HOW YOU CAN REDUCE MICROBIAL TESTING EFFORT THROUGH WATER ACTIVITY
Microbiological testing, Microbial Limit Testing or MLT, for pharmaceutical finished products is essential, but it is also resource- and time-intensive. If you work in Quality Control or Quality Assurance, you know that traditional MLT procedures often take several days. What if you could drastically reduce this testing frequency, accelerate release times, and lower costs, while doing so on a solid, scientifically and regulatorily recognized basis?
The solution lies in the strategic implementation of water activity measurement.
In this article, you will learn why water activity is the key to microbial control, which regulations this approach is based on, and how you can establish a risk-based implementation plan, within an SOP and GMP framework, in your company.
Water activity versus moisture content
A common misconception is that a “dry” product is automatically safe from microbes. In many cases, people look only at the pure moisture content. For microorganisms, however, the decisive factor is not the total amount of water, but the freely available water.
This is exactly what the water activity value measures: the energy status of the water in a system.
At a water activity value below 0.91, for example, the growth of dangerous gram-negative bacteria, such as Pseudomonas aeruginosa, E. coli, or Salmonella, is stopped.
Below 0.75, even resistant molds and yeasts can hardly reproduce. A water activity value below 0.60 is considered the absolute limit below which any microbial growth, even from extremophilic organisms, is excluded.
The regulatory basis: what you can rely on
Reducing microbiological testing through water activity measurements is not an experimental approach. Global guidelines actively support this procedure, but they require a risk-based and well-documented approach.
USP <1112>, Application of Water Activity Determination to Nonsterile Pharmaceutical Products: This is your most important guide. The chapter recommends that the pharmaceutical industry use water activity as a tool for microbial risk management. It provides the justification for why routine microbiological testing of every single batch can be omitted for products with a very low water activity value.
USP <922>, Water Activity: Since USP <1112> is primarily an informational chapter, concrete validation requirements were missing for a long time. USP <922> closes this gap and defines standardized, accurate methods for measuring water activity. For pharmaceutical QC, this makes the choice of measurement technology critical. Novasina’s electrolytic resistive sensor technology is designed to deliver the most precise and reliable water activity results, giving laboratories the confidence needed for GMP-relevant decisions.
ICH Q1A(R2) and ICH Q6A: These guidelines emphasize the role of the water activity value in stability studies and define “inherent dryness” for solid dosage forms.
FDA cGMP guidelines: The FDA also requires a stability assessment program that includes microbiological control. Water activity measurement is an accepted tool here for the prevention of contamination.
Far more than microbiology: further benefits of water activity measurement
When you implement a program for water activity measurement, you do not only benefit in the MLT laboratory. The water activity value also helps you with:
Preventing moisture migration: In multi-component products such as capsules, water always migrates from the area of high water activity to the area of low water activity. Controlling this helps prevent caking or decomposition of APIs.
Optimizing preservatives: By deliberately lowering the water activity value during the formulation process, for example through glycerin or sucrose, you can significantly increase the efficiency of antimicrobial preservatives, for example in nasal sprays.
Selecting the right packaging material: The measurement helps demonstrate that blisters or containers effectively prevent moisture ingress and therefore prevent an increase in the water activity value during shelf life.
What does implementation look like in practice? Your SOP roadmap
You cannot simply stop microbiological testing from one day to the next. USP requires an evidence-based risk-based approach. Such an implementation program typically looks like this:
Step 1: Historical data analysis, creating a baseline
Collect historical microbiological data for your products. Often, the last 20 batches are used as a guideline. This proves that your manufacturing process generally has a low bioburden.
Step 2: Parallel testing
Over a defined qualification period, measure both the water activity value and the microbial counts on the same batches. Use precise, approved measuring instruments for this.
Step 3: Risk assessment and definition of the testing strategy
Correlate the data. If you can demonstrate that your product consistently has, for example, a water activity value below 0.60 and that the historical MLT data are negative, you can justify an adjustment of your QC strategy. Possible approaches include:
- Skip-lot testing: Microbiological tests are no longer performed on every batch, but only on a sampling basis, for example every 10th batch.
- Elimination: For extremely low-risk products, such as dry powders, routine MLTs for release can in some cases be omitted entirely.
Step 4: Documentation and 21 CFR Part 11 compliance
Anchor these new limits in your SOPs. The most important prerequisite for this is that, because water activity measurement is now used as a release criterion, the measuring instrument used, such as the Novasina LabMaster-aw NEO, must strictly meet the FDA requirements according to 21 CFR Part 11. This includes tamper-proof audit trails, electronic signatures, and strict, password-protected user management.
Conclusion
Controlling water activity can be a powerful element of modern, data-driven pharmaceutical quality control. When combined with historical microbiological data, product-specific risk assessment, and a properly documented GMP framework, water activity measurement may help support a more efficient microbial control strategy.
However, the examples described in this article should be understood as possible approaches, not as general recommendations to reduce or eliminate Microbial Limit Testing. Any change to an existing QC release strategy must be evaluated case by case, based on the specific product, formulation, manufacturing process, historical data, regulatory requirements, and internal quality system.
Water activity does not replace microbiological testing by default. It can, however, provide valuable scientific evidence to better understand microbial risk and to justify a risk-based testing strategy where appropriate.
In this context, water activity measurement can help pharmaceutical manufacturers make better-informed decisions, reduce unnecessary testing effort where scientifically justified, and maintain a high level of product safety and quality confidence.
