Mammalian cell culture scale-up and fed-batch control using automated flow cytometry

Sitton, Greg; Srienc, Friedrich

doi:10.1016/j.jbiotec.2008.03.019

Cited by 57 publications

(45 citation statements)

References 41 publications

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“…A flow cytometer coupled with an autosampler and a flow injection system for sample processing has been used for online monitoring in yeast fermentation [210], and an automated cell preparation system for automatic sample withdrawal, staining, and FC analysis was employed for fed-batch control in mammalian cell cultivation [211]. The latter sample preparation system has been commercialized by MSP Corp. Another commercial system that includes automatic sampling and sample dilution for at-line measurement of particle size and shape has been developed by FlowCam [117].…”

Section: Flow Cytometrymentioning

confidence: 99%

“…For automation of counting cells, recording changes in cell morphology, and early recognition of contamination, the following techniques could be considered to have the capability for online operation: in situ microscopy with a flow cell installed in a bypass to the PBR, which provides real-time microscopic images from the culture [125] for counting cells and recognizing changes in morphology; a capacitance sensor installed in a microfluidic chip suitable for counting and distinguishing both living and dead cells [246]; monitoring the spectral signature of the culture [136] for detecting invasion of a Chlorella vulgaris culture by a cyanobacterium at mass ratios as small as 0.08; and an online adaptation of FC using a sampler [210,211]. Concerning contamination, in situ microscopic methods offer the advantage of providing raw microscopic images of the culture in real time, which can be visually evaluated by operators in parallel with image processing as an additional early warning measure.…”

Section: Cell Count Cell Morphology Contaminationmentioning

confidence: 99%

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Monitoring of Microalgal Processes

Havlík

Scheper

Reardon

2015

Microalgae Biotechnology

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Process monitoring, which can be defined as the measurement of process variables with the smallest possible delay, is combined with process models to form the basis for successful process control. Minimizing the measurement delay leads inevitably to employing online, in situ sensors where possible, preferably using noninvasive measurement methods with stable, low-cost sensors. Microalgal processes have similarities to traditional bioprocesses but also have unique monitoring requirements. In general, variables to be monitored in microalgal processes can be categorized as physical, chemical, and biological, and they are measured in gaseous, liquid, and solid (biological) phases. Physical and chemical process variables can be usually monitored online using standard industrial sensors. The monitoring of biological process variables, however, relies mostly on sensors developed and validated using laboratory-scale systems or uses offline methods because of difficulties in developing suitable online sensors. Here, we review current technologies for online, in situ monitoring of all types of process parameters of microalgal cultivations, with a focus on monitoring of biological parameters. We discuss newly introduced methods for measuring biological parameters that could be possibly adapted for routine online use, should be preferably noninvasive, and are based on approaches that have been proven in other bioprocesses. New sensor types for measuring physicochemical parameters using optical methods or ion-specific field effect transistor (ISFET) sensors are also discussed. Reviewed methods with online implementation or online potential include measurement of irradiance, biomass concentration by optical density and image analysis, cell count, chlorophyll fluorescence, growth rate, lipid concentration by infrared spectrophotometry, dielectric scattering, and nuclear magnetic resonance. Future perspectives are discussed, especially in the field of image analysis using in situ microscopy, infrared spectrophotometry, and software sensor systems.

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Section: Flow Cytometrymentioning

confidence: 99%

Section: Cell Count Cell Morphology Contaminationmentioning

confidence: 99%

Monitoring of Microalgal Processes

Havlík

Scheper

Reardon

2015

Microalgae Biotechnology

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“…Sitton and Srienc implemented two control strategies triggered by real-time flow cytometry data upon identical simultaneous cultures (Sitton and Srienc, 2008). Exhausted cell cultures are likely to produce lower quantities of correctly processed proteins.…”

Section: Controlmentioning

confidence: 99%

Process analytical technology (PAT) for biopharmaceutical products: Part I. concepts and applications

Read¹,

Park²,

Shah³

et al. 2009

Biotech & Bioengineering

197

118

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Process analytical technology (PAT) has been gaining momentum in the biotech community due to the potential for continuous real-time quality assurance resulting in improved operational control and compliance. In this two part series, we address PAT as it applies to processes that produce biotech therapeutic products. In the first part, we address evolution of the underlying concepts and applications in biopharmaceutical manufacturing. We also present a literature review of applications in the areas of upstream and downstream processing to illustrate how implementation of PAT can help realize advanced approaches to ensuring product quality in real time. In the second part, we will explore similar applications in the areas of drug product manufacturing, rapid microbiology, and chemometrics as well as evolution of PAT in biotech processing.

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“…5 On the other hand, indirect methodologies for both density and viability analysis are usually based on metabolic activity (glucose or oxygen uptake; lactic, pyruvic acid, or CO 2 production) or the expression of a product. 146,201 Cell density can also be indirectly assessed by total cell mass measurement through total protein or dry weight determination. 146 The indirect methods are not as accurate as the direct techniques, because the correlations between the specific metabolic rates measured and cell density/viability vary with the growth phase of cells.…”

Section: 171mentioning

confidence: 99%

“…This would allow a frequent or even continuous (real-time) monitoring, providing early indications of catastrophic events as contamination or cessation of growth, 183 and helping to ensure that medium additions to the culture occur at appropriate times. 201 Strategies for such measurements have been developed and include turbidity, 203 oxygen uptake rate, dielectric spectroscopy, 204 near-infrared (NIR) spectroscopy, 205 capacitance detection 204 flow injection flow cytometry, 206,207 optical microscopic imaging, 208 CEDEX cell counter, 201 and optical sensors. 143 However, most of these methods have low sensitivity or are affected by medium debris and are usually unable to measure cell concentrations below 5 Â 10 5 cells/mL.…”

Section: 171mentioning

confidence: 99%

Technological progresses in monoclonal antibody production systems

Rodrigues¹,

Costa²,

Henriques³

et al. 2009

Biotechnology Progress

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Monoclonal antibodies (mAbs) have become vitally important to modern medicine and are currently one of the major biopharmaceutical products in development. However, the high clinical dose requirements of mAbs demand a greater biomanufacturing capacity, leading to the development of new technologies for their large-scale production, with mammalian cell culture dominating the scenario. Although some companies have tried to meet these demands by creating bioreactors of increased capacity, the optimization of cell culture productivity in normal bioreactors appears as a better strategy. This review describes the main technological progresses made with this intent, presenting the advantages and limitations of each production system, as well as suggestions for improvements. New and upgraded bioreactors have emerged both for adherent and suspension cell culture, with disposable reactors attracting increased interest in the last years. Furthermore, the strategies and technologies used to control culture parameters are in constant evolution, aiming at the on-line multiparameter monitoring and considering now parameters not seen as relevant for process optimization in the past. All progresses being made have as primary goal the development of highly productive and economic mAb manufacturing processes that will allow the rapid introduction of the product in the biopharmaceutical market at more accessible prices.

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Mammalian cell culture scale-up and fed-batch control using automated flow cytometry

Cited by 57 publications

References 41 publications

Monitoring of Microalgal Processes

Monitoring of Microalgal Processes

Process analytical technology (PAT) for biopharmaceutical products: Part I. concepts and applications

Technological progresses in monoclonal antibody production systems

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