Origin, result and measurement of USP "essentially free" inspection for visible contaminating particles

The efficient mass production of pharmaceuticals requires scientifically replicable measurements. The measurements, in turn, must be capable of description in words and terms that can be universally understood and applied beyond national, corporate, or measurement laboratory boundaries. A notable present exception has been the required evaluation of visible particle contamination in injectable products. Beginning in USP23 <788> (1) and continuing in USP 24 there is official recognition that the results of the nondestructive inspection for "visible" particles cannot be described in simple terms. Although the call for injectable products to be free of any visible particle contamination has been repeated, variability in the results of the nondestructive inspection for contaminating particles has been officially recognized. This recognition is expressed in one sentence, "Injectable solutions, including solutions constituted from sterile solids intended for parenteral use, should be essentially free from particles that can be observed on visual inspection." This phrasing describes a probabilistic contaminating particle inspection result. Methodology with which to evaluate the effectiveness of the probabilistic manual, semi- or fully-automated inspection for contaminating particles in sealed containers has been well tested for the last 21 years. This paper provides a brief, nonmathematical review of the core concepts that are used.