The need to protect medicines against microbial spoilage

The need to protect foods against microbial spoilage is well appreciated because microbial growth results in obvious signs of deterioration.

However, there is a much lower level of awareness among members of the general public of the need to similarly protect cosmetics, toiletries and medicines. Although most medicines present a less favourable environment for microbial growth than foods, a wide variety of potentially hazardous organisms are nevertheless capable of growing to high concentrations in unprotected products.

The subject of preservation is therefore an important aspect of medicine formulation, simply because patients taking medicines are, by definition, unhealthy, and so quite possibly more vulnerable to infection.

It is important to distinguish between the words contamination and spoilage because they are sometimes used synonymously, which is incorrect.

Contamination, in this context, means the introduction of microorganisms into a product (i.e. it describes microbial ingress). Contaminating organisms can arise from many sources during the course of both product manufacture and
subsequent use of the product.

The procedures of good manufacturing practice (also considered later) are used to limit the first of these (Medicines and Healthcare products Regulatory Agency, 2017), but contamination arising from the patient is largely out of the control of the manufacturer except in the context of container design and labelling.

It is now commonplace to adopt containers that minimize contact between the patient’s body and the product; for example, collapsible tubes are used for creams and ointments rather than open-mouthed tubs or jars, into which fingers can be inserted, although the latter are still in use, particularly for products supplied in large volumes (e.g. Aqueous Cream BP).

Similarly, single-dose eye drops may be preferred to bottles where the dropper can come into contact with an infected eye and then be placed again in the eye drop solution.

Despite this, contamination by the
patient is still a problem to be considered in container design and product preservation.

Spoilage follows contamination and describes the process and consequences of microbial growth in the product.

Considering the potential for product spoilage and taking appropriate steps to
minimize the risk of it occurring are very much the responsibility of the formulation scientist and the manufacturer.

There are three principal reasons why microorganisms should be excluded totally from medicines or their presence should be subjected to stringent limits set by pharmacopoeias and regulatory agencies, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) or the UK’s
Medicines and Healthcare products Regulatory Agency (MHRA):

  • Products or raw materials contaminated with pathogenic organisms may be an infection hazard.
  • Microorganisms may cause chemical or physical changes in the product that render it less potent or effective.
  • Microbial growth is likely to make the product unacceptable to the patient or consumer even if there are no significant infection risks or loss of efficacy.

It is quite obvious that medicines should not contain pathogenic organisms that represent a source of infection. However, specifying the species and numbers of organisms representing an infection hazard is not straightforward.

Certain pathogens are recognized as ‘objectionable organisms’ and must be totally excluded from particular raw materials or product types, but the risk of infection is influenced not just by the number of organisms and their type but by other factors too.

For example, an organism may be present at a concentration that would be regarded as relatively harmless to a healthy individual but which may pose a problem for patients with impaired immunity.

Towards the end of the last century there were several reports in the pharmaceutical literature of infection occurring as a result of medicines containing pathogenic species (e.g. salmonellae, clostridia and Pseudomonas aeruginosa), but such reports became far less frequent with the adoption of more
rigorous quality standards and regulatory control of manufacture.

However, contaminated medicines are
by no means a thing of the past. The FDA publishes details of product recalls on its website, and in 2015 there were eight such recalls due to concerns about potential or confirmed microbial contamination in the ‘drugs’ category of products, and a further 11 in the ‘therapeutic biological products’ category.

It should be emphasized that there is the possibility of an infection arising from the use of a product contaminated with a concentration of organisms that is too low to be detectable by sight or smell.

This situation is potentially much more hazardous than that of a patient confronted with a medicine in which microbial growth is clearly evident.

Quite apart from representing an infection hazard, microorganisms may damage the medicine by degrading either the active ingredient or one or more excipients, thus compromising the quality and fitness for use of the product.

Degradation is usually due to either hydrolysis or oxidation, but decarboxylation, racemization and other
reactions may also occur. Active ingredients known to be susceptible to microbial attack include steroids,
alkaloids, analgesics and antibiotics; several specific examples are given by Bloomfield (2007) and Baird
(2011).

The numbers and variety of excipients that have been reported to be degraded are at least as great as those of active ingredients. Thus most categories of excipients contain materials that have been shown to be susceptible to microbial enzymes, acids or other metabolic products. Common examples of product instability or deterioration include emulsion phase separation due
to surfactant degradation, loss of viscosity due to microbial effects on gums, mucilages and cellulose
derivatives used as thickening agents, and alcohol and acid accumulation following fermentation of sugars.

Despite the very purpose of their use being to restrict microbial growth, some preservatives are vulnerable to inactivation by microorganisms that, in
exceptional cases, use them as a carbon and energy source.

Nor should it be assumed that products whose very purpose is to kill microorganisms will necessarily be self-sterilizing: previous FDA product recalls have involved antiseptic wipes containing alcohol and iodine which were designed to decontaminate skin before injection or surgery, but the wipes were, themselves, sources of microbial contamination.

If microbial growth within the product is sufficiently extensive, it is possible for the presence of the organisms to be detectable by:

  • their physical presence (cloudiness in liquid medicines, moulds on or in creams and syrups, or as discolouration of tablets stored in a damp environment);
  • changes in colour (pigment production);
  • smell (due, for example, to amines, acetic acid or other organic acids, or sulfides from protein breakdown); and
  • gas accumulation without any obvious odour
    (bubbles of carbon dioxide following sugar
    fermentation).

Clearly, any product manifesting such changes would be unlikely to be used by the patient. This may result in short-term problems for the patient of obtaining
alternative supplies and, possibly, longer-term problems for the manufacturer in terms of customer complaints, product recalls, adverse publicity and possible legal action.

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