We rely on the efficacy of the preservatives used in the protection of parenteral products. Dr Alan Davison (UK member of the PhEur microbiology group) suggested that for multidose formulations, preservation was not used to reduce the bioburden as such, but to prevent infection. In these circumstances, efficacy could not be predicted — it was usual to determine it empirically by resistance to microbial challenge in the original container over the expected shelf-life. The severity of pharmacopoeial criteria of preservative efficacy differred, therefore it was better to validate the system by conducting an in-use study of the incidence and level of opportunistic pathogens. Dr Davison reminded the audience that requirements would differ with clinical site and use, eg, they would be more stringent for containers of topical eye-drops and products for parenteral use. He then listed a series of bacterial and fungal organisms indicated to challenge the risk of systemic and topical infection using standard levels of inoculum.
Dr Davison proceeded to review the "difficult prospect "for harmonisation between compendia, with their "nuances in text "and differences in assessment according to standard categories of level of biological control achieved. He compared the draft ICH (PhEur) text with proposed USP XXIV (and JP) version. The tests showed differences in the logarithmic (decade) reduction expected over various times, from six hours to 28 days for bacterial challenge and from 1 to 4 weeks for fungal challenge for ophthalmic and parenteral preparations, and separate time scales for topical and oral products. He went on to summarise the major differences in assessment and how these might be reconciled, or at least reduced. But, in any event, "are these various tests adequately predictive?”, he asked. He described the work of a British Pharmacopoeia working-group which was evaluating PhEur options A and B for efficacy of sterile eye-drops. They had compared four distinct eye products, containing one of three different preservatives. Around 3 per cent contamination found in two products correlated with test A but not with test B, whereas higher contamination was exhibited in two other products despite passing efficacy tests A and B. The group had gone on to test some injectable preparations and topical products, which failed test A but passed test B — particularly when stored in jars rather than in tubes.
Dr Davison concluded that there had been good progress in harmonising methods but the assessment criteria "remain ruggedly different "between the USP and the PhEur. "However, "he said, "there is a good forum of preservation dialogue within the PDG. "One option, he suggested, might be to keep the PhEur test A for preservative development and adjust test B to the USP XXIV version for refined agreement. He concluded with a warning that there could be "major trouble ahead "in striving to harmonise criteria for microbiological limits.