MICROBIOLOGICAL SPOILAGE IN PHARMACEUTICALS AND COSMETICS 727 first indication that a gas-producing micro-organism has successfully adapted itself to what may have been considered inimical conditions. TYPES OF SUSCEPTIBLE PRODUCT The range and composition of pharmaceutical and cosmetic products is so varied and the species, and even strains, of micro-organism capable of causing spoilage are so multifarious that, as we have already emphasized, each spoilage incident tends to be unique. Generalizations about sus- ceptible products are therefore likely to be inaccurate and are made more difficult today because of the inclusion, particularly in cosmetics, of in- creasingly sophisticated and often highly. biodegradable ingredients. Never- theless some types of product are more susceptible than others to spoilage by specific organisms and those of which we have experience are described below. Liquids Water Water is a major constituent of living material and participates in many metabolic reactions. Bacteria, in particular, require high concentrations of water in their immediate environment and may be regarded as aquatic organisms. Hence, all products containing large amounts of free water can be particularly susceptible to spoilage by bacteria. Water supplied by water undertakings in this country is of high micro- biological quality and is generally suitable for the manufacture of pharma- ceuticals and cosmetics. Low-conductivity water, whether prepared by distillation or deionization, may be chemically purer but can constitute a greater microbiological hazard. Distilled water leaving the still can readily pick up organisms from pipes and tubing and ion-exchange columns may actually serve as a reservoir of organisms because nutrient organic residues are not removed by the process. Without effective treatment to minimize contamination, water can, within a few days, contain large numbers of initially Gram-negative and Gram-positive bacteria, and subsequently a wide variety of bacteria, moulds and yeasts. At this stage visible and ol- factory spoilage occurs and a foul taste may develop. Indeed contaminated deionized water has often been incriminated as the original source of spoilage in a formulation. Often the responsible organisms are pseudo- monads which are not only highly resistant to preservatives but are also able to use the widest range of organic compounds as substrates.

728 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Simple aqueous solutions Some moulds will grow on such unlikely media as strong solutions of copper sulphate or sulphuric acid and simple solutions of inorganic com- pounds will support the growth of many sorts of microbe. The presence of organic material greatly increases the chance of growth occurring as it not only provides a utilizable substrate but may serve to introduce contamin- ants into the solutions. We have detected deposits of turbidity due to algae, moulds, bacteria or yeasts in a multiplicity of different solutions including ammonium carbonate, neutral ammonium tartrate, calcium digluconate, potassium citrate and Amaranth Solution B.P., even when apparently preserved with chloroform. Many solutions are included in the great diversity of mixtures in the B.P.C. and other formularies. These are often prepared from aqueous con- centrates which are themselves adequately preserved. However, the pre- servative can be diluted out on mixing and the resulting preparation is then at risk. An example of recent interest is peppermint water which has been implicated as a source of contaminants in formulations containing this ingredient. In at least one case there is evidence that potential pathogens have been transmitted to patients from it (12). Suspensions Aqueous suspensions of inorganic material for pharmaceutical use fre- quently support microbial growth, particularly as added preservatives tend to be absorbed and inactivated by the suspended matter. Unless growth is at the surface, as with mould contaminants, it is not easily detected visually because of the opacity of these products. When the lid is removed spoilage is sometimes manifested by an offensive odour or an unpleasant taste, but otherwise large numbers of bacteria may unwittingly be taken with the preparation. Thus, a medicament for the treatment of an intestinal disorder may exacerbate, rather than alleviate, the condition. However, apart from visible growth, a variety of other changes in appear- ance may be seen and preparations of this type can thin, separate, de- colourize, or change colour. The sequential growth of an aerobic organism, particularly a pseudomonad, followed by an anaerobe can cause striking changes in pharmaceutical products. The sequence occurring in cutting oil emulsions, used for cooling during drilling operations in the engineering industry, has been studied by several workers (13). The oils often become blackened due to bacterial action, the first organism lowering the redox potential and allowing the proliferation of anaerobic sulphate-reducing