Different Sanitation Strategies for Sections of a WFI Systems?

Pharmaceutical systems for water for injection (WFI) must be sanitised. There are various methods and intervals for doing this. WFI storage and distribution systems have generally been designed as hot storage systems with continuous circulation at at least 70°C. In practice, however, it may be necessary to operate certain sections of the system at ambient temperature - for example, to supply consumers who require WFI at a maximum temperature of 25°C. These cooled sections must also be sanitised to ensure that the water meets the required quality standards. This raises the question of whether different sections of these systems can be sanitised differently.

System configuration and technical background

In typical cases, WFI at around 70°C is cooled within the system using a heat exchanger, either in a point-of-use cooler or in a cold sub-loop. Whether the water needs to be reheated before returning to the common tank depends on the tap arrangement, pipe routing, volume ratios, and other technical details. The storage tank and the hot areas of the system are typically thermally sanitised throughout. This hot storage is also helpful when cold WFI generation using membrane technology is used, as any germs coming from the treatment process are killed directly in the hot tank.

Cooled sections, in contrast, particularly withdrawal points operated at ambient temperature, must be considered separately.
The solution is simple for cold consumers that are only required for a few hours a day - in this case, the section is only cooled for the required duration and reheated for the remaining day. This approach becomes problematic when cold consumers are in operation 24 hours a day. The state of the art is to use cold WFI without sanitisation for a maximum of 24 hours - after that, the water is usually rejected or sanitised. It is therefore important to provide a suitable method for WFI cold systems that are required 24 hours a day. As a rule, redundant systems are then used to create the necessary time windows for sanitisation.

Alternatives & frequencies for discontinuous sanitisation

Today, cold WFI storage and distribution systems can alternatively be sanitised with ozone. It is important to assess the risk posed by residual ozone. The sanitisation of cold WFI production systems using membrane technology is also technically challenging. The bottleneck here is often the electro-deionisation (EDI) system, if one is installed. These EDI modules can typically only be thermally sanitised 150 times, after which the warranty expires and the risk of defects increases. These EDI modules are still relatively expensive today and, with the correct system design, should actually last 5-10 years. With weekly thermal sanitisation, the service life would be shortened to less than three years. For this reason, some plant manufacturers offer cold WFI treatment plants without EDI, provided that the conductivity of the drinking water feed allows it. However, this can mean higher operating costs and often a reduced water yield.

Against this background, the optimal design of cold WFI production systems with membrane technology must be specifically adapted in each case.
A reduction in the sanitisation frequency for cold WFI systems, e.g. from monthly to quarterly intervals, is technically possible in principle. However, this requires a comprehensive microbiological database that clearly demonstrates the consistent microbiological status over a longer period of time. An extended sanitisation frequency is only permissible if the microbiological tests do not reveal any microbiological deviations.
However, extending the sanitisation interval is rarely implemented in practice, as this raises the question of a new performance qualification (PQ). The costs and risks of a PQ are very high, so that the frequencies once established are usually not extended. On the other hand, it is relatively common to shorten the intervals due to problematic microbiological values.

In the past, with the agar plate method used in microbiological monitoring, this was sometimes problematic because elevated germ counts were only detected after 3-5 days (and in some cases, after 10 days for slow-growing problem germs). As a result, sanitisation was usually too late, and root cause analysis was also extremely difficult. This is where the new at-line monitoring systems (Rapid Microbiological Methods, RMM) offer real added value: they indicate deviations at an early stage, enabling early responses. Unfortunately, due to a lack of comparability with pharmacopoeia methods and the calibration of these devices, RMMs are not yet suitable as a replacement for the agar plate method.
Nevertheless, RMM systems allow better condition-based determination of sanitisation methods and intervals: decisions are made only when the data indicate that sanitisation is necessary, rather than in advance. This reduces unnecessary operational interruptions and expenses. In large WFI systems, this can offset the high costs of an RMM system.  

Conclusion

The different sanitisation of sections of a WFI system is technically possible, but only justifiable under certain regulatory conditions. The following factors are decisive:

• The microbiological stability of the system
• Comprehensive data to justify the methods and intervals
• Approval by the quality unit
• Use of other methods (e.g. ozonisation) where appropriate
• Examination of technical alternatives to the system design

Good documentation of the risk assessment, reliable data and a description of the sanitation concept are required in any case in order to justify the chosen approach to the authorities and during inspections.