You have come up with an innovative and potentially curative cell therapy product, you have worked tirelessly to develop a quality profile and production process and guided it through the various stages of clinical development. Now it is time to commercialize, but have you considered the question: “Is my process scalable?”
Once the biology of the product has been established, the production process is typically “thrown over the wall” for manufacturing engineers to retrofit scale without any previous input. This disconnected approach is ill-advised, as it is much more efficient to work across multiple disciplines to develop a process from day one with scalability in mind.
Cell therapy manufacture: Scale-up vs scale-out
Broadly speaking, there are two paradigms in cell therapy manufacture; off-the-shelf (always allogeneic) and patient-specific (commonly autologous) therapies. Off-the-shelf therapies represent a business model akin to current biopharmaceuticals, where one batch can be manufactured to treat multiple patients. This allows for increasing economies of scale, which drives down the per-dose cost of the final product. A good example of this is the manufacture of antibiotics, which can be produced in batches greater than 100,000 liters, treating many patients at relatively low cost. This means that there is a wealth of engineering knowledge and technology that can be leveraged to support the manufacture of off-the-shelf cell therapies at increasing scale, given a rigorous understanding of the product quality profile .
Patient-specific cell therapies offer a new and exciting challenge for process scalability, where the manufacturing process must be scaled out, in order to produce one batch for each patient. This introduces the concept of “personalized medicine,” where the cost of production per batch cannot be reduced by exploiting an increasing economy of scale by simply producing a larger batch. Reducing the cost of these patient-specific cell therapies must therefore be achieved by advances in engineering and manufacturing technology, reducing the number of complex, labor-intensive and open-process steps that are commonplace in cell therapy production. Given the impressive efficacy profile of a number of patient-specific cell therapies currently in clinical development, it is imperative that these processes can be transferred into a commercial manufacturing setting in a scalable and cost-effective manner so that they present a reasonable value proposition for their developers, increasing the likelihood that the therapies will have a transformative impact for patients.
Challenges in developing scale-up manufacturing processes
“Scale-up is about more than just making the pot bigger!” –Christopher Hewitt, Aston University, UK
Conventional scale-up bioprocesses typically use cells to produce therapeutic agents, which can then be isolated and purified without the need to recover the cell. For the manufacture of cell therapies, retention of cell function and quality is of primary importance in order to preserve product efficacy, as the cell is the product of interest. This means that the desired quality profile of the cell must be maintained through the entire manufacturing process, including the harvest, downstream processing, and delivery. Preservation of cellular quality throughout the entire manufacturing process is critical to off-the-shelf cell therapies and will require the development of scalable harvesting, and downstream and formulation technologies to cope with the large batch size produced.
Challenges in developing scale-out manufacturing processes
The unique challenge of scaling-out patient-specific cell therapy manufacturing processes is achieving a reduction in the cost per dose, given that there are currently few economies of scale to exploit. Therefore, minimizing the cost of idle capacity will be critical when ramping up towards commercial production. The construction and validation of additional manufacturing capacity must be carefully managed and aligned with projected patient accrual or product sales, to avoid incurring a high cost per dose caused by the large overhead cost of these idle facilities. That said, there are strategies that can be implemented within the labor-intensive scale-out manufacturing model, such as closed systems, automation and process simplification, to control the cost per dose and ensure scalability towards commercial production.
Looking to the future
What can you do to ensure scalability in your cell-based therapy manufacturing process? The key is to start as early in the product development cycle as possible and understand how scalability can be achieved for your particular process, be it off-the-shelf or patient-specific, and minimize the cost per dose as the production rate increases. This includes rigorous characterization of bioreactor platforms for off-the-shelf therapies at the small scale, so that comparability of the physical environment can be maintained based on sound engineering parameters as the scale increases throughout development. In addition, you should work closely with your manufacturing partners to leverage their knowledge and expertise to ensure that your process, including supply chain and logistics, is scalable and therefore will be commercially viable for the future. The timing, cost and comparability risk of modifying process steps during clinical development should be carefully managed and balanced against increasing cost advantages, to ensure the future sustainability of the cell therapy product.
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