Sensing and Control
Michael Cunningham, Ph.D., senior research scientist at Millipore, observes that early single-use bioreactors suffered from less-than-optimal cell densities, product titers, and oxygen delivery limits (e.g., as measured by kLa or volumetric oxygen transfer coefficient). Improvements were often accompanied by shear damage to cells.
Some blamed those engineering limitations on bag design and agitation methods, but “the problem was much more complex. There were probably other things going on.”
Today, Dr. Cunningham says, disposable systems—even very small ones—more closely mimic conventional bioreactors.
Indeed the gap is closing rapidly. During three conferences this past year, contract manufacturer Avid Bioservices presented data on the comparability between Thermo Fisher Scientific’s Single Use Bioreactor (SUB) and conventional stainless steel bioreactors.
In August, CMC Biologics installed a disposables-based manufacturing facility at its Seattle location. The multipurpose plant, undertaken in collaboration with Thermo Fisher Scientific, will produce early-stage clinical batches of monoclonal antibodies and other cell culture-derived therapeutic proteins.
Central to the upstream production capabilities are Hyclone/Thermo 100 L and 200 L SUBs and disposable mixers.
One way plastic is catching up to steel is through advanced sensing and control. Many suppliers are capitalizing on this user-driven trend, even in their smaller reactor bags. For example, Xcellerex expects to launch a line of single-use sensors for its disposable bioreactors and mixers by the end of 2010.
Earlier this year Finesse Solutions introduced a line of single-use TruFluor sensors for headspace pressure and dissolved oxygen or pH plus process temperature. The sensors are available in Thermo Scientific (HyClone) BioProcess Containers and SUBs as turnkey bioreactor components, in volumes from 25 L to 2,000 L. TruFluor sensors consist of a disposable sheath, optical reader, cable, and transmitter, and operate through real-time phase fluorimetry.
Also last summer, New Brunswick Scientific (NBS) and Pall announced a joint venture to produce single-use bioreactors with control capabilities. The collaboration is based on the combination of Pall’s Allegro™ single-use biocontainer with NBS’s CelliGen® bioprocess controller.
NBS also offers a CelliGen® disposable benchtop bioreactor that combines single-use and stirred-tank technologies. The pre-sterilized 5 or 14 L vessels feature a non-invasive sensor technology that significantly reduces turnaround time for reactors of this size from ten hours to about one hour, according to product manager Rich Mirro.
Millipore has entered the disposable bioreactor marketplace with a 3 L product, CellReady, which uses probes for controlling temperature, dissolved oxygen, and pH.
“Three liters is the workhorse in product development,” says Dr. Cunningham. The company recently made a development-stage 250 L single-use reactor available to select customers.
While built-in sensors and controls are becoming the norm, some off-line measurements still require old-fashioned sampling of a bioreactor’s contents. Sampling has always been problematic since not all bioreactors—whether steel or disposable—allow ready access to process fluids in real or near-real time.
Groton Biosystems recently introduced a sterilizable, disposable filter-sampling probe for automated and manual extraction of cell-free samples. The product simplifies analysis by eliminating filtration or centrifugation while reducing cross-contamination risk, according to CEO Bill Dinardo.
Single-use bioreactors have improved dramatically since the earliest implementations. And, while disposables’ benefits are now well known, other issues have arisen.
GE has begun investigating how supply issues affect customers because, says Gach, “some customers struggle with inventory management, particularly for bioreactors.” This is one reason GE expects to expand beyond rocking-type bag systems and eventually to cover the biomanufacturing space more comprehensively.
The company is also undertaking an analysis of the environmental impact and benefits of single-use bioreactors. This study goes beyond a comparative analysis of acquisition and operating costs for stainless steel and plastic to include carbon footprint, energy, and water consumption. “We made it one of our missions to understand these issues, and translate them to customers as they validate their decision on disposables.”
One might assume that single use is on everyone’s agenda, but that is not so. The worldwide capacity glut still puts off firms with large investments in stainless steel despite constant volumetric productivity improvements. Dr. Cunningham reports that at a recent meeting bioprocessors indicated a preference for running hard-piped equipment at less than full capacity, rather than switching to plastic.
Whether this trend comes to dominate large biopharma’s mindset toward disposable reactors, at least over the next five to ten years, is anyone’s guess.