From research to reality: how raw materials, media composition and process decisions shape T-cell therapies
As T-cell therapies continue to revolutionize cancer treatment and show promise across a growing range of therapeutic areas, the biopharmaceutical industry faces a critical challenge: how to efficiently scale these complex cellular products from promising research concepts to commercially viable treatments that can reach patients worldwide.
In this interview, Gonçalo Regalo explores the multifaceted challenges of T-cell therapy manufacturing with a focus on the critical decisions that developers must make early in the process to ensure successful scale-up. From navigating the complexities of variable patient starting materials in autologous therapies to selecting the right media compositions, raw materials and automation strategies, the discussion reveals how forward-thinking process development can make the difference between a promising therapy that remains in the lab and one that successfully reaches commercial production.
Gonçalo Regalo is a Senior Product Manager Cell Therapy at FUJIFILM Biosciences (CA, USA) and brings over 10 years of cell and gene therapy expertise, from manufacturing and quality assurance to compliance. His focus is on translating complex biology into compliant scalable workflows and providing solutions that lead to successful collaborations for FUJIFILM Biosciences’ internal and external partners. Goncçalo holds a PhD in Human Biology from Universidade do Porto (Portugal), a Bachelor of Science in Biology from Universidade do Minho (Braga, Portugal), and completed his postdoctoral fellowship at the Max Delbrueck Center (Berlin, Germany), specializing in cell and cancer biology.
What are the most critical bottlenecks in scaling T-cell therapy production from research to commercial manufacturing?
I would say there is an interplay between understanding the quality attributes of a cell therapy product as it progresses through a manufacturing workflow and having access to technology that enables hitting those attributes in a consistent fashion. In autologous settings, it is particularly challenging to establish process specifications that account for the significant variability inherent to starting materials derived from patients who are often severely ill and immunocompromised. Identifying ways to normalize manufacturing outcomes in process is essential to keeping the process in a state of control and mitigating the impact of those variations in process outcomes.
To minimize additional sources of variation, it is critical to use well-characterized and consistently defined reagents and process liquids, while also reducing the potential for human error through the careful integration of automated systems. Optimizing upstream process steps, such as cell separation, is critical to minimizing the carryover of undesirable blood components, including platelets and granulocytes, which can negatively affect subsequent culture steps. Equally important is the selection of a bioreactor or cell culture platform that maintains consistent and linear culture conditions from small-scale manipulations to large-scale cell expansions. Together, these strategies provide invaluable tools for reducing variability and improving overall process control.
How does media composition impact the consistency and functionality of T cells throughout the manufacturing process?
Early development of cellular therapies is often done in an academic setting, resorting to classical media formulations supplemented with serum (human or in some cases even bovine). It is essential that early developers understand the impact that serum has in cell culture, and how challenging it is to pinpoint functionality to a particular element of the “serum black box”, known to impact critical attributes of cellular products. At a time when cell therapies are under scrutiny for cost, safety, and manufacturability, developers are being pushed to demonstrate clear correlations between process choices, therapeutic mechanisms and patient outcomes. Relying on undefined components such as serum during critical stages of discovery and process development can introduce significant variability and risk, potentially creating insurmountable challenges later in the clinical and commercial lifecycle.
Another critical consideration in T-cell biology is cytokine selection, particularly when it comes to cell culture. Interleukin 2 has long served as the workhorse cytokine for T-cell scientists, driving activation, expansion and survival during ex vivo manufacturing. However, as the field seeks more control over cell phenotypes, IL-7 and IL-15 are gaining traction as alternative supplementation strategies. Like with other raw materials, and regardless of the supplementation strategy, selecting high-quality recombinant proteins is essential for process control at scale. In particular, lot-to-lot consistency of recombinant proteins enables tighter control over cellular outcomes at scale.
How do raw material selection and qualification strategies evolve as T-cell therapies move from early research through clinical trials to commercial production?
From early research to clinical development, adopting a risk-based approach to raw material selection is essential. It allows developers to justify and document decisions, minimize variability, and build a stronger foundation for regulatory compliance and scalability. For instance, considerations on the impact of serum or the quality of cytokines, as I previously mentioned, should be documented and weighed against the biological outcome needed at each process step. As a therapy progresses through the clinical approval process, other more nuanced aspects need to be considered. Security of supply, regulatory support, secondary supplier validation for critical materials to assure business continuity, and global suitability of raw material choices across different regulatory landscapes are all factors successful developers will eventually have to evaluate through their risk management system.
How can process development scientists better anticipate and prepare for the challenges of large-scale manufacturing while still in early development phases?
There must be a level of forward thinking in the choices developers make in early process development. Relying solely on plates and flasks during preclinical work may not prepare processes for the very different oxygenation and sheer profiles of stirred-tank bioreactors. These shifts in culture environment can impact cell behavior, making early-consideration of scale-relevant systems critical to achieving consistent and predicable outcomes.
This choice could pose challenges in extrapolating the biology developed in an early stage to a larger-scale setting. Likewise, single-box solutions provide attractive “one stop shops” for cell therapy manufacturing, which can be a great way to start getting familiar with the ins and outs of clinical manufacturing. Whether these are the best choice in terms of process outcomes at scale is a much more nuanced question, with developers risking locking in the process to a platform that will not be suitable to support later stages of clinical development.
How are modular approaches to scale-up changing the T-cell therapy landscape and what considerations should manufacturers keep in mind when selecting platforms that need to accommodate different scales of production?
Modular solutions have always played a role in the early days of cell therapy. Developers were incredibly resourceful, repurposing equipment from bioproduction, cell banking and medical devices to create modular setups that fit their unique needs. What we see now is an array of clever and elegant fit-for-purpose solutions that take into consideration from the very start the specificities of the processes they support. This paves the way for full optimization of each process step, ensuring that critical in-process attributes are consistently achieved and maintained within a state of control. What we are interested in at FUJIIFILM Biosciences is what solutions we can develop for raw materials and process liquids that fully enable these pieces of technology and maximize the outputs every step of the way.
As the field moves toward increased automation, what manual steps in T-cell manufacturing do you believe are most critical to automate?
More than just automation, adopting single-use technologies can enable developers to operate in fully closed systems, minimizing contamination risks and enhancing process controls.
This would have huge impacts on other critical aspects of manufacturing, such as facility design, clean room grading or the need to qualify isolators for manual steps. To take full advantage of the low-grade clean rooms, with associated lower operational costs, designing and validating fully closed process workflows is key. Some particular hands-on heavy process steps may be challenging to fully automate and maintain in a functionally-closed manufacturing scheme. Take Tumor Infiltrating Lymphocyte (TIL) manufacturing for instance, where some level of manual processing of tumor tissue is hard to avoid in the isolation of the infiltrating T cell populations. This is clearly a bottleneck in streamlining an otherwise extremely promising therapeutic strategy to tackle solid tumors.
In general, there is an increasing number of cell-processing technologies that now enable the establishment of previously challenging manual processes, like robust fill and finish modules. Ensuring the removal of ancillary materials through the use of high-quality, closed systems and well-defined buffers and process liquids cannot be overlooked.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Taylor & Francis Group.
In association with FUJIFILM Biosciences.