Automated measurement and monitoring of bioprocesses: key elements of the M(3)C strategy.
01 Jan 2012-Advances in Biochemical Engineering \/ Biotechnology (Springer, Berlin, Heidelberg)-Vol. 132, pp 1-33
TL;DR: This chapter surveys the principles of monitoring rather than compiling instruments, and some new(er) instrumental analytical tools, interfaced to bioprocesses, are explained.
Abstract: The state-of-routine monitoring items established in the bioprocess industry as well as some important state-of-the-art methods are briefly described and the potential pitfalls discussed. Among those are physical and chemical variables such as temperature, pressure, weight, volume, mass and volumetric flow rates, pH, redox potential, gas partial pressures in the liquid and molar fractions in the gas phase, infrared spectral analysis of the liquid phase, and calorimetry over an entire reactor. Classical as well as new optical versions are addressed. Biomass and bio-activity monitoring (as opposed to "measurement") via turbidity, permittivity, in situ microscopy, and fluorescence are critically analyzed. Some new(er) instrumental analytical tools, interfaced to bioprocesses, are explained. Among those are chromatographic methods, mass spectrometry, flow and sequential injection analyses, field flow fractionation, capillary electrophoresis, and flow cytometry. This chapter surveys the principles of monitoring rather than compiling instruments.
Citations
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TL;DR: A very familiar, yet underutilized, physical parameter—gas pressure—can serve as signal readout for highly sensitive bioanalysis and opens up a new way for simple, portable, yet highly sensitive biomedical analysis in a variety of settings.
Abstract: Herein, we demonstrate that a very familiar, yet underutilized, physical parameter—gas pressure—can serve as signal readout for highly sensitive bioanalysis. Integration of a catalyzed gas-generation reaction with a molecular recognition component leads to significant pressure changes, which can be measured with high sensitivity using a low-cost and portable pressure meter. This new signaling strategy opens up a new way for simple, portable, yet highly sensitive biomedical analysis in a variety of settings.
147 citations
TL;DR: In this paper, the authors provide an overview of current and emerging sensors for bioprocess monitoring and control, including sensors directly interfaced to bioreactors for measuring important variables from the gas phase, such as oxygen and carbon dioxide concentration, and sensors for the monitoring of the biomass concentration and morphology and of the changing medium composition.
Abstract: The ability to measure all process variables is of great importance in the field of bioprocess monitoring and control, and continuous, real-time measurements are highly desired. The more complete and real-time the measurements are, the more stable, reproducible, and efficient the process can be, leading to reproducibly high-quality products. This additional information allows the operator to better document the entire process. The process analytical technologies initiative of the US Food and Drug Administration is strongly related to the analysis and control of biopharmaceutical processes. The aim of the initiative is to create processes, generating products of ensured quality by measuring quality-related process variables. The quality of the product is enhanced by a deep understanding of the process, which is enabled by an effective and suitable sensor system. The aim of this review is to provide an overview of current and emerging sensors for bioprocess monitoring. Sensors directly interfaced to bioreactors for measuring important variables from the gas phase, such as oxygen and carbon dioxide concentration, are discussed, as well as sensors for the monitoring of the biomass concentration and morphology and of the changing medium composition. Furthermore, sensor systems are discussed. These involve sensors (especially biosensors) that are not implemented directly inside the bioreactor but rather are used in conjunction with sample-taking systems such as flow injection analysis. A major focus is given to spectroscopic sensors, which are noninvasive and offer interesting options for a simultaneous analysis of various compounds. Since data handling is extremely important for this kind of sensor, chemometrics are also included. Soft sensors are discussed as technology that allows a user to incorporate more process data as it become available. Finally, the current state of disposable sensor technology is presented. These sensors are needed for the growing area of disposable and continuous biomanufacturing.
145 citations
Cites background from "Automated measurement and monitorin..."
...Because water also adsorbs IR light, it must be removed via a gas cooler or dryer prior to measurement [14]....
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...Oxygen-sensitive indicators are complexes of ruthenium, palladium, or platinum such as Tris-4,7-diphenyl1,10-phenanthrolin-ruthenium(II) [14, 91]....
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...If particularly high sensitivity is needed, the proton-transfer-reaction-MS (PTR-MS), which is based on chemical ionization, is a good alternative [14]....
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...RQ allows one to make inferences about substrate utilization rates of the culture and has been proposed as a valuable parameter for monitoring and controlling cell cultures [14, 181, 182]....
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...However, in-line measurement in aqueous solutions is possible using appropriate fiber optic probes that incorporate attenuated total reflection (ATR) technology and Fourier transformation [14, 121, 122]....
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TL;DR: This review summarizes the main methods for translation of molecular signals to distance-based readout and discusses different microfluidic platforms in terms of applications in biomedical diagnostics, food safety monitoring, and environmental analysis.
Abstract: Equipment-free devices with quantitative readout are of great significance to point-of-care testing (POCT), which provides real-time readout to users and is especially important in low-resource settings. Among various equipment-free approaches, distance-based visual quantitative detection methods rely on reading the visual signal length for corresponding target concentrations, thus eliminating the need for sophisticated instruments. The distance-based methods are low-cost, user-friendly and can be integrated into portable analytical devices. Moreover, such methods enable quantitative detection of various targets by the naked eye. In this review, we first introduce the concept and history of distance-based visual quantitative detection methods. Then, we summarize the main methods for translation of molecular signals to distance-based readout and discuss different microfluidic platforms (glass, PDMS, paper and thread) in terms of applications in biomedical diagnostics, food safety monitoring, and environmental analysis. Finally, the potential and future perspectives are discussed.
139 citations
TL;DR: Although microbial phenotypic heterogeneity has been thoroughly investigated at a fundamental level, the implications of this phenomenon in the context of microbial bioprocesses are still subject to debate and automated flow cytometry is the best technique for investigating microbial heterogeneity under process conditions.
Abstract: Heterogeneity or segregation of microbial populations has been the subject of much research, but the real impact of this phenomenon on bioprocesses remains poorly understood. The main reason for this lack of knowledge is the difficulty in monitoring microbial population heterogeneity under dynamic process conditions. The main concepts resulting in microbial population heterogeneity in the context of bioprocesses have been summarized by two distinct hypotheses. The first involves the individual history of microbial cells or the "path" followed during their residence time inside the process equipment. The second hypothesis involves a coordinated response by the microbial population as a bet-hedging strategy, in order to cope with process-related stresses. The respective contribution of each hypothesis to microbial heterogeneity in bioprocesses is still unclear. This illustrates the fact that, although microbial phenotypic heterogeneity has been thoroughly investigated at a fundamental level, the implications of this phenomenon in the context of microbial bioprocesses are still subject to debate. At this time, automated flow cytometry is the best technique for investigating microbial heterogeneity under process conditions. However, dedicated software and relevant biomarkers are needed for the proper integration of flow cytometry as a bioprocess control tool.
130 citations
Additional excerpts
...optical analysis [88–90] and spectroscopy [91]....
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TL;DR: This review covers a range of strategies employed to use the feed rate as a manipulated variable in a control strategy, as it is seen that this variable may be used towards many different objectives depending on the process of interest, the characteristics of the strain, or the product being produced, which leads to different drivers for process optimisation.
126 citations
Cites background from "Automated measurement and monitorin..."
...The standard probes which are routinely used in industrial scale fermentation allow measurement of the temperature, pH, and dissolved oxygen tension (DO), and in addition there are on-line measurements of the stirrer speed, back pressure and flow rates (Alford, 2006; Sonnleitner, 2013)....
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...For this reason, variables which are derived from on-line gas data are interesting, and they provide important physiological information (Sonnleitner, 2013)....
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...Often off gas composition will also be measured as this provides a vital insight into the metabolic state (Sonnleitner, 2013)....
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...Dissolved oxygen is a relatively robust measurement which is considered fairly standard in industrial fermentation (Sonnleitner, 2013)....
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References
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TL;DR: This paper presents a meta-review of the Flow--Injection Literature and discusses theoretical Aspects of FIA Techniques, components of An FIA Apparatus, and Experimental Techniques and FIA Exercises.
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TL;DR: The methylotrophic yeast Pichia pastoris has been widely reported as a suitable expression system for heterologous protein production and the use of mixed substrates, on-line monitoring of the key fermentation parameters (methanol) and control algorithms applied to the bioprocess are reviewed and discussed in detail.
Abstract: The methylotrophic yeast Pichia pastoris has been widely reported as a suitable expression system for heterologous protein production. The use of different phenotypes under PAOX promoter, other alternative promoters, culture medium, and operational strategies with the objective to maximize either yield or productivity of the heterologous protein, but also to obtain a repetitive product batch to batch to get a robust process for the final industrial application have been reported. Medium composition, kinetics growth, fermentation operational strategies from fed-batch to continuous cultures using different phenotypes with the most common PAOX promoter and other novel promoters (GAP, FLD, ICL), the use of mixed substrates, on-line monitoring of the key fermentation parameters (methanol) and control algorithms applied to the bioprocess are reviewed and discussed in detail.
333 citations
TL;DR: Flow cytometry will be a mediator technology to gain a deeper insight into the heterogeneity of populations and the functioning of microbial communities as well as the pitfalls and problems in analysing cells without any further treatment.
Abstract: The still poorly explored world of microbial functioning is about to be uncovered by a combined application of old and new technologies. Bacteria, especially, are still in the dark with respect to their phylogenetic affiliations as well as their metabolic capabilities and functions. However, with the advent of sophisticated flow cytometric and cell sorting technologies in microbiological labs, there is now the possibility to gain this knowledge at the single-cell level without cumbersome cultivation approaches. Cytometry also facilitates the understanding of physiological diversity in seemingly likewise acting populations. Both individuality and diversity lead to the complex and concerted actions of microbial consortia. This review provides an overview of the state of the art in the field. It deals with the handling of microorganisms from the very beginning (i.e. sampling, and detachment and fixation procedures) and goes on to discuss the pitfalls and problems in analysing cells without any further treatment. If information cannot be gained by specific staining procedures, phylogenetic technologies, transcriptomic and proteomic approaches may be options for achieving advanced insights. All in all, flow cytometry will be a mediator technology to gain a deeper insight into the heterogeneity of populations and the functioning of microbial communities.
320 citations
TL;DR: This review seeks to highlight the advantages of this technique in microbial fermentations monitoring and control, as well as in the development of more accurate kinetic models directed to bioprocesses optimization.
277 citations