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November 15, 2009 (Vol. 29, No. 20)

Analytical Considerations in Formulation

Timing, Thoroughness, Simplicity, and Extensive Product Knowledge Are Essential Components

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    A thorough understanding of one's biological agent, route of administration, and pharmacokinetics is indispensable for a successful formulation program. (Olivier - fotolia.com)

    Formulation is arguably the most critical—and challenging—component of biopharmaceutical drug development, second only to the molecule itself. Formulation’s far-reaching consequences help sponsors satisfy the scientific, medical, and regulatory conditions for drug approval and, subsequently, support marketplace success.

    A biopharmaceutical formulation consists of active pharmaceutical ingredient and other ingredients that help maintain the drug product’s chemical, biochemical, and physical attributes, particularly those related to stability, safety, efficacy, and potency.

    Dosing and mode of action are two factors that strongly affect formulation design. Monoclonal antibodies (mAbs), which are typically delivered in high doses, require concentrated formulations that remain active and potent after extended storage without aggregation or precipitation. By contrast, vaccines are administered in extremely small doses so their formulations may be dilute.

    Monoclonal antibody and vaccine formulations, though quite different in composition and concentration, must both provide long-term stability, be amenable to the chosen route of administration, and ensure activity/potency while supporting regulatory requirements for stability and related analysis.

  • No One-Size-Fits-All

    Since nearly all biopharmaceuticals are administered by injection or infusion a platform approach to formulation might seem attractive as a way to streamline biopharmaceutical development. The diversity of biopharmaceuticals, however, even within certain molecular classes, unfortunately precludes a one-size-fits-all approach to formulation and formulation analysis. Platform formulations often fail to provide stability, deliverability, potency, and amenability to analytics.

    Most biotherapeutics are prepared and stored in buffers, but formulations differ significantly from basic compositions of protein, salt, and water. Even within specific molecular classes, balancing effectiveness, safety, and ease of analysis often requires the addition of excipients, modifiers, detergents, adjuvants, and/or stabilizers. Each additive introduces a new set of issues for the subsequent analysis of the drug product.

    For example, the common stabilizer human serum albumin, significantly increases ultraviolet absorption at 280 nm, a standard concentration measure used in HPLC analysis. Other formulation components may interfere with analysis by electrophoresis or HPLC. Introducing excipients or changing the buffer to improve stability, while scientifically justified, will cause at the very least a reassessment, if not an overhaul, of associated analytics.