Advanced iPSC bioprocessing: process improvements for scalable and quality-focused cell production

In this interview, Sarah Gilpin, Principal Scientist in Process Development Services at Sartorius (MA, USA), walks us through the early phases of stem cell therapy development – from proof-of-concept science to therapies that now offer hope to patients. She explores the critical considerations for developing a cell therapy, including ensuring functionality, navigating regulatory requirements, and defining quality standards. Sarah also discusses the importance of getting the details right when scaling up and manufacturing these therapies to reach patients beyond the bench.

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The demand for high-quality stem cells for regenerative medicine and cell therapy applications has grown significantly. Since the start of your career, how have you observed the trajectory of stem cell therapies evolve, and what is their current state today?

When I think about the trajectory of stem cell therapies, there have been many phases. The early phase in the field focused on discovery and biology, where the learnings from hematopoietic stem cell transplantation, for example, established the proofs-of-concept that the idea of cell therapy was viable. Then came the discovery of embryonic stem cells and their capabilities and potential in the late 1990s. From there, we began understanding how to link developmental biology with what was known about fundamental cell biology, and the emergence of this idea of cell therapy and how we could use these cells as tools. It was still very much academic, small-scale and discovery-based work.

Then the field moved into a translational period in the early 2000s through the 2010s. By this time, we’d discovered iPSC reprogramming in 2007 and started thinking about patient-specific cell sources for therapies. The question became: what could we do from a clinical perspective to really utilize this potential? New ideas emerged around cell engineering and differentiation and what we could truly accomplish from a therapeutic standpoint. That translates into the current state, which is bringing this to clinical reality. Now, you have all these considerations around manufacturing, regulatory requirements, and scale-up that are really maturing some of these early ideas into a clinical pipeline and practical clinical applications. Those are the three phases I’ve seen in the field throughout my career.

What are some of the recent successes in the clinical application of iPSC-based therapies, and how do these achievements influence the need for further process development and optimization?

Since we now know that cell therapy isn’t just hypothetical – that these cells can really become therapies – the real need is driving the success of them through the rigor of process development, manufacturing and engineering. These are the next phase developments and optimizations that are critical.

In terms of recent successes, there are a few notable early achievements. I think we can look at the ophthalmology field and iPSC-derived retinal cell transplantation, which has moved into clinical trials for macular degeneration, representing some of those first early successes. Now, a treatment like that involves localized delivery, small cell doses and really well-defined functional readouts. It is an important proof of concept that an iPSC can be differentiated into a different cell type and successfully delivered to patients.

Currently, we’ve seen significant progress in neurology. Parkinson’s disease therapies have entered clinical trials, as well as others. In oncology, platforms are making advances with natural killer cells, T cells and similar approaches. We’re really at this precipice of success where clinical trials are increasing globally.

All of these clinical successes drive new process development demands. We’ve achieved clinical validation, but now the question is: how do we tie that together with process robustness, scale-up and manufacturability? The proof-of-concept we’re seeing clinically is really driving the need for validated process development and optimization.

High standards of production are essential in any case, especially for complex treatments such as advanced therapies. Could you elaborate on why there is a pressing need to develop new methods for stem cell production?

When we think about cell therapy manufacturing, there’s a fundamental shift: the cells are the product now. They’re not a byproduct. We’re not making vectors or proteins. The cells themselves are ultimately what we provide to our patients. The cells are living things, highly plastic, and have a mind of their own much of the time. To develop these complex treatments, we really need complex, quality-focused production systems in place. Small changes in media, culture conditions, or handling can amplify and have significant consequences on cell function, which is really the most important thing. If the cells don’t do what we need at the end, there was no point in making them in the first place.

That really goes back to reproducibility, process robustness, and how that’s tied to safety and quality. Scalability is not trivial. In these long, expensive processes, every deviation or change in the biological system can really impact your end product. You can’t simply scale by making a bigger bioreactor. You have to think about all of these steps along the way – expansion, differentiation – and ensure that the phenotype and function is stable at the end of your process. This needs to be linked with GMP-compliant, closed, automated manufacturing processes so that the science can really succeed in a manufacturing context.

One thing that’s important to stress is that when we say “iPSC,” that is not one thing. These cells were all created from different donors and have their own personalities, if you will. From a process development perspective, we always start at the foundation and don’t assume that one set of parameters or one specific process with one iPSC line is going to operate and function the same way as the next, even though we see them as equivalent. It is important that process development stays rooted in biology.

There’s definitely variability in the cell lines that are used, and that’s really important in the field these days. Which cell line do you choose? You can’t change it very easily as you move through development and regulatory approval. So that choice of cell line and then developing the process around that specific cell line is a necessary part of the task.

I think it’s not simply external factors – the biology of the cell line itself is really coupled with the process.

How do you define high-quality stem cells?

It comes back to a fundamental principle: the cells are your product. They must meet all your critical quality attributes – the quality standards you establish before process development even begins. These typically fall into well-established categories like safety, purity, identity and potency – all integral to your quality control and regulatory strategy. Essentially, you need to make sure that you have the cell type that you want at the beginning (your pluripotent cells), verify they are truly pluripotent and function as such, and ensure you have the desired cell type at the end of differentiation, confirmed by phenotype and function. You need to also confirm that you don’t have contaminants or other safety concerns.

Importantly, we’re not just growing cells to have a whole bunch of cells – they have to do something. There’s a mechanism of action, a clinical effectiveness they need to achieve. This raises critical questions: What readouts do you need to assess for a “good” cell? Do they need to engraft? Secrete therapeutic factors? Kill other cells in an oncology setting? What must they do, and what assays confirm they’re capable of doing it?

Then there are the safety fundamentals: no genomic abnormalities or contaminations, and stability through storage, transportation and administration. There are many defined categories of quality, and it’s ultimately the development team’s responsibility to establish the assays and criteria that meet those standards.

What unique challenges do these modalities and cell types present when considering scale-up and manufacturing?

Cost is definitely a significant factor. Scale-up and manufacturing are long processes. CAR-T and other cell therapies might involve less than a week in culture, but iPSC processes in bioreactors can run 60 to 90 days. The cost of goods and the risks associated with these extended timelines directly impact variability and quality.

Additionally, the potential for expansion and differentiation varies not only by cell line but also by how you design your process. You want to have the best yield and the best output possible.

What further steps do you believe are necessary to ensure that once these high-quality therapies are developed, they can effectively reach patients who need them?

I think it really is about linking together this biological proof of concept. The ability to differentiate these cells is not enough – the goal is to deliver these therapies to patients and have a meaningful impact. I think that’s really the next hurdle, though I don’t know if it’s the last.

There’s the cost of these manufacturing processes when you’re bringing them to GMP standards – the length and just the cost of goods. These processes tend to use more expensive reagents. When bringing it to the patient, there must be an economic consideration as well. Some elements of that come from a process perspective – optimizing and intensifying your process to bring down costs – but also looking at manufacturers, supply chain, reimbursement, etc. I think that pressure is going to be felt more and more as we see increased clinical translation of these therapies.

Processes need to be scalable and reproducible, and that ties into regulatory interactions. It is essential to demonstrate that products are safe, consistently manufactured, and deliver the intended outcomes before patient administration. This requires thorough process development followed by strategic engagement with regulatory authorities as a critical step toward clinical application.

Given the novelty of these therapeutic modalities, regulatory precedent remains limited globally. This requires a collaborative approach. For first-in-human studies and initial indications, a lot of groundwork must be established to define appropriate frameworks, safety parameters, and quality standards that will guide future development in this field.

Healthcare infrastructure also requires more development. These aren’t medicines you simply take out of the fridge or ship in a box or pill container.

This goes hand in hand with manufacturing. Once you’ve produced the cells, how do you cryopreserve them? How do you store them? How do you transport them to the site where the patient is? How are they administered? All of this requires substantial groundwork because it’s new – fundamentally different from what we’ve done historically.

These are some of the major challenges in getting these therapies where we want them: to the patients.

How do you understand the needs of a therapy in process development and deliver on those needs?

Our philosophy around process development is fundamentally about partnership. We leverage our subject matter expertise, process knowledge, and regulatory and manufacturing capabilities to work collaboratively with anyone facing specific process challenges – whether that’s an academic group, a startup, or even large pharma. The goal is to apply biological and process experience to help move innovations toward the clinic through genuine partnership and collaboration.

We start with technical calls to understand where a process currently stands and what the goals are. Often, these conversations center on scalability. From there, we build out work packages and define the necessary steps. This typically involves initial design of experiments to understand the process, identify improvements and then scale up. We can also transfer that optimized process directly to our GMP clinical manufacturing facility. This makes tech transfer more seamless because the same teams are on both sides – you’re not transferring to a third party, which can be extremely challenging. The approach is: understand the process, understand the goals, build a stepwise project, and then hand that back so success can continue from there.

I use the words “partner” and “collaborator” deliberately – not because they sound nice, but because that’s genuinely how the relationship needs to be built. Continued communication and feedback are critical. You’re entrusting us with something you’ve created, and you should be involved in its development and success.

Visit cell therapy solutions at Sartorius

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Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Taylor & Francis.

In association with Sartorius.