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  • 1.
    Gerlach, Inga
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan. University of Applied Sciences, Bremen, Germany.
    Bruening, Simone
    University of Applied Sciences, Bremen, Germany .
    Gustavsson, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Mandenius, Carl-Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Hass, Volker C.
    University of Applied Sciences Furtwangen, Villingen-Schwenningen, Germany .
    Operator training in recombinant protein production using a structured simulator model2014Inngår i: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 177, s. 53-59Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Model-based operator training simulators ( OTS) could be powerful tools for virtual training of operational procedures and skills of production personnel in recombinant protein processes. The applied model should describe critical events in the bioprocess so accurately that the operators ability to observe and alertly act upon these events is trained with a high degree of efficiency. In this work is shown how this is accomplished in a structured multi-compartment model for the production of a recombinant protein in an Escherichia coli fed-batch process where in particular the induction procedure, the stress effects and overflow metabolism were highlighted. The structured model was applied on the OTS platform that virtually simulated the operational bioreactor procedures in real or accelerated time. Evaluation of training using the model-based OTS showed that trained groups of operators exhibited improved capability compared with the untrained groups when subsequently performing real laboratory scale cultivations. The results suggest that this model-based OTS may provide a valuable resource for enhancing operator skills in large scale recombinant protein manufacturing.

  • 2. Bestill onlineKjøp publikasjonen >>
    Gustavsson, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska fakulteten.
    Development of soft sensors for monitoring and control of bioprocesses2018Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics
    Åpne denne publikasjonen i ny fane eller vindu >>Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics
    2015 (engelsk)Inngår i: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 90, nr 2, s. 215-227Artikkel, forskningsoversikt (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Wiley, 2015
    Emneord
    Bioprocesses; Bioreactors; Monitoring; Process Control
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-114232 (URN)10.1002/jctb.4477 (DOI)000347778100002 ()
    Tilgjengelig fra: 2015-02-16 Laget: 2015-02-16 Sist oppdatert: 2019-01-22
    2. Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
    Åpne denne publikasjonen i ny fane eller vindu >>Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
    2013 (engelsk)Inngår i: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 36, nr 10, s. 1375-1384Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Springer Verlag (Germany), 2013
    Emneord
    Soft sensors, Software sensors, Bioprocess monitoring and control, Fed-batch cultivation control, Overflow metabolism, Mixed-acid fermentation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-98661 (URN)10.1007/s00449-012-0840-z (DOI)000324214400005 ()
    Merknad

    Funding Agencies|Linkoping University||

    Tilgjengelig fra: 2013-10-10 Laget: 2013-10-10 Sist oppdatert: 2019-01-22bibliografisk kontrollert
    3. Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor
    Åpne denne publikasjonen i ny fane eller vindu >>Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor
    2015 (engelsk)Inngår i: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 200, s. 44-51Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Elsevier, 2015
    Emneord
    Reproducibility; Variance; Carbon dioxide production rate; Bioprocess regulation; Monitoring; Software sensor
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-117361 (URN)10.1016/j.jbiotec.2015.02.030 (DOI)000352017700009 ()25746902 (PubMedID)
    Tilgjengelig fra: 2015-04-24 Laget: 2015-04-24 Sist oppdatert: 2019-01-22bibliografisk kontrollert
    4. A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals
    Åpne denne publikasjonen i ny fane eller vindu >>A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals
    2014 (engelsk)Inngår i: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 14, nr 10, s. 17864-17882Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    MDPI, 2014
    Emneord
    bioprocess control; bio-calorimetry; software sensors; soft sensor implementation; bioprocess user interface
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-112839 (URN)10.3390/s141017864 (DOI)000344455700001 ()25264951 (PubMedID)
    Tilgjengelig fra: 2015-01-08 Laget: 2014-12-17 Sist oppdatert: 2019-01-22
  • 3.
    Gustavsson, Robert
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Lukasser, Cornelia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Mandenius, Carl-Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor2015Inngår i: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 200, s. 44-51Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 4.
    Gustavsson, Robert
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Mandenius, Carl-Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein2013Inngår i: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 36, nr 10, s. 1375-1384Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 5.
    Mandenius, Carl-Fredrik
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Gustavsson, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics2015Inngår i: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 90, nr 2, s. 215-227Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 6.
    Mandenius, Carl-Fredrik
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska fakulteten.
    Gustavsson, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska fakulteten.
    Soft sensor design for bioreactor monitoring and control2016Inngår i: Bioreactors: design, operation and novel application / [ed] Carl-Fredrik Mandenius, Weinheim: Wiley-VCH Verlagsgesellschaft, 2016, s. 391-420Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 7.
    Paulsson, Dan
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Gustavsson, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    Mandenius, Carl-Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
    A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals2014Inngår i: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 14, nr 10, s. 17864-17882Artikkel i tidsskrift (Fagfellevurdert)
    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.

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