Analytical Quality by Design approach in the development of a CE method for the simultaneous determination of zolmitriptan and its impurities

Quality by Design (QbD) is a new paradigm of quality to be applied to pharmaceutical products and processes, described in International Conference on Harmonization (ICH) guideline Q8. The application of QbD to analytical methods is very attracting, because analytical QbD supports the development of a robust analytical method with adequate performances and increases the regulatory flexibility of the analytical method itself. This study was aimed to comprehensively apply QbD principles to the development of a CE method suitable for the simultaneous analysis of the antimigraine drug zolmitriptan (ZOL) and its five main impurities in pharmaceutical dosage forms, following the general workflow recently discussed. Voltage, temperature, buffer concentration and pH were investigated as critical process parameters (CPPs) that can influence the critical quality attributes (CQAs), represented by critical resolution values between peak pairs, analysis time and peak efficiency of ZOL-dimer. The effects of the CPPs throughout the knowledge space were evaluated in a screening phase by a symmetric screening matrix. Response surface methodology was performed by applying a Box-Behnken design and made it possible to obtain contour plots for each of the CQAs. The zone of the experimental domain which corresponded to the fulfillment of CQAs requirements was defined by means of the sweet spot plots. The design space was established by the combined use of response surface methodology and Monte-Carlo simulations, introducing a probability concept and thus allowing the quality of the analytical performances to be assured in a defined domain. Applying the selected working point conditions, the baseline separation of the analytes was achieved in less than 5 min. Implementation of QbD was demonstrated to provide not only a theoretical opportunity to achieve regulatory flexibility, but also a practical roadmap leading to obtain a high degree of analytical method understanding.