Table of Contents

  1. The Importance of Bioprocess Scale-Up
  2. Challenges with Bioprocess Scale-Up
  3. Best Practices for De-Risking Scale-Up

The Importance of Bioprocess Scale-Up

Scale-up is the process of transferring a process from small volume bench scale reactors to larger vessels for material generation for product testing or commercial production. Scale-up varies depending on the project and final projected scale of production, but it often involves a staged series of increasing volumetric scales for material generation and to verify strain performance at several steps of increased production volume. As part of this, the process is often transferred between different facilities, and new infrastructure may even be built to accommodate new processes.

Scale-up is critical, as changing strain performance at increasing scales can have serious economic and process implications. Below a certain threshold, decreased strain performance may even invalidate the commercial relevance of a product. Separately, changing bioproduct profiles when scaling up may complicate DSP processes or result in product impurities. With the proper preparation, the chance of costly mistakes during scale-up can be reduced.

Challenges with Bioprocess Scale-Up

While bench-scale fermentors offer an ideal platform for developing strains and fermentation processes in a controlled environment in a relatively economical manner, there are still differences between small scale and larger fermentors. The desired outcome of scale-up is that the fermentation process that has been developed is robust and performs predictably across scales. However, in reality, scale-up can be challenging and strain performance may vary across scales. 

The challenges around scale-up primarily center around the differences in the environment between bench-scale and larger fermentors. As strain performance is a result of an interaction between the microbe and the process, a change in the environment can also result in a change in performance. Due to the physical differences in scale, there are some differences, such as increased pressure at the bottom of large tanks and gradients in nutrient concentrations due to longer mixing times, that are difficult to avoid. However, there are other factors, such as oxygen transfer rates or differences in the seed train, that can be anticipated ahead of time.

Best Practices for De-Risking Scale-Up

There will always be risks associated with scale-up of fermentations, but with planning, common issues can be addressed in the planning process or by simulation at bench scale. 

Develop processes with constraints at scale in mind

Once fermentation processes reach larger scales there can be many physical and engineering constraints that can impact the process. These include limitations on physical factors such oxygen transfer rates, feed rates and even cooling capacity at scale. These limitations can be anticipated and factored into process design. The process design space for fermentation development is large, and placing upper limits on variables that would be impractical at scale can aid development of scalable processes while still leaving many variables to test.

Simulate process conditions observed at scale

While some of the factors at scale can be addressed by placing bounds on the process design, there are others that cannot be addressed in this manner. For example, in large tanks mixing times are on the order of minutes rather than seconds. This can result in gradients in substrate concentrations in the tank, resulting in cells experiencing periods of both excess and starvation. In the development of a robust process, these periods can be simulated in bench-scale tanks by oscillating the substrate concentration in the tank repeatedly in order to assess the impact on strain performance.