Bioprocess monitoring and computer control: Key roots of the current PAT initiative

Abstract

This review article has been written for the journal, Biotechnology and Bioengineering, to commemorate the 70th birthday of Daniel I.C. Wang, who served as doctoral thesis advisor to each of the co-authors, but a decade apart. Key roots of the current PAT initiative in bioprocess monitoring and control are described, focusing on the impact of Danny Wang's research as a professor at MIT. The history of computer control and monitoring in biochemical processing has been used to identify the areas that have already benefited and those that are most likely to benefit in the future from PAT applications. Past applications have included the use of indirect estimation methods for cell density, expansion of on-line/at-line and on-line/in situ measurement techniques, and development of models and expert systems for control and optimization. Future applications are likely to encompass additional novel measurement technologies, measurements for multi-scale and disposable bioreactors, real time batch release, and more efficient data utilization to achieve process validation and continuous improvement goals. Dan Wang's substantial contributions in this arena have been one key factor in steering the PAT initiative towards realistic and attainable industrial applications.

Multifrequency permittivity measurements enable on‐line monitoring of changes in intracellular conductivity due to nutrient limitations during batch cultivations of CHO cells

“…22 Intracellular monitoring techniques beyond simple viability measurements are needed to understand the physiological state of cells and to develop improved process models, combining extracellular and intracellular data. 2,26 The underlying mechanisms that caused a decrease of the intracellular conductivity still need to be identified, ideally using methods like dielectrophoresis or electrorotation. For now, it can only be speculated how nutrient depletions might cause changes in the cell's interior.…”

“…This shift can be characterized by the move of quality control key aspects from laboratory-based to process-based locations, that is, off-line to at-line/on-line. 2,3 On-line monitoring is furthermore critical to build better process models and develop reliable, well-controlled processes in a shorter period of time. 4 One of the most important parameters to monitor in any cell culture process is the viable, that is, metabolically active biomass.…”

Model Predictive Feeding Rate Control in Conventional and Single-use Lab-scale Bioreactors: A Study on Practical Application

“…While the first digital control units (DCU) for fermentation process control were introduced in the 1960's, many of the established techniques for fedbatch fermentation process control that are used today, such as on-line respiratory quotient (RQ) calculation for glucose feed-rate control or on-line estimation of biomass and substrate concentrations using O 2 and CO 2 measurements in off-gas, were introduced already in the following 20 years 2,3 . Further development of DCU capabilities lead to the expansion and the practical implementation of advanced fed-batch control techniques 4,5 such as adaptive control, soft sensoring (process models, artificial neural networks (ANN), principal component analysis (PCA)), intelligent control (fuzzy logic, ANN, hybrid models), and model predictive control (MPC) 6 introduced for pilot-scale and industrial applications 7,8,9 .…”

Stem cell bioprocessing: fundamentals and principles

“…Pore size and high surface area to volume ratio are also key parameters for cell spreading and expansion . For in vivo applications, the impact of pore size and osteogenic differentiation was studied using polyHIPE polymer; the minimum recommended pore size is suggested to be 100 mm (Hulbert et al 1970) and the maximum to be 500 mm (Karageorgiou & Kaplan 2005) with the larger pores registering formation of fibroblastic tissue (Wake et al 1994). Pore size affects cellular adhesion, viability, distribution and formation of an ECM by specific cell types; it has been suggested that the pore size in scaffolds can be used to preferentially support or prevent the ingrowth of specific cells.…”

“…However, bioprocess control in the manufacturing of biopharmaceutical products is critical in maintaining high product quality and consistency. Efforts are continuously being made in ( Junker & Wang 2006). Much of this work relies on the use of multivariate data analysis and principal component analysis (PCA) to generate models for the detection of process abnormalities and control of process variations (Gunther et al 2007).…”