Spectroscopic sensors for in-line bioprocess monitoring in research and pharmaceutical industrial application

The use of spectroscopic sensors for bioprocess monitoring is a powerful tool within the process analytical technology (PAT) initiative of the US Food and Drug Administration. Spectroscopic sensors enable the simultaneous real-time bioprocess monitoring of various critical process parameters including biological, chemical, and physical variables during the entire biotechnological production process. This potential can be realized through the combination of spectroscopic measurements (UV/Vis spectroscopy, IR spectroscopy, fluorescence spectroscopy, and Raman spectroscopy) with multivariate data analysis to obtain relevant process information out of an enormous amount of data. This review summarizes the newest results from science and industry after the establishment of the PAT initiative and gives a critical overview of the most common in-line spectroscopic techniques. Examples are provided of the wide range of possible applications in upstream processing and downstream processing of spectroscopic sensors for real-time monitoring to optimize productivity and ensure product quality in the pharmaceutical industry.

[1]  Harald Kolmar,et al.  At-line mid infrared spectroscopy for monitoring downstream processing unit operations , 2015 .

[2]  Terrence M. Dobrowsky,et al.  Quick generation of Raman spectroscopy based in‐process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture , 2016, Biotechnology progress.

[3]  Carl-Fredrik Mandenius,et al.  On-line multi-analyzer monitoring of biomass, glucose and acetate for growth rate control of a Vibrio cholerae fed-batch cultivation. , 2005, Journal of biotechnology.

[4]  Bernd Hitzmann,et al.  On-line monitoring of recombinant bacterial cultures using multi-wavelength fluorescence spectroscopy , 2011 .

[5]  J. Lakowicz.  Principles of fluorescence spectroscopy , 1983 .

[6]  Pedro A. G. Tizei,et al.  Raman spectroscopy and chemometrics for on‐line control of glucose fermentation by Saccharomyces cerevisiae , 2012, Biotechnology progress.

[7]  Nicholas R. Abu-Absi,et al.  Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. , 2011, Biotechnology and bioengineering.

[8]  Brian McNeil,et al.  Simultaneous determination of glycerol and clavulanic acid in an antibiotic bioprocess using attenuated total reflectance mid infrared spectroscopy. , 2007, Analytica chimica acta.

[9]  Jarka Glassey,et al.  Multivariate data analysis for advancing the interpretation of bioprocess measurement and monitoring data. , 2013, Advances in biochemical engineering/biotechnology.

[10]  Stephanus Büttgenbach,et al.  Microfluidic reactor for continuous cultivation of Saccharomyces cerevisiae , 2010, Biotechnology progress.

[11]  Geovanni Martinez,et al.  Optical inline measurement procedures for counting and sizing cells in bioprocess technology. , 2009, Advances in biochemical engineering/biotechnology.

[12]  Nanna Petersen,et al.  In situ near infrared spectroscopy for analyte‐specific monitoring of glucose and ammonium in streptomyces coelicolor fermentations , 2010, Biotechnology progress.

[13]  Urs von Stockar,et al.  Monitoring and control of Gluconacetobacter xylinus fed-batch cultures using in situ mid-IR spectroscopy. , 2004, Journal of biotechnology.

[14]  José Alves-Rausch,et al.  Real time in-line monitoring of large scale Bacillus fermentations with near-infrared spectroscopy. , 2014, Journal of biotechnology.

[15]  Joaquim P Cardoso,et al.  The use of NIR as a multi-parametric in situ monitoring technique in filamentous fermentation systems. , 2008, Talanta.

[16]  José Manuel Amigo,et al.  On-line parallel factor analysis. A step forward in the monitoring of bioprocesses in real time , 2008 .

[17]  R. Kessler.  Prozessanalytik: Strategien und Fallbeispiele aus der industriellen Praxis , 2006 .

[18]  Jonathon T. Olesberg,et al.  Advanced near‐infrared monitor for stable real‐time measurement and control of Pichia pastoris bioprocesses , 2014 .

[19]  Oxana Ye. Rodionova,et al.  Process analytical technology: a critical view of the chemometricians , 2012 .

[20]  K. Kiviharju,et al.  On-line biomass measurements in bioreactor cultivations: comparison study of two on-line probes , 2007, Journal of Industrial Microbiology & Biotechnology.

[21]  Xin Lu,et al.  In situ multi-wavelength fluorescence spectroscopy as effective tool to simultaneously monitor spore germination, metabolic activity and quantitative protein production in recombinant Aspergillus niger fed-batch cultures. , 2007, Journal of biotechnology.

[22]  Brian Glennon,et al.  In situ Raman spectroscopy for simultaneous monitoring of multiple process parameters in mammalian cell culture bioreactors , 2012, Biotechnology progress.

[23]  Seongkyu Yoon,et al.  Quantification of protein mixture in chromatographic separation using multi‐wavelength UV spectra , 2013, Biotechnology progress.

[24]  Catalina E. Alupoaei,et al.  Growth behavior of microorganisms using UV‐Vis spectroscopy:Escherichia coli , 2004, Biotechnology and bioengineering.

[25]  Jürgen Hubbuch,et al.  UV absorption‐based inverse modeling of protein chromatography , 2016 .

[26]  Thomas Scheper,et al.  In-situ microscopy and 2D fluorescence spectroscopy as online methods for monitoring CHO cells during cultivation , 2011, BMC proceedings.

[27]  B. K. Ahring,et al.  Quantitative monitoring of yeast fermentation using Raman spectroscopy , 2014, Analytical and Bioanalytical Chemistry.

[28]  Dörte Solle,et al.  Chemometric modelling with two-dimensional fluorescence data for Claviceps purpurea bioprocess characterization. , 2003, Journal of biotechnology.

[29]  Mario Jolicoeur,et al.  A multiwavelength fluorescence probe: is one probe capable for on-line monitoring of recombinant protein production and biomass activity? , 2005, Journal of Biotechnology.

[30]  Dörte Solle,et al.  Chemometric modeling and two-dimensional fluorescence analysis of bioprocess with a new strain of Klebsiella pneumoniae to convert residual glycerol into 1,3-propanediol , 2012, Journal of Industrial Microbiology & Biotechnology.

[31]  Daniel G. Bracewell,et al.  UV resonance Raman spectroscopy : a process analytical tool for host cell DNA and RNA dynamics in mammalian cell lines , 2015 .

[32]  Yves Roggo,et al.  Chemometrics and in-line near infrared spectroscopic monitoring of a biopharmaceutical Chinese hamster ovary cell culture: prediction of multiple cultivation variables. , 2013, Talanta.

[33]  Mark A. Arnold,et al.  On-line near infrared bioreactor monitoring of cell density and concentrations of glucose and lactate during insect cell cultivation. , 2014, Journal of biotechnology.

[34]  Hamidreza Mehdizadeh,et al.  Generic Raman‐based calibration models enabling real‐time monitoring of cell culture bioreactors , 2015, Biotechnology progress.

[35]  Gunnar Lidén,et al.  A Study of Long‐Term Effects on Plasmid‐Containing Escherichia coli in Carbon‐Limited Chemostat Using 2D‐Fluorescence Spectrofluorimetry , 2006, Biotechnology progress.

[36]  Joaquim M. S. Cabral,et al.  Real-time bioprocess monitoring: Part I: In situ sensors , 2006 .

[37]  Paula M Alves,et al.  Synchronous fluorescence spectroscopy as a novel tool to enable PAT applications in bioprocesses , 2011, Biotechnology and bioengineering.

[38]  Nikolai V. Tkachenko.  Chapter 5 – Steady State Absorption Spectroscopy , 2006 .

[39]  J. Menezes,et al.  Monitoring mammalian cell cultivations for monoclonal antibody production using near-infrared spectroscopy. , 2009, Advances in biochemical engineering/biotechnology.

[40]  Anurag S Rathore,et al.  Case study and application of process analytical technology (PAT) towards bioprocessing: Use of tryptophan fluorescence as at‐line tool for making pooling decisions for process chromatography , 2009, Biotechnology progress.

[41]  J. Hubbuch,et al.  Selective high throughput protein quantification based on UV absorption spectra , 2013, Biotechnology and bioengineering.

[42]  Y. Roggo,et al.  A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies. , 2007, Journal of pharmaceutical and biomedical analysis.

[43]  T. Schepera,et al.  Bioanalytics : detailed insight into bioprocesses , 1999 .

[44]  V. V. Lopes,et al.  Modelling, monitoring and control of plasmid bioproduction in Escherichia coli cultures , 2012, 2012 IEEE 2nd Portuguese Meeting in Bioengineering (ENBENG).

[45]  Krist V Gernaey,et al.  On-line estimation of biomass, glucose and ethanol in Saccharomyces cerevisiae cultivations using in-situ multi-wavelength fluorescence and software sensors. , 2009, Journal of biotechnology.

[46]  Emma Petiot,et al.  Short communicationIn situ quantification of microcarrier animal cell cultures using near-infrared spectroscopy☆ , 2010 .

[47]  H. Goicoechea,et al.  Monitoring substrate and products in a bioprocess with FTIR spectroscopy coupled to artificial neural networks enhanced with a genetic-algorithm-based method for wavelength selection. , 2006, Talanta.

[48]  Anurag S Rathore,et al.  Chemometrics applications in biotech processes: A review , 2011, Biotechnology progress.

[49]  Alan G. Ryder,et al.  Rapid characterization and quality control of complex cell culture media solutions using raman spectroscopy and chemometrics , 2010, Biotechnology and bioengineering.

[50]  Jaromir Růžička,et al.  Flow injection analysis , 1981 .

[51]  N D Lourenço,et al.  Bioreactor monitoring with spectroscopy and chemometrics: a review , 2012, Analytical and Bioanalytical Chemistry.

[52]  Michael Maiwald,et al.  Towards Process Spectroscopy in Complex Fermentation Samples and Mixtures , 2016 .

[53]  R. Das,et al.  Raman spectroscopy: Recent advancements, techniques and applications , 2011 .

[54]  Qing Xia,et al.  Monitoring microaerobic denitrification of Pseudomonas aeruginosa by online NAD(P)H fluorescence , 2005, Journal of Industrial Microbiology and Biotechnology.

[55]  Jürgen Hubbuch,et al.  A label‐free methodology for selective protein quantification by means of absorption measurements , 2011, Biotechnology and bioengineering.

[56]  Brian McNeil,et al.  The potential of mid infrared spectroscopy (MIRS) for real time bioprocess monitoring. , 2006, Analytica chimica acta.

[57]  Ludovic Duponchel,et al.  In-line and real-time prediction of recombinant antibody titer by in situ Raman spectroscopy. , 2015, Analytica chimica acta.

[58]  G. Montagnac,et al.  In situ monitoring by quantitative Raman spectroscopy of alcoholic fermentation by Saccharomyces cerevisiae under high pressure , 2007, Extremophiles.

[59]  K. Gernaey,et al.  Application of near‐infrared spectroscopy for monitoring and control of cell culture and fermentation , 2009, Biotechnology progress.

[60]  G. Sergeev,et al.  Sensitivity, Selectivity and Stability of Gas-Sensitive Metal-Oxide Nanostructures , 2010 .

[61]  Ian W. Marison,et al.  Potential of Mid-Infrared Spectroscopy for On-Line Monitoring of Mammalian Cell Culture Medium Components , 2012 .

[62]  Alois Jungbauer,et al.  Getting ready for PAT: Scale up and inline monitoring of protein refolding of Npro fusion proteins , 2014 .

[63]  Francisco Valero,et al.  Biomass estimation using fluorescence measurements in Pichia pastoris bioprocess , 2006 .

[64]  José Manuel Amigo,et al.  Parallel factor analysis combined with PLS regression applied to the on-line monitoring of Pichia pastoris cultures , 2006, Analytical and bioanalytical chemistry.

[65]  Dörte Solle,et al.  Sensor systems for bioprocess monitoring , 2015 .

[66]  Joaquim P Cardoso,et al.  Applying Near‐Infrared Spectroscopy in Downstream Processing: One Calibration for Multiple Clarification Processes of Fermentation Media , 2008, Biotechnology progress.

[67]  Thomas Becker,et al.  Future aspects of bioprocess monitoring. , 2007, Advances in biochemical engineering/biotechnology.

[68]  Thomas Scheper,et al.  Application of an Online-Biomass Sensor in an Optical Multisensory Platform Prototype for Growth Monitoring of Biotechnical Relevant Microorganism and Cell Lines in Single-Use Shake Flasks , 2014, Sensors.

[69]  Franz Clementschitsch,et al.  Sensor combination and chemometric modelling for improved process monitoring in recombinant E. coli fed-batch cultivations. , 2005, Journal of biotechnology.

[70]  Urs von Stockar,et al.  On-line monitoring of nine different batch cultures of E. coli by mid-infrared spectroscopy, using a single spectra library for calibration. , 2008, Journal of biotechnology.

[71]  J. Hubbuch,et al.  A tool for selective inline quantification of co‐eluting proteins in chromatography using spectral analysis and partial least squares regression , 2014, Biotechnology and bioengineering.

[72]  Frank Kensy,et al.  Validation of a high-throughput fermentation system based on online monitoring of biomass and fluorescence in continuously shaken microtiter plates , 2009, Microbial cell factories.

[73]  A S Rathore,et al.  Process analytical technology (PAT) for biopharmaceutical products , 2010, Analytical and bioanalytical chemistry.

[74]  Sascha Beutel,et al.  In situ sensor techniques in modern bioprocess monitoring , 2011, Applied Microbiology and Biotechnology.

[75]  Christoph Herwig.  Prozess Analytische Technologie in der Biotechnologie , 2010 .

[76]  Christoph Herwig,et al.  Combining Mechanistic Modeling and Raman Spectroscopy for Real‐Time Monitoring of Fed‐Batch Penicillin Production , 2016 .

[77]  Bernd Hitzmann,et al.  Sensors in disposable bioreactors status and trends. , 2009, Advances in biochemical engineering/biotechnology.

[78]  Urs von Stockar,et al.  pH prediction and control in bioprocesses using mid‐infrared spectroscopy , 2008, Biotechnology and bioengineering.

[79]  L. Olsson,et al.  Chemometric analysis of in‐line multi‐wavelength fluorescence measurements obtained during cultivations with a lipase producing Aspergillus oryzae strain , 2007, Biotechnology and bioengineering.

[80]  D. F. Swinehart,et al.  The Beer-Lambert Law , 1962 .

[81]  B Hitzmann,et al.  Two-dimensional fluorescence spectroscopy: a novel approach for controlling fed-batch cultivations. , 2006, Journal of biotechnology.

[82]  J Büchs,et al.  Quasi-continuous combined scattered light and fluorescence measurements: a novel measurement technique for shaken microtiter plates. , 2005, Biotechnology and bioengineering.

[83]  Ali Demirci,et al.  An On‐Line Approach To Monitor Ethanol Fermentation Using FTIR Spectroscopy , 2007, Biotechnology progress.

[84]  Brian Glennon,et al.  Glucose concentration control of a fed-batch mammalian cell bioprocess using a nonlinear model predictive controller , 2014 .

[85]  Martin Ebeling,et al.  Effects of copper on CHO cells: Insights from gene expression analyses , 2014, Biotechnology progress.

[86]  Urs von Stockar,et al.  Simplified Fourier-transform mid-infrared spectroscopy calibration based on a spectra library for the on-line monitoring of bioprocesses. , 2007, Analytica chimica acta.

[87]  Anurag S. Rathore,et al.  Application of process analytical technology for downstream purification of biotherapeutics , 2015 .

[88]  Urs von Stockar,et al.  A simple method to monitor and control methanol feeding of Pichia pastoris fermentations using mid-IR spectroscopy. , 2007, Journal of biotechnology.

[89]  David Littlejohn,et al.  In situ monitoring of the seed stage of a fermentation process using non-invasive NIR spectrometry. , 2008, The Analyst.

[90]  Emma Petiot,et al.  In situ quantification of microcarrier animal cell cultures using near-infrared spectroscopy ☆ , 2010 .

[91]  Brian McNeil,et al.  Multiplexing fibre optic near infrared (NIR) spectroscopy as an emerging technology to monitor industrial bioprocesses. , 2007, Analytica chimica acta.

[92]  Linda M. Harvey,et al.  Monitoring a high cell density recombinant Pichia pastoris fed-batch bioprocess using transmission and reflectance near infrared spectroscopy , 2005 .

[93]  T. Scheper,et al.  Comparative study of non-invasive monitoring via infrared spectroscopy for mammalian cell cultivations. , 2013, Journal of biotechnology.

[94]  M. Toft,et al.  A practical approach for exploration and modeling of the design space of a bacterial vaccine cultivation process , 2009, Biotechnology and bioengineering.

[95]  Carl Sullivan,et al.  Process Analytical Technology (PAT) and Multivariate Methods for Downstream Processes , 2015 .

[96]  Elo Harald Hansen,et al.  Flow injection analysis : Part X. theory, techniques and trends , 1978 .

[97]  Ashok K. Srivastava,et al.  Use of NAD(P)H Fluorescence Measurement for On-Line Monitoring of Metabolic State of Azohydromonas australica in Poly(3-hydroxybutyrate) Production , 2013, Applied Biochemistry and Biotechnology.

[98]  Kenneth F. Reardon,et al.  Sensors in Biotechnology , 2008 .

[99]  Andreas Prediger,et al.  Near-infrared spectroscopy in upstream bioprocesses , 2015 .

[100]  B. Lendl,et al.  On-Line Fermentation Monitoring by Mid-Infrared Spectroscopy , 2004, Applied spectroscopy.

[101]  R. Forbes,et al.  Development and validation of analytical methodology for near-infrared conformance testing of pharmaceutical intermediates. , 1996, Journal of pharmaceutical and biomedical analysis.

[102]  Christian Hakemeyer,et al.  At-line NIR spectroscopy as effective PAT monitoring technique in Mab cultivations during process development and manufacturing. , 2012, Talanta.

[103]  Eberhard Schlücker,et al.  Characterization of Escherichia coli suspensions using UV/Vis/NIR absorption spectroscopy , 2010 .

[104]  Jong Il Rhee,et al.  On-line process monitoring and chemometric modeling with 2D fluorescence spectra obtained in recombinant E. coli fermentations , 2007 .

[105]  Lisbeth Olsson,et al.  Determination of cell mass and polymyxin using multi-wavelength fluorescence. , 2006, Journal of biotechnology.

[106]  Bernd Hitzmann,et al.  Fluorescence Spectroscopy and Chemometric Modeling for Bioprocess Monitoring , 2015, Sensors.

[107]  Gerrit van Straten,et al.  Assessment of near infrared and “software sensor” for biomass monitoring and control , 2008 .

[108]  Rui Oliveira,et al.  In situ 2D fluorometry and chemometric monitoring of mammalian cell cultures , 2009, Biotechnology and bioengineering.