AQbD-based Headspace GC-MS/MS method development under ICH Q14 guideline for simultaneous analysis of residual solvents in pharmaceuticals

Abstract

A risk assessment–driven Analytical Quality by Design (AQbD) approach was applied to develop and validate a headspace GC–MS/MS method for simultaneous quantification of residual solvent impurities (RSIs) in pharmaceutical drug substances. The method enables concurrent analysis of 11 RSIs, including methanol, acetone, dichloromethane (DCM), ethanol, isopropyl alcohol (IPA), and ethyl acetate, in accordance with the Quality Target Product Profile (QTPP). Taguchi screening and Pareto analysis identified three critical method variables (CMVs): split ratio, agitator temperature, and ion source temperature. Method responses—number of theoretical plates, resolution, tailing factor, and retention time—were optimized using central composite design (CCD). The experimentally verified Method Operable Design Region (MODR) defined Proven Acceptable Ranges (PARs) for split ratio (1:20–1:25), agitator temperature (90–97 °C), and ion source temperature (265–285 °C). Using a fused silica column with helium and Advanced Electron Ionisation (AEI), retention times for methanol, ethanol, acetone, IPA, DCM, and ethyl acetate were 2.35 ± 0.1, 3.15 ± 0.1, 3.68 ± 0.1, 3.91 ± 0.1, 4.38 ± 0.1, and 6.39 ± 0.1 min, respectively. Validation confirmed specificity, resolution (≥ 2), tailing factor (≤ 2), theoretical plates (> 14,000), and linearity (R² > 0.98). Application to multiple drug substances demonstrated accurate and precise determination of target and additional RSIs, confirming the method’s suitability for regulatory compliance and quality control.