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Part II: A Quality-by-Design Methodology for Rapid LC Method Development

    Part II: A Quality-by-Design Methodology for Rapid LC Method Development

    Part I of this article described the application of Quality-by-Design (QbD) principles to the task of screening analytical columns. In a QbD approach a statistical experiment design plan (Design of Experiments, or DOE) [1] is used to systematically vary multiple study factors in combination through a series of experiment trials that, taken together, can comprehensively explore a multi-factor design space. Such a design can provide a data set from which the experimenter can identify and quantify interaction effects of the factors along with their linear additive effects, curvilinear effects, and even non-linear effects. This quantitation translates the design space into a knowledge space.

    As also described in Part I, in a traditional method development approach one would first study “easy to adjust” instrument parameters, meaning those for which no equipment configuration change was required. However, categorizing instrument parameters as easy versus hard to control is no longer valid in many cases due to the availability of multi-column and multi-solvent switching capabilities for most modern LC instrument systems. Therefore, one can now address up front the instrument parameters which are understood or expected to have the strongest effects on separation of the sample compounds. This is consistent with a QbD approach in which a Pareto analysis would first be carried out to rank instrument parameters in terms of their expected ability to affect compound separation; a manageable number of the top-ranked parameters are then included in the first phase of method development. Table I presents a phased method development approach using a rank-based partitioning of instrument parameters consistent with QbD-based practice.

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