the robotic autostem platform for gmp-compliant … · 2019. 11. 28. · 5. autostem project •...
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The Robotic AUTOSTEM Platform For GMP-Compliant Manufacture of Bone
Marrow-Derived Mesenchymal Stromal Cells
Mary Murphy
Professor in Regenerative MedicineREMEDI, National University of Ireland Galway
Oct 9, 2019
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AutostemDevelopment of closed, scalable and
AUTOmated robotic systems for therapeutic STEM cell manufacturing: aseptic systems
from “Donor-to-Patient”
Mesenchymal Stem/Stromal Cells (MSCs) from Human Bone Marrow
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AUTOSTEM Vision
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 667932. 5
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AUTOSTEM Project• Development of an automated “factory”
• Large-scale production of therapeutic mesenchymal stem/stromal cells (MSCs)
• GMP- and GAMP- compliant• Cost-effective production of adherent cells
• Produced as a sterile, cryopreserved product in vials
• Allogeneic use
• Modular platform• Adaptable for production of autologous MSCs
• Production of MSC-derived Exosomes/EVs
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AUTOSTEM Concept
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Autostem pipeline – requirements
• ClosedProcess is performed enclosed in a sterile cabinet
• Robot assistedNo direct interaction between user and product
• Integrative and modularImplementation of automated devices and modules for different steps in the protocol
• High capacityBioreactor based expansion of cells in the multi-liter scale
• Sterile and safeSystematic development of hardware according to GMP and VDI 2221 guidelines
• Supporting the regulatory processes Centralized control software for full platform control and data accessibility
• Engaged with HPRA
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AutoStem Cell Harvesting System(Crospon)
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Platform Concept
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Automated facility functionality
Open Cell Handling (Critical Step)
Marrow aspiration
Seeding (Bioreactor)
Expanding (Bioreactor)
Freezing
Cell delivery
Sampling Quality control
Harvesting
Filling
© WZL/Fraunhofer IPT
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Open cell processing
Autostem pipeline – Process workflow
Bone marrow aspiration
Isolation in Bioreactor
Expansion in Bioreactor
Sampling
Sample Analysis
FillingHarvesting Formulation Storage (-80°C)
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Transition
Grade D
Grade A
Autostem pipeline – GMP compliance - HPRA
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Platform Representation
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Autostem pipeline
Storages for disposables
Filling station
Centrifuge
Central robot arm
Decapper
Vial Hatch
Storage for disposables
Cell counter
Automated sampling
Seeder and expander bioreactors
-80 °C Freezer
Central robot arm
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 667932.
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Autostem pipeline – concept and flow
Transition
Grade D Grade A
Bone marrow aspiration Isolation Expansion
Sampling
Sample Analysis
Harvesting
Filling
Formulation
Cryo-preservation
Pick-up and final QC
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MANUAL (Stir Tank) vs Automated MSC Production
0.00
1.00
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Cel
l co
nce
ntr
atio
n [
10
^5
cel
ls /
ml]
Time in culture [days]
Manual Automated
MANUAL AUTOMATEDFold increase
20.68 ±0.92 21.49 ±2.56
Population doublings
4.37 ±0.06 4.42 ±0.17
Specific growth rate (h-1)
0.0115 ±0.0002
0.0116 ±0.0005
Doubling time (h)
60.4 ±0.9 59.8 ±2.3
D3 D7 D10
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Instrumentation enclosure
Probe
Gen1 Gen2
Autostem Sensors / Tyndall-UCC
Probe in Mobius bioreactor
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Sensor Performance
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(a) Lactate sensor in response to lactate titration in 10mM
PBS; (b) lactate sensor calibration plot
(a) Glucose sensor response to glucose
titration; (b) the resulting calibration plot from
these readings
(a) Ammonia sensor CV response to ammonia titration
in 10mM PBS; (b) ammonia sensor calibration plot.
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Other aspects
• Biological validation
• MSCs, MSC-derived EVs validated• Fracture/bone repair indications
• Regulatory compliance
• GMP and GAMP documentation
• Cost of Goods Analysis
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Autostem: the future
• Establish an AUTOSTEM Pilot Plant at a clinical or central production centre
• Ensure full GMP and GAMP compliance
• Extend functionality to other tissue sources
• Validate the production process with donor tissue
• Regulatory approval
• Clinical testing for equivalence
• Commercialisation
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AutoCRAT: the future EU Funded / Under negotiation
“Automated Cellular Robot-Assisted Technologies for translation of discovery-led stem cell therapy development for Osteoarthritis”
• Expansion to production of iPSC-derived MSCs and chondrocytes
• Automated production of extracellular vesicles (EVs)
• Finalise GMP and GAMP compliance of the expanded factory
• Test clinical product for osteoarthritis in horses
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AutoCRAT Factory Concept
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Autostem Partners
This project has received funding from the European Union’s Horizon 2020 research and
innovation programme under grant agreement no 667932.
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Acknowledgements
STARSTEM
We acknowledge funding/scientific input from Abbvie
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Working Autostem Factory
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https://youtu.be/GMQTK8JpcQ8