Evaluation of Preservatives

EVALUATION OF PRESERVATIVES

Preservatives are widely employed in the cosmetic and pharmaceutical industries as well as in a variety of other manufacturing industries. The addition of preservatives to pharmaceutical formulations to prevent microbial growth and subsequent spoilage, to retard product deterioration and to restrain growth of contaminating micro-organisms is commonplace for non-sterile pharmaceutical formulations as well as low-volume aseptically prepared formulations intended for multiple use from one container. Indeed, adequate preservation (and validation of effectiveness) is a legal requirement for certain formulations. Effective preservation prevents microbial and, as a consequence, related chemical, physical and aesthetic spoilage that could otherwise render the formulation unacceptable for patient use, therapeutically ineffective or harmful to the patient (due to presence of toxic metabolites, microbial toxins). The factors which influence the activity of the cidal agent employed as a preservative are largely those which affect disinfectant activity, however, when considering the activity of the cidal agent the interactions with formulation components (adsorption to suspended particles, oil-water partitioning, etc.) should be considered as additional factors which can potentially attenuate the preservative activity.

While the inhibitory or cidal activity of the chemical to be used as the preservative can be evaluated using an appropriate in vitro test system, its continued activity when combined with the other ingredients in the final manufactured product must be established. Problems clearly exist with some products, where partitioning into various phases may result in the absence of preservative in one of the phases, e.g. oil-in-water emulsions where the preservative may partition only into the oily phase, allowing any contaminant microorganisms to flourish in the aqueous phase. In addition, one or more of the components may inactivate the preservative. Consequently, suitably designed simulated use challenge tests involving the final product are, therefore, required in addition to direct potency testing of the pure preservative. In the challenge test, the final preserved product is deliberately inoculated with a suitable environmental microorganism which may be fungal (e.g. C. albicans or A. niger)or bacterial (e.g. Staph. aureus, E. coli, Ps. aeruginosa). For oral preparations with a high sucrose content, the osmophilic yeast Zygosaccharomyces rouxii is a recommended challenge organism. The subsequent survival (inhibition), death or growth of the inoculum is then assessed using viable count techniques. Different performance criteria are laid down for injectable and ophthalmic preparations, topical preparations and oral liquid preparations in the British Pharmacopoeia (Appendix XVI C) and the European Pharmacopoeia, which should be consulted for full details of the experimental procedures to be used. In some instances, the range and/or spectrum of preservation can be extended by using more than one preservative at a time. Thus a combination of parabens (p-hydroxybenzoic acid) with varying water solubilities may protect both the aqueous and oil phases of an emulsion, while a combination of Germall 115 and parabens results in a preservative system with both antibacterial (Germall 115) and antifungal (parabens) activity.