Is it a cGMP Requirement?
Background
Having questioned countless end-users, industry professionals and regulators over the years if they consider integrity testing of vent filters located on compendial water storage tanks to be a current Good Manufacturing Practice (#cGMP), the answer is always a definitive yes. Subsequent queries on the topic generally reveal that no one knows exactly what the requirements are – or what the standard is. The FDA Guide to Inspections of High Purity Water Systems, unfortunately the most recent U.S. regulatory guidance for pharmaceutical water systems, is vague on this topic:
“It is expected that there be some program for integrity testing this filter to assure that it is intact.”
The current edition of the ISPE Baseline Guide for Water & Steam Systems, the often referenced standard for cGMPs for pharmaceutical water systems, offers the following language:
“Vent filters for compendial water storage tanks should be integrity tested following installation in the housing [and] integrity tested in the housing at the end of service life.”
This guidance seems logical as the performance of a filter would be contingent upon the proper installation in the filter housing and the housing design. Testing both before and after the filters are in service is also consistent with guidance from the European Commission. Compendial water storage tanks here would refer to USP Purified Water and WFI, but the same logic would extend to pharmaceutical water systems for manufacturing operations with a non-compendial designation.
So, what are the options for complying with the “some program” guidance from FDA? Among the possible alternatives to meet the requirement for integrity testing of vent filters are:
Integrity test filter prior to use
Integrity test filter after use
Integrity test both before and after use
Perform a risk assessment to determine if filter performance is a critical design aspect
Rely of manufacturer’s data and batch certificates
Integrity Testing
Integrity testing of vent filters on pharmaceutical water storage tanks can be used as a tool to set maintenance intervals. However, most end-users will replace filters on a Preventive Maintenance basis every 6 to 12 months. The same logic should extend to vent filters on distillation unit condensers as well.
If an #integritytesting program is in place for vent filtration of a compendial water storage tank, in place or in-situ testing offers the most representative testing. So as not to compromise the integrity of the tank, duplex filters are often installed with each filter having the ability to be isolated from the tank and tested in place.
The logic for pre-use integrity testing is that it would detect if the filter had been damaged during shipment. Unlike aseptic vent filtration applications, pharmaceutical water storage tank vent filters are rarely sterilized before use. Since the application is not aseptic and there is little risk of damage in shipping or handling, pre-use testing probably introduces more risk than not testing since the filters are hydrophobic and need to be wetted, dried, and possibly steamed.
If integrity testing is to be performed, in-situ, post-use testing is probably the most logical. At this point there is little concern about damaging the filter or ensuring that it is adequately dried after testing. The concern, however, with only testing post-use is what is to be done in the event of a test failure.
Risk Assessment
Storage tank vent filters not only provide a barrier for airborne particles, but are primarily designed to minimize microbial contamination of the water. As such, they are hydrophobic in nature to allow for passage of air (or nitrogen) and absolute rated, usually for 0.2 micron particle retention. The possibility of atmospheric microbial contamination of the water is minimized in tanks that are continuously held hot (e.g. 65°C and above) or those that are continuously exposed to ozone. These designs are considered self-sanitizing and are common microbial control techniques for #WFI and Highly Purified Water Systems where microbial control is critical. Ironically, it is on these robustly designed systems where integrity testing is most commonly performed.
Conversely, integrity testing of storage tank vent filters occurs infrequently for less robust systems which are often sanitized by chemicals on a less often than thermally or ozonated systems. Many Purified Water Systems have vent filters that are never integrity tested. While these systems may have more relaxed specifications for microbials, it remains a cGMP requirement that the integrity of the systems should be maintained so as not to alter the purity of the product. In these cases, most end-users will reference manufacturer’s documentation and testing certificates. The most likely reasons for this are that they are not equipped to perform the testing in-house and the testing devices are expensive.
Manufacturer’s Documentation
Most sterilizing, pharmaceutical grade filters are available with some type of certificate of compliance from the manufacturer. Many end users will rely solely on this information and forgo any integrity testing much the same and referencing an RO or UF membrane certificate. These certificates are typically certificates of conformance to specific industry standards and may include data for each individual filter element or more commonly for a batch or lot of elements or filter media. This would be required at a a minimum especially if integrity testing is not performed.
Summary
In the absence of a regulatory requirement from FDA, a risk and science based approach should be used for all compendial water design, operation, and maintenance aspects. This includes the integrity testing of storage tank vent filters. Risk assessment results can vary depending on whether or not the tank was located in a classified area, if there are microbial reduction techniques in the storage and distribution system, and if a maintenance program associated with the vent filter exists. If testing is required for these filters, should it not also be required for terminal filtration unit operations from the water generation system including reverse osmosis membranes, ultrafilters, and other submicron filters? Most important is that integrity testing of vent filters on pharmaceutical water storage tanks should be performed because the testing is critical to ensure proper system operation and performance, and not the consequence of a perceived regulatory expectation.