This is the fifth in a series of Memos on microbial issues. It covers the applicability, or perhaps additionally the lack of applicability, of water activity for cleaning validation purposes. What will be covered first is the principles and history of water activity. We will then considerations of its applicability for cleaning validation program. Finally, to avoid concerns about perhaps misleading you, we will cover where water activity may be of concern for other aspects of pharmaceutical manufacturing.
What is “water activity”?
Water activity of a product or substance may be used to predict the ability of vegetative microorganisms to grow in the product. It is defined as the ratio of vapor pressure of water in any substance of the vapor pressure of pure water at the same temperature. In general, for dry drug products vegetative bacterial microorganisms will not grow or proliferate in products with water activities of 0.8 or less. For yeasts/molds (fungi) this “no growth” value is 0.6 or less. Lack of growth does not mean the microorganism will die; they may or may not die in the product, but below those threshold values microorganisms will not increase. For clarification this applies to vegetative bacterial organisms and not organisms in the bacterial spore state. Bacterial spores in the spore (dormant) state cannot proliferate unless the spores become un-dormant as vegetative organisms.
Water activity is NOT the same as water content. Water content is usually measured as the percent water on a wt./wt. basis. Yes, there is a general increase in water activity with increasing water content. But the threshold level for preventing microbial growth may vary significantly based on the product’s composition. For example, one of the first materials where the concept of water activity was discovered with honey. It was noticed that microorganisms would not grow in honey if the water content of the honey were less than about 20%. This discovery was not expected, because one would expect that such a composition like honey would allow ready proliferation of microorganisms. The science behind water activity was not explored until the 1950s by the Australian microbiologist W.J. Scott related to food safety. Water activity was then applied to pharmaceutical preparations beginning in the 1960s.
Water activity for pharmaceutical cleaning validation?
It is not generally appropriate to say microbial evaluation for that drug products can be avoided in a cleaning validation protocol or study solely based on a low water activity of product. Why is this the case? One reason is water activity only addresses the issue of microbial growth (reproduction or proliferation). The microbes may still be present at the end of a cleaning process even though they can’t reproduce, but that level may be unacceptable when actual specified cleaning validation limits are considered. Furthermore, the water activity of the clean product is not so important as the water activity of the residue left behind on equipment surfaces. This residue may include API, excipients, cleaning agents, and degradation species, and the ratios of the individual residues may be different from the ratios of those components in the cleaned product.
A related topic is the possibility of growth of microbes on cleaned surfaces during the clean hold time. I generally say that if the cleaned equipment is clean (low chemical residues) and dry throughout the clean hold time, microorganisms will not reproduce (proliferate). Now I have never heard of a company trying to actually measure the water activity of residues on cleaned surfaces, but the idea that the equipment is clean and dry is based on the principles of lack of microbial growth with low water activity. (I should also add here that I have emphasized maintenance of low water activity throughout the duration of the clean hold time. If residues are hygroscopic and would tend to pick up water from air, this may mean no microbial grow in an initial time period but possible significant increases in later time periods.)
Some may be tempted to consider the water activity of the next product made in the cleaned equipment. The good news is that if microbial limits are met in the prior cleaning and maintained during the clean hold time, it is unlikely that low activity products could be contaminated with microorganisms from the cleaned surfaces. Care should be use here. It is not just the water activity of the final drug product that is important, but also water activity at earlier stages during manufacture that should be evaluated. For example, if the process of materials for tablets involves wet processing, the water activity of that intermediate material prepared during wet processing should be considered.
The above are just a few of the considerations in trying to make sure actual microbial residues at the end of cleaning are as low as practical below the specified limits.
Other uses for water activity in pharmaceutical manufacturing
If you as a reader are cleaning validation scientist, you might also want to know how water activity is also important for other aspects of pharmaceutical product design and production. So only read on if you might want to see how water activity might be addressed in other functional areas in your company. Here are areas of such uses.
This is the last Memo of this series on bioburden issues. However, microbial control is an important part of cleaning validation and may be touched tangentially in future Memos.
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