Leverage advanced software to automate lab-scale mammalian cell cultures, increasing accuracy, reliability, and turnaround.
What is a bioreactor?
Combining real-time monitoring with advanced process control, bioreactors automate lab-scale mammalian cell cultures, detecting viable cell densities and glucose and lactate concentrations with high accuracy.
How does a bioreactor work?
By regulating biochemical processes, bioreactor control systems facilitate stable environments for microorganisms to yield certain substances. Biomass production may include cells, single cell proteins, enzymes, tissues, organelles, animal microalgae, organic acids, ethanol, antibiotics, aromatic compounds, and pigments.
Through in-line sensing and model predictive control software, Yokogawa’s bioreactors measure cell activities in real-time, automating feeding, sensing viable cell densities, and stabilizing glucose concentrations.
Technology to measure cell activity
Near-infrared (NIR) spectroscopy is used to measure in real time the concentration of nutrient sources taken in by cells and the concentration of metabolites expelled by cells in the extracellular space. Since nutrient sources and metabolites absorb near-infrared light, changes in concentration are captured by measuring the near-infrared absorption spectra of nutrient sources and metabolites with a measurement probe placed in the culture medium. Cells take up a nutrient source into the cell and metabolize it to produce antibodies, proteins and other drugs. By monitoring the nutrient source (glucose) taken up by cells and the metabolite (lactic acid) expelled from the cell by metabolism, it is possible to measure the activity of cells in culture.
Technology to measure the state of cells
The number of live cells is measured in real time by the electrical impedance measurement method. Live cells in an electric field cause dielectric relaxation, which polarizes the charges inside and outside the cell membrane. Dead cells, on the other hand, do not undergo charge polarization because their membranes are broken. As a result, the capacitance of the culture medium changes in proportion to the number of living cells. Using this characteristic, a measurement probe placed in the culture medium can measure the change in the capacitance of the culture medium to determine the number of living cells.
Technology to predict and control cellular metabolism
Mathematical modeling of cell movement predicts the metabolic state of cells and controls the cell's appropriate culture environment for the production of drugs. Changes in the metabolic state of cells are expressed in changes in the rate of cell growth and consumption of nutrient sources. Therefore, we build a mathematical model of cell metabolism based on real-time measurements of the number of living cells and the concentration of nutrient sources and metabolites to estimate and predict the growth rate of cells and the rate of consumption of nutrient sources. Based on these predictions, the culture environment can be controlled to maintain optimal cell activity.
Industrial Applications and Types of Bioreactors
- Continuous stirred tank bioreactors- yeast and bacteria cell production; primary metabolites, enzymes, amino acids, alcohol, activated sludge for wastewater treatment
- Bubble column bioreactors- plant cells, mold, and fermentation in chemical and pharmaceutical production
- Air-lift bioreactors- waste water treatment; methanol and single-cell protein production
- Packed bed reactors- waste water treatment
- Fluidized bed bioreactors- process and chemical engineering; bulk materials drying
- Photobioreactors- photosynthetic processes in vegetable biomass or microalgae growth
- Membrane bioreactors- wide range of research and commercial applications; widely used in waste water treatment
- Immersed membrane bioreactors- textile, tannery, and aquaculture wastewater treatment
A critical requirement in biopharmaceutical development is the integration and automation of process equipment and analytical instruments used in the laboratory. Bioprocess labs with multiple lab-scale bioreactors often execute cultivation experiments in parallel for research or process development purposes.
As part of a collaboration between Securecell (Zurich, SW) and Yokogawa Life Science (Tokyo, Japan), this application note demonstrates the effective use of the Lucullus® Process Information Management System (Lucullus®) to assist in the control of three Advanced Control Bioreactor Systems (BR1000) to study glucose utilization of CHO cells for optimal monoclonal antibody productivity.
This paper describes how the Yokogawa BR1000 bioreactor can be used to automate through real-time sensing and improve productivity through accurate and efficient glucose control.
The integration of all essential probes, instruments, software, and delivery systems for automated delivery of media concentrations of key components can be a daunting task. We have created a default control algorithm and next generation integrated system for CHO cell expression of biologics that can be customized in as little as three optimization runs.
By employing a proprietary self-learning predictive-control algorithm, continuous glucose adjustments are made, resulting in high cell counts, better viability, and improved biologic yield. The technology can speed process development and open new possibilities for control of biopharmaceutical production.
- Soft-sensor use for real-time process control
- Software use for accurate cell models
- Dynamic predictive control for glucose feeding
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