Problem: The bioprocessing industry is advancing the capability to monitor and control its manufacturing systems. Initiatives such as the US Food and Drugs Agency’s Process Analytical Techniques program and Quality by Design (QbD) are driving these changes as are demands for higher yielding, more repeatable and predictable processes.

To date, process monitoring and control has been separated into two primary methodologies.

Firstly, off-line analytical techniques such as spectroscopy have been used to determine the chemical composition of the media contained in the reactor vessel. The results accurately reflect the process, however, the skill required to obtain, prepare and analyze samples is significant and the elapsed time from sample extraction to presentation of results may, in fact, mean that the data is historical rather than current. Typically, samples are taken at timed intervals throughout the process run and are therefore ‘snapshots’ rather than a dynamic indication of the process’s actual status. Finally, the technique requires a physical sample to be removed from the reactor vessel, increasing the risk of contamination and batch rejection.

The alternative approach, although often used in conjunction with analytical techniques, is to use in-situ, real time sensors to determine specific physical characteristics such as temperature, pH value or dissolved oxygen (DO). These application-specific sensors are well suited to the requirement for dynamic process data, however, they typically provide only a single process parameter and give little indication of the chemical characteristics of the process media.

An ideal solution to improve process monitoring and control would be to provide real-time, in-situ sensors which indicate the dynamic state of the process media.

Refractive Index (RI) instruments, known as refractometers, have been employed in a range of benchtop bioprocess applications to determine media concentrations, for example. More recently these optical devices have been deployed in relatively small numbers in in-line applications. ‘In-line’ indicates connection to the reactor vessel media via parallel pipework rather than the more desirable ‘in-situ’ where the sensor is in direct contact with the process media. Whilst their performance and sensitivity have been adequate, the size, governed by free space optics, and cost of these sensors have inhibited mass deployment either in small process development systems or in manufacturing vessels where physical robustness is also a consideration. Refractive Index has therefore been accepted as a measurement technique however, the current physical implementation and costs are prohibitive.

Solution: One solution to the demand for dynamic process information has been developed by a UK company called Stratophase. Working with solid state silicon and fiber optic technology originally developed for mass market telecommunications, the company has developed the first refractive index sensor which is truly optimized for realtime, in-situ process monitoring and control. Stratophase has developed a manufacturing method which routes light around a small silicon chip that sits within the reactor vessel. The sensor measures the refractive index of the media directly and dynamically monitors metabolic rates, the effects of nutrient additions and the end of process. Where the process calls for nutrient feeds throughout its run time, known as fed-batch, the sensor can be used to determine the optimal feeding regime. The data is automatically generated in real-time. In addition to its performance characteristics the simple structure of the sensor means that it is lower cost and physically robust, making it a good fit for mass deployment in both development and manufacturing. Product development is now complete and the company has installations at a number of corporate launch sites.

In summary, the application-specific development of the Stratophase sensor makes it a suitable option for processes ranging from biofuel to mammalian cell culture and in media monitoring, media preparation and fill and finish.

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Stratophase refractive index media sensor