Water Activity: USP 795 Changes

Beyond-use dating in the newly proposed USP General Chapter <795> underwent significant changes, particularly to the recommended maximum beyond-use dates allowed for different types of formulations. One of the biggest changes is a new focus on microbial growth and preservative efficacy. The guidelines define aqueous preparations as those having a water activity (a_w) greater than or equal to 0.6, and only preparations with an a_w less than 0.6 are considered anhydrous dosage forms.¹

What is water activity?

Water activity is a measurement of the ratio of vapor pressure of the substance in question when at equilibrium with the surrounding air to the vapor pressure of distilled water under identical conditions.² So, for example, an a_w of 0.6 means that the vapor pressure of the substance in question is 60% that of pure water.

Water activity should not be mistaken for water content. Water content is a measure of how much water is in a particular substance by weight or volume, whereas a_w is a measure of water that is available for reaction or accessible to microbes. Even items with relatively low water content can still have relatively high a_w.

Why does water activity matter?

Water activity is a reliable measure of a microbe’s ability to grow in a particular substance. Generally, bacteria can grow at a_w greater than 0.85, and fungi such as yeasts and molds at a_w greater than 0.6.^3,4  Newly proposed USP <795> guidelines consider anything with an a_w less than 0.6 to be anhydrous, and therefore can be given longer recommended maximum beyond-use dates without necessarily having a preservative.¹

Water activity is also a useful reference parameter when considering how much water is available in a substance to act in chemical reactions, potentially resulting in degradation of active ingredients in that substance.⁵

What does this mean for my practice?

This new focus on a_w not only means a potential change in beyond-use dating guidelines, but also a new focus on preservatives and how to select one for a particular compounded preparation. Notably, USP clarifies that these new guidelines do not require compounders to measure a_w for particular compounds, but can use table 3, Water Activity (a) of Common Compounded Nonsterile Dosage Forms, presented in USP <795> to infer whether their preparation is aqueous or non-aqueous.⁶ General Chapter <1112> (Application of Water Activity Determination to Nonsterile Pharmaceutical Products) provides further information on the water activity of pharmaceutical products.^6,7 If a_w is not tested for a preparation known to contain water, such as a cream or aqueous suspension, the a_w should be assumed to be equal to or greater than 0.6 and, in the absence of an appropriate study, the beyond-use date should be consistent with the maximum beyond-use date listed in table 4 of new proposed USP <795> guidelines.¹ In the absence of explicit data on a particular compound, General Chapter <1112> and table 3 from the proposed revision to USP <795> provide good resources for justifying an assigned beyond-use date.

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Sources:

1. United States Pharmacopeia and National Formulary. USP <795> Pharmaceutical Compounding – Nonsterile Preparations.  Current DocID: GUID-98DCB48D-DC23-4A63-AD2E-01CA8979FB7E_5_en-US
2. Food and Drug Administration. 2014 Aug 27^th. Water Activity (aw) in Foods. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-technical-guides/water-activity-aw-foods. Accessed 03/04/22
3. Sperber W. Influence of water activity on foodborne bacteria – a review. Journal of Food Production. 1983; 46(2): 142-150.
4. Beuchat L. Influence of water activity on growth, metabolic activities and survival of yeasts and molds. Journal of Food Production. 1983; 46(2): 135-141.
5. Maltini E, Venir E. Relevance of physical properties in the stability of plant-based food products. Indian Journal of Experimental Biology. 2013; 51: 895-904.
6. United States Pharmacopeia and National Formulary (USP 1112). GCM2015 General Chapters- Microbiology; 2015. https://online.uspnf.com/uspnf/document/GUID-088FEEB1-8BD8-4120-AC2A-106AAE5E8E4E_1_en-US.         Accessed 03/04/22