Integrated Bioreactor Systems
The bioreactor has progressed immeasurably, as the early, noncomputerized models have evolved into smart descendants. Today’s sophisticated technology allows microorganisms to be cultivated under controlled conditions so that their cells or metabolic products may be harvested for the manufacture of pharmaceuticals. Sartorius has developed bioreactors as disposable systems to meet the regulatory requirements of the biopharmaceutical industry. The company’s goal is a vertical expansion of its product line, outfitting bioreactors with computer software, disposable components, and all the accoutrements necessary for a total, integrated system.
Sartorius signed a licensing deal with Fluorometrix (www.fluorometrix.com), a spin-off of the University of Maryland, Baltimore, for disposable bioreactor and mixing vessel sensors, another step in its quest for a fully integrated disposable process line.
Govind Rao, Ph.D., professor of chemical and biochemical engineering at the University of Maryland and co-founder of Fluorometrix, has developed oxygen, pH, and carbon dioxide sensors. The devices use patches immobilized with pH-, CO2- and O2-responsive dyes, and the signals are optically and noninvasively measured with commercially available LEDs and photo-detectors.
The control system consists of the patch, a coaster, an interface, and a computer. The patch, a hydrophobic silicone membrane containing dyes, utilizes a hydrogel. The patches are monitored by the coaster, which is a miniature fluorimeter, able to measure either excitation ratio for CO2 and pH or fluorescence lifetime for O2. This device, which measures the excitation ratio of the patch, is positioned outside the bioreactor and does not need to be sterilized. The patch assembly is sterilizable and ready to use.
The sensors are inexpensive thus they can be incorporated into disposable components of the bioreactors. They are precalibrated and do not require individual calibration. Low-cost sensors are essential for the standardization process when new products are in development, since many runs may be required. Such sensor technology will be useful for the FDA’s Process Analytical Technologies initiative as well.
Reinhard Vogt, senior vp of sales and marketing for the Sartorius Biotechnology Division, calls the new licensing contract an important milestone on the path ultimately leading to disposable solutions for the entire production process. "Disposable sensor technology is the backbone of any disposable process. Without disposable sensor technology, the existing status quo remains, which means either cleaning in-place, discarding expensive re-usable sensors, or avoiding sensors, which makes the process uncontrollable," says Vogt.
Florian Wurm, Ph.D., of the Swiss Federal Institute of Technology in Lausanne, working in collaboration with TPP (www.tpp.ch), developed specially designed, 50-mL tubes to be used as minibioreactors. "The TubeSpin reactor system is in our hands the closest scale-down system to the real bioreactor," he states. "Using tubes with semi-permeable caps for CO2 exchange we were able to achieve high throughput and mimic both batch and fed-batch processes."
Both TPP and Sartorius sell the TubeSpin bioreactors. The Tube Spin technology is based on orbital shaking, which will be the main principle for new larger volume bioreactors (1-100 L) under development with Sartorius.