A sensitive monitoring system for mammalian cell cultivation processes: a PAT approach

Winckler, Silvia; Krueger, Rolf; Schnitzler, Thomas; Zang, Werner; Fischer, R; Biselli, M.

doi:10.1007/s00449-013-1062-8

Cited by 10 publications

(17 citation statements)

References 21 publications

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“…Mandenius and Gustavsson (11) reviewed several software sensor solutions that are used to derive new information from true sensors by combining them with software models. These models range from high mathematical signal processing complexity (12)(13)(14) to those with emphasis on biological system modeling that describe specific biological systems (15,16). A general downside of these models is that either their implementation is of such complexity that they are difficult to realize and verify or that they are not suited for a general solution.…”

Section: Introductionmentioning

confidence: 99%

System characterization of dynamic biological cultivations through improved data analysis

Stouten

Douwenga²,

Hogendoorn

et al. 2021

Preprint

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Determining the functional development and dominant competitive strategy in microbial community enrichments is complicated by the extensive measurement campaigns required for off-line system analysis. This study demonstrates that detailed system characterization of aerobic pulse fed enrichments can be established using on-line measurements combined with automated data analysis. By incorporating the physicochemical processes in on-line data processing with a Particle Filter and kinetic process model, an accurate reconstruction of the dominant biological rates can be made. We hereby can differentiate between storage compound production and biomass growth in sequencing batch bioreactors. The method proposed allows for close monitoring of changes in functional behavior of long-running enrichment cultures, without the need for off-line samples, therewith enabling the identification of new insights in process dynamics with a minimal experimental effort. Even though a specific example application of the method proposed is described here, the approach can readily be extended to a wide range of dynamic experimental systems that can be characterized based on on-line measurements.

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Section: Introductionmentioning

confidence: 99%

System characterization of dynamic biological cultivations through improved data analysis

Stouten

Douwenga²,

Hogendoorn

et al. 2021

Preprint

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“…It should be noted that off-gas broadly consists of any gaseous components that go in and out of the bioreactor, and not limited to just oxygen and carbon dioxide although these two are the most commonly measured components. The use of paramagnetic and zirconium dioxide sensors for oxygen concentration determination and infra-red sensor for carbon dioxide concentration determination had been used traditionally [1][2][3][4]. These techniques have a limited detection range for the gases as well as inferior sensitivity when compared to the use of mass spectrometry (MS).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, while being similar to batch culture in terms of varying growth and metabolic states throughout the culture, fed-batch culture has the added complication of feed additions accompanied by volume changes. A search for more recent publications resulted in two instances where off-gas analysis was employed in fedbatch bioreactor cultures with one using mass spectrometry (MS) [1] and the other with a combination of non-MS based sensors [4].…”

Section: Introductionmentioning

confidence: 99%

Applications of off-gas mass spectrometry in fed-batch mammalian cell culture

Goh

Sulu

Alosert

et al. 2019

Bioprocess Biosyst Eng

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Off-gas analysis using a magnetic sector mass spectrometer was performed in mammalian cell cultures in the fed-batch mode at the 5 L bench and 50 L pilot scales. Factors affecting the MS gas traces were identified during the duration of the fed-batch cultures. Correlation between viable cell concentration (VCC) and oxygen concentration of the inlet gas into the bioreactor (O 2-in) resulted in R 2 ≈ 0.9; O 2-in could be used as a proxy for VCC. Oxygen mass transfer (kLa) was also quantified throughout the culture period with antifoam addition at different time points which is shown to lower the kLa. Realtime specific oxygen consumption rate (qO 2) of 2-20 pmol/cell/day throughout the bioreactor runs were within the range of values reported in literature for mammalian cell cultures. We also report, to our knowledge, the first instance of a distinct correlation between respiration quotient (RQ) and the metabolic state of the cell culture with regard to lactate production phase (average RQ > 1) and consumption phase (average RQ < 1).

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“…Furthermore, this method typically ignores adjustments to agitator speed or shifts in gas‐flow rates by assuming a constant oxygen mass transfer coefficient ( k L a ). Off‐gas analyzers have also been demonstrated as an effective tool to monitor and control mammalian cell cultures . However these sensors can be expensive and installation can be problematic on micro‐scale systems.…”

Section: Introductionmentioning

confidence: 99%

“…Off-gas analyzers have also been demonstrated as an effective tool to monitor and control mammalian cell cultures. [33][34][35] However these sensors can be expensive and installation can be problematic on micro-scale systems.…”

Section: Introductionmentioning

confidence: 99%

On‐Line Control of Glucose Concentration in High‐Yielding Mammalian Cell Cultures Enabled Through Oxygen Transfer Rate Measurements

Goldrick

Lee²,

Spencer³

et al. 2018

Biotechnology Journal

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Glucose control is vital to ensure consistent growth and protein production in mammalian cell cultures. The typical fed-batch glucose control strategy involving bolus glucose additions based on infrequent off-line daily samples results in cells experiencing significant glucose concentration fluctuations that can influence product quality and growth. This study proposes an online method to control and manipulate glucose utilizing readily available process measurements. The method generates a correlation between the cumulative oxygen transfer rate and the cumulative glucose consumed. This correlation generates an on-line prediction of glucose that has been successfully incorporated into a control algorithm manipulating the glucose feed-rate. This advanced process control (APC) strategy enables the glucose concentration to be maintained at an adjustable set-point and has been found to significantly reduce the deviation in glucose concentration in comparison to conventional operation. This method has been validated to produce various therapeutic proteins across cell lines with different glucose consumption demands and is successfully demonstrated on micro (15 mL), laboratory (7 L), and pilot (50 L) scale systems. This novel APC strategy is simple to implement and offers the potential to significantly enhance the glucose control strategy for scales spanning micro-scale systems through to full scale industrial bioreactors.

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A sensitive monitoring system for mammalian cell cultivation processes: a PAT approach

Cited by 10 publications

References 21 publications

System characterization of dynamic biological cultivations through improved data analysis

System characterization of dynamic biological cultivations through improved data analysis

Applications of off-gas mass spectrometry in fed-batch mammalian cell culture

On‐Line Control of Glucose Concentration in High‐Yielding Mammalian Cell Cultures Enabled Through Oxygen Transfer Rate Measurements

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