Xpansion™ Multiplate bioreactor Xpansion bioreactor design limits cell environment change while being compact, closed and controlled Drivers of SUT adoption Closed system Compact stack of polystyrene plates 1 Xpansion plate (612cm²): Hydrophilized Polystyrene material pH and DO control through gas exchange Controlled shear stress Media circulation in the bioreactor Laminar flow evenly distributed Constant linear speed during culture 17 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI solution: Integrity® Xpansion™ Multiplate bioreactor Xpansion bioreactor design limits cell environment change while being compact, closed and controlled http://www.atmi.com/lifesciences/products/bioreactors/xpansion.html Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI solution: Integrity® Xpansion™ Multiplate bioreactor Xpansion bioreactor design guarantees equivalent shear stress in the entire bioreactor. vx, Linear speed (m.s-1) Q=25L.h-1 19 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI solution: Integrity® Xpansion™ Multiplate bioreactor Keeping the shear stress constant while scaling up guarantees the same microenvironment. Linear speed - mm/s 8 6 Xpansion 10 4 Xpansion 180* 2 1mm/s = cst during scale-up 0 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 Stirring speed - RPM *Xpansion 180 is no more available and has been replaced by Xpansion 200 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Learning from our Customers In theory, Xpansion multiplate bioreactor is a fantastic concept. In practice, is it efficient? Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Studies Many stem cell types have been successfully cultivated in Xpansion Cardiac lineage committed mesenchymal stem cells Undifferentiated iPSC* Mesenchymal Stem Cells from Bone Marrow (BMSC) Human Heterologous Adult Liver Progenitor Cells (ADHLSCs) … Non public * undifferentiated iPSC amplification in XP10 - Successful proof of concept – presented at ECI Jan 2013 San-Diego Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #1 A comparative case study with Mesenchymal Stem Cells was independently performed by Lonza Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #1 A comparative case study with Mesenchymal Stem Cells was independently performed by Lonza : Xpansion Multiplate bioreactor was directly compared to CF10. Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #1 A comparative case study with Mesenchymal Stem Cells : Comparable yields as from the first runs with minimum process adaptation required Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #1 Cell quality was similar in both vessels Cytokine levels, immunoregulatory response and flow markers were similar Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #1 Finally, BMSC density and quality were equivalent in both systems Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #2 Promethera case study relates to the scale-up allogeneic production to support clinical phase and early commercialization of their therapy. Belgium Biotech company Cell therapy product to treat children suffering from serious congenital metabolic liver diseases. HepaStem: human heterologous adult liver progenitor cells (ADHLSCs) isolated from healthy human livers. Phase I/II clinical trials treatment of Crigler Najjar (CN) and Urea cycle disorders (UCD) in a pediatric setting Using Corning CellBind treated CellStacks 28 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #2 THAWING OF LIVER CELLS Current manufacturing process Phase I/II : OPEN process, involving lots of aseptic steps. P0: 20 T175 Manufacturing Status P1: 2 T175 • Fully open aseptic (class A) process from raw materials to cryopreserved drug substance • Major costs attributed to production raw materials & quality control testing • 80 batches/year suitable for clinical phases on low number of patients P2: 1CS2 P3: 4CS10 P4: 5CS10 P4: 5CS10 P5: 15CS10 P5: 15CS10 HARVEST HARVEST CRYOPRESERVATION OF Drug Substance BioProcessInternational online webinar – “Enabling Cell Therapy: Case Study on Scaling-Up Allogeneic Stem Cell Manufacturing From Multi-Tray Stacks Toand Confidential ©2013 ATMI, Inc. All Rights Reserved. Proprietary Xpansion™ Multiplate Bioreactor. “

Xpansion Multiplate bioreactor - Case Study #2 Cell density and quality were equivalent to control at all scale % of cell density VS CS2 control 140 120 100 80 Xpansion 60 CS2 CTRL 40 20 0 Xpansion 10 Xpansion 50 Xpansion 180 QC tests Viability at harvest 98,7% 99% FACS Pass Pass Pass ICC Pass Pass Pass Morphology Pass Pass Pass Activity of CYP3A4 Pass Pass Pass Urea secretion Pass Pass Pass Bilirubin conjugation 30 97% Pass Pass Pass Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #2 DO and pH trends were similar at small and large scales pH, DO and Temp trends in Xpansion multiplate bioreactor 10 and 180 plates 31 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #2 Conclusion from the case study: The Xpansion bioreactor design led to fast transfer and scale up of the initial 2D process 6 months to succesfully Transfer a Cellstack10 process to Xpansion and scale it up to 180 plates (110,000cm²). 32 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor – Cost Model Autologous process 3000patients/year Traditional technologies Xpansion 20 CS10/batch 1 Xpansion/batch Millions Capex € 35 € 30 (-50%) € 25 € 20 200 aseptic Operations/batch =2000 operations/day NO aseptic operations € 15 € 10 €5 # FTE* 111 (-62%) Building surface & Equipement 5738sq/m x 511 incubators x 84 biocabinets 2050sq/m (-65%) x 89 incubators x 3 biocabinets Thousands 377 €0 € 25 Opex € 20 € 15 (-40%) € 10 NOT VIABLE ENABLING NOT FEASIBLE TECHNOLOGY €5 €0 * Operators, QA/QC, supervisor, Planning Logistics 33 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Conclusions How will we fill the gap for large scale productions? Lot Size, billions/lot 1000 100 10 Current Platforms 1 2006 2009 2012 Sept. 2012 - ISCT webinar: Best Practices in Cell Therapy Process Development - Jon Rowley Chair, ISCT Process & Product Development Committee 2015 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Conclusions Cell therapy market = variety of business models SUT already established as a standard but need to be more “closed” for Phase III or commercial productions. Technology gap for cell amplification step ! Integrity Xpansion multiplate bioreactor = enabling technology Proven concept now Generates the same cells than CF10 in the same quantities while being more compact and controlled CONCLUSIONS Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Thank you Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion bioreactors : compact design Xpansion MPB10 Xpansion MPB50 Xpansion MPB100 Xpansion MPB200 10 50 100 200 Growth Surface Area 6120 cm² 30600 cm² 61200 cm² 122400 cm² Media working volume 1,6L 5,6L 11,2L 21,9L 29 cm (11.4 '') 47 cm (18.5 '') 55 cm (21.6 '') 81 cm (31.9 '') 1 5 10 20 # of plates Size Multitray 10-stack equivalent 37 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell therapy market is complex with different business models *Nov 1, 2012 (Vol. 32, No. 19) - Cellular Therapy Wave Finally Cresting - Lee Buckler, J.D., Enal Razvi, Ph.D. Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Xpansion Multiplate bioreactor - Case Study #2 Scaling-up with Xpansion™ multiplate bioreactor : Cost of Goods Evaluation & Results. Cost of Goods Decreased workload Increased yields Quality control Non-aseptic environment • For equivalent FTE /batch, higher yields were achieved (x24) • Fully closed and controlled system results in 80% reduction on QC per billion cells produced • Closed system offered by ATMI include bags for media & reagents – cost savings compared to bottles 39 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Consistency in DO trends on consecutive passages Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Cell layer homogeneity was checked on every (180) plate and showed to be equivalent to control Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

Value proposition In addition, XpansionTM has a significant impact on CoGs ATMI has a cost modeling tool that considers: Process steps, process variability from batch to batch Process-related equipment, footprint, level of CR classification Process steps Process variability (PDL) Implementation of a closed system combined with a bioreactor leads to: to >40% cost REDUCTION of CoGs Consistent dramatic decrease of level of investment, by 60-70% There is NO general rule, but categories of processes and applications Batch 2 Batch N # FTE # FTE # FTE # consumables ATMI can implement specific assumptions to model specific cases Batch 1 # consumables # consumables # equipments # equipments # equipments # FTE # equipment # consumables Building COGs 42 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI & Stem Cells manufacturing Xpansion bioreactor technology On 90% of the surface, shear stress is lower than 6mN/m², To be compared with mammalian cells agitated bioreactor, where shear is in the range of 1-5N/m² Shear stress chart [mPa] on surface at 30L/h Plate 5 % Plate 9 Plate 13 Plate 15 mPa 43 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

ATMI & Stem Cells manufacturing Xpansion bioreactor technology Design optimization by CFD analysis and physical characterization: Angle in between slots vs # slots Laminar tangential flow Overall circulation is axial Homogeneous distribution Very low shear stress generated kLA, mixing times, circulation times CFD helped to fix design, validation by experimental plans Numerical simulation highlighted evenlydistributed media circulation through Xpansion plates . Pathlines colored by time (s). 44 Proprietary and Confidential ©2013 ATMI, Inc. All Rights Reserved.

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