PID controls: the forgotten bioprocess parameters

Abstract

The ambr250 high-throughput bioreactor platform was adopted to provide a highly-controlled environment for a project investigating genome instability in Chinese hamster ovary (CHO) cells, where genome instability leads to lower protein productivity. Development of the baseline (control) and stressed process conditions highlighted the need to control critical process parameters, including the proportional, integral, and derivative (PID) control loops. Process parameters that are often considered scale-independent, include dissolved oxygen (DO) and pH; however, these parameters were observed to be sensitive to PID settings. For many bioreactors, control loops are cascaded such that the manipulated variables are adjusted concurrently. Conversely, for the ambr250 bioreactor system, the control levels are segmented and implemented sequentially. Consequently, each control level must be tuned independently, as the PID settings are independent by control level. For the CHO cell studies, it was observed that initial PID settings did not resulted in a robust process, which was observed as elevated lactate levels; which was caused by the pH being above the setpoint most of the experiment. After several PID tuning iterations, new PID settings were found that could respond appropriately to routine feed and antifoam additions. Furthermore, these new PID settings resulted in more robust cell growth and increased protein productivity. This work highlights the need to describe PID gains and manipulated variable ranges, as profoundly different outcomes can result from the same feeding protocol. Additionally, improved process models are needed to allow process simulations and tuning. Thus, these tuning experiments support the idea that PID settings should be fully described in bioreactor publications to allow for better reproducibility of results.

Microevolutionary dynamics of eccDNA in Chinese hamster ovary cells grown in fed-batch cultures under control and lactate-stressed conditions

“…The pH was maintained using CO 2 and sodium bicarbonate; dissolved oxygen (DO) was maintained at 50%. The PID settings have been previously reported as the results of the third tuning in Harcum et al 42 . A 10% antifoam solution (Cytiva) was added via a control loop as needed.…”

Generation of reference cell lines, media, and a process platform for CHO cell biomanufacturing

“…The PID setting for the DO used a sequence of manipulated variables and PID values. These values are described in Harcum et al (2022) as the third tuning final values (Harcum et al, 2022).…”

Microevolutionary dynamics of eccDNA in Chinese hamster ovary cells grown in fed-batch cultures under control and lactate-stressed conditions

“…The PID settings have been previously reported as the results of the third tuning in Harcum et. Al 2022 42 . A 10% antifoam solution (Cytiva) was added via a control loop as needed.…”