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20When using an analytical method, defining an Analytical Target Profile (ATP) focused on 21 quantitative performance represents a key input, and this will drive the method development 22 process. In this context, two case studies were selected in order to demonstrate the potential of 23 a Quality-by-Design (QbD) strategy when applied to two specific phases of the method 24 lifecycle: the pre-validation study and the validation step. The first case study focused on the 25 improvement of a Liquid Chromatography (LC) coupled to Mass Spectrometry (MS) 26 stability-indicating method by the means of the QbD concept. The Design of Experiments 27 (DoE) conducted during the optimization step (i.e. determination of the qualitative Design 28 Space (DS)) was performed a posteriori. Additional experiments were performed in order to 29 simultaneously conduct the pre-validation study to assist in defining the DoE to be conducted 30 during the formal validation step. This predicted protocol was compared to the one used 31 during the formal validation. A second case study based on the LC/MS-MS determination of 32 glucosamine and galactosamine in human plasma was considered in order to illustrate an 33 innovative strategy allowing the QbD methodology to be incorporated during the validation 34phase. An operational space, defined by the qualitative DS, was considered during the 35 validation process rather than a specific set of working conditions as conventionally 36 performed. Results of all the validation parameters conventionally studied were compared to 37 those obtained with this innovative approach for glucosamine and galactosamine. Using this 38 strategy, qualitative and quantitative information were obtained. Consequently, an analyst 39 using this approach would be able to select with great confidence several working conditions 40 within the operational space rather than a given condition for the routine use of the method. 41This innovative strategy combines both a learning process and a thorough assessment of the 42 risk involved. 43 3

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