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The tendency of protein pharmaceuticals to form aggregates is a major challenge during formulation development, as aggregation affects quality and safety of the product. In particular, the formation of large native-like particles in the context of liquid-air interfacial stress is a well-known but not fully understood problem. Focusing on the two most fundamental criteria of protein formulation affecting protein-protein interaction, the impact of pH and ionic strength on the interaction parameter A*2 and its link to aggregation upon mechanical stress was investigated. A*2 of two monoclonal antibodies (mABs) and a polyclonal IgG was determined using dynamic light scattering and was correlated to the number of particles formed upon shaking in vials analyzed by visual inspection, turbidity analysis, light obscuration and micro-flow imaging. A good correlation between aggregation induced by interfacial stress and formulation pH was given. It could be shown that A*2 was highest for mAB1 and lowest for IgG, what was in good accordance with the number of particles formed. Shaking of IgG resulted in overall higher numbers of particles compared to the two mABs. A*2 decreased and particle numbers increased with increasing pH. Different to pH, ionic strength only slightly affected A*2. Nevertheless, at high ionic (100 mM) strength the samples exhibited more pronounced particle formation, particularly of large particles >25 μm, which was most pronounced at high pH.Protein solutions were identified to form continuous films with an inhomogeneous protein distribution at the liquid-air interface. These areas of agglomerated, native-like protein material can be transferred into the bulk solution by compression-decompression of the interface. Whether or not those clusters lead to the appearance of large protein aggregates or fall apart depends on the attractive or repulsive forces between protein molecules. Thus, protein aggregation due to interfacial stress is correlated with the protein-protein interactions as determined by A*2. This enables to differentiate different antibodies according to their propensity to form particles upon mechanical stress and to identify optimum formulation conditions.