Bioprocess monitoring and control, although not as widespread as it should be, is nevertheless increasingly viewed as a routine part of doing business. Significant trends include interconnectivity between sensors, instruments, bioreactors, sampling systems, and software, collaborations among vendors to promote interoperability, and compatibility with single-use equipment. Yet, biotech still lags behind other industries in terms of manufacturing efficiency, and the deficiencies can be blamed in part on gaps in real-time monitoring.
“People still come in at night and on weekends to take care of processes that run 24 hours a day,” notes Brian O’Flaherty, Ph.D., sales director at Groton Biosystems. “Automation can free their time to perform higher-level tasks.”
One aspect of the PAT initiative involves bringing analytics closer to the process. FDA defines proximity as offline (usually in another room), at-line (nearby, but not connected), and online. Unfortunately, nobody imagined 15 years ago that instrumentation and controllers would need to be so close to a bank of development-scale bioreactors—or for that matter next to production reactors.
“If you start bringing in equipment that is normally offline, in another room, and transfer it to a process-development lab, you will encounter a space problem,” observes Dr. O’Flaherty. “As it is, all the equipment in these labs is shoehorned in.”
The solution, he says, is to design analytics and control into labs and manufacturing space, as one Groton customer recently did. “They were able to wheel in our sampling system and a Shimadzu HPLC, went online with them, and they’re working wonderfully.”
Groton has collaborations with DASGIP for advanced sampling interfaces to that company’s parallel reactor system, with Agilent Technologies for bioprocess HPLC, and with YSI for interfacing with a nutrient monitor.
Groton’s ARS-M sampling system consists of three basic models: the 140 interfaces to one reactor and four instruments, the 440 to four reactors and four instruments, and the 840 to eight reactors and four instruments. ARS-M is also compatible with single-use bags from major manufacturers and all stainless steel bioreactors. Groton’s principal market is process development, but it is beginning to break into GMP markets as well.
Interoperability and Collaboration
The integration of analyzers, bioreactors, and auto-samplers, particularly during product development, has been a notable trend in bioprocess monitoring. YSI, whose 2700 and 7200 biochemistry analyzers measure lactate, glutamate/glutamine, ammonium, glucose, lactate, and other analytes, has partnered with Groton on connecting the analyzers to its ARS autosamplers for real-time process monitoring.
The 2700-based systems are used mostly for process development, says Jamie Lussier, product manager at YSI. Another collaboration, with Groton and DASGIP integrates the YSI 7100, Groton’s automated reactor sample system, and the DASGIP bioreactors and control system.
YSI has also collaborated with Flownamics by coupling YSI nutrient analyzers to Flownamics’ SEG-FLOW™ sampling system. SEG-FLOW withdraws a cell-free sample from up to eight bioreactors, and sends them to up to four analyzers or fraction collectors. The sampling system can then control feed to the reactors based on set target concentrations in Flownamics’ Flow-Web™ software. The system activates a feed pump (or an existing feed system) based on the measured result and target concentrations. Users can determine sampling frequency and size.
Michael Biksacky, Flownamics president, says that two customers use the YSI 2700-SEG-FLOW combination to monitor and control delivery of glucose for cell culture processes. SEG-FLOW works with a variety of instruments from major vendors, like the Cedex cell density analyzer from Roche Innovatis. The key to success, says Biksacky, is to provide customers with flexibility. “You don’t want to get to the point where have to tell customers ‘you must use this analyzer.’”