PID controls: the forgotten bioprocess parameters

Sarah W. Harcum,Kathryn S. Elliott,Bradley A. Skelton,Stephanie R. Klaubert,Kelvin H. Lee,Hussain Dahodwala

doi:10.1007/s43938-022-00008-z

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.

Highlights

Academic and industrial research groups have spent over 30 years developing methods to control Chinese hamster ovary (CHO) cell bioreactors to maximize growth, productivity, and critical product quality attributes (CQAs), while minimizing waste product accumulation [1,2,3,4,5]
For most ambr250 studies, the pH, dissolved oxygen (DO), and temperature setpoints are provided by the authors, but rarely are any PID gains or manipulated variable ranges disclosed [11, 12]
Trial and error PID tuning is still required for the ambr®250 bioreactor system, as the sequential control levels increase the complexity to refine these PID gains and manipulated variable ranges

Summary

Introduction

Academic and industrial research groups have spent over 30 years developing methods to control Chinese hamster ovary (CHO) cell bioreactors to maximize growth, productivity, and critical product quality attributes (CQAs), while minimizing waste product accumulation [1,2,3,4,5]. Recent process intensification efforts have driven the desire for scale-down models, such as the ambr250 high-throughput (HT) bioreactor system [9, 10]. For most ambr250 studies, the pH, dissolved oxygen (DO), and temperature setpoints are provided by the authors, but rarely are any PID gains or manipulated variable ranges disclosed [11, 12]. There is very little literature on the effects of the PID control gain values and manipulated variables on growth and CQAs for mammalian cell cultures [13]

Methods

Results

Conclusion