Preservative efficacy tests in formulated nasal products: reproducibility and factors affecting preservative activity

Preservative efficacy tests were performed in triplicate on each of three batches of three formulated nasal spray preparations to assess the inter- and intra-batch variation in preservative performance which typically results from these procedures, and to assess the relative importance of factors influencing preservative performance in nasal products. Tests were conducted using procedures conforming, as far as possible, to both the European and the US pharmacopoeias and the results interpreted using the performance criteria of both. Despite the adoption of practices designed to maximize reproducibility, a marked variation in the degree of microbial inactivation was observed, both within and between batches of product. A preservative system comprising benzalkonium chloride and phenylethyl alcohol was found to be far superior to combinations of either benzalkonium chloride plus disodium edetate or potassium sorbate plus disodium edetate, both of which failed to satisfy the EP performance criteria on a number of occasions. Proposals are made for the adoption of inactivation criteria which incorporate realistic error limits reflecting the inherent problems of reproducibility of the viable counting procedures involved.