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Apr 1, 2008 (Vol. 28, No. 7)

Regulations Still Driving Stability Testing

Scope of Characterization and Validation Level Should Match the Phase of Development

  • While stability testing for small molecule drugs is well established, its counterpart for biologicals is still evolving. Dozens of techniques have emerged for characterizing proteins, ranging from the standard and reliable (electrophoresis and chromatography), to the cutting edge (calorimetry), to the downright mysterious (atomic force microscopy).

    Stability testing is broadly structured around ICH guidances Q1A through Q10, which cover pharmaceutical quality. ICH Q1A is devoted to small molecule drugs while Q5C deals with biologicals.

    “Stability testing for biomolecules is still quite a new field in many ways,” notes Emma Waite, Ph.D., laboratory manager for biopharmaceutical services at Tepnel, which provides a range of molecular analytical services. Perhaps due to the novelty and greater inherent uncertainty in the production of biotherapeutics, regulators increasingly expect developers to choose multifaceted, orthogonal analysis techniques that clearly demonstrate stability and activity.

    Part of a Package

    Companies providing stability testing services generally offer a range of related services. NewLab Bioquality’s pharmaceutical-development assistance includes cell line characterization, molecular biology, protein chemistry, and viral process validation in addition to stability testing of intermediates, actives, and formulated products.

    As a product matures through its life cycle, so does the sophistication of stability testing. Bioprocessors enjoy significant leeway early in development to apply tests they think make sense, particularly those that provide feedback on process optimization. Testing becomes more formalized as a product enters human testing. “ICH guidelines call for stability studies, at least of the accelerated variety, before Phase I,” says Guy Berg, Ph.D., svp at NewLab. “There are check-off lists of tests to conduct depending on the clinical phase and molecule.”

    Erythropoietin, for example, is tested for appearance, pH, peptide sequence, types and extent of post-translational modifications, aggregation, and potency. Many more assays are possible and would surely yield more information, “but at some point, one must limit the number of tests for no reason other than cost,” observes Dr. Berg.

    Similarly, Pharmaceutical Product Development (PPD) performs stability testing, methods development, validation, and QC release in more than 60,000 cubic feet of controlled-environment space. Large, walk-in units maintain standard ICH temperature and humidity conditions, while reach-in units can duplicate any reasonable condition that might affect stability like photodegradation at variable temperature. A central computer system controls condition monitoring for all stability chambers, which are protected from power grid failures by backup electrical generators. Larger walk-in chambers employ redundant monitoring.

    Early in a drug’s development, samples will be subjected to their most likely storage conditions, for example, frozen, refrigerated, or ambient temperature, notes Chris Lively, Ph.D., director of biopharmaceutical services. “We will also likely add challenge conditions such as higher temperature or humidity, which will indicate the conditions under which products are likely to degrade.”

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