Particulate matter test in small volume parenterals: critical aspects in sampling methodology.

The following critical steps of the particulate matter test sampling methodology for small volume parenteral products (SVPs), conduct by light blockage method, were considered: 1) reliability of the small volume aspirator sampler for different sample volumes; 2) particulate matter distribution inside each ampoule in liquid products (8 liquid SVPs tested); 3) influence of the sample preparation method on the evaluation of the final contamination of the sample. Nine liquid SVPs were tested by preparing samples following the three U.S.P. XXI methods: 1) unit as it is (direct analysis), II) unit diluted, III) sample obtained by combining several units. Particles counts were performed by a HIAC/ROYCO model 3000 counter fitted with a small volume sampler. The validation of the sampler shows that it should be improved. A more accurate and strict validation than the one stated by U.S.P. XXI is suggested. The particulate matter distribution in liquid products is found to be uniform inside the ampoule in the size range greater than or equal to 2 microns-greater than or equal to 10 microns; the analysis can be performed examining only a portion of the whole content. The three sample preparation methods lead to significantly different contamination results. The particulate control test should be conduct by direct analysis, as it is carried out under the same conditions as for product use. The combining method (III) is suggested for products of less than 2 ml volume that cannot be examined by direct analysis.