Scaling MSC Therapies: Overcoming Risks and Barriers

In recent decades, significant advancements have been made in MSC manufacturing. The increasing number of companies with approved therapies on the market indicates a promising trend for future success. On the other hand, MSC manufacturers also face risks and challenges in scaling MSC therapies. Sharma said these generally fall into two categories: operational challenges and biological challenges.

One operational challenge is supply assurance. To ensure access to key supplies, manufacturers "should have a secondary supplier available for some types of products," Sharma said. A second risk is the potential for contamination, an area that regulators are closely monitoring. For this reason, Sharma said, cell therapy manufacturers are seeking ways to produce MSCs in contained environments and need to incorporate closed system operations.

Another operational challenge is space constraint, and the need to keep manufacturing facilities near hospitals and patients. Sharma explained that having manufacturing facilities in or near the hospital can be important for autologous therapies, or in any case where patients need urgent treatment.

In terms of biological challenges, while manufacturers have established protocols for growing MSCs, several factors can impact the stability and consistency of MSCs during manufacturing.

According to Tsai, variability among donors can be a challenge because many MSC products are derived from healthy donors. Factors such as age, health, and the genetic background of the donor can affect the growth and expansion of MSCs once they're in culture.

In addition, MSC senescence, or age-related functional decline, can impact therapeutic efficacy and be accelerated by cellular stress.

MSC manufacturers are employing multiple strategies to overcome these biological challenges. Some researchers use biochemical or biophysical interventions to prevent senescence in MSCs, while others use data to predict which healthy donors might provide MSCs that proliferate faster.

Another strategy is the use of induced MSCs—MSCs derived from iPSCs—which can themselves be derived from patient cell samples. Induced MSCs tend to have greater proliferative abilities than primary MSCs, which may help manufacturers overcome supply limitations associated with patient-derived MSCs.

Fortunately, there are solutions to help manufacturers overcome some of these challenges. For example, closed systems for cell production help reduce risk in multiple ways. "The very first reason why people choose closed systems is because they can reduce contamination risk," Tsai said. Closed systems help companies fulfill regulatory and Good Manufacturing Practices (GMP) requirements, she explained, because they eliminate the need for manual manipulation with the cells and culture media.

To reduce manual manipulation, some companies use robotic systems to handle cell culture vessels, Tsai said. "But that can be very costly, especially for a smaller company trying to start a new manufacturing process. In that situation, Corning closed systems can provide a relatively economically-friendly approach for those customers." Furthermore, she said, stackable closed vessels, such as Corning CellSTACK^® culture chambers, can be manifolded together using connectors or tube welding, and filling/emptying can include automation via pumps. This saves labor and reduces the potential for human error during handling. Corning's closed system vessels have a proven track record of high performance and reproducibility. In addition, Corning provides supply assurance to mitigate supply-related risks.

According to Sharma, another advantage of Corning's closed systems is consistent surface chemistry. "Starting from the various small-scale vessels like T-flasks up to the largest production scale, Corning provides the same type of surface chemistry. So, for example, if they are growing their cells on a CellBIND surface from the beginning, they do not need to do any process development when they move into a scale-up or a scale-out model."

This plug-and-play aspect of Corning's closed system products enables users to easily change out vessels to meet their needs at various points in the development and manufacturing process, while maintaining reproducibility. For example, a company could perform pre-clinical stage cell biology experiments, scale-up for therapeutic product manufacturing, and relocate manufacturing to a new site, all using Corning vessels with the same surface chemistry, thereby minimizing changes to the cell growth environment.

Sharma explained how products, such as Corning CellSTACK and Corning HYPERStack^® vessels, can support scale-out as a less risky alternative to scale-up. "When we are scaling out, it means we are using the same type of vessel; we are just multiplying the number of vessels. So, if by any chance there is contamination, or any other issue with one HYPERStack vessel, I can continue with my batch with the other HYPERStacks." With traditional scale-up, cells may be grown in 1,000-liter vessels, which risks losing the whole batch in the case of contamination.

Another advantage of scaling out using modular vessels is that manufacturers can customize the production scale simply by adjusting the number of vessels, Sharma said. This means that cells can continue growing in a consistent environment, from the research lab to the manufacturing facility, without the need to transition from adherent to suspension culture or make other significant changes in conditions. Tsai added that this can save time in validation, reducing the time required for validation of a scaled-up microcarrier process from 6 to 12 months or more, to 1 to 2 months for process validation using CellSTACK or HYPERStack vessels.

A modular system can also simplify planning batch processing steps, such as centrifugation, because you can adjust the number of vessels used based on the centrifugation system's capacity. This can help protect cell quality, Tsai said, by minimizing the time that passes between harvest and processing.

On the other hand, there are situations where scale-out with a static system, such as the HYPERStack system, would not be suitable. For example, when a manufacturer requires very high cell yields or needs to automate system monitoring. This is where scale-up with a dynamic system, such as the Corning CellCube^® cell culture system, can be beneficial. In the compact, scalable CellCube system, a peristaltic pump circulates cell culture media from a bioreactor through the cell growth area and back, ensuring consistent gas and nutrient distribution.

The CellCube system combines the advantage of direct cell observation found in static culture systems together with the advanced capabilities of bioreactors, such as real-time parameter monitoring and regulation. Sharma explained that a dynamic system like the CellCube system can open up opportunities to automate the monitoring of parameters such as glucose consumption, and lactate accumulation within the system. "I can see all those parameters on the go. People choose these dynamic technologies based on the economy of scale, and the second reason is automation or labor," he said.

Tsai agreed, saying customers come to her to discuss dynamic systems and scale-up options when they need to produce high cell yields but have limited incubator space and operators. Transitioning from a static system to a dynamic system, such as the CellCube system, can further reduce labor and space requirements as cell yields are scaled up.

Because many cell therapy manufacturers face similar challenges, collaborating with an experienced vendor offers significant benefits. Corning's application scientists share information across regions, giving customers a playbook to follow and the ability to tap into the knowledge base of a global team with MSC experience.

Corning's scientific teams can provide manufacturers with support in overcoming both biological challenges, such as selecting the right surface, and operational challenges, like optimizing the configuration of vessels, Sharma said.

For Corning cell and gene therapy manufacturing products classified as medical devices in the United States, Corning's regulatory and quality teams can provide manufacturers with the necessary documentation for regulatory approval processes.

Learn more about Corning closed system products, or visit our resource library to learn about Corning's work with MSCs.