An essential element in ensuring aseptic conditions is the
maintenance of HEPA filter integrity. Integrity testing should be
performed at installation to detect leaks around the sealing gaskets,
through the frames or through various points on the filter media.
Thereafter, integrity 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 for the aseptic
processing room. Additional testing may be needed when air quality is
found to be unacceptable, or as part of an investigation into a media
fill or drug product sterility failure. Among the filters that should
be integrity tested are those installed in dry heat depyrogenation
tunnels commonly used to depyrogenate glass vials.
One recognized method of testing the integrity of HEPA filters is use
of a dioctylphthalate (DOP) aerosol challenge. However, alternative
aerosols may be acceptable. Poly-alpha-olefin can also be used,
provided it meets specifications for critical physicochemical attributes
such as viscosity. Some alternative aerosols are problematic because
they pose a risk of microbial contamination of the environment being
tested. Firms should ensure that any alternative does not promote
microbial growth.An intact HEPA filter is capable of retaining at least 99.97 percent of particulates greater than 0.3 micron in diameter. It is important to ensure that the aerosol used for the challenge has a sufficient number of particles of this size range. Performing an integrity test without introducing particles of known size upstream of the filter is ineffective for detecting leaks. The DOP challenge should introduce the aerosol upstream of the filter in a concentration of 80 to l00 micrograms/liter of air at the filter's designed airflow rating. The downstream side of the filter is then scanned with an appropriate photometer probe at a sampling rate of at least one cubic foot per minute. Scanning 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. While vendors often provide these services, the drug manufacturer is responsible for ensuring that these essential certification activities are conducted satisfactorily. A single probe reading equivalent to 0.01 percent of the upstream challenge should be considered as indicative of a significant leak and should result in replacement of the HEPA filter or perhaps repair in a limited area. A subsequent confirmatory re-test should be performed in the area of any repair.
There is a major
difference between filter integrity testing and efficiency testing. The
purpose of regularly scheduled integrity testing is to detect leaks
from the filter media, filter frame and seal. The challenge is a
polydispersed aerosol usually composed of particles ranging in size from
one to three microns. The test is done in place and the filter face is
scanned with a probe; the measured downstream leakage is taken as a
percent of the upstream challenge. The efficiency test, on the other
hand, is a test used only to determine the rating of the filter.
HEPA filter integrity testing alone is not
sufficient to monitor filter performance. This testing is usually done
only on a semi-annual basis. 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
generally increase the possibility of contamination, as these changes
(e.g., velocity reduction) can have an effect on the laminarity of the
airflow. Airflow velocities are measured six inches from the filter
face or at a defined distance proximal to the work surface for each HEPA
filter. For example, velocity monitoring as frequently as weekly may
be appropriate for the clean zone in which aseptic processing is
performed. HEPA filters should be replaced when inadequate airflow
(e.g., due to blockage) or non-uniformity of air velocity across an area
of the filter is detected.
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