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Development of closed, scalable and AUTOmated robotic systems for therapeutic STEM cell manufacturing: aseptic systems from “Donor-to-Patient”

Periodic Reporting for period 2 - AUTOSTEM (Development of closed, scalable and AUTOmated robotic systems for therapeutic STEM cell manufacturing: aseptic systems from “Donor-to-Patient”)

Reporting period: 2017-07-01 to 2018-12-31

Mesenchymal stromal cells (MSCs) are important to the emerging field of regenerative medicine because of their unique qualities and their effect on surrounding tissue, stimulating tissue repair and modifying the body’s immune response. It is possible to use MSCs for autologous (patient specific) and for allogenic (patient to patient) cell therapies.

Numerous studies report the use of MSCs for different treatments, from tissue repair to inflammatory diseases. However, in order to facilitate the transition from bench to broad clinical application, new ways must be found to increase cell production capabilities.

The manufacture of cell based products brings novel challenges due to the inherent complexity of the final therapeutic agent. Up to now, cells for therapeutic use have mainly been produced manually, giving rise to many issues, such as risk of contamination and increased variability between batches. The use of closed automated systems will reduce the likelihood of human error and improve the quality and throughput of cell production. Increased automation will also address regulatory concerns, by delivering reliable replication and allowing comprehensive and centralized recording and storage of production data.

The AUTOSTEM project is developing a closed robotic platform to achieve fully automated manufacture of MSCs that requires no direct human interaction with the product. In AUTOSTEM, bone marrow is harvested from patients using a novel harvesting device. This bone marrow is then delivered into the pipeline, where MSCs are isolated, cultured and expanded. The environment in the pipeline bioreactors can be monitored (using customised sensor technology) to ensure optimum conditions are maintained. Progress through the pipeline is fully automated. The output of the pipeline will ultimately be clinical quantities of high quality MSCs. Thus, the AUTOSTEM project aims to enable lower-cost, higher quality and more consistent MSCs to be produced, ultimately helping patients to benefit from new cell therapies.
The key output from the project is the AUTOSTEM manufacturing platform itself. The related work has been broken down into several different workstreams.

We have explored and optimised conditions for isolating and culturing MSCs at the litre scale. We devised detailed protocols for use in the AUOTSTEM automated platform and validated these protocols in the laboratory. The team at Fraunhofer IPT built the AUTOSTEM automated platform and devised bespoke automated solutions for the pipeline. We tested the platform with a sterile broth test run. We then successfully cultured MSCs in an expansion run in the automated platform, proving that our automated platform can successfully culture MSCs.

As part of our work a flexible and scalable electrochemical sensor probe for glucose, lactate and ammonia was also developed. The work successfully produced a novel solution for multi parametric sensing that can be used in the AUTOSTEM platform but is also scalable and configurable to support other requirements in the cell therapy and biopharma industries.

We have provided proof of concept in the laboratory for selection of a purified population of MSCs on functionalised micro-carriers. We have proven that our selection techniques work in the lab and there is potential for applying this approach in the next generation of the AUTOSTEM platform and in other bioreactor settings.

We have shown the efficacy and the benefits of using xeno-free medium (no animal-derived components) for culturing MSCs. This is important because it will increase product safety. We envisage xeno-free medium can be used in the AUTOSTEM platform in the future.

We have carried out in vitro and in vivo validations of cells produced during the project and we have seen the therapeutic potential of the MSCs produced, the related extracellular vesicles and conditioned medium.

Finally, in AUTOSTEM a novel bone marrow extraction unit has been developed. This aims to improve on current manual systems for harvesting marrow, to make the extraction process easier for clinicians and to enhance the patient experience. The new system has potential for broad application beyond the AUTOSTEM platform.
AUTOSTEM builds on the work of the StemCellFactory project (with whom we share key partners). StemCellFactory built and demonstrated an automated robotic pipeline for the production of induced pluripotent stem cell lines. AUTOSTEM takes this technology to a new level and has developed an automated, closed and Good Manufacturing Practice (GMP)-aware MSC production pipeline. The project delivers several important new innovations, including:

• A new device to harvest bone marrow, designed to minimise patient discomfort which will feed into the AUTOSTEM platform.
• Functionalised culture surfaces with antibodies for selection of MSCs from marrow.
• Novel use of GMP-compliant, xeno-free medium for the culture of cells.
• Optimised bioreactor processes for large scale, economically viable production of cell products.
• Tailored sensors that can provide real-time in-process monitoring, and incorporating anti-fouling measures.
• A flexible, automated cell production platform with related software and fully integrated functional modules.
• Biological validation of the cells produced in vitro and in vivo to ensure a clinically-relevant AUTOSTEM product.

Commercial Benefits: Many of the above innovations bring potential for the development of new product lines and improvement of existing products. We believe the AUTOSTEM platform will address technology gaps for commercial stem cell therapy production. Importantly, the AUTOSTEM pipeline addresses the need for product consistency. Our technology takes account of emerging regulation in the sector. There is potential to adapt the AUTOSTEM platform for the automated production of other cell types, such as induced pluripotent stem cells or suspension cultures.

Research Benefits: The project has generated new knowledge about cell selection and expansion, bioreactor systems, sensor technology and MSC action. This knowledge presents new opportunities for further research and collaboration by the partners and third parties in academia and industry.

Clinical and Societal Benefits: The AUTOSTEM platform will enable the manufacture of safer, more consistent and more effective therapeutic product. We ultimately hope to deliver high quality and high volume MSCs at an affordable cost. This will benefit industry and researchers and will ultimately yield significant benefits for clinicians and patients. We believe that the AUTOSTEM platform will open the door to MSC therapies for patients in the future, which will have health and wider societal benefits.

The AUTOSTEM project has demonstrated the feasibility of fully automated, end-to-end production of therapeutically relevant cells in the litre scale. We have developed and tested a prototype of the platform. The next step towards clinical application will be the demonstration of full GMP compliance and therapeutic efficacy of the cells produced in a clinical setting. Further optimisation of the system is also planned.
Autostem Partner Details
Screenshot from Autostem Website Homepage
Members of the AUTOSTEM team in Aachen December 2018