Q What are the main considerations regarding the use of antimicrobial preservatives?
Microbiological safety is important for all pharmaceutical products, and should be considered during development, manufacturing
and, importantly, in the product's subsequent storage and use. Any product that contains water offers an environment in which
microorganisms can proliferate in from very low levels. A product that is susceptible to microbiological growth is deficient
in several ways:
- It may pose a risk to the patient if it supports the growth of pathogenic microorganisms.
- The API may degrade due to microbial metabolism, leading to loss of product efficacy.
- Microbial growth may render the product organoleptically unacceptable to the patient.
- The metabolites of microorganisms may modify the API chemically, resulting in physical instability.
Pharmacopoeias require the manufacturer to show that the product will both not support the growth of organisms if exposed
to microbiological contamination and reduce the magnitude of contamination to acceptable levels. The necessary test is called
a challenge test or a preservative efficacy (PE) test.
If the preparation itself does not possess sufficient anti-microbial properties, then preservatives must be added. In these
cases, preservatives can extend a product's shelf life and are essential to prevent the growth of microbes and stop product
degradation. Common preservatives in use in the pharma industry include parabens (such as methyl or propyl), benzyl alcohol,
chlorobutanol and a variety of acids such as benzoic or salicylic.
However, there is an upward trend in the industry to reduce the level of preservatives. This makes the requirement to show
that the preparation itself is effective in preventing microbial contamination even more important.
Q Is simply adding a recognised preservative sufficient to control contamination?
Even if a preservative is known to be efficacious, it is still important to consider its potential interactions with the preparation.
The API and the formulation into which the preservative is incorporated can decrease, or possibly increase, the preservative's
efficacy. For example, the preservative may react with the formulation in such a way that it reduces the concentration over
time or renders it unavailable to interact with the microorganisms. Both instances could result in contamination being uncontrolled.
There is also a consideration around the expected activity of the preservative against different types of microorganism. Some
preservatives may not be as efficacious against fungi as they may be against bacteria (or the other way round), in which case
a combination may be necessary.
Q How can packaging material affect a preservative?
Packaging can also affect a preservative, particularly if a volatile preservative is used. If the preservative leaches into
the packaging it can reduce the preservative levels below active concentrations. This factor is especially important to consider
when moving a product to a new container material, such as from glass to PET or from PET to something like PPE.
Q And what about storage conditions?
Although it is true that a large number of pathogenic organisms will not proliferate at low temperatures, there are still
plenty that aren't as inhibited by refrigeration as you may think. If these start metabolising, then you can end up with
some interesting by-products that may not interact particularly well with the preparation—not to mention the risk introducing
high levels of microorganisms to the patient.
There's also the human factor to consider. Just because it says 'keep in the fridge' doesn't guarantee that someone won't
leave it out! Some bacteria have impressively fast growth cycles. E.coli, for example, can double every 20 minutes.