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Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
2015 (English)In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 200, p. 44-51Article in journal (Refereed) Published
Abstract [en]

The feeding of a fed-batch cultivation producing recombinant protein was controlled by a soft sensor setup. It was assumed that the control approach could be based on the cells production of carbon dioxide and that this parameter indicates the metabolic state occurring at induced protein expression. The soft sensor used the on-line signals from a carbon dioxide analyser and a near-infrared (NIR) probe for biomass to estimate the specific production rate (q(CO2)). Control experiments were carried out with various q(CO2) set-points where we observe that the feeding of nutrients to the culture could easily be controlled and resulted in a decreased variability compared to uncontrolled cultivations. We therefore suggest that this control approach could serve as an alternative to other commonly applied methods such as controlling the cells overflow metabolism of acetate or the cells specific growth rate. However, further studies of the internal metabolic fluxes of CO2 during protein expression would be recommended for a more precise characterization of the relationship between q(CO2) and protein expression in order to fully interpret the control behaviour.

Place, publisher, year, edition, pages
Elsevier , 2015. Vol. 200, p. 44-51
Keywords [en]
Reproducibility; Variance; Carbon dioxide production rate; Bioprocess regulation; Monitoring; Software sensor
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:liu:diva-117361DOI: 10.1016/j.jbiotec.2015.02.030ISI: 000352017700009PubMedID: 25746902OAI: oai:DiVA.org:liu-117361DiVA, id: diva2:807872
Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2018-10-31Bibliographically approved
In thesis
1. Development of soft sensors for monitoring and control of bioprocesses
Open this publication in new window or tab >>Development of soft sensors for monitoring and control of bioprocesses
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the manufacture of bio-therapeutics the importance of a well-known process is key for a high product titer and low batch to batch variations. Soft sensors are based on the concept that online sensor signals can be used as inputs to mathematical models to derive new valuable process information. This information could then be used for better monitoring and control of the bioprocess.

The aim of the present thesis has been to develop soft sensor solutions for upstream bioprocessing and demonstrate their usefulness in improving robustness and increase the batch-to-batch reproducibility in bioprocesses. The thesis reviews the potential and possibilities with soft sensors for use in production of bio-therapeutics to realize FDA´s process analytical technology (PAT) initiative. Modelling and hardware sensor alternatives which could be used in a soft sensor setup are described and critically analyzed. Different soft sensor approaches to control glucose feeding in fed-batch cultures of Escherichia coli are described. Measurements of metabolic fluxes and specific carbon dioxide production was used as control parameters to increase product yield and decrease the variability of produced recombinant proteins. Metabolic heat signals were used in uninduced cultures to estimate and control the specific growth rate at a desired level and thereby also estimate the biomass concentration online. The introduction of sequential filtering of the signal enabled this method to be used in a down-scaled system. The risk and high impact of contaminations in cell cultures are also described. An in situ microscope (ISM) was used as an online tool to estimate cell concentration and also to determine cell diameter size which enabled the detection of contaminant cells at an early stage.

The work presented in this thesis supports the idea that soft sensors can be a useful tool in the strive towards robust and reliable bioprocesses, to ensure high product quality and increased economic profit.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 55
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1954
National Category
Biological Sciences Bioprocess Technology
Identifiers
urn:nbn:se:liu:diva-152439 (URN)10.3384/diss.diva-152439 (DOI)9789176852071 (ISBN)
Public defence
2018-10-26, Planck, Fysikhuset, Campus Valla, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-10-31Bibliographically approved

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Gustavsson, RobertMandenius, Carl-Fredrik

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