What Water Quality Is Required for Air Humidification in GMP Cleanrooms?

In GMP-regulated cleanrooms, air humidity is typically monitored and controlled. During summer months, outdoor air often requires dehumidification, whereas in winter - especially during cold and dry conditions - humidification becomes necessary. Air that is too dry can irritate employees' mucous membranes, which is problematic in cleanrooms where coughing must be avoided. Furthermore, dry air can lead to increased electrostatic charges, and disinfectants may behave differently under low humidity, e.g., by evaporating too quickly, which could reduce required contact times. As a result, humidity in cleanrooms is typically controlled to maintain a minimum relative humidity of 40%.
If there are specific product-related requirements regarding air humidity (e.g. in effervescent tablet production), these must, of course, also be considered. But how should such humidification be performed in a GMP-compliant manner? And what quality should the water respectively its condensate meet?

Humidification with Steam - Common in Sterile Areas

In GMP-regulated production environments - especially in sterile zones as defined in EU GMP Annex 1 (Grades A, B, and in some cases C) - steam humidification is typically used. Steam is considered microbiologically safe and has the added benefit of contributing to heating the supply air during colder months, providing an energy-efficient advantage.

Steam Quality from a GMP Perspective: Pure Steam as the Reference Standard

From a regulatory standpoint, only one steam quality is clearly defined in the pharmaceutical context: Pure Steam, as described in the USP. This quality is assessed based on the condensate, which must meet the requirements for Water for Injection (WFI). If the humidification steam has indirect contact with sterile products via room air, only this quality is acceptable-since only materials of defined pharmaceutical quality may come into contact with the product.

However, in practice, the use of Pure Steam for humidification is not universally implemented. Instead, steam quality is often aligned pragmatically with the water quality used in production:

• If Purified Water (PW) is used in production, the condensate of the humidification steam should also meet PW quality.
• If WFI is used, the condensate of the steam used should likewise meet WFI quality.

In terminology, a distinction is often made between Clean Steam and Pure Steam. It is worth noting, however, that both EU GMP Annex 1 and ISPE guidelines treat these two terms as equivalent. The decisive factor is a documented risk assessment defining which steam quality is appropriate for the specific application. Key factors to be considered include:

• Cleanroom classification
• Type of product handling (open/closed)
• Requirements for electrostatic discharge
• Contact materials (e.g. packaging)
• Occupational safety considerations
• Microbiological requirements

Humidification in Grade D and Non-Sterile Areas

In GMP Grade D areas or solid dosage (non-sterile) production zones, filtered plant steam (black steam) with food-grade approval may be used for humidification. However, the following points are critical:

• The corrosion inhibitor used must be approved for food use.
• A risk assessment or hazard analysis must demonstrate compatibility with the products and equipment surfaces.

Inspectors may request documentation on the corrosion inhibitor used, filter maintenance records, and functional verification.

Adiabatic Humidification with Pressurized Water - A Hygiene Risk

Another method commonly used in storage or utility areas (black zones) is adiabatic humidification using pressurized water (e.g. softened or partially treated potable water).
The main challenge with this method is intermittent operation, often due to seasonal weather conditions. If the water system remains unused for longer periods, microbial contamination will likely develop-Pseudomonas and Legionella have been reported in extremely high counts, posing a significant risk if aerosolized and released into the air.
The VDI 6022 guideline provides practical recommendations for the hygienic operation and maintenance of air handling and humidification systems. In all cases, thorough documentation is required to remain compliant during inspections.

Economic Considerations

Selecting a suitable humidification concept requires balancing technical, hygienic, and economic aspects. While Pure Steam is the ideal choice from a microbiological standpoint, it can lead to very high operational costs, especially in systems with a high rate of fresh air.
In many cases, the steam required for air humidification - particularly in winter - far exceeds the steam needed for production processes. As such, not only must the demineralized water or PW systems be appropriately sized, but also the black steam systems used to supply heating energy to the Pure Steam generator, even if these are only required for a few weeks per year.