(456d) The Importance of Selecting Appropriate Scale-up Concepts: One Example of Mixing Issues in an Industrial Fermentation Process

Mixing characteristics of fermentation reactors play a crucial role in an efficient operation. This is particularly important when processes are scaled-up into production scale reactors, with dimensions strongly diverging from small- and pilot-scale and leading to larger mixing times.

In this work, a fungal fed-batch process was scaled-up into an 80 m³ production-scale fermenter based on common scaling approaches. Against the expectations from the process design in small scale, the process showed a different growth behavior in large scale with a strong increase in biomass and a decrease in productivity. In the root cause analysis for this behavior, the liquid flow of the reactor was simulated by CFD coupled with a metabolic model to mimic the glucose consumption and resulting in a spatial concentration distribution in the reactor. The results revealed inhomogeneities of the glucose due to a suboptimal position of the substrate feed inlet. Based on these findings, a sensitivity of the organism towards glucose gradients was considered as possible reason for the observed behavior in growth. In order to confirm this hypothesis, the glucose inhomogeneities were scaled down by applying the substrate feed discontinuous as pulses in a small-scale reactor with ideal mixing behavior. This method allows to emulate the spatial concentration differences between high glucose concentrations around the feeding position and low concentration in less mixed zones, over time. The resulting process in small scale showed a similar behavior in terms of biomass growth and decrease in productivity as the unsuccessful process in large scale, confirming the hypothesis. Based on these findings, several measures were taken to reduce mixing inhomogeneities in large-scale. The following production campaign was successful with an increased productivity as anticipated from the small-scale.

This example illustrates the importance of including the appropriate scaling concepts for a process transfer. Some organisms and processes might be influenced by parameters that are changing during scale-up. Especially when scaling into large industrial scale reactors, intermediate scales are important to reveal potential sensitivities but are mostly not considered due to a lack of time and resources.