In mesenchymal stem cell (MSC) therapy, promising early data does not guarantee long-term success. Many programs falter when the realities of manufacturing begin to challenge processes designed at small scale.
At Corning Life Sciences, Chief Scientific Officer and Director of Commercial Technology, Yoshi Shyu has worked alongside developers navigating this transition – from early research through to commercial production. Having supported three globally approved MSC therapies, as well as a growing pipeline of pre-commercial programs, Shyu highlights the impact of early, strategic manufacturing decisions.
“Teams typically realize their process won’t scale as planned when they attempt their first true scale-up process,” he says. “This is often the point when the ‘science’ that held at smaller scales begins to change.”
Here, Shyu reflects on the most common missteps in MSC development, and how a more integrated approach can help therapies reach patients.
You’ve worked closely with many developers advancing mesenchymal stem cell (MSC) therapies. From your experience, what are the most common reasons these programs struggle to progress beyond early clinical stages?
From a biological point of view, one of the most common reasons MSC therapies fail to progress beyond early clinical stages is managing donor-to-donor variability. This can make it difficult to consistently demonstrate efficacy and to replicate outcomes.
Equally as important is early-stage trial design – patient populations tend to be heterogenous, which makes it challenging to clearly interpret efficacy endpoints.
Looking back across different MSC programs, what early development decisions tend to have the biggest impact on whether a therapy can ultimately be manufactured at scale?
This one is easy, the choice of cell culture system. There are multiple platforms, technologies, and modalities to grow MSCs and each have different value propositions that can emerge at different stages – from early development to manufacturing. Some cell culture systems will be easier to scale-up, while others are better suited for scale-out approaches to meet the desired batch size requirements.
The most successful programs tend to choose platforms that allow them to maintain the same underlying surface chemistry and workflow as they scale. That continuity reduces the need to redevelop or revalidate the process later, which can save significant time and risk as programs move toward commercialization.
At what point in development do teams typically realise their process won’t scale as planned – and what kinds of issues usually trigger that moment?
Teams typically realize their process won’t scale as planned when they attempt their first true scale-up process. This is often the point when the ‘science’ that held at smaller scales begins to change. A typical trigger is when revalidation must be done during the scale-up as the changes in the cell biology start to appear (cell health, doubling time, productivity, viability, and so on).
What are some of the most overlooked factors when designing a manufacturing process for MSC therapies?
One of the most overlooked factors is a clear understanding cost of goods (COGS), especially because early process decisions can lock-in cost structures that are difficult to change at later manufacturing stages. COGS isn’t just about the price of materials, it’s also driven by how complex the process is to run. Systems that require extensive manual handling or open steps can increase labor, contamination risk, and facility burden, which all add cost over time. Failing to account for COGS often results in a process that is technically viable but cannot be sustained at the commercial scale.
As MSC programs move toward late-stage trials and commercialization, how do regulatory expectations shape the way developers approach manufacturing and process design?
As MSC programs approach late-stage trials and commercialization, regulatory expectations fundamentally shift development priorities. Across regulatory agencies, the focus moves away from flexibility and toward predictability, control, and sustainability. It is important to keep this in mind as early-stage development is largely about proving the biology and mechanism of action, while in later stages, regulators expect the manufacturing process to be locked, reproducible across the different batches, and controls are in place to deliver consistent endpoint deliverables.
You’ve been involved in supporting multiple MSC therapies that have reached commercial manufacturing. What lessons from those successes could help newer programs avoid costly pivots later on?
I recommend working with manufacturers and suppliers who can support you across the entire development journey, from early research through commercial manufacturing. These partners have a deep understanding of how their products integrate into the overall workflow, which is especially critical at later stages where their guidance can help teams reach commercial-scale and regulatory requirements.
We have supported multiple MSC therapies globally that have successfully reached commercial manufacturing, and in each case the partnership began early, with close collaboration across multiple functions including R&D, manufacturing operations, quality, and regulatory teams.
Looking ahead, what changes in manufacturing technologies or development strategies could make MSC therapies easier to scale and deliver to patients?
I think we’re going to see MSC therapies become much easier to scale and deliver as manufacturing moves toward more standardized, closed, and automated systems. Technologies like optimized microcarriers, perfusion bioreactors, and engineered culture surfaces are already improving yields and consistency, which is critical for commercial viability.
Also, I believe there should be more focus on MSC therapy transportation and logistics with validated cold chain and cryogenic shipping, reducing handling complexity and risk as products move between sites. When you combine those advances with defined, xeno free media, improved potency assays, and a development strategy designed with the end in mind, it becomes much more feasible to industrialize MSC therapies and reliably deliver them to patients at scale.
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