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Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
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.ORCID iD: 0000-0001-9711-794X
2013 (English)In: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 36, no 10, p. 1375-1384Article in journal (Refereed) Published
Abstract [en]

A soft sensor approach is described for controlling metabolic overflow from mixed-acid fermentation and glucose overflow metabolism in a fed-batch cultivation for production of recombinant green fluorescence protein (GFP) in Escherichia coli. The hardware part of the sensor consisted of a near-infrared in situ probe that monitored the E. coli biomass and an HPLC analyzer equipped with a filtration unit that measured the overflow metabolites. The computational part of the soft sensor used basic kinetic equations and summations for estimation of specific rates and total metabolite concentrations. Two control strategies for media feeding of the fed-batch cultivation were evaluated: (1) controlling the specific rates of overflow metabolism and mixed-acid fermentation metabolites at a fixed pre-set target values, and (2) controlling the concentration of the sum of these metabolites at a set level. The results indicate that the latter strategy was more efficient for maintaining a high titer and low variability of the produced recombinant GFP protein.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2013. Vol. 36, no 10, p. 1375-1384
Keywords [en]
Soft sensors, Software sensors, Bioprocess monitoring and control, Fed-batch cultivation control, Overflow metabolism, Mixed-acid fermentation
National Category
Engineering and Technology
Identifiers
URN: urn:nbn:se:liu:diva-98661DOI: 10.1007/s00449-012-0840-zISI: 000324214400005OAI: oai:DiVA.org:liu-98661DiVA, id: diva2:655273
Note

Funding Agencies|Linkoping University||

Available from: 2013-10-10 Created: 2013-10-10 Last updated: 2019-01-22Bibliographically 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: 2019-09-30Bibliographically approved

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Gustavsson, RobertMandenius, Carl-Fredrik

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