When Smaller Is Better
To accelerate product development, drug companies are scaling down early-stage bioprocesses to analyze and better define a range of parameters and to optimize media preparations and process conditions. Miniaturization represents a strong trend in the bioprocess industry today as companies look for innovative ways to save time, labor, and resources.
In the area of small-scale systems, Applikon offers the MicroFlask which, company officials say, can replace orbital shake flasks for the rapid growth of microbial strains, clonal libraries, and cell lines in 24- or 96-well plates. The firm’s Micro 24 bioreactor system can perform high-throughput fermentation or cell culture in 7 mL volumes with automated, independent monitoring and control of 24 individual microreactors on one microtiter plate, explains Howard Weber, director of sales and marketing.
Frank Kensy, managing director at m2p-labs reports strong demand from industry for miniaturized fermentation systems for clone screening and media development. The company’s BioLector system can perform 48 parallel fermentation runs at a scale of 300 to 1,500 µL, with online optical monitoring of biomass, pH, and dissolved oxygen, and the ability to detect fluorescent proteins. Being able to measure labeled biomolecules allows users to “study protein expression, characterize promoters, and study regulation by culturing different knock-outs on different substrates,” says Kensy. The benchtop system can be integrated with automated liquid-handling platforms or operated manually.
Kensy also reports interest from the biofuels sector, which is using the BioLector to study the effects of different gases in the bioreactor chamber, to develop anaerobic processes, to screen clones for desired metabolic pathways, and to study various carbon sources to identify less costly media preparations.
Last year, m2p released the Flowerplate microbioreactor platform for microbial cell culture, which features flower-shaped well geometry to improve mixing and gas/liquid mass transfer. The flower-shaped wells function akin to baffles in shaker flasks to disrupt the liquid stream and increase gas exchange during orbital shaking. The company reports achieving an oxygen transfer rate of 0.2 mol/L/h. The Flowerplate has 48 wells to enable parallel batch fermentation, with filling volumes of 0.3–0.5 mL.
Dasgip introduced a new edition of control software for the Dasgip Parallel Bioreactor System, the Dasgip Control 4.0 OPC Edition, which supports the openness, productivity, and collaboration (OPC) standards for network-wide exchange of real-time data across third-party hardware platforms.
The Dasgip control system was designed for use with glass bioreactors from 50 mL to 5 L and supporting the Thermo Scientific Hyclone S.U.B. for scale-up features mass flow controlled gas mixing, up to six liquid feeds per reactor, overpressure detection and gas flow cutoff, and integration with Hyclone temperature and agitation control.
Falk Schneider, Ph.D., director of software engineering at Dasgip, identifies two key trends that his company’s technology is addressing: miniaturization and parallelization, to allow for scaled-down applications such as cell line screening, media optimization, and stem cell applications. The goal is to minimize process volumes, maximize the number of runs in the shortest timeframe, while still generating ample process information.
The trend toward OPC control of the bioreactor system is driven by the FDA’s PAT initiative, and control technology, including online and at-line autosamplers, sensors, analytical devices, and integrated control software, is rapidly moving into smaller scale bioreactor systems.
A critical gap “in many installations exists between the bioreactor data and the sampling data,” says Dr. Schneider. “We need to integrate analyzer values into process controllers in real time.” Automated process monitoring is not enough; it is important “to close the feedback loop for nutrients as an example,” he adds.
HexaScreen Culture Technologies, a spin-off from Universitat Autònoma de Barcelona, Universitat Politècnica de Catalunya and Fundació ASCAMM, plans to introduce its first commercial bioreactor for mammalian cell culture in January. The company’s patented technology mimics traditional T-flask cultures in single-use plastic plates, each housing six individual minibioreactors, combined with noninvasive temperature, pH, and optical density control.
“The 10 to 15 mL working volumes are small enough to save a lot of preparation time and money, but are still sufficient to collect samples for quality assurance measurements, as well as obtaining reliable data for bioprocess optimization,” says Francesc Gòdia, a founder of the company and professor of chemical engineering at the University. He describes the minibioreactors as homogeneous systems in which the internal liquid gradients and microenvironments that can form in microwell plates are avoided.
Gòdia believes customers will find the parallel bioreactor system especially useful for replicate experiments, screening of cell lines, scale-down studies, media development, and toxicity testing. HexaScreen anticipates introducing a second model capable of performing automated fed-batch fermentation and pH control in early 2011.