Anthony Ting, PhD
ISCT Chief Commercialization Officer
Kiji Therapeutics
Paris, France
At the Bioprocessing Summit Europe held in Barcelona from 19-21 March, 2024, the ISCT was asked to organize two panel discussions for the Cell Therapy CMC and Analytics track. The panels focused on the challenges and common threads in the manufacturing of allogeneic or autologous cell therapy. The panels were chaired by Anthony Ting, CSO, Kiji Therapeutics and Chief Commercialization of ISCT.
The first panel which focused on the manufacturing of allogeneic cell therapy consisted of Rob Allen, Managing Partner, Dark Horse Consulting; Julie Allickson, Director, Mayo Clinic Center for Regenerative Medicine; Kathryn Golden, SVP Techical Operations & Cell Manufacturing, bit bio; and Cenk Sumen, Advisor, Maxcyte. The discussion was free flowing with additional insights provided by audience participants including Chris Bravery and Lee Buckler. Ideally, allogeneic cell therapies would increase patient access and reduce the cost of goods (COGS). In some instances, the cells may require some immune cloaking to avoid detection from the host immune system. Rob set the tone by emphasizing that cell therapy developers need to start with the end in mind, and to consider the commercialization goals when designing the manufacturing plan. The first topic was focused on starting cellular materials. Tony brought up iPSCs and why they have not delivered the unlimited allogeneic therapeutic products as initially envisioned. Several panelists commented on the difficulties of reproducibility with differentiation of iPSC, lack of efficacy (particularly with respect to CAR-T therapies) and scaling the manufacturing process from static to suspension cultures. Kathryn mentioned the development of technologies that could enable fine-tuning of the differentiation process and creating a more homogenous product. Julie brought up mesenchymal stem cells (MSC), and that Mayo was conducting nearly 30 clinical trials while the initiation of iPSC cells required substantially more effort given the complexity of iPSC differentiation and manufacturing that require many steps that are not yet automated.
Anthony Ting chaired the first ISCT panel that included: Cenk Sumen, Kathryn Golden, Rob Allen and Julie Allickson.
This led to the next topic, the high costs of cell therapy manufacturing and why there is a lack of automation in current manufacturing processes. Cenk mentioned that Maxcyte has a device used in the commercial setting but that it still required manual labor and others commented that most of the products in development came out of academic labs where the focus was on the generating the most beautifully engineered cell but one that may not be suitable for commercial manufacturing. Rob made a comment that the “Golden Handcuffs” needed to be removed and the technology transferred sooner than later to CDMOs who could evaluate and adapt the manufacturing process to existing tools and technologies.
On several occasions, panelists noted that the cell therapy field is similar to the early days of monoclonal antibodies where many different approaches were initially employed but ultimately standards did arise that enable scalability and reduction in COGS. Julie mentioned that ISCT was interested in helping to develop workforce training programs and that having standards would greatly accelerate the productivity. Others mentioned that the increasing adoption of digitalization in the manufacturing process would further enhance the development of standards.
While it was noted that standards would help to increase the adoption of technology, Chris commented that you need to have demand for your product before see investment in the space, pointing out that MSC have not had great clinical and commercial success while the therapeutic efficacy of autologous CAR-Ts being used for the treatment of hematological malignancies have spurred greater advancement of technologies for their manufacturing. Ultimately, overcoming the challenges of manufacturing an allogeneic product will depend on the success in the clinic.
The second panel focused on the manufacturing of autologous cell therapy and included: Steve Binninger, Head of Collaborative Technology Development and Commercializaiton, Sartorius; Dominic Clarke, Vice President of Technical Operations, Cryoport; Ali Mohammed, Vice President, CMC Immatics; and Joaquim Vives, Group leader at Banc de Sang i Teixits.
Prior to the panel discussion, there had already been a discussion of centralized vs decentralized manufacturing as well as presentations from Sarah Snykers, Legend Biotech and Chris Crowell, Kite. Tony kicked off the discussion regarding the implementation of quality systems when moving from centralized to decentralized manufacturing. Joaquim mentioned that in Barcelona, they were already using a hub and spoke model to provide autologous cell therapies to nearby hospitals using a centralized quality system. Steve mentioned that there are several closed system manufacturing systems available for autologous systems that enable centralized quality systems. Ali challenged that having a quality management system at a hospital site for many different autologous cell therapy products was not tenable and best used in a few sites with limited products as is being done at Legend and Kite. Lee challenged that assumption and that developing technologies (including digitalization) that include a fixed set of systems and SOPS would allow for centralized quality systems. Ali suggested that we are not there yet. Dominic suggested that there was a place for having both centralized and decentralized quality systems, as he mentioned the need for standards in apheresis collection that would reduce variability and allow decentralization and also discussed the need for decentralization of cryopreserved products that can be removed from collection sites but localized sites that can adopt standard operating procedures.
Tony then brought up the need for flexibility in workforce development as we move from centralized to decentralized systems and as we move forward to automation of the manufacturing processes. Steve mentioned that while current developments within automation are geared towards manufacturing there will be a need for the automation of quality control. As autologous manufacturers lower the manufacturing times (e.g. recent Kite changes), the gatekeeper will be quality control. Therefore, it is important to consider not only current technologies but future technologies when developing training plans for the cell and gene therapy workforce. One example mentioned was flow cytometry which has gone from complicated machines requiring extensive training to a device that requires a single use chip. As technologies develop, they not only enable decentralized manufacturing but will lead to densification of centralized manufacturing facilities. Both Dominic and Steve mentioned the need for flexibility in both workforce skills and the design of manufacturing facilities as the technologies evolve.
The next challenge for the release of autologous products is the development of approved rapid QC assays. Steve mentioned that within the context of oncology, a risk-based approach may allow for the use of rapid sterility tests (especially if 17% of apheresed patients don’t get dosed!). Ali emphasized that developers need to provide data to regulators to support rapid QC testing. Dominic mentioned that as a new industry, cell and gene therapy developers need to work with the regulators to educate and adopt QC assays.
Anthony Ting chaired the second ISCT panel that included: Ali Mohammed, Joaquim Vives, Dominic Clarke and Steve Binninger.
The last topic discussed was the need for digitalization in manufacturing and QC. Joaquim mentioned that the implementation of electronic batch records is costly and the implementation from paper to electronic requires lots of training. All the panelists agreed on the need for moving toward digitalization that would reduce the errors that occur during manufacturing and reduce the release of cell therapy products. All agreed that while the benefits are worthwhile, the costs and implementations are definite barriers. Chris, from Kite, mentioned that it was a long and painful process to move to full digitalization. It was suggested to start small and incorporate one component (e.g. QC) and work to further digitize other processes. Unfortunately, the session had to close at this time and we were unable to discuss the next big challenge for both allogeneic and autologous cell and gene manufacturing - the incorporation of AI.
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