High-Efficiency Particulate Air (HEPA) and Its Significance in Sterile Pharmaceutical Preparations

High-Efficiency Particulate Air (HEPA) and Its Significance in Sterile Pharmaceutical Preparations

Everything about HEPA filters as pore size, leak test, DOP test and importance in sterile pharmaceutical manufacturing and analysis.

HEPA filter integrity should be maintained to ensure aseptic conditions. Leak testing should be performed at installation to detect integrity breaches around the sealing gaskets, through the frames, or through various points on the filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. For example, such testing should be performed twice a year in the aseptic processing room.

Additional testing may be appropriate when air quality is found to be unacceptable, facility renovations might be the cause of disturbances to ceiling or wall structures, or as part of an investigation into a media fill or drug product sterility failure. Among the filters that should be leak tested are those installed in dry heat depyrogenation tunnels and ovens commonly used to depyrogenate glass vials. Where justified, alternate methods can be used to test HEPA filters in the hot zones of these tunnels and ovens. The same broad principles can be applied to ULPA filters.

Any aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity. Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols. Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested. Accordingly, the evaluation of any alternative aerosol involves ensuring it does not promote microbial growth.

There is a major difference between filter leak testing and efficiency testing. An efficiency test is a general test used to determine the rating of the filter. An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 μm in diameter.

The purpose of performing regularly scheduled leak tests, on the other hand, is to detect leaks from the filter media, filter frame, or seal. The challenge involves the use of a polydispersed aerosol usually composed of particles with a light-scattering mean droplet diameter in the submicron size range,9 including a sufficient number of particles at approximately 0.3 μm. Performing a leak test without introducing a sufficient upstream challenge of particles of known size upstream of the filter is ineffective for detecting leaks.

It is important to introduce an aerosol upstream of the filter in a concentration that is appropriate for the accuracy of the aerosol photometer. The leak test should be done in place, and the filter face scanned on the downstream side with an appropriate photometer probe, at a sampling rate of at least one cubic foot per minute. The downstream leakage measured by the probe should then be calculated as a percent of the upstream challenge. An appropriate scan should be conducted on the entire filter face and frame, at a position about one to two inches from the face of the filter. This comprehensive scanning of HEPA filters should be fully documented.

A single probe reading equivalent to 0.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for the replacement of the HEPA filter or, when appropriate, repair in a limited area. A subsequent confirmatory retest should be performed in the area of any repair.

HEPA filter leak testing alone is insufficient to monitor filter performance. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). Variations in velocity can cause turbulence that increases the possibility of contamination. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area.

Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is detected or airflow patterns may be adversely affected.

The efficiency test uses a monodispersed aerosol of 0.3 micron sized particles and assesses filter media. Downstream readings represent an average over the entire filter surface. Efficiency tests are not intended to test for filter leaks. Although the mean is normally less than one micron, it is greater than 0.3μm.

Although contractors often provide these services, drug manufacturers are responsible for ensuring that equipment specifications, test methods, and acceptance criteria are defined and that these essential certification activities are conducted satisfactorily.