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Aug 1, 2013 (Vol. 33, No. 14)

Still a Place for Steel and Glass

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    A major driver for bioreactor R&D comes from the renewable energy sector. Here, an Infors scientist per-forms an SSF (simultaneous saccharification and fermentation) where cellulose is transformed into bioethanol.

    The diverse bioreactor market, consisting of glass, stainless steel, and plastic, has been heating up as the center of gravity for industrial and pharmaceutical biotechnology disperses away from Europe and the U.S. to Asia, South America, and the Pacific Rim.

    “New markets are emerging especially in biofuels and second- and third-generation bioprocesses,” says Eric Abellan, product manager for bioreactors at Infors. Interest in application-specific bioreactors and incubation shakers for photosynthesis and simultaneous scarification and fermentation is increasing, as well.

    Bioreactors have always been specified on the basis of performance and quality, but increasingly the emphasis is shifting to capabilities that provide process understanding to support quality by design. Thus, increased demand for new sensors or measurement systems, adaptive software environments, design of experiment capability, and a renewed interest in glass and stainless reactors.

    Each bioreactor, Abellan says, sits at the center of a bioprocess “ecosystem” where flexibility, particularly with respect to sensor technology, is highly desirable. These factors continue to make glass and stainless steel bioreactors the process vessels of choice for many nonmammalian cells and organisms, and for several key industries.

    For one of Infors’ niche markets, biofuels, single-use equipment is mostly limited to downstream processing and what Abellan calls “peripheral equipment such as harvest bags or media prep tanks.”

    He notes that for smaller fermentations and development-stage processes, glass bioreactors may be superior to stainless steel due to greater ease of cleaning. Infors recently launched LabCIP, a cleaning and sterilization-in-place device developed for the company’s Labfors 5 benchtop glass bioreactor. “This allows a faster turnover thanks to the overnight automatic cleaning and sterilization of the vessel, which shifts operator effort away from cleaning to more productive tasks,” he says.

    Erik Kakes, co-owner of Applikon Biotechnology, observes that glass bioreactors dominate in many development settings. Applikon sells uncontrolled bioreactors (without sensors) as small as 200 µL in volume. Its controlled units range from 3 mL working volume, through benchtop scale and up to 4,000 liters.

    Smaller systems used in R&D provide all the benefits of parallelism: The ability to run multiple conditions, collect data simultaneously, and fit reactors with sensors, mixers, pressure devices, and other goodies that would be difficult to implement in plastic. Single-use systems at the same scale lack this level of flexibility.

    “With disposables, you have to work with what you get,” Kakes tells GEN. Applikon claims full scalability, up to production levels. Depending on the scale, units are autoclaved in multiples, which reduces cleaning effort. “The advantages of running things in parallel extend to cleaning,” Kakes says.

    Universities, which lack the resources to replace a bioreactor after each use, are another sweet spot for stainless and glass. The versatility provided by stainless steel and glass are exactly what research centers look for, Kakes says. “They want to customize, play around with the design, and build whatever it is they’re thinking of,” he says.

    Another preferred venue for fixed tanks are single-product facilities. Yes, cleaning and related validation can be a burden for these facilities, mainly in terms of time and facility utilization. “However, labor related to sanitization is minimal as cleaning regimens are virtually automatic. You lose some time, but you need not invest in large quantities of plastics,” says Kakes.

  • High Energy Requirements

    “Energy requirements for microbial fermentations are pretty high,” explains Brady Cole, vp of commercial operations at Abec. “The processes are fast, and require addition of a lot of oxygen and removal of a fair amount of heat. This usually precludes using a bag.”

    A microbial fermentation lasts days, whereas mammalian cultures proceed for several weeks, which—size considerations notwithstanding—would require a greater number of bags for the former. Under this scenario bioprocessors must inventory bags, and may find themselves at the mercy of suppliers. “There’s more inherent cost and risk for disposables in microbial systems,” Cole notes.

    In addition to its line of stainless steel reactors, Abec is working on a multisupplier single-use strategy. “We will design the bags as we would a stainless steel reactor, shop it out to multiple manufacturers, and sell it under our brand,” Cole says. In the past, Abec has integrated with single-use products from top vendors, but noted problems of scalability and poor user friendliness. “Those are the issues we’re working on for our own disposable bioreactors,” he says. “Eventually, our single-use strategy dovetails with our overall strategy. It will not be-all and end-all, but we’ll apply it where it makes sense, whether that’s upstream, downstream, or through hybrid systems.”

    Abec’s core philosophy in bioreactor design and fabrication is, according to Cole, to “start with a clean sheet of paper every time, versus applying platform designs. Standard designs are often limited to processes, operations, and facility fit. When you can’t easily make a utility connection or obtain the oxygen transfer you need, you’re pushing problems down the road. The up-front cost for custom design will be higher, but the money you save later on far outweighs that.”

    That is why, in the face of a single-use revolution, sales of glass and stainless steel bioreactors remain strong.

    “Glass and stainless steel are well-characterized materials,” explains Richard Mirro, executive director for portfolio management, bioprocess, at Eppendorf’s New Brunswick Scientific business unit. “Concerns regarding plastic materials of construction, and information on leachables and extractables, remain important to many customers,” he says.

    Stainless steel and/or glass are in many cases superior to, or more desirable than, their disposable counterparts. “Particularly where large production tanks are required, stainless steel continues to be the standard, whereas at lab scale and for low volume production, single-use bioreactors have become a much more viable option,” Mirro says.

    Stainless steel and glass offer elements of run-to-run flexibility with respect to sensors, impellers, and process control limits to extents that single-use bioreactors cannot. Rapid temperature shifts, pressure holds, and pressure control may not be attainable with some single-use designs.

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