Column chromatography is of central importance for the manufacturing of biotechnologically derived active pharmaceutical ingredients. Stringent monitoring of the equipment used in those steps is crucial to successful and reliable manufacturing. Packed bed integrity in particular needs to be under continuous monitoring due to its criticality in the separation process. We propose a mathematical model that describes the inherent characteristics of the separation process, especially adapted to the circumstances of large-scale column chromatography. Parameters derived from that model allow a sensitive monitoring of the packed bed integrity and of the fluid dynamics involved. Changes in these parameters either seen as drifts, or sudden in nature can be interpreted mechanistically, because the circumstances, the respective parameter is influenced by, are known. Such knowledge leads to a better process comprehension for routine operations. The integrated form of the exponentially modified Gaussian distribution function is used to model the signal. Data from breakthrough curves from the column outlet can therefore be used to monitor the process continuously with high sensitivity towards perturbations within and around the packed matrix. Thus, orthogonal methods, in addition to the routine in-process controls, are installed in full agreement with health authorities’ expectations towards improving process monitoring and process knowledge throughout the lifetime of the manufacturing processes.