Because it covers such a broad end-use range from single-cell assays through mega-processing, one could say that as cell culture goes, so goes biotechnology. Among the emerging, perennial trends in cell culture are automation, disposable systems, the ongoing evolution of cell culture media, and increased interest in cell culture for vaccine production.
The Automation Partnership (TAP; www.automationpartnership.com) focuses on automating the research end of the business, which is rapidly growing due to interest in cell-based assays and cell line engineering. TAP’s SelecT™ and CompacT SelecT instruments streamline manual culture of multiple cell lines in an assay-ready plate format. TAP’s Cello™ provides automated clone selection from multiple cell lines cultured in parallel, while Piccolo™ optimizes protein production from microbial or insect cell lines. Moving up a notch, the company’s Cellmate offers larger-volume cultured cells for roller bottles and T-flasks.
According to Tim Ward, director of cell culture, TAP’s goal is to improve the efficiency with which biologists turn ideas into productive cell lines. Traditionally, researchers perform experiments sequentially. Cello, Piccolo, and the SelecT line help optimize cells through parallel culture of tens of thousands of clones.
“By applying automation, scientists do not need to make deductions from the first experiment,” says Ward. Another automated, parallel instrument is in the works for testing media.
Heidi McIntosh, product manager for cell culture at Nalge Nunc International (www.nalgenunc.com), sees a lot of specialty cells cultured for cell-based assays and corresponding interest in specially coated roller bottles and consumables (e.g., media, buffers, reagents).
Nalge Nunc’s line of flasks, roller bottles, and microtiter plates include products coated with poly D-lysine (PDL), a poly amino acid that enhances cell adherence. The company also offers a chemical mimic of PDL, CC3™, which unlike PDL is sterilizable and has a five-year shelf life (as opposed to three for PDL). Nunc also offers low-binding coatings suitable for stem cell research.
Rising protein titers and cell densities continue to blur the distinction between large- and small-scale cell culture, to the point where small-scale equipment is increasingly used for manufacturing. For medium-sized batches of vaccines, antibodies, or therapeutic proteins, Nalge Nunc’s Nunclon™ Cell Factory uses stackable trays with working volumes of 200 to 8,000 mL. Up to four 8-liter cell factory units can be daisy-chained.
According to McIntosh, demand for small- to mid-sized cell culture equipment is rising as customers seek inexpensive alternatives to bioreactors during early product development. “These are not competing with 10,000-liter stainless steel bioreactors,” she says, “but they provide a way to research a process at a low capital investment.”
New Brunswick Scientific (www.nbsc.com) just introduced a benchtop bioreactor for R&D through small-scale production. The CelliGen® 310 bioreactor with advanced touchscreen controller provides built-in control of up to 32 process parameters per vessel and the ability to control up to four reactor vessels, or over 120 control loops, simultaneously.
Features include the ability to choose up to five thermal mass flow controllers for sparge and gas overlay and connect over 10 external devices, including sensors, scales, gas analyzers, and more, for optimized process control. A variety of specialized vessels and impellers are offered, including the packed-bed basket.
SAFC Biosciences (www.sigmaaldrich.com), a supplier of equipment and raw materials to companies producing proteins through cell culture, offers buffers, reagents, liquid and powdered media (serum-based and -free), single-use bags, pre-assembled tubing and filter sets, filters, sera and serum-free media, and cell culture development services. Among the company’s latest products are ExCell™ 302 serum-free media for CHO cells and the BIOEAZE™ lines of polyethylene and ethyl vinyl acetate storage bags.
According to Denise DeTommaso, market manager for single-use products, interest in disposable process equipment continues. The economic and logistic advantages of single-use equipment remain compelling at all scales, she says, but handling 2,000-L bags presents certain ergonomic issues. “How do you move such a large bag around after it’s filled, how do you get it into the rigid container, and how do you fill it?” Although hardly insurmountable, these problems demand novel facility and equipment solutions. Luckily, processes continue to shrink through productivity improvements.
Along with continuing growth in disposable storage and cell culture bags look for more disposable downstream process equipment such as process-scale filtration devices. Vijay Singh, Ph.D., president of Wave Biotech(www.wavebiotech.com), expects disposable chromatography will be “widespread in the near future. With these developments, purification will evolve to a more closed system with the benefits of lower cost and higher quality.”
In the cell culture arena, Dr. Singh sees disposables as central to patient-specific (personalized) therapies, particularly for gene therapy vectors, cell therapy, stem cell culture, and ex vivo applications. “Many of these technologies are already in advanced clinical trials using our single-use Wave bioreactors.”
Disposables will also gain from smaller cell culture batches (thanks to titer improvements), as well as for microbial applications. Wave recently introduced the WavePOD instrument module, which integrates a bioreactor’s analytical instrumentation for dissolved oxygen, pH, and gas composition controls in a single, portable device.
Experts increasingly credit rising protein titers to superior media composition, to the point where time and investment on media development can reap hundred- or thousand-fold returns by eliminating the need for plant expansions and new construction.