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On-line Monitoring of Bioprocesses

IONICON PTR-MS systems can analyze trace gas concentrations of volatile metabolites in the off-gas of bio-pharmaceutical fermentations in real-time. This highly relevant process related information can be used for on-line process monitoring and process control.  

On-line Monitoring in the Biopharmaceutical Industry

Modern biopharmaceutical drugs are produced in biotechnological fermentation processes. The monitoring of these processes is becoming increasingly relevant, especially in the manufacturing sector to promote cost-effective production. To date, biotechnical processes are generally monitored using off-line analysis, which is labor and cost intensive, providing results often too late for corrective actions. IONICON PTR-MS can provide highly relevant process information on-line and in real-time.

PTR-MS measuremenst - FermentationIn a bioreactor, volatile organic compounds (VOCs) are emitted as metabolic by-products of microbial growth and production. Real-time monitoring of these emitted volatile metabolites in the off-gas of a bioreactor with PTR-MS allows gauging the activity of the micro-organisms for quality assurance and process control. In E.Coli fermentations we observe up to 70 VOCs with notable concentrations and distinct variations over time - prominent examples are shown in the figure.

Process Monitoring – PTR-MS Setup

IONICON has conducted extensive research projects in the frame of the Austrian Center for industrial Biotechnology (ACIB), where, together with leading companies in the biotech industry, the potential of on-line process monitoring has been assessed.

PTR-MS biotech - SetupOf central importance in this context is a fast and quantitative transfer of the sample to the PTR-MS. IONICON has developed an optimized coupling system for biotech applications, see figure, which provides dilution of the sample gas, safety measures, multiplexing and automated calibration for quality assurance. The whole system, consisting of the IONICON PTR-MS and the purpose-built coupling system, proved to be very robust. It has been up and running at different industrial test sites for several years. As part of our customized PTR-MS solutions, IONICON provides an integrated PTR-MS bio system, optimized for the biotech industry.

Approach for Advanced Bioprocess Monitoring with PTR-MS

PTR-MS bio system - ReproducibilityIONICON PTR-MS systems allow for monitoring of a large variety of volatile metabolites. In the figure we show an example of the reproducibility of results from three fermentations, which is only possible when parameters of three cultivations are carefully kept identical. Slight deviations, intentional or accidental, are reflected in the monitored concentrations of one or more markers.

Even without the knowledge of the metabolic relationships of the measured VOCs, bioprocesses monitoring with PTR-MS can be used as a tool for on-line quality assurance. This type of direct monitoring technique is part of Process Analytical Technology (PAT) initiative being recommended by the US Food and Drugs Administration (FDA) to improve quality, safety and efficiency in drug manufacturing processes.

Process Control and Optimization

Metabolic overload - Fermentations Knowledge about the underlying system allows to relate monitored signals directly to metabolic activity. This has been demonstrated by Luchner at al.. The variation in specific signals can be used to detect a metabolic overload of the cells. This opens promising perspectives in terms of advanced process control. 

IONICON PTR-MS systems in GMP Production

Fermenter - Copyright Boehringer IngelheimAfter the successful testing in research fermentations, the IONICON PTR-technology could recently make another important step and has been utilized for real-time process monitoring in an industrial, GMP (Good Manufacturing Practice) controlled fermentation process. The ability to monitor volatile microbial metabolites in the off-gas, without an adaptation to the existing process, has enabled the introduction of PTR-MS to this highly regulated area. Read our blog entry