A systematic screening protocol was used to develop an ultra-high performance liquid chromatography (UHPLC) method for the analysis of naphazoline hydrochloride (HCl) and pheniramine maleate active pharmaceutical ingredients (APIs) and their associated related substances. Following a predefined experimental plan, the major selectivity factors were systematically screened during the study, enabling efficient method development. An Arc Premier System integrated with a PDA detector and an ACQUITY QDa Mass Detector was used to develop a method.