Quality by Design (QbD) is well established in the pharmaceutical industry for manufacturing processes, including active pharmaceutical ingredients and drug products. The novelty of the multivariate approach over the more traditional one-factor-at-a-time (OFAT) type of study is the ability to evaluate both the individual factor effects and the factor-factor interactions that can also be significant. These same QbD principles have been applied to the development of analytical methods. In this case study, a QbD approach was used to solve a high-performance liquid chromatography (HPLC) analytical method problem where impurity peaks had shifting retention times making identification and quantitation problematic.