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This concluding article of the publication series provides an overarching summary of all study results presented in the three previous articles (1-3). Their interdependency in achieving a holistic approach to the integrity assurance of single-use systems (SUSs) employed in (bio)pharmaceutical manufacturing is finally illustrated. Two of those three studies were conducted to understand microbial ingress and liquid leak mechanisms in polymeric film material as determinants of the maximum allowable leakage limit (MALL) for SUSs using artificially created defects. The third study characterized gas flow through these defects-an essential variable for robust validation of physical integrity test methodologies based on gas flow. In all studies, the test samples used were 50 mm round patches of two ethylene vinyl acetate (EVA) multilayer films (300 lm and 360 lm thick) and a polyethylene (PE) multilayer film (400 lm thick). More than 1400 test samples with artificially created leaks were used in sizes ranging from 1 lm to 130 lm. The leaks were laser-drilled into the center of each patch. Microbial ingress and liquid leak testing under various process conditions resulted in a MALL of 2 lm for microbial integrity and the prevention of liquid leakages under most severe usecase conditions. The studies also demonstrated a close relationship between the occurrence of liquid leakage and microbial contamination. Different model solutions were used to evaluate the impact of liquid characteristics, mainly surface tension. The data were applied to build mathematical models for predicting the MALL under any intended use-case condition. By characterizing gas flow behavior over a broad pressure range using various defect sizes, it was possible to create formulas for three different flow regimes. These were suitable for calculating leak size in a defective product directly from the corresponding flow rate or vice versa. Finally, compilation of these different aspects enabled the authors to design and validate non-destructive physical integrity test methods having detection limits correlated to the MALL for SUSs.