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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

  • A Contractor's View

    Click Image To Enlarge +
    According to Paragon Bioservices, one of the most straightforward ways to improve expression is by increasing cell density while optimizing the expression and promoter systems.

    Service companies like contract manufacturing/research firm Paragon Bioservices, Cytovance, and Sheffield Bio-Science have distinct but similar perspectives on how best to optimize cell cultures. Ever practical, contractors seek constant improvement while facing stringent deadlines and tight output requirements.

    Paragon, which specializes in microbial, mammalian, and insect cell culture, receives projects at any stage from discovery through early clinical testing. “Quality and quantity are always concerns, but development projects usually focus on quantity—getting enough material for the client to reach the next development phase,” says Paul Price, Ph.D., an immunologist at the company. Quality, assisted by analytics, moves to the forefront as the project develops, and later on quantity and quality become “inseparable.”

    Dr. Price puts cell lines and culture media and feeds at the top of the list for optimizing both cell growth and product quality for mammalian and microbial cultures. On the microbial side, one of the most straightforward ways to improve expression is by increasing cell density while optimizing the expression and promoter systems.

    Technology transfer from sponsor to contractor, particularly at early stages, may be quite variable, mostly because process/culture data are not yet available. Tech-transfer gains in significance later on, yet even then contractors do not always get everything they want or need. “Process knowledge is not as available, all the time, as we would like,” Dr. Price says.

    Cytovance, similarly, receives projects from as early as gene sequences to late-stage clinical development. Time is of the essence, says Jeffrey Su, Ph.D., chief scientist, who relies on commercial basal media and feeds to achieve “adequately productive” processes for preclinical and early-stage clinical testing. One of the company’s preferred platforms is CD OptiCHO™ Medium from Invitrogen (part of Life Technologies), and supplements designed to work with that product. Optimization is often limited to feed scheduling, followed by tweaking bioreactor and environmental conditions, which Dr. Su refers to as a type of process “polishing.”

    “At this stage our customers want it fast and cheap,” he says. “Yet CMOs have to balance their sponsors’ time lines and productivity.”

    PAT has a role in cell-culture optimization at CMOs, but not as an ongoing means of characterizing the process. “We’re looking for fairly obvious changes in early-stage process development,” says Dr. Su. “Given the expense and complexity of systems that perform real-time online monitoring and feedback control, PAT would probably not be of much help [at that stage].”

    It could be useful later on, he notes, for ongoing fine-tuning of a process with a successful manufacturing history behind it. “But PAT generates a lot of information, and with it the burden of having to make use of that information. It’s a double-edged sword.”

    Sheffield Bio-Science, a manufacturer of supplements for upstream cell-culture optimization and provider of related services, understandably feels that media and feed optimization is where the lion’s share of improvement in cell culture occurs (a sentiment shared by most cell-culture experts).

    “We have our own in-house bioreactors, and we do study fed-batch conditions as well, but it’s always within the context of how that interfaces with supplementation,” says R&D director Chris Wilcox, Ph.D.

    Yet Dr. Gilbride notes that for most contract manufacturers and some cell-culture development service firms as well, sponsors provide little leeway in how cells are maintained, grown, and fed. “They often specify their own media, supplements, and feeding schedules.”

    The focus changes somewhat with customer projects where specific conditions are specified to vary, but even there the focus remains primarily on reactor conditions as they relate to supplementation.

    A major challenge is transferring processes to animal-derived component-free (ADCF) media and supplements. Where most U.S. and European developers have been taught to “think” in terms of ADCF products, many companies in the Asia-Pacific region still cling to bovine or porcine-based media.

    Sheffield’s job in optimizing its processes involves either significantly reducing the ADCF burden, or completely replacing those ingredients with less risky hydrolysates or chemically defined ingredients. The latter, Robert Shaw, director of commercial development for EMD Millipore, admits, “take more time and involve design of experiment around what impacts on yield defined metabolic enhancers may have.”

    Sheffield scientists usually begin with a “lean and mean” medium so the full impact of each supplement can be determined without interference.

    Sheffield is undoubtedly biased toward media-feed strategies, but this is merely a reflection of the business of cell-culture optimization, and the needs of firms that seek the assistance of service companies. “What holds true in the U.S. and EU may not hold in India, China, and Brazil.” Many of Sheffield’s overseas clients lack the resources to devote effort to upstream cell-line development or molecular biology. “A lot of the bang for the buck they get is from media development,” Shaw says.

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