The next phase of the study sought to verify the results obtained using the SimCell platform in bench-scale bioreactors. For this, a subset of 11 conditions was selected from the factorial design and run in 3 L bioreactors with 1 L working volume, one run per condition. The process parameters used in the bioreactor scale-up study were as close as possible to those used in the microbioreactors given the differences between the platforms.
The correlation between the specific productivity obtained in the microbioreactors and bench-scale bioreactors for all 11 conditions are plotted in Figure 2. In general, the specific productivity measured in the microbioreactor is slightly higher than that of the bench-scale bioreactor. This is partially due to differences in cell quantification between the two platforms. However, from the figure, it is clear that there is a strong correlation between the two scales with a calculated R2 value of 0.90.
In addition to specific productivity, a more detailed comparison was made for one of the conditions run in both microbioreactors and bench-scale bioreactors. For this condition, intact IgG, purity, and percent nonfully glycosylated forms were compared using microchip-SDS on a Caliper Life Sciences LC90 system.
The need for comprehensive process understanding as part of QbD and other initiatives requires large numbers of experiments to be executed. Current scale-down bioreactor models typically do not have the throughput to satisfy these experimental demands.
Simplified scale-down models such as shaken flasks and well plates generally do not have the process measurement and control capabilities to provide comparable data sets. Therefore, a bioreactor scale-down model with higher throughput is required to meet this demand. The SimCell platform offers the ability to execute large statistically designed experiments with automated feeding, measurement, and control comparable to bench-scale bioreactors. The high data content allows statistical analyses to be conducted across a variety of metrics, such as IVCC, titer, specific productivity, and product quality, to identify which factors significantly affect the process.
In the example study presented here, four process factors were varied across a total of 36 unique experimental conditions. Specific productivity was chosen as the primary metric and the SimCell platform identified feed 1 and pH set point as having statistically significant effects. In order for these results to be of value, the trends identified by the SimCell platform must correlate to those obtained in larger scale systems.
The results of this study demonstrated a good correlation between the microbioreactor and bench-scale platforms across 11 different process conditions. Based on this level of correlation, the SimCell platform and the concepts described in this study can be extended to larger experimental designs to quickly and efficiently explore a larger knowledge space and identify the design space in cell culture process development.