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CAV - Online measurement ensures optimum yield

Cell cultures in pharmaceutical development react very sensitive to their environment. That's why the conditions in the bioreactor are subject to precise monitoring. In order to react quickly, online measurement systems have been established. They monitor pH value, dissolved oxygen and other parameters. With the Hamilton Incyte and Dencytee sensors it is now possible to measure cell density online.

Online measurements of pH or dissolved oxygen have long been established for biological processes.  Influencing factors that provide really important information about cell physiology previously required time-consuming and less precise offline measurement. The Incyte and Dencytee sensors by Hamilton embody a big step forward. They allow direct real-time measurement of the viable or the total cell density to obtain advanced control with never-before instantly available data. Up-to-date information about critical events that could have been missed between offline samples, are now immediately recognizable. With these sensors production processes can be automated and product developments in the research and development departments can be strategized.  The most important information about a culture is found during the growth and stationary phase of the cells – i.e. before they die. With the help of online measurement it is now possible to recognise process deviations and to quickly make the required adjustments. Detecting when cells begin to die can be difficult when only looking at the total cell density. Monitoring the viable shows an immediate change and depending on the culture and timing indicates the next steps to take to maximize the yield.


Dissolved oxygen and pH measurement

The simultaneous online control of the pH value is critical to generate the right product and maximize yield. Online pH control enables more frequent and small adjustments to pH in order to minimize this stress factor and maintain a constant environment. The dissolved oxygen content is important for the majority of bioprocesses: a lack of oxygen leads to apoptosis (sudden cell death) or anaerobic digestion, reducing the viability and yield significantly. Online measurement and control of dissolved oxygen ensures  an optimal amount of oxygen to maintain high-quality products. All in all, online measurement allows earlier detection of process deviations, reduces labor and the risk of contamination from grab sampling and increases the product yield.


Determination of the viable cell density

The Incyte sensor was especially developed for use with mammalian cells, yeast as well as high density bacterial fermentations. Neither changes to the medium nor microcarriers or cell debris influence the measurement. The functional principle is based on capacitance measurement: in an alternating electrical field the viable cells behave like small capacitors. Their charging and discharging, resp. their permittivity are measured. The optimization of the harvest time, a higher yield and the low costs are the benefits of this technology. A precise control ensures optimum environmental conditions and  the very early determination of process deviations are the basis for the successful use of the Incyte sensor.


Optical Density Measurement

The Dencytee sensor, on the other hand, is based on an optical technology, that measures the total cell density, resp. the turbidity of a cell suspension. Near Infrared wavelengths are used for the measurement making it insensitive to changes in media color . All particles and molecules, that scatter light at 880 nm, are detected – both viable and dead cells. This technology is most effective when cells are growing quickly because at that time almost only viable cells are present. Quick and easy measurement of cell growth, reliable values during the growth phase as well as the early detection of process deviations are amongst the real strengths of the sensor.


No more undetected events

The quality and reliability of the measurement of individual parameters as well as the measurement of various combined factors has been proven by Hamilton in a pilot project. The precision of the measurements were evaluated with additional offline measurements. An optimum cultivation of CHO cells (Chinese hamster ovary) was established in the bioreactor as part of a project to create monoclonal antibodies. In order to attain a high level of reproducibility in the test procedure,  continuous  monitoring of all relevant parameters, including pH, dissolved oxygen as well as the viable and total cell density. In these cultures, even minor process deviations sometimes cause major effects on the cell growth. The measurement of pH values and dissolved oxygen are only indirectly linked to cell status and growth. Combined with pH and dissolved oxygen sensors, the capacitive Incyte sensors allow the continuous measurement of all relevant bioprocess data. This makes the biological processes significantly more transparent and eases future optimizations. The Hamilton sensors are therefore able to reliably measure online leading to an optimized process monitoring.

Hall 11.1, booth F43


Dr Knut Georgy
 Senior Market Segment Manager
Process Analytics,
Hamilton Bonaduz

The Incyte (above) and Dencytee sensors by Hamilton allow a direct real-time measurement of the living or the entire cell density

An optimum cultivation of CHO cells was established in the bioreactor as part of a pilot project to create monoclonal antibodies.