liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Development of soft sensors for monitoring and control of bioprocesses
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
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: urn:nbn:se:liu:diva-152439DOI: 10.3384/diss.diva-152439ISBN: 9789176852071 (print)OAI: oai:DiVA.org:liu-152439DiVA, id: diva2:1259826
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
List of papers
1. Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics
Open this publication in new window or tab >>Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics
2015 (English)In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 90, no 2, p. 215-227Article, review/survey (Refereed) Published
Abstract [en]

This mini-review discusses how soft sensors can contribute to accomplish FDAs process analytical technology (PAT) ambitions in the manufacture of bio-therapeutics. Focus is on applications with protein-based drugs (proteins, antibodies), but also gene therapy vectors as well as cell cultures are considered where chemical and bio-analytical as well as mathematical and statistical methods are used as tools. An overview of existing soft sensor alternatives and how these can be configured to meet typical industrial needs is provided. It is noted how several of these needs coincide with the PAT regulatory incentives but do also address process economic aspects of bio-therapeutic manufacture. Evaluation of soft sensor alternatives is highlighted in relation to the production targets, quality attributes and the specification of these as well as shortcomings and needs for further improvements.

Place, publisher, year, edition, pages
Wiley, 2015
Keywords
Bioprocesses; Bioreactors; Monitoring; Process Control
National Category
Biological Sciences
Identifiers
urn:nbn:se:liu:diva-114232 (URN)10.1002/jctb.4477 (DOI)000347778100002 ()
Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2019-01-22
2. Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
Open this publication in new window or tab >>Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
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
Keywords
Soft sensors, Software sensors, Bioprocess monitoring and control, Fed-batch cultivation control, Overflow metabolism, Mixed-acid fermentation
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-98661 (URN)10.1007/s00449-012-0840-z (DOI)000324214400005 ()
Note

Funding Agencies|Linkoping University||

Available from: 2013-10-10 Created: 2013-10-10 Last updated: 2019-01-22Bibliographically approved
3. Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor
Open this publication in new window or tab >>Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor
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
Keywords
Reproducibility; Variance; Carbon dioxide production rate; Bioprocess regulation; Monitoring; Software sensor
National Category
Biological Sciences
Identifiers
urn:nbn:se:liu:diva-117361 (URN)10.1016/j.jbiotec.2015.02.030 (DOI)000352017700009 ()25746902 (PubMedID)
Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2019-01-22Bibliographically approved
4. A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals
Open this publication in new window or tab >>A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals
2014 (English)In: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 14, no 10, p. 17864-17882Article in journal (Refereed) Published
Abstract [en]

Soft sensors are the combination of robust on-line sensor signals with mathematical models for deriving additional process information. Here, we apply this principle to a microbial recombinant protein production process in a bioreactor by exploiting bio-calorimetric methodology. Temperature sensor signals from the cooling system of the bioreactor were used for estimating the metabolic heat of the microbial culture and from that the specific growth rate and active biomass concentration were derived. By applying sequential digital signal filtering, the soft sensor was made more robust for industrial practice with cultures generating low metabolic heat in environments with high noise level. The estimated specific growth rate signal obtained from the three stage sequential filter allowed controlled feeding of substrate during the fed-batch phase of the production process. The biomass and growth rate estimates from the soft sensor were also compared with an alternative sensor probe and a capacitance on-line sensor, for the same variables. The comparison showed similar or better sensitivity and lower variability for the metabolic heat soft sensor suggesting that using permanent temperature sensors of a bioreactor is a realistic and inexpensive alternative for monitoring and control. However, both alternatives are easy to implement in a soft sensor, alone or in parallel.

Place, publisher, year, edition, pages
MDPI, 2014
Keywords
bioprocess control; bio-calorimetry; software sensors; soft sensor implementation; bioprocess user interface
National Category
Biological Sciences
Identifiers
urn:nbn:se:liu:diva-112839 (URN)10.3390/s141017864 (DOI)000344455700001 ()25264951 (PubMedID)
Available from: 2015-01-08 Created: 2014-12-17 Last updated: 2019-01-22

Open Access in DiVA

Development of soft sensors for monitoring and control of bioprocesses(994 kB)529 downloads
File information
File name FULLTEXT01.pdfFile size 994 kBChecksum SHA-512
272bfb837774041f9f7ff202f95486df55fc203250f420d93a8de30b98c2630b626196ba98283422cc733af08a9043be790e942f338e23c1b5b3f7364ab75e23
Type fulltextMimetype application/pdf
omslag(86 kB)4 downloads
File information
File name COVER01.pdfFile size 86 kBChecksum SHA-512
6ac3193c04423d1f29d97aabc6c05626daf13c97a83f61157c138cfcab24c23537156c64a43fedb75f83274f2207f7ab2eb290b68a6e23522abb7d89421b4a97
Type coverMimetype application/pdf
Order online >>

Other links

Publisher's full text

Authority records BETA

Gustavsson, Robert

Search in DiVA

By author/editor
Gustavsson, Robert
By organisation
BiotechnologyFaculty of Science & Engineering
Biological SciencesBioprocess Technology

Search outside of DiVA

GoogleGoogle Scholar
Total: 529 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 405 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf