Analytical Quality by Design in RP-HPLC Method Development for Pharmaceutical Analysis

Reversed-phase high-performance liquid chromatography (RP-HPLC) is the dominant technique for drug assay, impurity testing and stability work but many methods are still developed by changing one factor at a time. Analytical Quality by Design (AQbD) provides a structured alternative that connects method performance with scientific knowledge and risk control. This review discusses the application of AQbD to RP-HPLC method development, including regulatory background, risk assessment, design of experiments (DoE), the method operable design region (MODR), dosage-form applications, stability-indicating work and green analytical chemistry. Forty-four peer-reviewed sources published between 2021 and 2025 were selected, and then synthesized using qualitative synthesis. Optimization was dominated by Box-Behnken and central composite designs (often post-Plackett-Burman or similar screening), whereas the MODR was increasingly defined by Monte Carlo simulation. The studies included tablets, nanocarriers, biological fluids and degradation products, with several using ethanol based mobile phases with greenness scoring. AQbD results in more robust and better documented RP-HPLC methods, but reporting of control strategy, method transfer and lifecycle monitoring is still patchy. The next step is to close these gaps and align practice with ICH Q14 and Q2(R2).