Water activity USP 922 standard in pharma

Though rarely mentioned in industry headlines, new water activity technologies and applications have steadily accumulated and gained acceptance. In recent years, water activity has joined the ranks of long-favored methods like Karl Fischer titration, HPLC, GC, and others in the pharma industry – and the development pipeline is more productive because of it. With water activity’s greater popularity has come new regulations and standards. The latest related standard—US Pharmacopeia (USP) General Chapter <922> “Water Activity”—has been finalized and will be published in May 2021.

Why water activity?

Rather than measuring the total amount of water in a system, water activity measures how much of that water is unbound and free to react with other substances.

At first, the implications may seem insignificant. In application, they’re considerable. Water activity has a clear and direct influence on microbial growth, API degradation, product stability, and dissolution rates. In addition, water activity is generally a more accessible and direct method of understanding these factors than other, more time- and expertise-intensive analytical measurements.

New regulations recognize water activity’s versatility

More than a decade ago, the USP introduced General Chapter <1112>, the pharmaceutical industry’s first significant approval of water activity. The chapter describes water activity as an aid to:

  • Providing a tool for the rationale for reducing the frequency of microbial limit testing and screening for objectionable microorganisms
  • Optimizing product formulations to improve antimicrobial effectiveness of preservative systems
  • Reducing the degradation of active pharmaceutical ingredients within product formulations susceptible to chemical hydrolysis
  • Reducing the susceptibility of formulations (especially liquids, ointments, lotions and creams) to microbial contamination

The chapter also references several methods for determining water activity in the Official Methods of Analysis of AOAC International.

Supporting the USP’s recognition of water activity, the ICH laid out additional information supporting the use of water activity in Q1A, Q6A and their associated decision trees. 

Over time, acceptance has grown, and with it has come the realization that while water activity saves significant time in microbial testing, the potential for profitable applications in quality testing, R&D, and other areas is just as significant.

More recently, USP has introduced two more water activity-related chapters – USP <795> and a draft of <922>. The former focuses on microbial growth and preservative efficacy, while the latter “is intended to provide guidance for performing measurements of water activity,” and will “specify methods for qualification of instruments, calibration of instruments, methods for performing water activity measurements, and reporting of results.”

New technologies accepted, new applications discovered

Technological innovation hasn’t slowed its pace since the introduction of USP <1112>, and water activity instruments have seen the benefits. Significant advances have been made – both adding new methods for measurement and improving existing ones.

One such advancement is the adoption of the tunable diode laser (TDL). Capable of isolating water’s signature on a molecular level, the TDL allows material scientists to make quick, direct measurements of previously unreadable, highly volatile substances. This enables researchers to use a greater range of substances to test hydrate formation and API stability without the risks associated with using theoretical data. 

Other new instruments incorporate machine learning and AI to deliver readings in far less time – where older instruments require upward of 20 minutes, recent ones produce precise measurements in little more than one minute. In applications requiring repeated measurements, the time savings are significant.

Beyond reducing microbial risk and accelerating API stability research, water activity is now being used to maximize excipient effectiveness, develop and assess packaging, achieve ideal tablet hardness, influence dissolution rates and more.

Replacing Karl Fischer and other methods

As applications for water activity multiply, some begin to overlap with longer-established methods of measurement. Often, the investment in education and validation hinders water activity’s adoption to a new role, but in the long term, the speed, accuracy and usefulness of water activity bring significant returns.

Replacing Karl Fischer titration is the most obvious example, but perhaps the most misunderstood. Scientific investigation concludes that water activity is a far better predictor of product safety and stability than Karl Fischer water content. Even so, misconceptions continue – possibly because the relationship between moisture content and water activity can be counterintuitive. 

A product with a high percentage of overall water content may have a very low water activity, or the other way around – a key factor when it comes to chemical and biological reaction rates.

Water activity does not provide the same information as Karl Fischer, but it does provide more useful information. The results will look different, but once understood, provide better correlations to microbial safety, chemical stability, and physical properties. Not only that, water activity instruments generally don’t require extensive training and leave comparatively little opportunity for mistakes during testing. 

Though water activity’s relationship to other measurements like HPLC or GC differs, many of the same advantages apply – less need for training, quicker results, more direct measurements, less risk of instrument misuse, and no need for dangerous chemicals.

Potential for new applications

Water activity is more than a tool to meet regulatory standards. In the last few years, it has helped drive innovation, improve scientific productivity, and shorten the drug pipeline at many of the world’s largest pharmaceutical companies – and there are many more applications to be discovered.

Related references

Enigl, Davin C., and Kent M. Sorrells. “Water activity and self-preserving formulas.” Cosmetic Science And Technology Series (1997): 45-74.

Friedel, R. R. “The application of water activity measurement to microbiological attributes testing of raw materials used in the manufacture of nonsterile pharmaceutical products.” In Pharmacopeial forum, vol. 25, no. 5, pp. 8974-8981. United States Pharmacopeial Convention, 1999. Article link.

Heidemann, D. R., and P. J. Jarosz. “Preformulation Studies Involving Uptake in Solid Dosage Forms.” Pharmaceutical Research 8, no. 3. (1991): 292-97. Article link.

Pader, Morton. Oral hygiene products and practice. Dekker, 1988. Book link.

Pader, M. “Glycerine in oral care products.” Cosmetic science and technology series 11 (1991): 381-393. Article link.

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