The "Corps de Manufacturing:" Defining Flexibility In Cell & Gene Therapy Tech Platforms
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
At 28, I walked into a ballet studio for the first time in my life. Since then, I have continued to put myself through a variety of balletic activities with which my limbs often take offense. On the surface, it may seem as though this has absolutely nothing to do with ATMP manufacturing. But I daresay my experiences sustaining countless injuries have equipped me with a different understanding and appreciation for the physical strength that comes from being flexible — a concept I’d argue also extends into the ATMP manufacturing world.
In the ATMP space, we hear the term “flexible” used almost daily in a variety of contexts. Most frequently, however, we emphasize the importance of flexibility when we talk about the development of our manufacturing technology platforms. It may seem oxymoronic to emphasize “flexibility” when “control” and “reproducibility” are two of the most important mottos of our space. But as any corps de ballet knows well, flexibility and strength must go hand-in-hand, and in the manufacturing platform technology space, we can argue flexibility will only make for a “stronger” manufacturing paradigm.
Though the word “flexible” will inevitably appear in any conversation about a manufacturing facility, paradigm, or platform, we rarely stop to flesh out what such flexibility can mean and/or may look like in the CGT space. Luckily, I had a chance to get more clarity on this topic during a recent conversation with Abe Maingi, VP of business development and co-founder of Inceptor Bio, and Jason C. Foster, CEO and executive director of Ori Biotech. In part one of this two-part article, we discussed how manufacturing partnership dynamics are shifting in the ATMP space, in part thanks to the scientific and technical complexities of these new modalities. However, in addition to identifying how biotechs and their manufacturing partners are sharing risk/value in their cell therapy partnerships, I also wanted to learn how these two partners are defining “flexibility” in manufacturing partnerships and technology development. Here, in part two, Maingi and Foster help me chisel out how they are both thinking about flexibility today and what this may mean for biotechs and tech provider partnerships in the heterogenous ATMP space.
Uniting R&D And CMC: Where Flexibility Meets Strength
As my previous article unpacked, there are a few unique reasons behind why the ATMP space in general — and the autologous cell therapy space, in particular — demands new approaches to CDMO and supplier partnerships. Whether it be economics, variable manufacturing processes and patient access goals, or the diversity in cell types, raw material needs, and delivery vehicles, it can feel as though we’re a single industry playing a particularly “twisty” game of Twister.
Typically, our discussions defining a flexible manufacturing technology and platform begin — and also end — with the statement that we as innovators don’t want to retool our process to suit said technology/platform. Some level of optimization likely will always be a necessity — even in a plug and play future. But our biggest priority is to not have to “round out” our “square-peg” process to fit the “round hole” of a technology/platform.
Of course, there are a few therapeutic-agnostic ways we can define flexibility in terms of manufacturing technology platforms. First and foremost, a technology platform will need to demonstrate it can be used across multiple sites and that it will generate reproducible results. We’re also seeing an increasing emphasis on digital capabilities to improve visibility into our processes. Finally, we also hope that a technology’s capabilities will ease the burden of the most time-consuming processes — especially tech transfer — to decrease our overall development timelines.
But there are a few ATMP-specific ways we can start to define technological flexibility today. For Inceptor Bio, a biotech working in the autologous cell therapy space with a CAR-T, CAR-M, and CAR-NK therapy, a central tenet of a flexible manufacturing technology/platform will be one that can be applied to all three cell types in the future.
“Though T-cells are the most well-known of all cell types and our CAR-T program is the most advanced in our pipeline, when we thought about manufacturing technology partnerships, we were also thinking about the applicability of each platform to multiple cell types,” Maingi explained. “A platform limited strictly to T-cells wouldn’t be the most scalable option for our company’s long-term goals.”
Beyond the nuances of cell type, however, both Maingi and Foster also pointed to the nascency of the industry and its ongoing quest to find the most optimal “recipes” for each therapy — a quest typically carried out manually in small-scale lab equipment and bags. Given that these lab-based tools are well proven and oft-used, technology platforms striving to meet the needs of preclinical or early-stage companies must be “flexible” in that they enable companies to “play” with all the variables needed to arrive at the best cocktail.
However, it’s unrealistic to believe that a technology platform can and will be all things to every company. That’s why Foster emphasized the importance of thinking about flexibility within a framework. “There will be boundaries as to what any tech platform can do,” he acknowledged. “But as tech providers, we can try to make those boundaries as wide as possible to encompass as many cell types, process differences, and volumes as we can.”
Behind every cell therapy product are several typical steps — including cell culture, genetic reprogramming, and activation. Throughout these “basic” steps of the process, a biotech will work with different volumes of materials, add in raw materials at various stages, and collect and characterize samples offline to learn what’s happening within that process. The hope is that a technology platform will enable a company to explore and optimize all the variables comprising the best therapeutic cocktail without relying on the manual, unscalable efforts/tools used frequently today (i.e., micropipetting, tube welding, biological safety cabinets [BSC]). In other words, we can define a flexible tool/platform as one that industrializes the preclinical work from the earliest stages and makes it scalable long-term without limiting early-stage companies in their critical preclinical process development efforts.
Given that the CGT space is struggling to find the necessary talent, we can also look at flexibility through a human resource lens. In addition to enabling the user to explore different recipes/approaches, we should also evaluate a platform’s ability to free up operational talent to focus on more valuable activities. After all, in the autologous/ex-vivo spaces, scaling out isn’t just limited to equipment/operational units; there’s also a significant operational headcount that comes with it. In turn, the more capable our technologies are of eliminating rote manufacturing tasks — for example, waiting to take and move samples from one place to another — the more we can apply our talent where it matters most. Though we can certainly hope a technology will scale in terms of volume as a program progresses through the clinic to the market, we can also hope such platforms help optimize our operational efforts, as well.
Beyond Technological Flexibility: Embracing Cognitive Flexibility
Throughout my conversation with Maingi and Foster, I found my mind drifting back to an argument (one of four) I made earlier this year following Advanced Therapies Week 2022: We aren’t currently built to be a standardized industry. Though there are many scientific and technology-oriented reasons underpinning this argument, there’s also a mental component as well. Flexibility isn’t just an important characteristic of a technology; it must also be an essential part of how we think about and build the future.
Our goal may be to achieve “flexibility” in the future. But interestingly, how we envision that future today demonstrates a degree of cognitive inflexibility. As we discussed in part 1 of this article, our continued reversion to the success and standardization of the mAB platform — though comforting — might not actually be the “right” future for many of us in the ATMP space. Our future — or at least our near-term future — will not be an exercise in “plugging in” the recipe and scaling up (up and away!) to thousands and thousands of liters to treat hundreds of thousands of patients. Seeing as scale-up has been our forte for quite some time, it’s not surprising that we would try to solve our own challenges using that blueprint. However, I’d refer you to Moderna’s efforts to globally scale-out its mRNA vaccine using a kit approach as a beautiful example of how scale-out can also be a successful global exercise, as long as we don’t underestimate the complexities of comparability and tech transfer.
Though our patient populations/indications may not demand nearly as much as mABs in terms of scale/volume today, we still have significant economies of scale challenges facing us. We must solve for significant affordability and accessibility challenges, which necessitate technological optimization to enable flexible scale-up or out (and down), as needed.
For both Maingi and Foster, one of the answers to this challenge is to explore different forms of partnerships to achieve the “round hole” technology platform and “round peg” process from the beginning. Of course, this is easier said than done. As both Foster and Maingi pointed out, technology providers in the bioprocessing space are first and foremost engineers, with the goal of creating a piece of equipment that will then be sold and passed off to the customer to use in-house. Though they both admit this approach can work depending on the underlying needs, in a biologically diverse space like the ATMP space, this can’t be the only model.
Generally speaking, we can call any partnership a “meeting of the minds.” But throughout my discussion with Maingi and Foster, it became clear that partnerships between innovators and tech providers in the ATMP space are defined by a little something extra. In addition to the same interests in collaborating and furthering science and technology, they are also in the important position of defining what the future of each ATMP therapeutic modality can look like in the future. There are a few things we as an industry know we want to accomplish, including shortening development timelines and improving patients’ clinical outcomes. But the strategies we employ to arrive at that future can — and should — be much more than employing all the same tricks we’ve relied upon in the past.
As Foster concluded, partners need to be asking themselves, “Is this potential partner consistently looking in the past and not to the future? Are they stuck in their way of thinking? Even though we can’t know what the future holds, do we at least share the same vision for the future and a willingness to keep all the options on the table?”