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Oct 15, 2011 (Vol. 31, No. 18)

Tracking Key Biomanufacturing Trends

Researchers Seek to Produce Safer and Highly Effective Products in More Economical Manner

  • Risk Mitigation

    Wade Nudson, a technical manager at SAFC, discussed his company’s efforts to design effective risk-mitigation strategies for cell culture reagents.

    Over the last 20 years, media evaluation has become much more demanding and complex as the number of reagents and media options grows and as more and more production volume shifts to biopharmaceutical uses. Quality control is one of the most pressing concerns.

    “We deal with approximately 400 different raw materials in our production schedule,” said Nudson. “We put an enhanced program in place over the last two years that evaluates them analytically and biologically, especially when chemical characterization may not be sufficient.

    “We establish dose-response growth curves that are precise and allow accurate, repeatable characterization of our products. We are constantly refining our evaluation procedures, doing a lot more mass spectroscopy, HPLC, and similar studies.”

    While the company’s raw materials are purchased only from approved, qualified vendors, quality is not the only issue. There is also availability of the materials used in cell culture.

    For example, single-source components like specific plant-derived hydrolysates have experienced supply issues in the past. Any changes in raw materials are carefully planned in advance. Change control and change notification are extremely important in this industry.

    “If you lose a bioreactor run in a drug production process because of medium or other raw material failure it could cost the client $50 million in final product or more,” according to Nudson. “Therefore, we make no changes in major components without an extended consultation with the client.”

    For single chemicals, it is usually relatively straightforward to check identity and to certify that they are sufficiently pure. For other more complex components, it can be much more difficult. This is a particular problem for undefined components, such as hydrolysates, whose composition is naturally variable, even between batches from the same supplier.

    A rule of thumb employed within the industry is that 10–15% biological variability from batch to batch is to be anticipated, and could represent the lower limit of acceptability. To deal with this issue, Nudson describes a chemically defined hydrolysate option offered by SAFC in which the components (such as peptides, amino acids, vitamins, and trace elements) are known and reproducibly formulated.

    Investigation of growth parameters has established that this defined medium option supports growth as well or better than the previous undefined product, noted Nudson. This represents a long-term trend in the industry aimed at the eventual elimination of all undefined components in cell culture media formulations.

    “That’s what we’re striving for,” Nudson stated, “as this would lessen our dependence on biological assays for quality assurance.”

  • Novel Resin Technology

    Layered beads is a novel resin design with the potential to provide molecular functionalities that can take on the challenge of complex separation problems, according to Klas Allmér, Ph.D., director of R&D at GE Healthcare.

    The approach is essentially an onion design with differing functional layers building out from an agarose bead core.

    “By designing the beads with different ligands in the inner and outer layers, new properties and features of the chromatography resins can be realized,” explained Dr. Allmér. “We feel the layered beads technology will solve difficult separation problems while at the same time offering significant economic benefits.”

    Current downstream vaccine processes use centrifugation with sucrose gradients or size exclusion chromatography, a strategy providing quite limited throughput. One possible configuration of the layered bead technology is using an inert shell and a functionalized core.

    This bead design can eliminate host cell proteins and DNA fragments in a single chromatographic step, using multimodal ligands in combination with size exclusion. If the ligand is located in the core of the bead, large entities, such as whole virus particles, pass through the column for collection, while smaller contaminating proteins are retained.

    “An additional advantage is the scalable nature of the layered beads technology that makes it applicable to small lab-scale operation or industrial procedures,” said Dr. Allmér.

  • Single-Use Systems

    In light of the increasing popularity of single-use systems, Thermo Fisher Scientific is rapidly expanding its technology base in this area, according to Justin Hutchinson, product manager, single-use technology. Hutchinson will be involved in a strategy discussion forum at the Long Beach meeting.

    He pointed out that when Thermo Fisher Scientific first began building single-use containers they were just simple bags.

    “But over the years we’ve created a new generation of delivery systems,” he said. “Now we’re developing complex options that are more than just static units for holding the culture medium. We have a vision to turn the entire bioprocess operation cycle into a single-use function, and we’ll be looking to both enhance our current product lines and move into complete, integrated bioprocessing platform solutions.”

    Noting that single-use containers are, by definition, disposable, Hutchinson explained that Thermo Fisher Scientific has invested substantial effort into creating recycling technology for the materials after they have been used. There are a number of cost-effective ways that polyethylene and other components can be used as fuel sources for the operation of water-purification systems and other energy-intensive tasks.

    Recycling can be carried out in-house or at large facilities that are able to deal with waste that may consist of several types of plastic and even some stainless steel and electronic components mixed in.

    “The challenge of pure recycling is significant since these devices are laminated and difficult to disassemble,” said Hutchinson. “Yet, in the final analysis, we note a wealth of data establishing the green credentials of single-use devices as being much more energy efficient compared to reusable hardware.”

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