Sensor Technology Automates Feeding Control in Single Use Bioreactors

Sensors Insights by Bill Campbell

Bioprocessing dates back over 100 years, in fact, beer manufacturing is a bioprocess operation and original bioreactors could be as simple as oak casks. The more recent history of bioreactors is dominated by either glass reactor vessels, which are typically used in process development and sized at 2 to 25 liters, or stainless steel, which are used in pilot plants and manufacturing.

Stainless steel reactors can range from a few 100 liters to 10,000 liters or more. Back in the 1980s, control of these reactors was mainly via off-line sampling and analog controls. By the 1990s, the vessels were very much the same; however control had become digitally based. Participants were converting a number of off-line measurements, pH for example, to in-situ, real time measurement.

Today, we see an industry where the process and media are much more complex, development times are extending and the rate of drug discovery is increasing. At the same time stainless steel facilities require high capital investment, significant build and commissioning times and are inflexible to changes to output demand. They do have the advantage of re-usability but, in many cases, this is more than offset by the cost of cleaning, sterilization and maintenance.

In an effort to decrease the cost base and increase flexibility a paradigm shift is underway employing single-use, disposable technologies, which require significantly less up-front investment, are highly modular and are faster to implement. The 'new' bioreactor is a sterilized, disposable, plastic bag. Single use reactors are currently sized up to 2,000 liters and require no on-going maintenance. Forecasted growth in single use for manufacturing is expected to be 55% per annum over the next three years in a market valued at $2.8B by 2016. The paradigm shift from re-useable stainless and glass to single-use is a significant response to the industry challenges.

As the industry moves to disposable reactors for manufacturing it is also seeking to reduce its process development costs and timescales. This is leading to the adoption of highly parallel mini-reactors, which can be less than 250 ml and look similar to Tic-Tac boxes. These systems allow process development engineers to run multiple concurrent process 'trials' as they seek to optimize their process. These fundamental changes in both process development and manufacturing highlight a number of control and measurement issues.

Firstly, C&M sensors now need to fit into much smaller reactor vessels. Secondly, they need to be at a 'disposable' price point and, thirdly, they must be usable across the entire range of reactor vessels. Some of the existing technologies may make the transition to this new operating model. Others may be more limited in their use.

Finally, as well as the physical requirement imposed on sensors by this paradigm shift, the industry is looking for sensors and systems which offer new measurement parameters to complement their existing techniques and allow users better process control and ultimately higher process yields and shorter development times. That is where a micro-optical sensor is proving to be of great value.

Working with solid state silicon and fiber optic technology, Stratophase, for example, has developed a micro optical sensor that is truly optimized for real-time, in-situ bioprocess control and monitoring across the full reactor range. A patented manufacturing process produces optical structures that route light around a small silicon chip. By immersing the sensor in the process media the refractive index of the media is measured directly. This real time measurement responds to the metabolic rate, any nutrient additions and indicates the end point of the process.

Stratophase micro optical sensor capable of performing real-time, in-situ bioprocess control and monitoring across the full reactor range.
Stratophase micro optical sensor capable of
performing real-time, in-situ bioprocess control
and monitoring across the full reactor range.

The micro-optical sensor is part of the Ranger System, which is composed of two components: the Ranger Manager unit providing controls and the Ranger Probe, a real-time sensor residing within the process media. Communication between the two devices is via noise-immune fiber optic cable. Manager contains a laser light source, detectors, data reduction components, communication modules, and user interface components. The system features standard outputs such as OPC and 4 mA to 40 mA to enable communication to process-control systems.

A two-part paradigm, the Ranger System employs the Ranger Manager for control functions and the Ranger Probe, a real-time sensor.
A two-part paradigm, the Ranger System employs the Ranger Manager for control functions and the Ranger Probe, a real-time sensor.

The micro-optical sensor and its control system enable process development teams to rapidly optimize their reactor feeding strategy which is then used in manufacturing independent of the reactor style. As a small silicon device it meets key parameters of size and cost and provides a new, high value, measurement parameter to the industry.


The biotechnology industry is implementing significant changes in the type and usage of bioreactor vessels. The deployment of single use system is advancing rapidly. This presents both a challenge and an opportunity for new technologies to emerge, which are useable in all bioreactor form factors.

Additionally, increasing complexity, higher value products, and regulatory directives demand advances be made in process control. Processing equipment is leading the way with smaller, massively parallel reactors and single-use systems. Control and measurement technologies must advance rapidly to track these trends and offer new capability, which directly contribute to the profitability and cost effectiveness of the industry.

About the Author
Bill Campbell has a wealth of Chief Executive and commercial experience gained over the past 25 years. Prior to joining Stratophase he was CEO at Splashpower, a wireless power technology company, and Microemissive Displays (MED), a developer of P-OLED micro displays. Bill led the commercial development of both companies, through IP licensing in the case of Splashpower and through product development in the case of MED.

Before moving to his first CEO position, Bill had 20 years of commercial success with a number of electronics based companies – IP licensing of microprocessors with Tensilica, Design Automation, most notably with Synopsys, and Automatic Test Equipment with GenRad. He can be reached via email at [email protected] or via telephone at +44 (0) 1794 511226.