Analytical Target Profile: establishment of precision requirements for assay

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Abstract

Approaches are presented to establish precision (or target measurement uncertainty) requirements to drug substance and drug product assays. They are based on the simple and well-known concept of the normal distribution probability around true content values represented either by manufacturing range limits, or by the manufacturing target (usually 100% label claim). A maximum acceptable precision is derived which allows a defined probability of analytical results within the established acceptance limits of the specification and thus an objective and rational establishment of precision acceptance criteria. By this approach, α or type-I-errors are controlled, i.e. the maximum probability of failure for intrinsically acceptable results is limited. The combination of this normal distribution probability approach with guard bands allows controlling ß or type-II-errors, i.e. the acceptance of intrinsically not conforming results is limited. Here, no assumptions concerning the manufacturing range are needed; therefore this approach can also be applied for quantitation of impurities. The guard band approach allows the highest level of control, but requires in turn high demands on the precision. Therefore, it should be restricted to drug product assays or impurity determinations with larger risks, i.e. justified by a corresponding clinical relevance, such as narrow therapeutic ranges or substantial toxicity.

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