The short answer is yes for WFI applications and possibly for Purified Water tanks, but confusion still surrounds the topic. If you were to ask most process engineers or quality assurance professionals whether they consider integrity testing of vent filters on pharmaceutical water storage tanks to be a cGMP requirement, the answer would almost always be a definitive yes. However, further inquiries often reveal a lack of clarity regarding the specific requirements and standards.

The FDA’s Guide to Inspections of High Purity Water Systems—unfortunately the most recent U.S. regulatory guidance for pharmaceutical water systems—is vague on this matter: “It is expected that there be some program for integrity testing of this filter to assure that it is intact.”

So, what options are available for complying with the FDA’s “some program” guidance? Possible alternatives for integrity testing vent filters include:

• Integrity testing the filter prior to use, including pre-use post-sterilization integrity testing (PUPSIT) performed in place.
• Integrity testing the filter after use.
• Integrity testing both before and after use (potentially including PUPSIT).
• Conducting a risk assessment to determine if filter performance is a critical design aspect.
• Relying on manufacturer data and batch certificates.

Volume 4 Annex 1 of the EU GMPs (2022) clarifies the requirement to integrity test vent filters specifically for WFI storage tanks: “Where WFI storage tanks are equipped with hydrophobic bacteria-retentive vent filters, the filters should not be a source of contamination, and the integrity of the filter should be tested before installation and after use.”

While not specifically addressing Purified Water applications, many concepts in Annex 1 have been widely adopted within the industry. Therefore, there may be an expectation that similar logic applies to vent filters for Purified Water tanks. Additionally, Annex 1 mentions PUPSIT only in the context of sterile process filtration, not in reference to WFI storage tanks. This could imply that pre-sterilization of WFI vent filters may not be strictly necessary, even if it is considered cGMP following pre-use integrity testing, although some may interpret that pre-use sterilization is implied.

Integrity Testing:

Most end-users replace filters on a preventive maintenance schedule every 6 to 12 months, and the same principle should apply to vent filters on distillation unit condensers. If there is an integrity testing program in place for vent filtration of a compendial water storage tank, in-situ testing offers the most accurate results. To maintain the integrity of the tank, duplex filters are often installed, allowing each filter to be isolated from the tank and tested in place.

The rationale for pre-use integrity testing is to detect any damage to the filter that may have occurred during shipping or sterilization. However, unlike aseptic vent filtration applications, pharmaceutical water storage tank vent filters are less often sterilized before use. Given that the application is not aseptic and the risk of damage during shipping or handling is minimal, pre-use testing may introduce more risk than benefit, as hydrophobic filters need to be wetted, dried, and possibly steamed.

If integrity testing is to be conducted, in-situ post-use testing is likely the most logical approach. At this stage, concerns about damaging the filter or ensuring it is adequately dried after testing are less significant. However, a potential drawback of relying solely on post-use testing is the uncertainty of how to respond in the event of a test failure.

Risk Assessment:

Storage tank vent filters serve not only as barriers to airborne particles but are primarily designed to minimize microbial contamination in water. They are hydrophobic, allowing for the passage of air (or nitrogen) and are typically rated for absolute retention of 0.2 microns. The risk of atmospheric microbial contamination is reduced in tanks that are continuously maintained at elevated temperatures (e.g., 65°C and above) or those that are consistently exposed to ozone. These designs are considered self-sanitizing and are common microbial control strategies for WFI and Purified Water Systems where microbial control is essential. Thus, one could argue that the integrity of the vent filter itself may not be as critical in these cases because the tanks themselves are self-sanitizing.

Ironically, integrity testing of storage tank vent filters is often infrequent in less robust systems that rely on chemical sanitization or intermittent heat or ozone treatments. Many Purified Water Systems have vent filters that are never integrity tested—much to the chagrin of many QA professionals who assume such testing is standard practice. While these systems may have less stringent specifications for microbial control, it remains a cGMP requirement that the integrity of the systems is upheld to ensure the purity of the product. In these instances, most end-users rely on manufacturer documentation and testing certificates. The primary reasons for this approach are often a lack of in-house testing capabilities and the expense and time required for testing.

Manufacturer’s Documentation:

Most sterilizing, pharmaceutical-grade filters are provided with some form of certificate of compliance from the manufacturer. Many end users, particularly in USP Purified Water applications, often rely solely on this documentation and skip integrity testing, similar to how they reference an RO or UF membrane certificate. These certificates typically indicate conformance to specific industry standards and may provide data for individual filter elements or, more commonly, for a batch or lot of elements or filter media. At a minimum, such documentation is essential, especially when integrity testing is not conducted for Purified Water Systems.

Summary:

In the absence of specific regulatory requirements from the FDA or other governing authorities, or a clear process need, a risk- and science-based approach should guide all aspects of compendial water design, operation, and maintenance. This includes the integrity testing of pharmaceutical storage tank vent filters. The sole exception is WFI tank vent applications, where Annex 1 mandates testing both before and after use.

Risk assessment outcomes can differ based on factors such as whether the tank is located in a classified area, the presence of microbial reduction techniques in the storage and distribution system, and whether a maintenance program for the vent filter is in place. If testing is deemed necessary for these filters, it raises the question of whether integrity testing should also be conducted for terminal filtration operations in the water generation system, including reverse osmosis membranes, ultrafilters, and other submicron filters.

Ultimately, integrity testing of vent filters on pharmaceutical water storage tanks is logical, as it is critical for ensuring proper system operation and performance, as well as verifying the integrity of the overall process.