IMPORTANT PUBLICATIONS ON VALIDATION (FROM 1991 TO PRESENT) A review on validation of bioanalytical methods was published by Karnes et al. in 1991 which was intended to provide guidance for bioanalytical chemists. One year later, Shah et al. published their report on the conference on ��Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies�� held in Washington in 1990 (Conference Report). During this conference, consensus was reached on which parameters of bioanalytical methods should be evaluated, and some acceptance criteria were established. In the following years, this report was actually used as guidance by bioanalysts. Despite the fact, however, that some principle questions had been answered during this conference, no specific recommendations on practical issues like experimental designs or statistical evaluation had been made.

In 1994, Hartmann et al. analyzed the Conference Report performing statistical experiments on the established acceptance criteria for accuracy and precision. Requirements for Registration of Pharmaceuticals for Human Use (ICH) were approved by the regulatory agencies of the European Union, the United States of America and Japan. Despite the fact that these were focused on analytical methods for pharmaceutical products rather than bioanalysis, they still contain helpful guidance on some principal questions and definitions in the field of analytical method validation. The first document, approved in 1994, concentrated on the theoretical background and definitions, and the second one, approved in 1996, concentrated on methodology and practical issues.

TERMINOLOGY Validation It is accepted that during the course of a typical drug development program, a defined bioanalytical method will undergo many modifications. These evolutionary changes [e.g. addition of a metabolite, lowering of the lower limit of quantification (LLOQ)] require different levels of validation to demonstrate continuity of the validity of an assay’s performance. Three different levels/types of method validations, full validation, partial validation, and cross-validation, are defined Cilengitide and characterized as follows. Full validation Full validation is necessary when developing and implementing a bioanalytical method for the first time for a new drug entity. If metabolites are added to an existing assay for quantification, then full validation of the revised assay is necessary for all analytes measured.[3] Partial validation Partial validations are modifications of validated bioanalytical methods that do not necessarily require full revalidations.

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