A Unified Approach for Design and Analysis of Transfer Studies for Analytical Methods

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Various approaches are compared for the design and analysis of studies to assess the transfer of an analytical method from a research and development site to one or more other sites: comparison of observed bias and precision to acceptance limits, statistical quality control-type analysis, statistical difference tests, and statistical equivalence tests. These approaches are evaluated in terms of the extent to which the risks of incorrect decisions (consumer risk of failing to detect that a site is unacceptable, and producer risk of rejecting an acceptable site) are known and/or controlled. Comparison of observed accuracy and precision to acceptance limits is a flawed approach because both the consumer and producer risks are unknown and uncontrolled. For technology transfer, where the objective is to demonstrate sufficient acceptability or similarity, the statistical quality control and difference tests are well known to suffer from illogical characteristics (decreasing true acceptance probabilities as the sample size increases). The equivalence test is the preferred approach because it alone controls the more important consumer risk and performs in a scientifically logical manner. Acceptance limits for accuracy and precision in the equivalence test should be based on need for intended use (ie, ensuring that good batches will pass, and bad batches will fail, during future release testing and stability testing), and a rigorous method for selection of well-conceived limits is presented. Methods for sample size determination are also included. The proposed approach is illustrated with two examples.