Ozone Concentration during the Sanitization of PW and WFI Systems

Ozone is one of the proven means of sanitizing pharmaceutical water systems, especially purified water (PW) and water for injection (WFI). But how high should the ozone level be to achieve sufficient germ reduction?

Application Area: Suitable Only for Cold Systems

The use of ozone is only appropriate in systems where water is stored and distributed cold or at room temperature. In practice, ozone is typically used up to a maximum of 35 °C. At temperatures above approx. 40 °C, the half-life of ozone decreases so significantly that a stable and effective concentration can no longer be ensured. Additionally, hot-stored PW or WFI systems already provide a germicidal effect due to their elevated temperature, making the use of ozone in such systems neither necessary nor efficient.

Focus on Cold Systems

When water is stored and distributed at room temperature, the risk of microbial contamination increases significantly compared to hot systems. In these so-called "cold systems", the key question is whether ozone is used short-term (1-2 hours) or continuously over longer periods (> 6 hours):

• Short-term ozone use: Typically requires ozone concentrations of > 50 ppb to achieve effective microbial reduction.
• Long-term ozone use: Concentrations of >= 20 ppb may already be sufficient if exposure time is extended.

Additional Practical Considerations

In large distribution systems or areas with low flow rates, ozone demand may be higher. Therefore, the above concentrations should ideally also be achieved at the return of the distribution system. The target concentration should be defined as part of the Design Qualification (DQ) for the water system.

Ozone Monitoring

Whenever ozone is used, its effectiveness must be verified - both indirectly (by monitoring bioburden or CFU levels) and directly through ozone measurement at various points in the system. The ISPE Baseline Guide recommends at least the following three measuring points:

• Before the UV unit (outlet of the storage tank)
• After the UV unit
• In the return loop

The ozone level before the UV system demonstrates that the ozone generator is functioning correctly and that sufficient ozone concentration is maintained in the storage tank during continuous ozonation. The post-UV measurement during water withdrawal shows that the ozone is being broken down in the water used for production. The return loop measurement confirms that the ozone concentration is sufficiently high throughout the entire system during sanitization.

Determining the Ozone Half-Life

From a technical perspective, it is advisable to compare pre-UV and return loop values in order to calculate the system-specific half-life of ozone. In heavily loaded systems, this is typically around 15 minutes, whereas in very clean systems, it can exceed 60 minutes.
Knowing the half-life is essential because UV systems do not completely eliminate ozone, and current ozone sensors typically have a lower detection limit of 5-10 ppb (measured after the UV lamp). For critical applications where the water comes into direct contact with the product, understanding the system-specific ozone half-life is vital for a robust risk assessment.