Using Fluorescence-Based Sensing to Accelerate Process Development - A prove-free system monitors accurately at very small scale - BioPharm International


Using Fluorescence-Based Sensing to Accelerate Process Development
A prove-free system monitors accurately at very small scale

BioPharm International
Volume 22, Issue 6


In recent years, several systems have been introduced that attempt to address the conflicting needs of maximizing information while minimizing expense. Some of these systems, such as automated plate readers and similar devices, provide an adequate degree of parallelism while providing at least some information about what transpires during culturing. However, process control in such systems is generally absent or inadequate. Newer, novel systems using microreactors or chips provide increased capabilities but are quite expensive compared to traditional systems and raise the question of how best to scale up to large-capacity systems for production purposes.

Another approach to high throughput design is typified by systems, such as Infors Profors sparged column reactors, DasGIP Fedbatch-Pro stirred tank reactors, Infors Sixfors stirred tank reactors, and Sartorius Q stirred-tank reactors. These systems incorporate a number of stirred-tank bioreactors ranging from a few to a dozen or more, ganged together. The vessels are offered in a variety of small sizes (less than a few liters) that have volumes sufficiently large to allow repeated sampling without disruption of the process. These systems address the need for measurement and control of process parameters in a parallel processing environment, and simplify scale-up issues by means of the familiar nature of the vessels. Although they provide capabilities similar to those of an equivalent number of individual bioreactors, virtually all of the high throughput systems shown economize on bench space, provide a simple, common interface for laboratory utilities, and use a single integrated control system. Moreover, each of the systems uses common and universally accepted measurement technology so that the data generated by these systems can be readily used in the scale-up process.

The measurement technology used in these systems is both an advantage and a drawback. The advantage is that the technology is decades old and already familiar to the operator. The drawback is that the systems, while facilitating parallel processing, are quite labor intensive: setup, calibration, and teardown and cleaning times are virtually the same as they would be for multiple experiments in an equivalent number of individual reactors. The reason for this is that the systems use conventional probe-type sensors: each vessel has its own set which must be sterilized before use, calibrated in place, and cleaned again after use. In addition, these probes must be inserted into the vessel to contact the liquid to work. This limits the system's smallest practical vessel size, even if miniature probes are used. Because of this, the volumes of required media (and thus supply costs) are nearly the same as they would be if banks of individual bioreactors were used in place of these high throughput systems. Because there is no appreciable savings in supply costs or labor costs, the attractiveness of these high throughput systems is limited.


There is another approach to high throughput design using a technology that's been known for many years, but has not, until recently, seen widespread adoption. Fluorescence-based sensing technology combines novel chemistry, optics, and electronics in the design of a sensor that's virtually calibration-free, can be miniaturized to accommodate the smallest vessels or well plates, isolates the sensing electronics from the cell culture broth, and can be multiplexed easily, if needed, to measure values of process parameters in a large number of vessels without concern for contamination.

Figure 2
Figure 2 shows such a sensor schematically. The sensor consists of two major components: a sensing head that contains both optics and electronics; and a peel-and-stick sensing patch or foil that is affixed to the inside of the vessel being monitored.

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