By Dr Ryan Roberts, cell processing leader at Cellular Origins
Despite the rapidly emerging innovations in the fields of cell and gene therapy, bottlenecks in the manufacturing process for cell therapies prevent these transformative drugs from reaching patients.
There are several broad challenges to the scalability and affordability of cell therapy, including reliance on manual intervention, specialist expertise, lack of space efficiency, poor allocation of capital, lack of physical and digital integration, process complexity, and high overall costs, to name a few.
These challenges create an urgent need for innovative solutions that enable the creation of scalable, cost-effective and automated cell therapies.
A closer look at the cell therapy challenge
First, the high intensity of labor and capital presents a major challenge for the industry.
Manufacturing workflows can involve hundreds, even thousands of manual interventions, creating significant scope for human error. Additionally, therapy developers using partially closed systems must operate in expensive controlled environments, called clean rooms, to meet regulatory requirements.
Most controlled Grade A (ISO 5) cleanrooms are inherently more expensive to operate than Grade C (ISO 7) or lower, so it is critical to transition operations to lower cleanroom grades. The only way to achieve this is to implement closed automated systems throughout the process, thereby reducing facility operating costs while ensuring regulatory standards are upheld.
Cell therapy manufacturing and quality control (QC) processes are complex, with low levels of standardization. Many companies will use their own unique combination of specialist equipment and bespoke testing strategies in addition to customized identity, purity and potency tests to suit their unique biological product. This results in a demand for specialist skills, with skills that cannot be easily transferred between facilities. This requires intensive investment in training, but this, coupled with high turnover, results in relatively low productivity and significant recruiting effort, adding to already high operational costs.
Space efficiency is another challenge to the scalability and affordability of cell therapy. Current manufacturing technologies often offer limited potential for process intensification. Opportunities to improve space efficiency may not be realized because these limitations, coupled with the need for continuous manual intervention in semi-automated workflows, can create unacceptable risks of cross-contamination and introduce potential errors. Thus, scaling from hundreds of patient batches per year to tens of thousands requires significant investment to scale the production footprint. This is not sustainable, on grounds of affordability, accessibility, or the environment.
Space costs are often exacerbated by inefficient allocation of capital. Leveraging high-cost processing equipment, most of which lack digital integration, for lengthy processing activities, can increase production costs, through over-capitalization, rather than reduce them by eliminating labour. For example, autologous CAR-T, TCR-T or TIL may use a high-cost automated bioreactor for incubation, thereby using the equipment for days, or weeks.
In contrast, the less capital-intensive and more manual option proved to be a viable option, despite the added consumption and labor costs. This option can offer comparative compactness, and the potential for more intensive facility utilization, but getting this to full effect requires new end-to-end automation approaches and in-line process analytics test integration.
Given the uncertainty of advances in manufacturing technology to address these challenges, therapeutic developers are primarily driven by new biological innovations. Allogeneic therapy is arguably more amenable to process intensification, thus justifying the capitalization involved in centralized manufacturing. Autologous therapy, on the other hand, continues to innovate in ways that allow for more limited processing and the elimination of the expansion step, to decentralize manufacturing.
Both approaches, however, forced therapy developers to go through significant rebuilds. Ultimately, this means that the therapies that are most advanced in their clinical development and have the strongest clinical evidence for their efficacy are not prioritized, as the route to achieving their commercialization within the existing manufacturing paradigm proves to be commercially unviable.
Innovative solutions on the horizon
Despite these challenges, there are innovative manufacturing solutions on the way, but their adoption is not guaranteed. New automation platforms must prove that they can accommodate the entire cell therapy manufacturing process while offering more integrated process analytical testing and complex input preparation integration. Moreover, they must demonstrate this while mitigating the risk that rebuilding processes give rise to the complex biologic qualities of cellular therapy. They must also convince an increasingly skeptical and discerning audience of therapy developers that this future of automated generation is achievable now, not the distant future.
For this to be achieved, solutions for cell therapies must, above all, be flexible to the particular biological requirements of the therapy. To achieve complexity and variety of dosing regimens, for example, flexibility is essential. Technology developers must offer scalable solutions that can accommodate, in partnership with therapy and fellow technology developers, the current and future needs of the therapy process, to be truly successful. In the end, collaboration is the key to this.
At Cellular Origins, we believe that robotic fluid integration is a critical part of making this possible, without the need for redevelopment, but for this approach to be adopted by therapy developers on the cusp of commercialization partnerships with instrument developers, best-in-class in performing surgery units are critical to unlocking the potential space and capital efficiency of a modular approach to cell therapy manufacturing.
Through a network of partnerships and collaborations, we are confident of achieving our mission of reducing labor intensity and increasing space efficiency to ultimately lower the cost of manufacturing life-changing cell therapies, to make them more affordable and accessible to patients who need them. , in scale.