Industrial manufacture of parenteral products in The Netherlands. A survey of eight years of media fills and sterility testing.

Sterility testing and media fills are essential requirements in the pharmaceutical industry. With the results obtained the manufacturer must ensure that the aseptic filling process is under control. In an eight year (1988-1995) retrospective survey of three major Dutch pharmaceutical companies the performance of the sterility test, of media fills and their relationship have been statistically evaluated. The products included human and veterinary pharmaceuticals and biologicals, and were divided into six different groups according to their production process and primary containers. A distinction was made between the results from the period 1985-1991 and the period 1992-1995, because this made the statistical analyses of a number of types of products possible, and because some significant changes in the production process were made in 1991 at some of the production sites. The results of the evaluation of the sterility test show that the frequency of false positives has not changed significantly. The overall rate of false positives of 0.17% is a factor ten better than considered acceptable by USP XXIII. For all product groups the frequency of positive sterility tests has decreased during the period of investigation. During the period 1992-1995 there was no significant difference between the results of product sterility tests and the negative controls for any of the product groups. This indicates that given the present state-of-the-art production the sterility test offers little or no additional security. The overall contamination of the media fills done in the more recent period is a factor twenty better than the limit given in the PDA Technical Monograph No. 2. In the more recent period there is a good agreement between the observed positive rate of the sterility tests and the positive rate that had been estimated from the results of the media fills. This indicates that despite some shortcomings, media fills are an adequate simulation of the production process and can be used to give an estimate of the rejection rate for the various product groups. The overall conclusion is that the production conditions of the participating Dutch pharmaceutical companies comply with the current international guidelines for aseptic production and sterility testing.