Giovanni Campolongo introduces advancements in measuring technology that enable a true control strategy for dissolved CO2 in bioreactors
Manufacturing of biopharmaceutical products such as monoclonal antibodies (mAbs) or vaccines is a complex process. The complexity is due to the heterogeneity typical for bioprocesses and minimal variations of the environment, particularly variations within critical process parameters (CPP) may result in higher – or lower – product yield.
Dissolved CO2 (DCO2) is one of the CPP’s that plays a major role in bioprocesses. It is both a product and reactant of metabolic processes and a component of the most used buffer systems, such as the bicarbonate one. It has also been shown to be an important factor of the lactate consumption shift. Just like pH and dissolved oxygen (DO), DCO2 should have its own defined set-point and a control strategy. This means it is required to control it in real-time to enable the automatic self-regulation during the bioprocesses. This applies to the entire scale-up: from R&D laboratories to the production floor. Compared to isolated off-line measurements, real-time in-line dissolved CO2 control strategies help to deliver higher viable cell density, a prolonged growth phase and higher product yield within the expected quality.
There are many ways to monitor dissolved CO2 in the bioreactor and many factors to consider when choosing the most appropriate method for a given application. Soft sensors based on other measurements are complex and too high in effort for accurate and matrix-independent DCO2 analysis. Offline measurements can be very useful for comparison against reference standards but do not provide data frequently enough to enable the implementation of a true control strategy. Another option is online off-gas measurements that provide more continuous information but do not truly measure dissolved DCO2.
To get the maximum process enhancement however, there is no way around in-line DCO2 measurements. For this purpose, there are currently two alternatives available on the market. The historical alternative is represented by the Severinghaus-based electrochemical sensors. They have been available for years and measure DCO2 indirectly by combining a pH and electrochemical dissolved oxygen (DO) measurement in one sensor. Their maintenance however is laborious as multiple sources of drift must be compensated by time-consuming product calibrations.
A new approach
To overcome this drawback, Hamilton has recently launched a new alternative: optical sensors named “CO2ntrol”. They are aimed to satisfy the requirements of biopharma industry in terms of accuracy, robustness (SIP/CIP compliance) and cleanability (EHEDG compliant hygienic design). According to the manufacturer, this new technology is completely maintenance free thanks to its solid-state-design and the direct DCO2 measurement guaranteed by its innovative optical technology results in interference-free, therefore accurate measurement, and with the lowest cost of ownership. To accomplish this, the firm had to reduce the Severinghaus complexity by eliminating any liquid components as well as avoiding the need for replacement parts. The R&D team developed a solid state mid-infrared (MIR) optical technology.
These new sensors enable Hamilton’s biopharma users to set-up dissolved CO2 real-time control. First reactions from biopharmaceutical manufacturers confirm the sensors’ easy handling and hassle-free operation.
Giovanni Campolongo is with Hamilton Bonaduz