Cell culture monitoring via an auto‐sampler and an integrated multi‐functional off‐line analyzer

Derfus, Gayle E.; Abramzon, Daniel; Tung, Meg; Chang, David W.; Kiss, Róbert; Amanullah, Ashraf

doi:10.1002/btpr.303

Cited by 30 publications

(17 citation statements)

References 19 publications

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“…Moreover, adoption of PAT for continuous monitoring is encouraged by regulatory agencies as PAT should reduce process variability and provide a more consistent quality of product . Several efforts towards continuous monitoring of bioreactors have been made that utilize well known offline methods coupled with automated sampling . Derfus et al (2009) utilized an online sampler with a BioProfile FLEX system (NOVA Biomedical, Waltham MA) to continuously monitor nutrients/metabolites, cell concentration, and osmolality .…”

Section: Introductionmentioning

confidence: 99%

Development of generic raman models for a GS‐KO^TM CHO platform process

Webster

Hadley

Hilliard

et al. 2018

Biotechnology Progress

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The monitoring and control of bioprocesses is of the utmost importance in order to provide a consistent, safe, and high-quality product for consumers. Current monitoring and control schemes rely on infrequent and time consuming offline sampling methods, which inherently leads to some variability in the process which may impact the product quality profile. As part of Lonza's dedication to process analytical technology (PAT) initiatives this study evaluated the ability to generate generic calibration models, which are independent of the cell line, using Raman probes to monitor changes in glucose, lactate, glutamate, ammonium, viable cell concentration (VCC), total cell concentration (TCC) and product concentration. Calibration models were developed from cell culture using two different CHOK1SV GS-KO cell lines producing different monoclonal antibodies (mAbs). Developed predictive models, measured changes in glucose, lactate, ammonium, VCC, and TCC with average prediction errors of 0.44, 0.23, 0.03 g L , 1.90 × 10 cells mL , and 1.85 × 10 cells mL , respectively over the course of cell culture with minimal cell line dependence. The development of these generic models allows the application of spectroscopic PAT techniques in clinical and commercial manufacturing environments, where processes are typically run once or twice in GMP manufacturing based on a common platform process. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:730-737, 2018.

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Section: Introductionmentioning

confidence: 99%

Development of generic raman models for a GS‐KO^TM CHO platform process

Webster

Hadley

Hilliard

et al. 2018

Biotechnology Progress

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“…The industry standard instrument, the Bioprofile Analyzer, quantifies lactate concentration using an amperometric immobilized enzyme biosensor (Biomedical, 2016). Even though this analysis can be automated (Derfus et al, 2010), a large sample volume is required (at least 1 mL) and the lower limit of detection is in the millimolar range, limiting its application to later stages of culture. Enzymatic lactate detection kits, based on the lactate oxidase enzyme are also commercially available.…”

Section: Introductionmentioning

confidence: 99%

Whole‐cell Escherichia coli lactate biosensor for monitoring mammalian cell cultures during biopharmaceutical production

Goers

Ainsworth

Goey

et al. 2017

Biotech & Bioengineering

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Many high‐value added recombinant proteins, such as therapeutic glycoproteins, are produced using mammalian cell cultures. In order to optimize the productivity of these cultures it is important to monitor cellular metabolism, for example the utilization of nutrients and the accumulation of metabolic waste products. One metabolic waste product of interest is lactic acid (lactate), overaccumulation of which can decrease cellular growth and protein production. Current methods for the detection of lactate are limited in terms of cost, sensitivity, and robustness. Therefore, we developed a whole‐cell Escherichia coli lactate biosensor based on the lldPRD operon and successfully used it to monitor lactate concentration in mammalian cell cultures. Using real samples and analytical validation we demonstrate that our biosensor can be used for absolute quantification of metabolites in complex samples with high accuracy, sensitivity, and robustness. Importantly, our whole‐cell biosensor was able to detect lactate at concentrations more than two orders of magnitude lower than the industry standard method, making it useful for monitoring lactate concentrations in early phase culture. Given the importance of lactate in a variety of both industrial and clinical contexts we anticipate that our whole‐cell biosensor can be used to address a range of interesting biological questions. It also serves as a blueprint for how to capitalize on the wealth of genetic operons for metabolite sensing available in nature for the development of other whole‐cell biosensors. Biotechnol. Bioeng. 2017;114: 1290–1300. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

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“…[4] Hence, controlling lactate and ammonia are common goals in cell culture process development. Glucose, lactate and ammonium are usually measured using commercially available multi-functional analyzers [5], and are usually measured using daily off-line samples during both development and commercial/clinical production batches.…”

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confidence: 99%