Spectroscopic methods and their applicability for high‐throughput characterization of mammalian cell cultures in automated cell culture systems

Musmann, Carsten; Joeris, Klaus; Markert, Sven; Solle, Dörte; Scheper, Thomas

doi:10.1002/elsc.201500122

Cited by 15 publications

(22 citation statements)

References 77 publications

(118 reference statements)

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“…The goal of the second study was therefore to investigate the effect of scale-up critical preparation parameters such as temperature, specific power input, and preparation time. These parameters might not be constant between all scales and facilities, especially the preparation time in large-scale is much longer than in small-scale due to different mixing characteristics and surface to volume ratios T A B L E 3 Comparison of MIR and 2D FL online spectroscopy for application in cell culture media preparation based on the presented results and literature [19,20,56] of the preparation vessels. The impact of preparation parameters on media quality was investigated in a comprehensive DoE approach.…”

Section: Impact Of Preparation Parameters On Media Quality-2 Nd Studymentioning

confidence: 99%

Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Brunner

Brosig

Losing

et al. 2019

Engineering in Life Sciences

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Biopharmaceutical manufacturing processes can be affected by variability in cell culture media, e.g. caused by raw material impurities. Although efforts have been made in industry and academia to characterize cell culture media and raw materials with advanced analytics, the process of industrial cell culture media preparation itself has not been reported so far. Within this publication, we first compare mid‐infrared and two‐dimensional fluorescence spectroscopy with respect to their suitability as online monitoring tools during cell culture media preparation, followed by a thorough assessment of the impact of preparation parameters on media quality. Through the application of spectroscopic methods, we can show that media variability and its corresponding root cause can be detected online during the preparation process. This methodology is a powerful tool to avoid batch failure and is a valuable technology for media troubleshooting activities. Moreover, in a design of experiments approach, including additional liquid chromatography–mass spectrometry analytics, it is shown that variable preparation parameters such as temperature, power input and preparation time can have a strong impact on the physico‐chemical composition of the media. The effect on cell culture process performance and product quality in subsequent fed‐batch processes was also investigated. The presented results reveal the need for online spectroscopic methods during the preparation process and show that media variability can already be introduced by variation in media preparation parameters, with a potential impact on scale‐up to a commercial manufacturing process.

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Section: Impact Of Preparation Parameters On Media Quality-2 Nd Studymentioning

confidence: 99%

Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Brunner

Brosig

Losing

et al. 2019

Engineering in Life Sciences

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“…Furthermore, state variables are controlled via process variables such as the addition of base, acid, substrates, and salts, as well as the adjustment of stirrer rates, air flow, and heating/cooling temperatures [9]. The ability for measurement, analysis, monitoring, and controlling of variables, preferably online, is strongly dependent on the state (i.e., physical, chemical, biological), the variable itself, and available sensor techniques [2,10]. An online estimation of difficult to measure variables can be achieved by implementing macroscopic kinetic models into bioprocesses [11].…”

Section: Introductionmentioning

confidence: 99%

Accelerating Biologics Manufacturing by Upstream Process Modelling

Kornecki

Strube

2019

Processes

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Intensified and accelerated development processes are being demanded by the market, as innovative biopharmaceuticals such as virus-like particles, exosomes, cell and gene therapy, as well as recombinant proteins and peptides will possess no available platform approach. Therefore, methods that are able to accelerate this development are preferred. Especially, physicochemical rigorous process models, based on all relevant effects of fluid dynamics, phase equilibrium, and mass transfer, can be predictive, if the model is verified and distinctly quantitatively validated. In this approach, a macroscopic kinetic model based on Monod kinetics for mammalian cell cultivation is developed and verified according to a general valid model validation workflow. The macroscopic model is verified and validated on the basis of four decision criteria (plausibility, sensitivity, accuracy and precision as well as equality). The process model workflow is subjected to a case study, comprising a Chinese hamster ovary fed-batch cultivation for the production of a monoclonal antibody. By performing the workflow, it was found that, based on design of experiments and Monte Carlo simulation, the maximum growth rate µmax exhibited the greatest influence on model variables such as viable cell concentration XV and product concentration. In addition, partial least squares regressions statistically evaluate the correlations between a higher µmax and a higher cell and product concentration, as well as a higher substrate consumption.

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“…For example, glucose, lactate, and ammonium are routinely measured by taking offline measurements with bioanalysers such as Nova BioProfile 400 (Nova Biomedical). The small volume of MB cultures (15 mL) is, however, incompatible with the large sample volume required for this analyser (600 µL), preventing daily offline samples . Moreover, it would take approximately 3 h to analyze all 48 vessels of a typical MB system.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8][9][10] The primary focus, however, has been on their use for online monitoring at laboratory scale (e.g., 5-10 L). The applicability of spectroscopic methods for miniature bioreactor (MB) cultures has been reviewed 11 ; however, the authors are not aware of any literature experimentally comparing the ability of spectroscopy techniques to monitor multiple analytes under suitable operational constraints required for daily monitoring of MB cultures.…”

Section: Introductionmentioning

confidence: 99%

“…The small volume of MB cultures (15 mL) is, however, incompatible with the large sample volume required for this analyser (600 mL), preventing daily offline samples. 11 Moreover, it would take approximately 3 h to analyze all 48 vessels of a typical MB system. This constraint results in a tradeoff between data quantity and experimental throughput, 12 and spectroscopy technologies may be used to resolve this constraint.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of spectroscopy technologies for improved monitoring of cell culture processes in miniature bioreactors

Rowland‐Jones

Berg

Racher

et al. 2017

Biotechnology Progress

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Cell culture process development requires the screening of large numbers of cell lines and process conditions. The development of miniature bioreactor systems has increased the throughput of such studies; however, there are limitations with their use. One important constraint is the limited number of offline samples that can be taken compared to those taken for monitoring cultures in large‐scale bioreactors. The small volume of miniature bioreactor cultures (15 mL) is incompatible with the large sample volume (600 µL) required for bioanalysers routinely used. Spectroscopy technologies may be used to resolve this limitation. The purpose of this study was to compare the use of NIR, Raman, and 2D‐fluorescence to measure multiple analytes simultaneously in volumes suitable for daily monitoring of a miniature bioreactor system. A novel design‐of‐experiment approach is described that utilizes previously analyzed cell culture supernatant to assess metabolite concentrations under various conditions while providing optimal coverage of the desired design space. Multivariate data analysis techniques were used to develop predictive models. Model performance was compared to determine which technology is more suitable for this application. 2D‐fluorescence could more accurately measure ammonium concentration (RMSECV 0.031 g L−1) than Raman and NIR. Raman spectroscopy, however, was more robust at measuring lactate and glucose concentrations (RMSECV 1.11 and 0.92 g L−1, respectively) than the other two techniques. The findings suggest that Raman spectroscopy is more suited for this application than NIR and 2D‐fluorescence. The implementation of Raman spectroscopy increases at‐line measuring capabilities, enabling daily monitoring of key cell culture components within miniature bioreactor cultures. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:337–346, 2017

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Spectroscopic methods and their applicability for high‐throughput characterization of mammalian cell cultures in automated cell culture systems

Cited by 15 publications

References 77 publications

Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Towards robust cell culture processes — Unraveling the impact of media preparation by spectroscopic online monitoring

Accelerating Biologics Manufacturing by Upstream Process Modelling

Comparison of spectroscopy technologies for improved monitoring of cell culture processes in miniature bioreactors

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