Visualizing integrated bioprocess designs through ?windows of operation?

Abstract

This paper demonstrates a simple graphical approach for the design and analysis of a bioprocess flowsheet in which process interactions are significant. Results are presented showing how the feasible space for operation can be simulated and used both to address key design and operating decisions and to identify suitable trade‐offs between operating variables, such as fermentation growth rate and disruption conditions, in order to achieve prespecified levels of process performance. Using verified models to describe the production and isolation of an intracellular protein alcohol dehydrogenase (ADH) in yeast as a test bed, a series of so‐called “windows of operation” are developed at growth rates in the range of 0.06–0.28 h−1 and for a range of overall process specifications. The effects of altering the process design performance specification as defined by the level of cell debris removal and the overall process productivity on the size and position of the feasible space were investigated to demonstrate the sensitivity of the flowsheet to changes in process objectives. Using the approach it has been possible to visualise the processing trade‐offs required to increase performance in terms of the level of cell debris removal by 50% and the overall process productivity by 400% from a defined base level. The approach provides a convenient tool when designing integrated bioprocesses by enabling process options to be compared visually and can help in achieving better process designs and accelerating process development for the biological process industry. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 65: 550–557, 1999.

Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma

“…This study illustrates the benefits of a methodology termed “windows of operation” that has previously been employed by the bio‐processing community to assist optimization of large scale protein/antibody manufacture (Salte et al, 2006; Woodley and Titchener‐Hooker, 1996; Zhou and Titchener‐Hooker, 1999). The “windows of operation” methodology allows visualization of data to aid decision making by mapping out the feasible operating space for achieving a user‐defined level of performance.…”

“…“Windows of operation” plots are two‐dimensional maps showing regions of feasible operating ranges for input variables after applying user‐defined constraints indicative of a required level of performance or functioning for measurable output variables. The construction of such two‐dimensional maps has previously been described by researchers in the bio‐processing industries where they were applied in the optimization of large scale protein/antibody manufacturing processes (Salte et al, 2006; Woodley and Titchener‐Hooker, 1996; Zhou and Titchener‐Hooker, 1999). For example, the performance levels of different centrifuge types were assessed with respect to their clarification, dewatering and product yield capabilities based on the limits of their individual operating capacities (Salte et al, 2006).…”

Downstream process development strategies for effective bioprocesses: Trends, progress, and combinatorial approaches

“…The study was performed by in silico modeling of both setups in all possible combinations while the output pool of the first column served as the input signal of the following step. Zhou and Titchener-Hooker [171,172] presented the technology of integrated bioprocess design based on operation windows and multi-objective Pareto optimization. The sweet spots of different unit operations can be analyzed graphically to make decisions on feasible combinations as shown for an integrated optimization of cell homogenization and debris removal of an intracellular Saccharomyces cerevisiae enzyme process.…”

Model‐based risk analysis of coupled process steps

“…At the same time, such processes pose an experimental challenge due to the amount of work and raw material required to perform recirculation in experiments. Mechanistic models provide a more detailed process description and have been shown to be useful for the design and analysis of single unit operations (Chhatre et al, 2008b;Kaltenbrunner et al, 2007), for evaluating the performance, process economy, and critical process parameters of bioprocess designs (Chhatre et al, 2008a;Petrides et al, 1995), and for identifying the possible "windows of operation" of a sequence of unit operations (Woodley and TitchenerHooker, 1996;Zhou and Titchener-Hooker, 1999). Mechanistic models provide a high degree of process understanding and enable the testing of various process scenarios that are difficult to perform experimentally.…”