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Mar 1, 2009 (Vol. 29, No. 5)

Grappling With Biologic Manufacturing Concerns

Complexity of Pathways for Product Development Requires Nimble Efforts

  • Developmental Black Holes?

    “Frequently, investigative drug research projects become mired down when their management is not properly integrated,” stated Mark Cunningham, Ph.D., drug discovery researcher at Centocor. The company’s decision to form cross-functioning teams, referred to as pharmaceutical development advisory committees (PDAC), was based on a monoclonal antibody development project that became bogged down when standard optimization protocols failed to produced the desired results.

    Introduction of mutations into the CDR region of the antibody, while they improved performance, resulted in low expression levels and precipitate formation, and after a year the project was abandoned. So the formation of a multidisciplinary team was conceived of as a means of overcoming roadblocks early on, and moving to a successful conclusion.

    “The primary aim of the PDAC is to act as advisory committee, guiding the research forward,” Dr. Cunningham explained. “This means that the discovery teams present their findings on the biophysical properties of candidate molecules, and the interaction provides guidance to move the work forward through any issues posed by the investigation.”

    As the process has been in effect since 2005, it has accumulated a considerable track record, and at this time four monoclonal antibodies and two other biologics are working their way through to the goal at which an optimized lead compound is identified.

    In one case, the existence of labile methionine residues in the CDR was identified as a source of chemical instability. However, since replacing all the methionines resulted in a loss of affinity, the team recommended a stress analysis of the molecule to determine which replacements would be the most satisfactory.

    In another case study, a biologic displayed excessive cleavage and aggregation. The recommendation was to redesign the molecule with a glycosylation site and an engineered peptide sequence, thereby overcoming these issues.

    Dr. Cunningham emphasized the ongoing nature of the pharmaceutical design advisory committees. “This process incorporates quality by design attributes, and is constantly evolving,” he emphasized.

    The vast complexity of developmental pathways in biologic product development calls for the management skills of Solomon, but this in turn requires suitable technology, otherwise the baby may be cut in half without benefit to the advancement of the project.

    One theme that has been prominent in this and other bioprocessing conferences is the need to make decisions early on that endure through upscaling and clinical trials. Yet this admonition conflicts with the need for quick and dirty in the early stages. Even with the wisdom of Solomon, experience, acute judgment, and luck are critical factors.

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