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

Still a Place for Steel and Glass

  • Current wisdom holds that microbial fermentations—particularly larger production processes—still rely heavily on glass and stainless steel construction. But that is beginning to change. Due to growing demand for single-use products for microbial cultures, Eppendorf has introduced the BioBLU® 0.3f, a 250 mL single-use vessel designed specifically for microbial fermentation. Eppendorf sees market potential for these products, and plans to address growing demand with additional single-use products for fermentation.

    Where this will lead remains to be seen, as process developers lack a clear upward scalability path for single-use fermentors. But Mirro is optimistic. “Years of development, and ample comparative data, show process comparability and cell-line compatibility for stainless steel and single-use bioreactors,” he says. He hints that the same factors that justify single use in cell culture processes may one day apply to fermentation, even at large scale.

    Gross physical design characteristics for fixed tank bioreactors do not change much: “The basic parameters have been around forever,” notes Jeff Watkins, principal at Blue Star Engineering. Blue Star designs glass and stainless steel bioreactors, as well as single-use systems, for many of the top bioreactor OEMs.

    The main variables include the ratio of height to diameter, and matching the impeller and gassing mechanism to the volume, cell type, and process. For mammalian cell cultures, disposable reactors have achieved performance characteristics comparable to stainless, which allows direct scaleup from smaller single-use bioreactors to stainless steel.

    What has emerged from design orthodoxy is a keen interest in bioprocessors in process understanding, for monitoring reaction conditions in real time, and employing that information to control the process.

    “As processes become more complex, operators watch for more process parameters, to introduce later into their recipes,” Watkins says. “That’s good for us because it indicates that customers want custom-designed systems, not just something off-the-shelf.”

    Custom designs are also an option with single-use bioreactors, but there the challenge is incorporating measurement instruments and probes into the bags, before it reaches the customer, without compromising sterility. Most plastic bioprocess containers are sterilized at the manufacturer, and intended for use directly out of the box, with no modification.

    “Having customers insert their own sensors goes against the whole idea of presterilization,” Watkins observes. By contrast, users can insert sensors and other devices into glass or stainless reactors, then sterilize the entire assembly in place.

  • Dollars and Sense

    Click Image To Enlarge +
    Sartorius Stedim Biotech manufactures traditional glass and stainless-steel bioreactors as well as single-use upstream processing equipment.

    Watkins refers to single use as a persistent “buzz”—still topical, still highly desirable, but outside of North America and Europe (and, as noted, with microbial fermentations), stainless steel and glass still rule the world of bioprocessing. Lower labor costs in growing Asian and Pacific markets allow biomanufacturers the luxury of investing in fixed tank processes and cleaning/validating, and to do so economically.

    Some other factors also play in determining the relative value of single-use vs. fixed-tank reactors. “Not every company in every market benefits from the traditional advantages of single-use bioreactors,” observes Michelle Mitcho, fermentation product manager at Sartorius Stedim Biotech. “Single use is attractive for companies that need to move quickly and reduce time to market, particularly large biopharmaceutical companies. For them the benefits of reduced cleaning and cleaning validation outweigh the cost of disposables. Not every company is in that category, however.”

    Sartorius Stedim Biotech manufactures traditional glass and stainless steel bioreactors, as well as a broad portfolio of single-use upstream processing equipment.

    A development-stage cell culture project for a monoclonal antibody therapeutic, for example, might use 50 bench-scale bioreactors. As many single-use vendors have demonstrated, the time, cost, and diversion of human resources toward prepping and cleaning that many bioreactors presents a huge burden. But smaller firms operating in nontherapeutic areas, at a lower level of parallelism, or working with nonmammalian systems, would probably stick to reusable reactors.

    “Industries like foods, beverages, additives, even antibiotics, frequently don’t consider the same factors as traditional biopharma when determining costs and time savings,” Mitcho says. “Stainless steel or glass may be more compatible with the process as well, for example when high agitation, pressure, or gas flow rates are required.”

    Nonpharmaceutical processes are not regulated as stringently as biopharmaceuticals, for example with respect to cleaning and validation. These factors loom large in any cost justification for single-use systems.

    Another consideration is maintaining consistency in materials of construction as processes scale up. The largest single-use cell culture system today runs 2,000 liters, and at least one vendor has introduced 200 liter single-use reactors for microbial fermentations, according to Mitcho. “Larger systems for microbials are coming, but they will have limitations. At very large scale, systems have to be rugged and durable,” she says. Many industrial-scale microbial fermentations, for example, are carried out in tens of thousands of liters.

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