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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 transfec where the objective is to demonstrate sufSicient 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 manne,: Acceptance limits for accuracy and precision in the equivalence test should be based on need for intended use (ie, ensuring thar 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.

Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by Sanofi is one of the most widely prescribed LMWHs and has been used since 1993 in the USA. In 2010, US Food and Drug Administration approval for supplying generic enoxaparin was granted to Sandoz and subsequently to Amphastar. Little is known, however, of the differences in composition of these preparations. In this study, samples from several batches of generic enoxaparins were purchased on the US market and analyzed with state of the art methodologies, including disaccharide building blocks quantification, nuclear magnetic resonance (NMR), and a combination of orthogonal separation techniques. Direct high-performance liquid chromatography analysis of the different enoxaparin batches revealed distinct process fingerprints associated with each manufacturer. Disaccharide building block analysis showed differences in the degree of sulfation, the presence of glycoserine derivatives, as well as in proportions of disaccharides. Results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a clear distinction to be made between the enoxaparin batches according to their manufacturer. These results were further confirmed by orthogonal analytical techniques, including NMR, which revealed compositional differences of oligosaccharides both in low- and high-affinity antithrombin fractions of enoxaparin.

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