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Oct 15, 2010 (Vol. 30, No. 18)

Optimizing Cell-Culture Technologies

Myriad of Enabling Strategies Must Be Deployed from Beginning to End of Product Life Cycle

  • Vaccine Cell Culture: A Special Case?

    Optimization efforts differ for cell cultures that produce antibodies and those that make vaccines. MedImmune works on both. Its FluMist® live-virus influenza vaccine is currently manufactured in eggs, but the company is developing a cell culture-based process.

    Vaccine-makers are interested in switching from eggs to cells because the former are more labor-intensive. Controlling process variability and product quality are also issues for eggs, whose characteristics change depending on the season.

    MedImmune also makes Synagis®, a monoclonal antibody for preventing respiratory syncytial virus.

    While antibody production can employ a range of cells, cells that grow viruses are limited to lines that are susceptible to the virus. MedImmune uses MDCK cells for this purpose.

    Optimization for mAb manufacturing is an ongoing process, says Ben Machielse, executive vp of operations. “We want to be done with major optimization efforts before Phase III, but we continue to fine-tune the process afterward to assure there are no issues related to scale-up.”

    Yield may be the key to optimizing a mAb process, but as Machielse points out, rising productivity creates issues of matching upstream and downstream operations and avoiding bottlenecks. “You don’t want the yield to be too high. You should optimize it to fit the plant, to strive for maximum utilization end to end.”

    Optimizing cell cultures for viral vaccines is more straightforward despite the cell-line limitations. Purification steps are fewer for vaccines than for antibodies, and facility design constraints far less daunting. “Because vaccine doses are small to begin with, and FluMist doses less than 1% of the dose for an inactivated vaccine, we don’t need a big plant to produce millions of doses.”

  • Nature vs. Nurture

    The question of nature (cell-line engineering) vs. nurture (media, feed, and culture strategies) inevitably arises during any discussion of cell-culture optimization. “You can do a lot of things in the way of nurturing cells, but you cannot change the fundamental nature of a cell once it’s set,” notes Eileen Skaletsky, Ph.D., CEO of QED Bioscience, a contract cell culture services company.

    “If it’s an inherently low producer, there’s only so much you can do to ramp that up because the cell probably lacks the signaling machinery required to pump out lots of product.” Media and feed strategies can help, but turning a poor producer into a high producer is unlikely to succeed.

    Despite the homage paid to nature, most experts—Dr. Goldsborough included—believe that nurture has thus far paid the most dividends. “Nurture, including media, supplements, and control over bioreactor conditions, is still the predominant activity today.” Nevertheless, researchers are looking into “nature” as well as into cell processes and signaling, which has the potential to harness all the cell’s activities and recruit them toward production. “So it’s clear the two, nature and nurture, have to work together,” Dr. Goldsborough says.

    “Nature and nurture go hand in hand,” adds Machielse. While cells are initially selected based on growth and productivity, “you can do a lot once you have selected them through the right feeding strategy. And with refined media the exercise becomes a lot more manageable.”

    Machielse believes that in the future cell phenotype and genotype will help processors predict the type of feeding strategies that are likely to improve productivity. And at some point, those characteristics may be designed in.

  • Characteristics of a Good Cell Line

    A “good” cell line grows readily, is stable for the duration of the culture, is a high producer, and generates high-quality product. According to Eileen Skaletsky, Ph.D., CEO of QED Bioscience, there are three important characteristics of a good cell line:

    1 Stability: The ability of cells to grow predictably over multiple passages, while producing consistently. Cells that don’t thrive in culture make poor candidates for long-term production.

    2 Overall health or viability: How long will cells survive in culture? Some continue to reproduce indefinitely, while others cannot be kept alive for more than two weeks.

    3 Productivity: How well do cells produce over the course of the culture? Production capacity is often negatively affected by limitations imposed by the client, for example on the use of animal component-derived ingredients such as serum. “Some cells adapt relatively easily to serum-free conditions, others don’t survive.”

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