Is your process scalable?

When we first initiated the viral-specific T cell clinical trial NCT02048332, we experienced the challenge of reaching the right dose while managing the patient-to-patient variability; dose was based on patient weight and body surface area which varies between patients. Our process though was designed to produce the needed dose (variable) within the culture period (constant).

In a previous post “Is my process suitable for clinic?” I listed the scalability as a criterion of a clinic-suitable process. In this post, I’ll discuss this in greater details to cover what scalability involves, and why it is important to consider it early on in the process development stage.

Scalability of a cell therapy process is the ability of the process to increase the output while maintaining the quality of the final product. Production of cell and gene therapy products for autologous use would involve some degrees of variability as I mentioned in the example above. However, production of allogeneic cell and gene therapy products for off-the-shelf (OTS) use is an entirely different arena. For OTS production, the cell therapy process would be designed to generate very high quantity of final cell and gene therapy product, and here is where close attention needs to be paid during process development to ensure the process is scalable at OTS scale.

Some of the factors that impact scalability are more obvious than others, but all factors need to considered for the process to be successful. I’ll next list and discuss few major factors.

1. Production Platforms

Most, if not all, cell and gene therapy processes are developed in culture plates or flasks, which serves both the purpose and the time well. However, scaling those plates or flasks for clinical production may be challenging, or even impossible, depending on the process.

For clinical production, the production platform needs to be able to scale while maintaining quality. If the ultimate goal is to do clinical production in a certain platform, e.g. a bioreactor, the researchers need to try a bioreactor prototype at some stage of process development to determine if such a production platform is suitable for their specific cell and gene therapy product. Based on prototype testing, researchers can then decide what changes need to be made, if any.

2. Material

Scaling a cell and gene therapy process usually involves more disposables, more reagents, more equipment, or higher capacity thereof. Planning of increased material consumption makes production goes well most of the times. Such planning though may experience turbulence when it comes to reagent the production of which is an on-demand type, such as viral vectors. Viral vector production is a complex and expensive process, and if not timed well, a delayed or rejected viral vector batch can throw clinical production several months behind schedule. Therefore, careful planning of material is needed, and especially for on-demand materials.

3. Quality

Maintaining the quality of cell and gene therapy products throughout production is especially challenging when high quantities are being produced. To maintain quality, the process may need to utilize more equipment, more personnel, or more facility space to limit the time where the product is being manipulated at suboptimal conditions. As a result, scaled production would generate more in-process samples and would require more testing for products, for personnel, and for facility.

4. Cost

Researchers may have some leeway in the first three factors (production platform, material, and quality) but not on the production cost, simply because the cost is the result of the previous factors. If a process is designed to utilize a specific production platform, to use high quantity of expensive material, or to exhibit a strict quality profile, the production cost will definitely be high. While all factors are critical, the production cost might be the most critical one because it directly impacts the patient. High-cost product would limit patient access to the product, which is counterproductive to inventing a product that would provide a solution to patients that ran out of options.

So, researchers, keep doing the great job you are doing; inventing well needed therapies for our patient community. Just keep in mind for your hard work to bear fruit, your innovative process needs to be scalable without impacting the quality or the cost in an adverse way. This would ensure easier implementation, and better access to patients.

Let us know if we missed anything, or if you would like a specific subject to be discussed, write to us. 

About the author

Naseem Almezel, earned his MSc degree in Cellular Therapies in 2010, since then his career focus is to support Bone Marrow Transplant and Oncology programs. Naseem likes to work in the lab doing translational research, or in the cleanroom doing GMP production. When he is not working, Naseem likes to read and to spend time outdoors. Find more about Naseem here