Definition of Particle Visibility Threshold in Parenteral Drug Products-Towards Standardization of Visual Inspection Operator Qualification.

The detectability size threshold of visible particles ("visibility" size) in the context of visual inspection of parenteral drug products has been an elusive target for several decades. The current common sense, also reflected in official guidelines, dictates that particles of different shapes and morphologies have different "visibility" size thresholds, which can range between hundreds and thousands of micrometers. This study demonstrates experimentally for the first time that it is possible to define a single, shape- and morphology-independent detectability size threshold, identical across particles of various types, provided that observation conditions and product attributes are kept constant. We propose that, based on the physiology of human visual perception instead of single-dimension measures of particle size (e.g., diameter or length), such a single size-threshold requires the use of area-based size parameters (such as "equivalent circular diameter", or ECD. The experimental results reported here clearly demonstrate that the "visibility" thresholds for particles of various morphologies converge on a single ECD value. In addition, the data reported here show that product attributes, such as container configuration, fill volume, etc. influence the threshold of visibility. Collectively, the findings reported in this paper provide substantial evidence and scientific rationale, as well as unanticipated prospects for standardization of visual inspection qualification practices, ultimately leading to improvement of pharmaceutical product quality.