Integrated control and sensing platform for biopharmaceutical cultivation process high-throughput development and production

Livrables

Transferrable and generic chemometric model procedures are ready for application (models obtained by MBR can be used in STR)

The results of the transferability of models developed using MBR to apply in STR are obtained. The conditions and procedures how to transfer are determined. Under which conditions and how models obtained by MBR can be used in STR.

Off-line glycosylation/titre assays after sample purification/preparation on fluidic platform

Different glycan assay formats will be tested for integration into microfluidic platform.

Mechanistic models with different complexity levels related to their use (description/soft sensor/control)

Mechanistic models will be derived from the experimental data and obtained through ordinary differential equation systems to describe the component concentration evolutions with respect to a kinetics and b transfersdilutions The general model complexity related to the number of considered pseudobioreactions will be based on the physical knowledge while the parameters will be identified by a dedicated identification procedure validated with the datasets

Multivariable predictive robust controllers of the metabolites

In accordance with available online measurements from hardware and software sensors a robust minimax nonlinear model predictive control strategy Robust NMPC will be developed to control the main metabolites ie to respect a priori optimal metabolite levels Process optimality will be described by the nonlinear constrained problem solved by the NMPController

Spectrophotometric method decision-diagram for specification of best method

Spectrophotometric method decisiondiagram for specification of best method Raman NIR MIR 2D fluorescence or wavelength combinations for specific applications

Data-driven models with different complexity levels related to their use (description/soft sensor/control)

Data-driven models will be derived by applying MLPCA to the datasets to determine the data-driven required number of pseudo-bioreactions. In a second step, a decision on the kinetic structure (grey-box vs black-box) will be taken with respect to the data content. Eventually, an adapted identification procedure will be applied and validated with the datasets.

Software sensors using the previously obtained models

A general observability mapping will be determined based on the previously obtained models from D8.1 and D8.2. Necessary on-line measurements will be selected and software sensors will be derived from the models and these measurements. First off-line validations of the resulting software sensors will be achieved and used as basis for further on-line validations using closed-loop controllers.

Procedures for life cycle management of chemometric models

Procedures for model maintenance for small changes of process conditions are defined; conditions and methods for recalibration of chemometric models are determined as well as procedures which assess the chemometric models with respect to their prediction ability to validate or disprove their further applicability.

Algorithms to reduce measurement effort using model-based calibration (MBR)

Data driven modelling will be combined with process models to reduce the measurement effort necessary for the calibration procedure.

Chemometric models methodology is fixed and can be utilized by partners

The best modeling methodology is determined (such as PCR, PLS or neural network, support vector regression) and can be applied by the partners

Spectral pre-processing procedures (such as outlier detection, noise reduction and smoothing) are implemented

The algorithms of outlier detection, noise reduction and smoothing are implemented and validated. Furthermore preprocessing procedures like deviation-, distance- and density-based approaches are implemented in the evaluation program.

Publications

Recent capillary electrophoresis applications for upstream and downstream biopharmaceutical process monitoring

Auteurs: van der Burg, D., Josefsson, L., Emmer, Å. and Sänger–van de Griend, C.E.
Publié dans: TrAC Trends in Analytical Chemistry, 2023, Page(s) 116975, ISSN 0165-9936
Éditeur: Elsevier BV
DOI: 10.1016/j.trac.2023.116975

Online Process State Estimation for Hansenula polymorpha Cultivation with 2D Fluorescence Spectra-Based Chemometric Model Calibrated from a Theoretical Model in Place of Offline Measurements.

Auteurs: Babor, M.; Paquet-Durand, O.; Berg, C.; Büchs, J.; Hitzmann, B.
Publié dans: Fermentation, Numéro 9, 2023, Page(s) 95, ISSN 2311-5637
Éditeur: Basel : MDPI
DOI: 10.3390/fermentation9020095

Analysis of cationic vitamins in cell culture medium samples by capillary zone electrophoresis

Auteurs: van der Burg, D., Wätzig, H., Sänger‐van de Griend, C. E.
Publié dans: Journal of Analytical Methods in Chemistry, Numéro 2819855, 2022, ISSN 2090-8873
Éditeur: Hindawi
DOI: 10.1155/2022/2819855

Non‐invasive and time‐resolved measurement of the respiration activity of Chinese hamster ovary cells enables prediction of key culture parameters in shake flasks

Auteurs: Ihling N, Munkler LP, Paul R, Berg C, Reichenbächer B, Kadisch M, Lang D, Büchs J.
Publié dans: Biotechnology journal, Numéro 17(8), 2022, Page(s) 2100677, ISSN 1860-7314
Éditeur: Wiley-Blackwell
DOI: 10.1002/biot.202100677

Capillary and microchip electrophoresis method development for amino acid monitoring during biopharmaceutical cultivation

Auteurs: S. Mikkonen, L. Josefsson, M. E.-L. Mäkinen, V. Chotteau, Å. Emmer
Publié dans: Biotechnology Journal, Numéro 17, 2022, Page(s) 2100325, ISSN 1860-7314
Éditeur: Wiley-Blackwell
DOI: 10.1002/biot.202100325

Monitoring of amino acids and antibody N-glycosylation in high cell density perfusion culture based on Raman spectroscopy.

Auteurs: Schwarz, H., Mäkinen, M.E., Castan, A. and Chotteau, V., 2022.
Publié dans: Biochemical Engineering Journal, Numéro 182, 2022, Page(s) 108426, ISSN 1873-295X
Éditeur: Elsevier
DOI: 10.1016/j.bej.2022.108426

Introducing oxygen transfer rate measurements as a novel method for time-resolved cytotoxicity assessment in shake flasks

Auteurs: Ihling N, Munkler LP, Paul R, Lang D, Büchs J
Publié dans: Environmental Sciences Europe, Numéro 34(1), 2022, Page(s) 37, ISSN 2190-4715
Éditeur: Berlin ; Heidelberg : Springer
DOI: 10.1186/s12302-022-00673-5

Online 2D Fluorescence Monitoring in Microtiter Plates Allows Prediction of Cultivation Parameters and Considerable Reduction in Sampling Efforts for Parallel Cultivations of Hansenula polymorpha

Auteurs: Berg C, Ihling N, Finger M, Paquet-Durand O, Hitzmann B, Büchs J.
Publié dans: Bioengineering, Numéro 9(9), 2022, Page(s) 438, ISSN 2306-5354
Éditeur: Basel : MDPI
DOI: 10.3390/bioengineering9090438

Practical data-driven modeling and robust predictive control of mammalian cell fed-batch process  

Auteurs: L. Dewasme, M. Mäkinen, V. Chotteau
Publié dans: Computers and Chemical Engineering, Numéro 171, 2023, Page(s) 108164, ISSN 0098-1354
Éditeur: Pergamon Press Ltd.
DOI: 10.1016/j.compchemeng.2023.108164

Analysis of amino acids in cell culture supernatant using capillary electrophoresis with contactless conductivity detection

Auteurs: Saara Mikkonen, Åsa Emmer
Publié dans: ELECTROPHORESIS, 2021, ISSN 0173-0835
Éditeur: John Wiley & Sons Ltd.
DOI: 10.1002/elps.202100122

Generic Chemometric Models for Metabolite Concentration Prediction Based on Raman Spectra

Auteurs: Yousefi-Darani, A., Paquet-Durand, O., Von Wrochem, A., Classen, J., Tränkle, J., Mertens, M., Snelders, J., Chotteau, V., Mäkinen, M., Handl, A., Kadisch, M., Lang, D., Dumas, P. and Hitzmann, B.
Publié dans: Sensors, Numéro 22(15), 2022, Page(s) 5581, ISSN 1424-8220
Éditeur: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/s22155581

Time-Resolved Monitoring of the Oxygen Transfer Rate of Chinese Hamster Ovary Cells Provides Insights Into Culture Behavior in Shake Flasks

Auteurs: Ihling N, Munkler LP, Berg C, Reichenbächer B, Wirth J, Lang D, Wagner R, Büchs J.
Publié dans: Frontiers in Bioengineering and Biotechnology, Numéro 9:725498, 2022, ISSN 2296-4185
Éditeur: Frontiers Media
DOI: 10.3389/fbioe.2021.725498

Method development for mono‐and disaccharides monitoring in cell culture medium by capillary and microchip electrophoresis

Auteurs: van der Burg, D., Josefsson, L., Mikkonen, S., Chotteau, V., Emmer, Å., Wätzig, H., Sänger‐van de Griend, C. E.
Publié dans: ELECTROPHORESIS, Numéro 43, 2021, Page(s) 922-929, ISSN 1522-2683
Éditeur: Wiley-VCH GmbH, Weinheim
DOI: 10.1002/elps.202100213

Auteurs: Inês F Pinto, Saara Mikkonen, Leila Josefsson, Meeri E-L Mäkinen, Ruben RG Soares, Aman Russom, Åsa Emmer, Veronique Chotteau
Publié dans: Current Opinion in Biotechnology, Numéro 71, 2021, Page(s) 55-64, ISSN 0958-1669
Éditeur: Elsevier BV
DOI: 10.1016/j.copbio.2021.06.018

Assessing the capabilities of 2D fluorescence monitoring in microtiter plates with data-driven modeling for secondary substrate limitation experiments of Hansenula polymorpha.

Auteurs: Berg, Christoph ; Herbst, Laura Marie ; Gremm, Lisa ; Ihling, Nina ; Paquet-Durand, Olivier ; Hitzmann, Bernd; Büchs, Jochen
Publié dans: Journal of biological engineering, Numéro 17, 2023, Page(s) 12, ISSN 1754-1611
Éditeur: BioMed Central
DOI: 10.1186/s13036-023-00332-0

Multiplexed Microfluidic Cartridge for At-Line Protein Monitoring in Mammalian Cell Culture Processes for Biopharmaceutical Production

Auteurs: Inês F. Pinto, Ruben R. G. Soares, Meeri E.-L. Mäkinen, Veronique Chotteau, Aman Russom
Publié dans: ACS Sensors, Numéro 6/3, 2021, Page(s) 842-851, ISSN 2379-3694
Éditeur: ACS Publications
DOI: 10.1021/acssensors.0c01884

Method development for quantitative monitoring of monoclonal antibodies in upstream cell culture process samples with limited sample preparation – evaluation of various capillary coatings.

Auteurs: van der Burg, D., Wätzig, H., Sänger‐van de Griend, C. E.
Publié dans: ELECTROPHORESIS, 2022, ISSN 1522-2683
Éditeur: Wiley-VCH GmbH, Weinheim
DOI: 10.1002/elps.202200144

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