Understanding of shelf-life, expiry periods, degradation kinetics, stability indications, and impurity profiling is of major concern. The present review focuses on the quality-by-design (QbD) approach for optimizing forced degradation conditions for impurity profiling. Analytical issues occurring at the last stage of long-term stability studies are related to unpredicted impurities, which can disturb monitoring of characterized impurities and raise many regulatory issues. The QbD multivariate approach was evaluated within the framework of the liquid chromatography (LC) method. The initial investigation is concerned with critical process parameters which can impact on critical quality attributes. Selection of primary and secondary parameters to define a design space with the help of a polynomial equation and Derringer’s desirability value is considered next. Sorting impurities using the multivariate design-of-experiments (DoE) approach can also be beneficial to reduce time and cost, whilst providing a robust process. Much emphasis is given to application of Q8 and Q9 International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines to improve quality, safety, and efficacy studies.