Vial fogging is a typical cosmetic cake appearance issue in lyophilized products, mostly occurring in amphiphilic protein-like freeze-dried formulations, especially antibody drug conjugate (ADC) formulations. Although fogging is currently believed to have no directly impact on product quality, its occurrence can raise concerns about container closure integrity, leading to an increased product rejection rate in pharmaceutical production. Vial fogging is typically believed to be related to the driving force from the interfacial energy at the liquid/solid interface, which is impacted by several factors. This study delves into fogging impacting factors including vial types, depyrogenation process, and formulation with the aim of appearance enhancement. Employing a Surface Tensiometer and a Drop Shape Analyzer to ascertain surface tension, surface energy, and contact angle measurements, this study incorporated results from lyophilization processes as well and discerned that the degree of fogging is directly proportional to the increase in surface energy and inversely related to surface tension. Consequently, this research identified the critical parameters for forecasting the fogging level prior to lyophilization, offering innovative strategies for enhancing the visual quality of lyophilized pharmaceuticals in subsequent developments.