Managing the regulatory oversight of a cell therapy process as it moves toward commercialization is a unique challenge. Remember that the process is the product. Because absolute product characterization is extremely difficult, a company must demonstrate that it can consistently reproduce the manufacturing process with every patient, every batch, every facility, every time.
Funding availability increases as you pass each clinical trial milestone (Figure 3), but critically it becomes increasingly more difficult to make process changes. So, for most cell therapy companies, investing in new processing technology during clinical trials — when there is no certainty of regulatory approval — presents a significant decision to be made (Figure 3). It is therefore important for cell therapy companies to select and use technologies during clinical trials that can meet the needs of comparability, CoG, and scale-up when they get product approval.
By investigating the details of any therapeutic cellular process, you will invariably find that a unique combination of technologies must be assembled to complete it. Each cell therapy requires its own process solution. And the current status of the service sector for this market is that many process technologies suitable for cell therapies are not very readily integrated with one another.
Investing in a customized, automated, and integrated commercial-scale production system can be very easy to justify once regulatory approval is received, but developing such a system to suit a very specific process would be difficult for most companies to justify during clinical trials. However, not addressing that issue during clinical trials can profoundly affect the commercial success of a therapy. Post-approval-process changes are often both difficult and expensive to implement. Managing the transition from clinical trials to commercial-scale production therefore warrants considerable thought and planning. As John F. Kennedy is reported to have said, “There are risks and costs to a program of action. But they are far less than the long-range risks and costs of comfortable inaction.”
Figure 4 summarizes typical development stages my company applies in development of a cell therapy manufacturing process. The probable CoG and investment in process technology can be anticipated early through this approach to provide visibility of commercial outcomes. It is also important to involve regulators in this vision of the process implementation and scale-up strategy. As an implementation of quality by design (QbD), it can be viewed as a path to “profit by design.”
Stage 1 activity creates an opportunity to explore different process technologies and select a configuration that will integrate to reflect your process intent. Cost-modeling tools provide visibility of the cost structure that drives preferences. For example, magnetic-bead selection technologies provide robust selection methodologies but represent a systematic impost on end-product cost that is worth scrutiny.
The outcome of that activity is identification of one or more preferred directions for the integrated process. Commonly, several steps have novel elements that interact uniquely with surrounding operations. QbD strategy will highlight those novel elements as high risk, encouraging early resolution through testing.
The Stage 2 program is defined by that information after addressing uncertainties in process capability with practical testing. This usually involves the process development team of the process owner. Once unit processes have been verified as competent for integration into a production system, our task becomes weaving that process into the clinical trials program.
A common investment dilemma often occurs at this point. Although the need for consolidating a process for clinical trial operations is important, early clinical trials represent a difficult point in a fundraising cycle, especially for start-up organizations. Investment in fully automated production equipment, disposables and tooling, control software, and a validation package is difficult to justify when a therapy’s efficacy has yet to be proven.