Periodic Reporting for period 4 - iConsensus (Integrated control and sensing platform for biopharmaceutical cultivation process high-throughput development and production)
Période du rapport: 2021-05-01 au 2022-10-31
1. What was the problem/issue being addressed?
Biopharmaceuticals are large molecules used for therapy, e.g. antibodies (mAb). The biopharmaceuticals are produced using cells in well-regulated processes ('bioprocess') in bioreactor.
Health technology is highly profitable but spending very high parts of its revenues on R&D. The development of a new drug costs about 1 billion dollars and takes ≥ 10 years. Reducing cost and time for the development of the manufacturing process gives very large savings and is essential to be first to market.
The worldwide community of bioprocessing is in quest for more rational tools to understand, predict and optimize industrial biopharmaceutical manufacturing.
2. Why was it important for society?
iConsensus aims were to bring a disruptive new technology platform for cell based production of biopharmaceuticals, to reduce the time and costs for the process development and lead to better manufacturing control. These improvements could influence the time-to-market and give competitiveness advantage, higher consistency, efficacy and robustness for the biopharmaceutical industry, generating as well reduced cost, failure and risk for product shortage.
The project clearly supported European Innovation, competitiveness and industrial leadership while giving tools to improve the European well-being and societal challenges.
3. What were the overall objectives?
Cell cultures of mammalian cells, e.g. Chinese Hamster Ovary (CHO) cells, used for the production of a biopharmaceutical are complex mixtures of ≥ 70 components, of which monitoring provide process knowledge however is a very large and tedious task. All these components can have an effect on the process performance, its purification or on the product quality, which is the reason why monitoring all these compounds is advantageous.
To address this, iConsensus provided innovative analytical, hardware, software and high-throughput solutions for the development, monitoring and control of cell culture, with an analytical platform including on-line/at-line sensors and methods measuring multiple factors. The analytical platform aimed to be integrated to bioreactor, enabling feedback control implementation.
Biopharmaceuticals are large molecules used for therapy, e.g. antibodies (mAb). The biopharmaceuticals are produced using cells in well-regulated processes ('bioprocess') in bioreactor.
Health technology is highly profitable but spending very high parts of its revenues on R&D. The development of a new drug costs about 1 billion dollars and takes ≥ 10 years. Reducing cost and time for the development of the manufacturing process gives very large savings and is essential to be first to market.
The worldwide community of bioprocessing is in quest for more rational tools to understand, predict and optimize industrial biopharmaceutical manufacturing.
2. Why was it important for society?
iConsensus aims were to bring a disruptive new technology platform for cell based production of biopharmaceuticals, to reduce the time and costs for the process development and lead to better manufacturing control. These improvements could influence the time-to-market and give competitiveness advantage, higher consistency, efficacy and robustness for the biopharmaceutical industry, generating as well reduced cost, failure and risk for product shortage.
The project clearly supported European Innovation, competitiveness and industrial leadership while giving tools to improve the European well-being and societal challenges.
3. What were the overall objectives?
Cell cultures of mammalian cells, e.g. Chinese Hamster Ovary (CHO) cells, used for the production of a biopharmaceutical are complex mixtures of ≥ 70 components, of which monitoring provide process knowledge however is a very large and tedious task. All these components can have an effect on the process performance, its purification or on the product quality, which is the reason why monitoring all these compounds is advantageous.
To address this, iConsensus provided innovative analytical, hardware, software and high-throughput solutions for the development, monitoring and control of cell culture, with an analytical platform including on-line/at-line sensors and methods measuring multiple factors. The analytical platform aimed to be integrated to bioreactor, enabling feedback control implementation.
Novel high-throughput microbioreactors for screening in mammalian cell cultures verified with CHO cells with pH and DO controls (m2p/Beckman, RWTH)
https://publications.rwth-aachen.de/record/854042
https://publications.rwth-aachen.de/record/825312
https://publications.rwth-aachen.de/record/843965
New methods of capillary electrophoresis (CE), also in chip format for analysis of culture components, e.g. amino acids, sugars (KTH, Kantisto), and new CE methods for vitamins and antibody
https://doi.org/10.1002/elps.202100122
https://doi.org/10.1002/biot.202100325
https://doi.org/10.1002/elps.202100213
https://doi.org/10.1155/2022/2819855
https://doi.org/10.1002/elps.202200144
https://doi.org/10.1016/j.trac.2023.116975
New optical on-line sensors (Presens) with successful tests by industry
https://www.presens.de/knowledge/publications/application-note/cell-culture-monitoring-in-stirred-tank-bioreactor-with-optical-ph-sensors-1717
https://www.presens.de/knowledge/publications/application-note/evaluation-of-an-optical-co2-probe-for-long-term-monitoring-in-stirred-tank-bioreactors-1715
https://www.presens.de/knowledge/publications/application-note/evaluation-of-an-optical-o2-probe-and-sensor-spots-for-long-term-measurements-in-stirred-tank-bioreactors-1713
https://www.presens.de/knowledge/publications/application-note/online-co2-monitoring-in-cho-cell-culture-1759
Generic chemometric partial least square (PLS) prediction model (Hohenheim Univ.) to predict glucose, glutamate and lactate levels using Raman spectra from various CHO cultures and spectrometers
doi.org/10.3390/s22155581
Prediction of amino acids and glycosylation in perfusion process (KTH)
https://doi.org/10.1016/j.bej.2022.108426
2D fluorescence for monitoring in microtiter plates
https://www.mdpi.com/2306-5354/9/9/438
https://doi.org/10.1186/s13036-023-00332-0
https://doi.org/10.3390/fermentation9020095
New quantification of cell density by holographic image (Iprasense), with successful test at GSK and integration to high-through put bioreactors.
https://www.iprasense.com/wp-content/uploads/2023/02/NORMA-4S-APPLICATION-NOTE-A-fully-Automatic-Cell-Counter-for-High-Throughput.pdf
https://www.iprasense.com/applications/viable-cell-density-monitoring-in-bioreactor/#
Novel microfluidic bead-based immunoassays validated with antibody producing CHO cell bioreactor culture (KTH), with Micronit’s COC devices, for host cell proteins and antibody detections in stand-alone module (Ipratech), and fast DNA quantification by bead-based detection
10.1021/acssensors.0c01884
10.1016/j.copbio.2021.06.018
Validation of PAIA’s lectin-based detection of glycosylation with Bayer, and successful transfer to microfluidics.
Monitoring Information Database (MID) to enable effortless integration of various on-line and off-line measurements.
At-Line Integrated Analytical System (ALIAS) designed as versatile platform for multiple analytical methods such as affinity-based microfluidics, optical sensing, and CE-chip, with shared sample preparation and distribution system.
Mechanistic kinetic model of a fed-batch process by column generation and statistical approach for the kinetics (KTH), and data-driven models (Univ. Mons), able to predict the process behaviour
https://doi.org/10.1016/j.compchemeng.2023.108164
Software sensors predicting unmeasurable variables and robust model predictive control with several external disturbances validated in simulations.
Exploitation and dissemination
The achievements of iConsensus have been numerous and bearing high promises, thanks to the collaboration of the experts of academia with the SME’s and the EFPIA partners. The new analytical stand-alone modules and ALIAS have good commercial potential, which will be pushed forward, by partners beyond iConsensus. The sustainability of these achievements is also guaranteed by the publications in 17 peer-reviewed articles, 6 application notes and two patent applications as well as the dissemination at conferences as 20 lectures and 8 posters.
https://publications.rwth-aachen.de/record/854042
https://publications.rwth-aachen.de/record/825312
https://publications.rwth-aachen.de/record/843965
New methods of capillary electrophoresis (CE), also in chip format for analysis of culture components, e.g. amino acids, sugars (KTH, Kantisto), and new CE methods for vitamins and antibody
https://doi.org/10.1002/elps.202100122
https://doi.org/10.1002/biot.202100325
https://doi.org/10.1002/elps.202100213
https://doi.org/10.1155/2022/2819855
https://doi.org/10.1002/elps.202200144
https://doi.org/10.1016/j.trac.2023.116975
New optical on-line sensors (Presens) with successful tests by industry
https://www.presens.de/knowledge/publications/application-note/cell-culture-monitoring-in-stirred-tank-bioreactor-with-optical-ph-sensors-1717
https://www.presens.de/knowledge/publications/application-note/evaluation-of-an-optical-co2-probe-for-long-term-monitoring-in-stirred-tank-bioreactors-1715
https://www.presens.de/knowledge/publications/application-note/evaluation-of-an-optical-o2-probe-and-sensor-spots-for-long-term-measurements-in-stirred-tank-bioreactors-1713
https://www.presens.de/knowledge/publications/application-note/online-co2-monitoring-in-cho-cell-culture-1759
Generic chemometric partial least square (PLS) prediction model (Hohenheim Univ.) to predict glucose, glutamate and lactate levels using Raman spectra from various CHO cultures and spectrometers
doi.org/10.3390/s22155581
Prediction of amino acids and glycosylation in perfusion process (KTH)
https://doi.org/10.1016/j.bej.2022.108426
2D fluorescence for monitoring in microtiter plates
https://www.mdpi.com/2306-5354/9/9/438
https://doi.org/10.1186/s13036-023-00332-0
https://doi.org/10.3390/fermentation9020095
New quantification of cell density by holographic image (Iprasense), with successful test at GSK and integration to high-through put bioreactors.
https://www.iprasense.com/wp-content/uploads/2023/02/NORMA-4S-APPLICATION-NOTE-A-fully-Automatic-Cell-Counter-for-High-Throughput.pdf
https://www.iprasense.com/applications/viable-cell-density-monitoring-in-bioreactor/#
Novel microfluidic bead-based immunoassays validated with antibody producing CHO cell bioreactor culture (KTH), with Micronit’s COC devices, for host cell proteins and antibody detections in stand-alone module (Ipratech), and fast DNA quantification by bead-based detection
10.1021/acssensors.0c01884
10.1016/j.copbio.2021.06.018
Validation of PAIA’s lectin-based detection of glycosylation with Bayer, and successful transfer to microfluidics.
Monitoring Information Database (MID) to enable effortless integration of various on-line and off-line measurements.
At-Line Integrated Analytical System (ALIAS) designed as versatile platform for multiple analytical methods such as affinity-based microfluidics, optical sensing, and CE-chip, with shared sample preparation and distribution system.
Mechanistic kinetic model of a fed-batch process by column generation and statistical approach for the kinetics (KTH), and data-driven models (Univ. Mons), able to predict the process behaviour
https://doi.org/10.1016/j.compchemeng.2023.108164
Software sensors predicting unmeasurable variables and robust model predictive control with several external disturbances validated in simulations.
Exploitation and dissemination
The achievements of iConsensus have been numerous and bearing high promises, thanks to the collaboration of the experts of academia with the SME’s and the EFPIA partners. The new analytical stand-alone modules and ALIAS have good commercial potential, which will be pushed forward, by partners beyond iConsensus. The sustainability of these achievements is also guaranteed by the publications in 17 peer-reviewed articles, 6 application notes and two patent applications as well as the dissemination at conferences as 20 lectures and 8 posters.
iConsensus aimed at developing a new platform for real time analysis of the culture.
Today, the process development uses empirical methods supported by statistics, and high-throughput, where only very few parameters are easily quantified, leading to suboptimal outcome. Larger efforts on the analytical technology require enormous resources and time. iConsensus proposed solutions by far pioneer, with no equivalent product today, with real-time solutions and advanced MBR. Besides the importance of innovative tools in R&D, it is also crucial to have reliable, fast and qualified analytical tools for manufacturing processes. Data and knowledge gained during development should be usable in a straight line in the final manufacturing process. To use the same analytical tools throughout the development and life cycle management of a process/product can be highly beneficial for the control and robustness of the final manufacturing process.
Today, the process development uses empirical methods supported by statistics, and high-throughput, where only very few parameters are easily quantified, leading to suboptimal outcome. Larger efforts on the analytical technology require enormous resources and time. iConsensus proposed solutions by far pioneer, with no equivalent product today, with real-time solutions and advanced MBR. Besides the importance of innovative tools in R&D, it is also crucial to have reliable, fast and qualified analytical tools for manufacturing processes. Data and knowledge gained during development should be usable in a straight line in the final manufacturing process. To use the same analytical tools throughout the development and life cycle management of a process/product can be highly beneficial for the control and robustness of the final manufacturing process.