A lot of CDMO customers ask about scale-out and scale-up, and what approach might be right for their prospective cell therapy application. The answer can be a little convoluted and is not necessarily dictated by whether the cell therapy is an autologous or allogeneic application.
Scaling-out refers to multiples of a process. In concrete terms, this often means more flasks, more incubators, more roller bottles, etc. It is most relevant but not strictly limited to autologous cell therapies, where one batch is one dose for one patient.
Scaling-up, on the other hand, refers to producing more cells and/or more volume of a product, usually across several stages (small to medium to large). It is most relevant but not strictly limited to allogeneic cell therapies, where one batch comprises many doses for multiple patients.
Autologous manufacturing is one dose for one patient. This means that the process for creating the dose is what needs to be replicated and increased in numbers, rather than increasing the number of cells or volume of production. This expansion of multiple parallel processes is what is referred to when we talk about “scaling-out.” Typically, when CDMO customers increase production for more patients, they need to scale out. One example of this is CAR-T production in a Xuri™ bioreactor. If you have 20 patients, you will need 20 bioreactors, or 20 production runs. However, during process development, CDMOs are often tasked to take a developer’s proprietary autologous biology application in a T-flask and scale it up to an intermediate scale in a Hyperstack™ or Cell Factory™ and continue to scale it up into an automated and closed manufacturing platform, like the Xuri bioreactor.
In this example, the autologous therapy was scaled up in the process development lab and would then be scaled out as the GMP manufacturing need increases with larger patient numbers. This is a core competency of CDMO process development groups. To claim this competency, the CDMO must have both the infrastructure and experience required to scale up autologous cell therapies to GMP standards and scale out to meet the clinical demand.
Allogeneic therapies, on the other hand, are one batch, with many doses for many patients. However, with a new allogeneic cell therapy, scale-up carries significant risk if a batch should fail or become contaminated. Therefore, many allogeneic therapy developers opt for a strategy that caps the manufacturing scale to limit the risk involved. To give an example, let’s say that the therapy developer wants 1000L of production developed. Due to the high risk and high cost associated with a potential batch failure, they may choose to execute five 200L runs to segregate the risk. In this GMP manufacturing example, an allogeneic cell therapy developer has chosen to scale out (5x) the scaled-up (200L) process.
The proprietary allogeneic biology application described above may be delivered to the CDMO in a T-flask, and it is then the task of the CDMO to transfer the process to a bioreactor for the first time. Here there are certainly aspects of scale-up, and the transition from adherent cell culture to bioreactor culture is a unique challenge that the CDMO must be equipped to meet. Once this has been completed successfully, the new process may be transferred from a small-scale bioreactor to a larger bioreactor in a pure scale-up transition.
Previously in “Scaling-Up Production of Pluripotent Stem Cells Part 1: Begin with the End in Mind,” we outlined how cell culture scale-up, regardless of the cell type, is based on the concept of a seed train. The goal of the seed train is to generate increasing cell numbers, in a step-wise process, to seed a larger production-scale bioreactor. Read about the four major steps for PSC scale-up by establishing a seed train in the full post. In “Scaling-Up Production of Pluripotent Stem Cells Part 2 – Key Considerations for Successful Scale-Up,” we take a deeper look at important considerations for process development and optimization of large-scale PSC culture.
The concepts of scale-out and scale-up are not necessarily limited to autologous and allogeneic cell therapies, respectively. The concept of expanding the process, either per production line (scale-out) or volumetrically (scale-up), both have their places in both therapy classes and at different stages in the development and manufacturing journey.
For expert advice on scale-up and scale-out, contact CCRM’s CDMO team here. The process development team at CCRM has the required infrastructure and has developed the necessary scaling factors and experience to scale-up manufacturing workflows across the 10-100mL scale to the 20-50L scale. Our specialized teams have also worked in partnership to develop a CAR-T process that has been successfully deployed in customers’ clinical trial manufacturing campaigns and scaled out to meet increasing patient numbers.