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Solving scale-up and manufacturing challenges in cell and gene therapies

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Dr. Nandu Deorkar, senior vice president, research & development at Avantor, addresses the manufacturing challenges that remain when developing cell and gene therapies at scale.

Key insights:

One of the most exciting and revolutionary trends driving biopharmaceutical growth and innovation is cell and gene therapy. It is exciting not only because of the growth of successful trials and approved therapies, but also for the technology’s ability to impact patients’ lives.

Initially, these therapies targeted diseases with small defined patient populations, including paediatric diseases with very limited treatment options. Many of the first patients treated for acute lymphoblastic leukaemia are thriving, four to six years later. Recently (November 2022, FDA-2021-D-0776), the FDA issued a guidance document entitled: “Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial”; this is indicative of significant industry developments. We are seeing leading research institutions, biotech and major biopharma companies moving onto larger populations — starting with leukaemia, lymphomas, multiple myeloma and autoimmune and inflammatory diseases.

Critical challenge: Scaling up manufacturing

We are currently setting a new, historic pace at which new therapies are being taken from research to full-scale manufacturing. Therein lies a major challenge: To take advantage of these opportunities to advance these therapies requires that we address the challenges in manufacturing processes that remain.

The industry needs to continue to find efficiencies and optimise manufacturing to deploy cell and gene therapies economically and at a scale that can make a difference for patients globally. Across the board, we need to implement improvements in raw material inputs and drive innovations in manufacturing technology to deploy gene therapies economically and at scale.

For example, adherent cell culture systems are inefficient. Given the magnitude of the therapy being delivered to the patient, it is clear the industry does not have the ability to produce enough to satisfy growing demand.

Either something must change with the process itself or massive manufacturing capacity will need to be built to sustain current production methods, which will make it difficult to make these therapies more affordable for wider patient populations.

Importance of process standardisation

Equally important is the need for process standardisation to improve scalability. Variables and failure modes must be taken out of the process — this is where innovations in process technology can make a real difference. Production systems can be standardised and closed so they are less exposed to failure modes. Processes can be minimised to drive cost efficiencies and, perhaps, better clinical outcomes.

We can employ better workflow technologies, such as single-use sterile fluid transfer. It is also probable that fill/finish requirements will be different for cell and viral products, so improved excipient technologies will play a large part in better patient experience and response.

What are some approaches the industry can pursue to advance optimisation?

There are two major pathways to process optimisation: First, we must anticipate innovation and optimisation coming from advances in academia. Second, we expect step changes in process improvements from contract development and manufacturing organisations (CDMOs) and other producers. This can be done with close monitoring and, where relevant, partnering with these organisations early on.

Developing partnerships with providers as soon as possible should increase process efficiency and minimise later missteps, even on joint approaches to regulators. In raw materials, specifically, manufacturers are receiving more requests for cGMP grades of materials that have never needed to be made at scale or to cGMP specifications before.

Even if these are available at the correct analytical grade, there is considerable raw material expense associated with components such as plasmid DNA. The requirement for biological activity to be retained limits the use of harsh purification methods and adds a special sensitivity, so that potentially harmful or adventitious agents cannot be introduced through the raw material supply chain.

This is an area that greatly benefits from close partnerships between manufacturers and their raw material suppliers, to better understand the requirements for cGMP materials and use them early in the therapy development and manufacturing process. Additionally, partnering helps with tracking and measuring a raw material supplier’s quality system, to ensure consistency over time. The importance of collaborations and quality agreements with raw materials suppliers cannot be understated.

New solutions to improve manufacturability

In areas such as cell culture components, production chemicals, single-use technologies, sterile fluid transfer, excipients and the technology surrounding those process components, there is value in trying new solutions to address improving the manufacturability of cell and gene therapies.

Even at the early stages of trials, we can better understand the variability that comes from research data and use it to correlate with clinical and process outcomes. Taking out manual steps as early as possible is important, as well as creating closed systems using sterile fluid transfer technologies to eliminate process risk.

Hopefully, one outcome of these efforts will be to find scalable ways to address costs for cell and gene therapies, which are still exorbitant. Ultimately, these drugs must be developed in a more cost-effective manner. That is an area where technology providers and suppliers can play a significant role by closing and automating systems and by understanding the contribution of labour, overhead and possible economies of scale from reducing processes.

With the amount of strong research into developing, understanding and characterising drug targets, and figuring out how to make these in production-level volumes, this will be a constantly changing landscape. And there will be many parts to patient treatment options going forward.

Conclusion

Cell and gene therapy has the potential to change patient outcomes for the better as treatments and therapies evolve, adding one more healing tool to monoclonals and biologics. As with other treatments that moved from theoretical possibilities to real results, the industry is developing a clearer and more complete understanding of the issues that need to be addressed to drive better patient outcomes. Through collaborative partnerships among researchers, manufacturers and suppliers, the industry as a whole has the opportunity to move science forward.

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