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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

  • Comparability Studies

    In these situations comparability studies may be required. Comparability studies compare quality attributes of product produced before the manufacturing change with that manufactured afterward, against a reference standard. Comparability studies encompass a variety of tests, sometimes including cell-based assays or potency assays in animals.

    According to ICH guidelines, the purpose of a comparability study is to “assess the comparability of biotechnological/biological products before and after changes are made in the manufacturing process for the drug substance or drug product. Comparability can be deduced from quality studies (partial or comprehensive), but might sometimes need to be supported by comparability bridging studies.” Comparability studies introduce timing and scheduling issues and may cause delays in a development project.

  • Formulation Matrix

    A formulation matrix can assist in achieving an optimal formulation by simultaneously investigating multiple parameters that may include pH, buffer composition, drug-substance concentration, salts, and excipients. The samples are formulated and stored at ideal and accelerated degradation conditions, and analyzed over time. Specific tests employed during the formulation matrix include electrophoresis, chromatography, spectroscopy, and visual examination to assess gross changes such as the presence of particles or precipitates.

    A formulation matrix is ideally run as early as possible during development. A formulation matrix conducted during Phase I or earlier may uncover stability issues that may be addressed, through reformulation, before considerable resources are devoted to clinical or analytics development. However, due to financial limitations the formulation matrix may be performed as late as Phase II.