Method development and validations: characterization of critical elements in the development of pharmaceuticals

This review discusses the conceptual aspects of method validation, its management, processes and schemes and highlights method validation key performance characteristics. Although a thorough validation cannot rule out all potential problems, the process of method development and validation should address the most common ones. Examples of typical problems that can be minimized or avoided are synthesis impurities that co-elute with the analyte peak in an HPLC assay; a particular type of column that no longer produces the separation needed because the supplier of the column has changed the manufacturing process; an assay method that is transferred to a second laboratory where they are unable to achieve the same detection limit; and a quality assurance audit of a validation report that finds no documentation on how the method was performed during the validation. Problems increase as additional people, laboratories, and equipment are used to perform the method. When the method is used in the developer's laboratory, a small adjustment can usually be made to make the method work, but the flexibility to change it is lost once the method is transferred to other laboratories or used for official product testing. This is especially true in the pharmaceutical industry, where methods are submitted to regulatory agencies and changes may require formal approval before they can be implemented for official testing. The best way to minimize method problems is to perform adequate validation experiments during development.