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.However, quaternary ammoniumantimicrobial agents are only slowly attacked.Organomercurial preservatives dischargedinto rivers from paper mills have been extensively converted to insidiously toxicalkylmercury compounds which could reach humans via an ascending food chain.Degradation of agents at 'use' concentrations in pharmacy and medicine is lesscommonly reported, but there are incidents of the growth of pseudomonads in stocksolutions of quaternary ammonium antiseptics and chlorhexidine with resultant infectionof patients.Pseudomonas spp.have metabolized 4-hydroxybenzoate ester preservativescontained in eye-drops and caused serious eye infections, and metabolized them in oralsuspensions and solutions.It is important to remember this possibility when selectingpreservatives for formulations.1.2.4 Observable effects of microbial attack on pharmaceutical productsMicrobial contaminants will usually need to be able to attack ingredients of a medicineand create substrates necessary for biosynthesis and energy production before they canreplicate to levels where obvious spoilage becomes apparent since, for example, 106microbes will have an overall degradative effect around 106 time faster than one cell.However, growth and attack may well be localized in surface moisture films or veryunevenly distributed within the bulk of viscous formulations such as creams.EarlyMicrobial spoilage and preservation of pharmaceutical products 359 Fig.18.1 Section (xl.5)through an inadequatelypreserved olive oil, oil-in-water,emulsion in an advanced state ofmicrobial spoilage showing:A, discoloured, oil-depleted,aqueous phase; B, oil globule-rich creamed layer; C, coalescedoil layer from 'cracked'emulsion; D, fungal mycelialgrowth on surface.Also presentare a foul taste and evil smell!indications of spoilage are often organoleptic, with the release of very unpleasantsmelling and tasting metabolites such as 'sour' fatty acids, 'fishy' amines, 'bad eggs',bitter, 'earthy' or sickly tastes and smells.Products frequently become unappealinglydiscoloured by microbial pigments of various shades.Thickening and suspending agentssuch as tragacanth, acacia or carboxymethylcellulose can be depolymerized, resultingin loss of viscosity, and sedimentation of suspended ingredients.Alternatively, microbialpolymerization of sugars and surfactant molecules can produce slimy, viscous, massesin syrups, shampoos and creams, and fungal growth in creams has produced 'gritty'textures.Changes in product pH can occur depending on whether acidic or basicmetabolites are released, and become so modified as to permit secondary attack bymicrobes previously inhibited by the initial product pH.Gaseous metabolites may beseen as trapped bubbles within viscous formulations.When a complex formulation such as an oil-in-water emulsion is attacked, a grossand progressive spoilage sequence may be observed.Metabolism of surfactants willreduce stability and accelerate 'creaming' of the oil globules.Lipolytic release of fattyacids from oils will lower pH and encourage coalescence of oil globules and 'cracking'of the emulsion.Fatty acids and their ketonic oxidation products will provide a sourtaste and unpleasant smell, whilst bubbles of gaseous metabolites may be visible, trappedin the product, and pigments may discolour the product (see Fig.18.1).1.3 Factors affecting microbial spoilage of pharmaceutical productsAn understanding of the influence of the chemical and physico-chemical parameters ofan environment on microorganisms might allow for subtle manipulation of a formulationto create conditions which are as unfavourable as possible for growth and spoilage,360 Chapter 18 within the limitations of patient acceptability and therapeutic efficacy.Additionally,the overall characteristics of a particular formulation will indicate its susceptibility toattack by various classes of microorganisms.1.3.1 Types, and size, of contaminant inoculumWhilst there will be some chance that a particularly aggressive microbe may enter andcontaminate a medicine, some element of prediction is possible if one considers theenvironment and usage to which the product is likely to be subjected during its life andthe history of similar medicines (see Chapters 17 and 19).A formulator can then buildin as much protection as possible against non-standard encounters, such as additionalpreservation for a syrup if osmotolerant yeast contamination is particularly likely.Should failure subsequently occur, a knowledge of microbial ecology and carefulidentification of the contaminant(s) can be most useful in tracking down the defectivesteps in the design or production process.Very low levels of contaminants which areunable to replicate in a product might not cause appreciable spoilage but, should anunexpected surge in the contaminant bioburden occur, the built-in protection couldbecome swamped and spoilage ensue.This might arise if:1 raw materials were unusually contaminated;2 a lapse of the plant-cleaning protocol occurred;3 large microbial growths detached themselves from within supplying pipework;4 a change in production procedures allowed unexpected growth of contaminantsduring the modified operation;5 there was demolition work in the vicinity of the manufacturing site or;6 there had been gross misuse of the product during administration.However, inoculum size alone is not always a reliable indicator of likely spoilagepotential.A very low level of, say, aggressive pseudomonads in a weakly preservedsolution may suggest a greater risk than tablets containing fairly high numbers of fungaland bacterial spores.When an aggressive contaminant enters a medicine, there may be an appreciablelag period before significant spoilage begins, the duration of which decreasesdisproportionately with increasing contaminant loading.It is possible to provide somecontrol over extemporaneously dispensed formulations by specifying short shelf-livesof, say, 2 weeks.However, since there is usually a long delay between manufactureand administration of factory-made medicines, growth and attack could ensue duringthis period unless additional steps are taken to prevent it.The isolation of a particular microorganism from a markedly spoiled product doesnot necessarily mean that it was the initiator of the attack.It could be a secondaryopportunist contaminant which has overgrown the primary spoilage organism once thephysico-chemical properties had been favourably modified by the primary spoiler.1.3.2 Nutritional factorsThe simple nutritional requirements and metabolic adaptability of many commonsaprophytic spoilage microorganisms enable them to utilize many of the componentsof medicines as substrates for biosynthesis and growth, including not only the intendedMicrobial spoilage and preservation of pharmaceutical products 361 ingredients but also the wide array of trace materials contained in them.The use ofcrude vegetable or animal products in a formulation provides an additionally nutritiousenvironment.Even demineralized water prepared by good ion-exchange methods willnormally contain sufficient nutrients to allow significant growth of many water-borneGram-negative bacteria such as Pseudomonas spp.When such contaminants fail togrow in a medicine it is unlikely to be as a result of nutrient limitation but due to other,non-supportive, physico-chemical or toxic properties
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