Pharmacopeial sterility test: The statistical limitations of sampling

Abstract

For aseptically filled products, as well as for many terminally filled products, the sterility test is a mandatory product release test. It is, however, statistically poor at detecting anything other than gross contamination (this limitation has been addressed in a number of studies (1)). This limitation relates to the few numbers of articles tested (2). For batches in excess of 500 filled containers, the pharmacopeia only require that twenty samples are included in the sterility test set. This sample size appears to have been set arbitrarily, and it does not provide a statistically significant population with which to estimate sterility (3). Although it is unclear how this sample size was derived, the number is grounded, in part, through the sterility test being a destructive test (each article tested via the sterility test is not available for the patient) and therefore to maximise the availability of the batch by using as few units as possible. It remains, nonetheless, that the sample size of 20 provides no confidence that the sterility of a batch of pharmaceutical items has not been compromised. In relation to sampling, limitations not only apply to the low number of samples tested but also to the difficulties in selecting a sample representative of all significant events during batch filling (4). This is important because contamination is unlikely to be uniformly distributed throughout the batch and thus random sampling cannot detect contamination with absolute certainty. This is of particular importance with aseptic filling where batch specific events can occur. It is possible that certain events can be captured, such as interventions into the aseptic core, where the vials exposed at the time of the activity can be incorporated into the sterility test set (notwithstanding that all events cannot be captured in this way).