title: "Absolute" sterility and "absolute" freedom from particle contamination.
abstract: Until the recent past, sterility of an injectable product was only discussed in absolute terms. Any description of sterility other than as an absolute could simply not be envisioned. While dealing in absolute yes/no statements is philosophically satisfying, these yes/no statements can't accommodate all real world scientific problems. Among these problems is the sterility problems faced in the mass production of injectable compounds. Many descriptions of procedures employed to achieve sterility in parenteral production batches were reported in the literature. The theoretical framework that could unite the widespread observations and practices into practical methodology was missing until recently. Production line control of the sterility of injectable products was essentially based on gut evaluations. The present achievement of rational, production line control of product sterility is based on the recognition that product sterility could not be simply regarded as a sharply edged yes/no affair. The present rational control is based on the fact that the sterility of a product is determined by the degree of contamination in the product prior to sterilization and to the parameters of the sterilization process. The end result of the sterilization process is now described as a probabalistic reduction of the initial contamination. The essential laboratory measurements on which this conclusion was based is due to Pflug (1-3). He assembled a theoretical framework, based on experimental data, that characterizes the sterility achieved in an injectable product with a single number. The end result of the sterilization process is now described as a probabalistic reduction of the initial contamination. As in many disciplines, the ability to achieve an objective evaluation of this important attribute provided the basis for scientific analysis, improved control and thus improved production and reduced cost. An equivalent framework is essential for the communication and standardization of the results of a visual inspection for contaminating particles. The control of particle contamination in injectable products is a two-fold problem for the pharmaceutical industry. The two parts of the problem are 1) achieving contamination free product and 2) achieving this contamination free quality at an economic cost acceptable to the user. Today, there is no commonly accepted framework for the definition or analysis of the results of a manual inspection for "visible" particles. Any progress toward global harmonization of the results of a visual particle inspection must commence with the development of a common scientific language with which inspection security and economic effectiveness of an inspection can be discussed and rationally evaluated. The tools with which to define and control the results of this inspection have been developed in biophysics, illumination engineering, optics, pharmaceutical manufacturing and statistics. With them, statistically replicable measures have been developed. The statistically replicable measures are then used to evaluate the results of semi- and fully automated particle inspection systems in terms of human inspection performance. The numerical evaluation of both the freedom from contamination achieved with an inspection for particle contamination and the economic effectiveness of the inspection are compared to Pflug's sterility index. In the case of particle contamination, the final product quality depends on product quality prior to inspection and to the parameters of the inspection process.
authors.affiliation: Research & Development Associates, Incorporated, Somerset, N.J., USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Knapp
mesh_terms: D004340:Drug Contamination; D006801:Humans; D010316:Particle Size; D011336:Probability; D013242:Sterilization