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Apr 1, 2011 (Vol. 31, No. 7)

Taking Cell Cultivation to Another Level

New Optimization Strategies Help to Make a Good Thing Even Better

  • Over Baseline

    Click Image To Enlarge +
    The Automation Partnership says that ambr™ mimics the characteristics of classical bioreactors at microscale (10–15 mL) by using cost-effective, disposable microbioreactors controlled by an automated workstation. DO and pH spots on the base of the ambr bioreactor are shown.

    A problem faced during cell process development is discerning the real effects of varying conditions from the noise. The use of extremely simple media during feed and supplement optimization, mentioned earlier, is an example of how to assure that real effects stand out.

    Human variability is another area that may drown out signs of significant improvement (or problems).

    “Cell culture involves a lot of manual processing,” observes Tim Ward, director of strategic marketing at The Automation Partnership (TAP). “Automation eliminates dependence on workers, while completing repetitive processes with a lot less labor and improved efficiency.”

    Despite practice, consistency is difficult to achieve with manual manipulations. Small differences in how a task is performed from day to day, between or among individuals, even when they are following the same protocol, can result in cells experiencing different conditions.

    The efficiency and consistency of automation, Ward says, “opens up a whole spectrum of ways to employ automated systems to change the way cell culture is done, for everything from producing cells for experimentation through process development and manufacturing.”

    Readers are well aware of the value of automation in carrying out repetitive tasks on large numbers of small samples, e.g., in microtiter plates. The same level of automation, consistency, and control are available for cell-culture optimization as well. For example, TAP’s ambr™ cell culture workstation carries out up to 48 bioreactor experiments simultaneously in microreactors that mimic bioreactors in most important physical/mechanical respects.

    With 10–15 mL of working volume, ambr microreactors are much larger than microwells. The TAP reactors also employ impeller stirring, constantly monitor pH and dissolved oxygen, and feature independent control of oxygen and carbon dioxide.

    “Customers want to do many more early experiments, and the ambr system allows that,” says Shaw, who opines that ambr compliments but does not replace microplates. “You still need two stages. The first should still be a front-end screen, some form of selection pressure or colony picking, which is best done in 96-deep-well plates.”

  • Stem Cells Are Different

    Optimizing stem cell cultures is hampered by the relative newness of stem cell technology and the diversity of nonpluripotent progenitor cells. Nothing close to CHO or any other standard production-worthy mammalian or microbial cell exists in the stem cell world. Scales are much smaller, and the goal is not a cell-derived product but the cells themselves.

    Most CHO cells developed for new processes are expanded to production scale in serum-free or chemically defined media, whereas stem cell cultures still rely heavily on serum-based ingredients. And while some attachment-dependent cells are still employed in legacy processes, particularly for vaccines, nearly all stem cells exist in that format. “We’re still very early in the game,” says Robert Shaw, director of commercial development for EMD Millipore.

    Stem cell specialists recognize the need to move toward better defined media, and to modernize stem cell culture to permit industrial-scale production. “Individual companies have their own strategies for achieving that,” Shaw observes, but a thorough understanding of what makes stem cells tick stands in the way. Where CHO cells tolerate a relatively wide range of conditions, including media, feed, and supplementation, slight alterations in conditions can profoundly affect a stem cell’s fate, or its utility toward its intended purpose.

    Shaw believes it will be possible, eventually, to create stem cell processes that are as robust and industrialized as CHO processes. “But if it is not possible, it will be a major limitation for stem cell therapy.”

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