An increasing tendency for structured development of analytical methods using the Qualityby-design approach has been emerging recently. A similar approach is now well accepted in the development of pharmaceutical products. Many guidelines describe how to gain as much knowledge about processes in order to set relevant control parameters and improve the robustness of manufacturing process, while the overall quality-by-design process for development of the analytical procedures is currently not fully defined. The development process of an analytical procedure with built-in quality starts with a definition of analytical method purpose and creation of an analytical target profile (ATP).Development is continued with a risk assessment analysis to identify all potential sources of variation and identification of critical factors. Evaluation of these critical factors is done by using experimental designs, as such approach provides us with a comprehensive insight of the analytical method operable design region. This thesis presents a comprehensive approach of quality-by-design development, optimization and validation of two different chromatographic analytical methods. All potential sources of variation and critical factors of a HPLC analytical method for assay
determination of BKC in pharmaceutical products were evaluated using C&E matrix risk assessment tool. Statistical model was generated and used for sweet-spot analysis to predict optimal factor settings and defining the analytical method design region, which was also graphically presented. Different experimental designs were used to evaluate the effect of these factors on the measured responses. Using two different types of experimental designs enabled us to compare the obtained results. The comparison showed that the use of fractional factorial design gives a better defined design region than the use of Plackett-Burman experimental design. Additionally, sample preparation step of the analytical method was optimized using the fractional factorial experimental design. Sample preparation is a crucial step for ensuring good accuracy and precision of the results. By modifying the composition of the solvent and increasing the sample concentration the interfering effect of the active component and placebo were minimized and the accuracy of the BKC assay was improved. The optimized method was validated according to the ICH guidelines requirements. The analysis of two different types of pharmaceutical preparations with different active component with the
optimized analytical method confirmed improved accuracy and repeatability of the results. The above approach was also successfully applied to development of the UPLC analytical method for determination of rosuvastatin impurities in pharmaceutical preparations. Fractional factorial experimental design was used for optimization of chromatographic conditions. Sweet-spot analysis was repeated without performing additional experiments, by weighting the significance of individual responses in order to find the final optimal chromatographic conditions that would ensure appropriate separation of all components in chromatogram. The method was validated and the results showed its suitability according to
the requirements set in the analytical target profile.
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