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Innovating Process Development for Sustainable Manufacturing

Optimizing a product through process development is a natural step in translating the therapeutic to the clinic. While this is a critical milestone, many of the processes have not been optimized for larger-scale industrialization. This session will evaluate how industry innovators are implementing new processing platforms and strategies to position future products for sustainable industrialization.


Dominic Clarke - Global Head of Cell Therapy at HemaCare Corporation, Winston-Salem, North Carolina, USA


Stuart Curbishley (Head of Business and Project Development, Advanced Therapies Facility, University of Birmingham, UK)
Jean-François Chaubard (Chief Technology Officer at MaSTherCell Global, France)
David Smith (Head, Cell Therapy Manufacturing, Lonza, USA/Healios KK, Japan)


Dominic Clarke, the chairperson, began this fascinating session with a brief introduction. While the progress in the cell and gene therapy industry has been remarkable, a number of key challenges have arisen that can impact the ability to translate and commercialize these therapies globally. Navigating these challenges is a cornerstone of the ISCT and a key aspect to process/product development committee.

Stuart Curbishley – Challenges in Translating Academic and Start-Up Companies to First-in-Man and Early Phase Clinical Trials

Stuart Curbishley set out to provide an overview of how the University of Birmingham has implemented pathways to help improve the development and delivery of advanced therapies. He notes that while modern drug discovery occurs inside global pharmaceutical companies, most cell therapies have evolved from academic institutions; therefore, you need a different outlook. So, how did the University of Birmingham deal with this challenge?

Stuart Curbishley began by discussing an early clinical trial (2008) of a dendritic cell (DC) vaccine in patients with end-stage hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. The DCs employed were manufactured from monocytes after isolation by plastic adherence and used non-GMP materials; at this stage, they recognized that they needed to understand how the cell therapies behaved and how they could improve the manufacturing/delivery process by studying the behavior of DCs in patients. This led to a study that tracked radiolabeled DCs following intravenous or intrahepatic infusion in patients with advanced HCC. During this evaluation, they looked to replace problematic parts of the cell isolation and production materials to develop the process for manufacturing further. The next clinical trial moved further toward a closed system with defined factors at every stage in a manufacturing platform that used the Miltenyi Biotech – CliniMACS Prodigy setup. From patients to the vaccine, there were no open stages of the process; however, the entire process was very much “hands-on,” non-automated, and not amenable to scale out.

A subsequent collaboration with the University of Nottingham and AstraZeneca sought to develop a novel DC therapy, which took circulating DCs from patient blood and reprogrammed them ex vivo to make them more competent (via p38 MAPK inhibition) before administering them back to the patient. Again, Miltenyi Biotech helped to create a closed end-to-end system that required only minimal external input at the start of the process to load the necessary factors into the CliniMACS Prodigy system and again at the final stages for product release. As the intermediate stages were now automated, they were not able to look at how to scale-out this and similar approaches to take the products to market—an all-important step.

Stuart Curbishley noted that these steps generally require interactions with third parties: as small and medium enterprises (SMEs) generally have maximum product knowledge, some process development, and little GMP, they contract CMOs and CROs to help with clinical trials out to hospitals. Contract manufacturing organization (CMO) or contract development and manufacturing organizations (CDMO) have little product knowledge, but aid in process development and GMP, while contract research organizations (CRO) organize trial management and regulatory aspects. Unfortunately, SMEs learn little from this interaction, although the CMOs and CROs learn a great deal.

At the University of Birmingham, they have tried to bring all of the different aspects from SMEs/CMOs/CROs under one roof in the Birmingham Advanced Therapies Facility, which is located on-campus and surrounded by numerous associated research institutes and hospital units. Here, they have been able to undertake point-of-care manufacturing for advanced therapy medicinal products (ATMPS, in this case, the DCs), which allows them to pass from patient to manufacturing site and then back to the patient within 4 months.

Stuart Curbishley then asked the question, can you imbed an SME within an academic institution? The University of Birmingham has managed this feat with Orbsen Therapeutics (“Redefining Cell Therapy”), a spin-out from the University of Ireland Galway, who have already elaborated four clinical trials used as an example. While Orbsen Therapeutics has experience of the process associated with their specific product, they had no GMP knowledge, but the interaction with the University of Birmingham allowed for technology transfer, staff training, process development, and clinical trials in the short term and process control, scalability, resilience, and future-proofing in the longer term.

What gets forgotten in the interactions? Minor details in the manufacturing process that may seem insignificant in the research side may be vital for GMP, and this is perhaps due to historical changes being poorly documented in a research background. Furthermore, the need for redundancy in the supply chain in GMP is a particular challenge. But what works well? The rapid transition from the lab bench to GMP and the ability to move process development forward quickly, reduced financial constraints (compared with academic research) as companies tend to be better funded than academic research units, and the ability to solve problems in real-time, which provides massive benefits. What´s in it for the University of Birmingham? The access to manufacturing platforms that academia may find it challenging to implement, the increased headcount to reduce time consumed in the day-to-day activities, while seeing the success is a massive benefit for the team. Finally, what is in it for the company? They get quality and regulatory oversight, ownership of their process development, the massive upskilling of their workforce, and the readiness for scale-up and out.

The next arising question is how we get the product to the patient. The University of Birmingham is managing this with centers across the UK as a part of the Advanced Therapy Treatment Centres—“Working together to accelerate patient access to advanced therapies.” This infrastructure enables ATMP companies to reach the clinical market and provides increased national patient access to ATMPs. They have established the best practice for near-patient manufacturing and final preparation of ATMPs, safe and effective delivery of ATMPs to the patient, robustly connected supply chains for ATMP manufacture and delivery within the NHS, compliant and compatible systems to allow traceability and tracking of ATMP, and patient follow-up and data capture. The particular focus of Stuart Curbishley is on the preservation and delivery of ATMPs, i.e., logistics and orchestration. This requires a robust understanding of the needs associated with distinct categories of ATMPs, involves end-to-end cryochain solutions using hardware systems to ensure cell viability and preservation of ATMP products, and integrates bespoke software to enable tracking and review of data to simplify performance qualification. The final step involved represents the move toward coordinating clinical trials; at the University of Birmingham, they have also set up the Therapy Acceleration Program for Cellular Therapies (TAP-CT) to aid with this endeavor.

Jean-François Chaubard – Allogeneic T-Cell Therapies: Shifting Toward Commercial Manufacturing

Jean-François Chaubard began his presentation by noting that Catalent had just bought out MaSTherCell as well as Paragon Gene Therapy in the hope that this synergy will provide end-to-end integrated advanced biotherapeutic solutions with enhanced ability to help biologics inventors develop better treatments faster and supply them around the world.

Jean-François Chaubard began by discussing the accelerated status of clinical trials for advanced therapeutics thanks to their clinical success and fast track status, leading to the increased entry. Data from 2019 highlights regenerative medicine/advanced therapeutics as an emerging market with the most clinical treatments in the past 3 years. Indeed, 1,071 clinical trials that involve gene therapy, gene-modified cell therapy, cell therapy, and tissue engineering are mainly in phase I and II, although nearly 100 are also in phase III.

Overall, the cell therapy market is continuously evolving with ever-growing investment; while autologous therapies will lead the market in the near-term, allogeneic therapies will represent a disruptive force in the long-term, with a growing pipeline. Additionally, cell therapy technologies are shifting from autologous, single-modification platforms toward induced pluripotent stem cell-derived cells with genome-edited therapies. Overall, the cell therapy/gene therapy market is expected to grow at a 22% compound annual growth rate, with global funding reaching 25 billion dollars by 2026.

Jean-François Chaubard then shifted to Catalent´s position in the field by discussing their first-to-scale allogeneic cell therapy manufacturing with regard to an anticipated first allogeneic CAR-T therapy brought to market. Catalent Cell Therapy is in a unique position in the field with 50% of its customer programs being allogeneic; this makes it likely that they will produce the first CAR-T allogeneic product to gain market authorization

He then discusses autologous vs. allogeneic manufacturing, under the assumption that “one size does not fit all.” Indeed each product has corresponding specificity challenges. Autologous therapies suffer from starting material variability (major challenge) and suffer from important logistic issues. In contrast, allogeneic therapies suffer from problems at the other end of the scale with regard to scale-of-cell expansion and the fill-and-finish capacity. Indeed, autologous and allogeneic therapies are at varying stages of their product lifecycles; while autologous modalities have already acquired commercial approval, allogeneic CAR-T therapy are just now beginning to shift to late-stage clinical development

In this sense, Catalent aims to deliver scale-up excellence to late-stage allogeneic therapies; their allogeneic scale-up strategy optimizes infrastructure to deliver large-scale batches and optimizes the supply chain to assure high-quality production. One can move from allogeneic clinical manufacturing to commercial manufacturing by concentrating on following a “manufacturing by design” strategy that involves establishing commercial facilities and process validation for process performance qualification production.

The manufacturing by design strategy identifies attributes critical to cell therapy scale-up and focuses on alleviating T-cell manufacturing challenges by elevating attributes that are absent when using quality by design methodology. Manufacturing by design involves multiple facets associated with economics, process efficiency, regulatory concerns, intellectual property, and having a true end-to-end vision. Overall, the real bottleneck that has been identified by this process comes at the end, with the fill-and-finish process. Therefore, Catalent has created some innovative Initiatives regarding their allogeneic fill-and-finish service for particular products based on product specificity, processability and robustness, and overall capacity. This platform provides a customized process based on product specificity and takes into consideration the formulation, filling, container integrity testing, visual inspection, labeling, control rate freezing, and storage in vapor phase nitrogen. Furthermore, they have a high-fill capacity for optimized batch efficiency, which involves an increase in the visual inspection throughput, semi-automating the filling, using a higher capacity control rate freezer, and using new isolator technology.

To finish off his presentation, Jean-François Chaubard discusses how Catalent is improving its worldwide presence by expanding their global network to grow with clients. They are now combining clinical sites in Europe and the U.S. with soon-to-come commercial sites that will feature multiple modalities and end-to-end services. In summary, Catalent hopes to be able to be a partner and provide innovative technology to grow your project

David Smith – Survival Guide to Contract Development and Manufacturing Organization

David Smith discussed his experience from working with Lonza and his newer role with Healios, a Japanese pharmaceuticals/regenerative medicine company. In doing so, he aimed to describe his survival guide to contract development and manufacturing organization and establish how to commercialize cell therapies.

He started by posing the question of whether we are in the “golden age” of cell and gene therapy. Rapid changes in regulatory settings have allowed for rapid approval, and these include a decrease in clinical trial demands (e.g., fewer patients required per trial), more frequent regulatory interactions, and rolling submission and fast track. Furthermore, the field is moving out of the funding valley of death; funds raised in 2018 have hugely increased in gene-based therapy, cell-based therapy, and tissue engineering, and emerging markets such as Japan and China are joining the game.

Indeed, the Asian market for cell and gene therapies is growing rapidly (23.8% compound annual growth rate). The Asia Pacific cell therapy market reached 17.6 billion dollars in 2017 and should reach nearly 51.4 billion by 2024. The market drivers include the aggressive entrance into the market by Japan and China led by Shinya Yamanaka (Nobel for iPSCs) and the Nanjing Legend success with CAR-Ts, the flexible regulatory environment, investments by the government and private companies, well-developed infrastructure and research facilities, and an increase in investments in healthcare research.

David Smith then introduced MultiStem, asomatic stem cell product derived from adult bone marrow developed by Athersys. Lonza produced the first master cell banks in 2006 and is now licensed for the Japanese market from Athersys to Healios. MultiStem promotes healing and tissue repair after “off-the-shelf” intravenous administration (no tissue matching needed) through multiple mechanisms and has completed a US/UK phase II trial in acute ischemic stroke and a US/UK phase I/II trial in acute respiratory distress syndrome (ARDS), which is hugely relevant to the ongoing COVID-19 crisis.

The results of Athersys’ phase I/II trial of MultiStem in ARDS confirmed tolerability and favorable safety profile, and the results from the double-blinded placebo-controlled study after 28 days of administration showed an improved trend in the group receiving MultiStem. Post hoc analysis of patients in severe condition with pneumonia-induced ARDS showed significant differences (which, again, is of obvious importance to COVID-19). ARDS represents a massive problem in Japan; the sudden onset of severe respiratory failure in severely ill patients (typically 24 to 48 hours after injury or illness) following severe pneumonia, septicemia, and trauma is caused by activated inflammatory cells causing damage to lung tissue that leads to water accumulation and acute respiratory failure. The mortality rate lies somewhere between 30% to 58%, and the standard treatment of care is ventilator use; unfortunately, prolonged ventilator use worsens prognosis. There are an estimated 7,000 to 12,000 cases of ARDS in Japan, with one third due to pneumonia, and there currently exist no therapeutic drugs. Can MultiStem help?

David Smith then returns to his question as to whether we are in the “golden age” of cell and gene therapy? There are several problems related to the marketing commercialization of products such as MultiStem, which relate to manufacturing challenges, a lack of characterization of a complex product, poorly developed regulations that lack harmonization, and an underdeveloped global supplier network. The suggested solution is the use of contract development and manufacturing organizations or CDMOs, and the speaker discussed how customers and CDMOs could work together toward an optimal outcome and outlined their positives and negatives, as was addressed in the previous presentations.

More from the Speakers

Dominic Clarke

STEM CELLS Translational Medicine - Concise Review: Guidance in Developing Commercializable Autologous/Patient‐Specific Cell Therapy Manufacturing