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Coordinated by Ed White
[
For more Author ABOUT THE AUTHOR
information, Ed White is a QA validation specialist at Baxter Healthcare Bioscience, Thousand Oaks, CA.
go to He may be reached at ed_white@baxter.com.
gxpandjvt.com/bios
a given space. Some ULPA filters are constructed of or defined areas or such other control systems for the
expanded PTFE fluoropolymer (ePTFE). These filters firms operations as are necessary to prevent contami-
are typically used for specialized applications or in the nation or mix-ups during the course of the following
semiconductor industry, as they are incompatible with procedures: (10) Aseptic processing, which includes
polyalphaolefin (PAO). as appropriate: (iii) An air supply filtered through
S
eparators. The separators are used to keep the pleats high-efficiency particulate air filters under positive
apart, maximizing the effective filter area of the HEPA. pressure, regardless of whether flow is laminar or
The separators can be constructed of corrugated alumi- non-laminar
num or be of the minipleat design. In the minipleat 21 CFR 211.46(c) (2) states, Air filtration systems,
design, shown in Figure 1 and Figure 2, pleated filter including pre-filters and particulate matter air filters,
media is separated by strips of filter media or adhesive. shall be used when appropriate on air supplies to pro-
This design allows the media to be more closely packed duction areas
than in a HEPA filter with aluminum separators. The The FDA aseptic processing guidance document (3)
majority of HEPA filters used in pharmaceutical facili- states, HEPA-filtered air should be supplied in critical
ties is of the minipleat design. areas at a velocity sufficient to sweep particles away
B
ond material. The bond material is used to attach from the filling/closing area and maintain unidirec-
the filter media to the filter frame. The bond material tional airflow during operations. The velocity param-
may be made of several different adhesives, including eters established for each processing line should be
epoxy, silicone, and polyurethane. justified and appropriate to maintain unidirectional
G
asket or gel seal. This ensures that air flows airflow and air quality under dynamic conditions
through, rather than around, the filter media. Filters within the critical area.
may have gasket seals or gel seals, depending on the EU GMP Annex 1 (4) states, The manufacture of sterile
installation type. Gaskets are either adhesive bonded products should be carried out in clean areas, entry to
to the filter frame or are formed in place. which should be through airlocks for personnel and/or
for equipment and materials. Clean areas should be
el seal filters have special channels into which sili-
G maintained to an appropriate cleanliness standard and
cone or urethane gel is poured. When installed, the gel supplied with air, which has passed through filters of
channel mates with a knife edge installed in the ceiling an appropriate efficiency.
grid or filter module. A metal tab typically holds the
filter in place, allowing the knife edge to float in the The requirement for HEPA filtration of air entering asep-
gel. It is important that the knife edge stays above the tic process areas is critical to maintaining the cleanliness of
bottom of the gel channel to ensure a positive seal. the aseptic processing environment and in maintaining the
Figure 3 illustrates a typical gel seal. sterility of aseptically processed products. Because there is
no additional bioburden reduction for aseptically processed
HEPA and ULPA filters only differ in their efficiency products, a single contamination event will compromise
ratings. HEPA stands for high efficiency particulate air the sterility of the product. By supplying HEPA-filtered air
filter. A HEPA filter is capable of filtering out >99.97% to the aseptic processing area, the pharmaceutical manufac-
of particulate matter averaging 0.3 micrometers in diam- turer significantly reduces the probability of a contamina-
eter. ULPA stands for ultra-low penetration air filter. An tion event. The aseptic processing guidance (3) document
ULPA filter is capable of filtering >99.999% of particulate summarizes this concept in the following statement:
matter at the most penetrating particle size (MPPS). For To maintain product sterility, it is essential that
most filters, including HEPA filters, the most penetrat- the environment in which aseptic operations (e.g.,
ing particle size is in the range from 0.1 micrometers to equipment setup, filling) are conducted be controlled
0.2 micrometers. and maintained at an appropriate quality. One aspect
of environmental quality is the particle content of
WHY USE HEPA FILTERS? the air. Particles are significant because they can
The use of HEPA filtration in critical areas is mandated enter a product as an extraneous contaminant, and
in the US Food and Drug Administration and interna- can also contaminate it biologically by acting as a
tional regulations for critical processing areas, including vehicle for microorganisms. Appropriately designed
the following: air handling systems minimize particle content of
21 CFR 211.42(c) (1) states, There shall be separate a critical area.
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 49
The Aseptic Core.
Frame
HEPA AND ULPA FILTER TESTING
HEPA and ULPA filters are typically tested as part of
Gasket certification of a cleanroom environment. Tests specific
Epoxy bond
to HEPA and ULPA filters only are discussed. Tests for
the larger cleanroom environment will be discussed in
HOW DO HEPA FILTERS WORK? an upcoming column. Tests specific to the HEPA and
Because of the filter media used, HEPA filters are more ULPA filters include the following:
analogous to depth filters than to membrane filters. Airflow velocity is mandatory for unidirectional
HEPA filters capture airborne particles through several cleanrooms or clean zones, optional for non-uni-
mechanisms including the sieve effect, impaction, inter- directional cleanrooms or clean zones
ception, and diffusion, as follows: Airflow volume is mandatory for unidirectional or
S ieve effect. This effect occurs for large particles non-unidirectional cleanrooms or clean zones
(>5 micrometers in diameter). These particles are Installed filter system leakage test (ISO 14644-3,
just too large to fit through the open areas in the Clause B.6) for all cleanrooms.
filter media. Removal efficiency for large particles
due to the sieve effect is typically >99.9999%. Airflow Velocity Test
I nertial impaction. Inertial impaction occurs as For the airflow velocity test, the filter is checked for veloc-
particles are carried through the filter media by the ity at several points using an airflow velocity meter or
airstream. As the airstream shifts to flow around airflow hood. The filter is typically divided into a grid
fibers, inertia causes the particles carried by the of equal surface areas, not to exceed 4 ft2 or 0.4 m2. The
airstream to impact the fibers. This mechanism average velocity of each filter should be within the range
typically occurs for particles in the 0.5 micrometer of 0.37 meters/second to 0.54 meters/second (0.45 m/s
to 5 micrometer range. 20%). The relative standard deviation (RSD) across
I nterception. Smaller particles may be intercepted the filter bank (or filter for individual filter installations)
by the fibers when they come within 1 particle diam- should be 15% or less. The RSD is calculated by divid-
eter of a fiber when following the gas stream. This ing the standard deviation of the readings by the average
mechanism can be effective because of the high of the readings, and multiplying the result by 100. The
fiber density of HEPA and ULPA filter media. This airflow velocity for a particular clean room may differ
mechanism is effective in the 0.1 micrometer to 1 and should be based on maintaining a proper airflow
micrometer range. over critical zones. Higher or lower velocities may be
Brownian diffusion. Brownian diffusion occurs appropriate, especially in specialized installations such
with very fine particles that are small enough to be as isolators, depyrogenation tunnels, and depyrogena-
affected by collision with the gas molecules in the tion ovens.
airstream. Brownian motion causes these particles
to move randomly within the airstream, increasing Airflow Volume Test
the probability of the particles contacting a fiber. This test is typically performed using an electronic
micromanometer with an appropriate airflow hood.
50 Journal of Validation T echnology [Summer 2009] iv thome.com
Ed White, Coordinator.
Table: IEST RP-CC001 and EN1822-1 filter classifications typically used for pharmaceutical
and biotech applications.
Filter Minimum % Particle
Integrity Test Method Application
Type Efficiency Size m
B 99.97% 0.3 MMD Two flow leak test HEPA filters for low classification areas
H14
99.995% MPPS Photometer-polydisperse PAO General use HEPA filters
(EN1822)
The term polystyrene latex beads is somewhat mislead- ucts in the European UnionVolume 4EU Guidelines to Good
ing, as this material does not contain any natural rubber Manufacturing PracticeMedicinal Products for Human and
latex. The term latex in this case refers to a stable, uniform Veterinary Use, Annex 1: Manufacture of Sterile Medicinal
suspension of particles in an aqueous medium. Because of Products (corrected version), 2008.
the confusion between polystyrene latex and natural rubber 5. Institute of Environmental Sciences and Technology, Recom-
or plant-based latex, the term polystyrene microspheres is mended Practice, IEST-RP-CC001, 2005. JVT
becoming a common synonym for PSL.
Scanning: Method of testing for leaks in HEPA or ULPA fil- GENERAL REFERENCES
ters. During a filter scan, an aerosol photometer or discrete Institute of Environmental Sciences and Technology, IEST-RP-
particle counter sampling probe is slowly moved across the CC001.4, HEPA and ULPA Filters, 2005.
filter in a series of parallel overlapping strokes. The sampling IEST, IEST-RP-CC006.3, Testing Cleanrooms, 2004.
probe is typically kept about 1 inch away from the filter sur- IEST, IEST-RP-CC007.2, Testing ULPA Filters, 2007.
face. When a potential leak is detected, the probe is held IEST, IEST-RP-CC021.2, Testing HEPA and ULPA Filter Media,
stationary for a short period of time to verify the leak. 2005.
IEST, IEST-RP-CC034.2, HEPA and ULPA Filter Leak Tests,
Standard leak penetration: Standard leak penetration is 2005.
the leak penetration measured by a stationary probe using International Organization for Standardization (ISO). ISO
a particle counter or photometer with a flow rate of 1 cubic 14644-1, Cleanrooms and associated controlled environ-
foot per minute (28.3 liters per minute). ments, Part 1: Classification of Air Cleanliness, 1999.
ISO, ISO 14644-2, Cleanrooms and associated controlled envi-
ULPA (ultra-low penetration air) filter: An ULPA filter is a ronmentsPart 2: Specifications for testing and monitoring
dry extended media filter in a rigid frame, with a minimum to prove continued compliance with ISO 14644-1, 2000.
particle-collection efficiency of 99.999%. Depending on the ISO, ISO 14644-3, Cleanrooms and associated controlled en-
filter, the particle-collection efficiency can be measured at vironmentsPart 3: Test Methods, 2005.
0.3 m or at MPPS. ULPA filters can be used in most applica- European Committee for Standardization. EN 1822-1:1998:
tions where HEPA filters are used. High efficiency air filters (HEPA and ULPA) Part 1: Classifica-
tion, performance testing, marking, 1998.
REFERENCES
1. FDA, Code of Federal Regulations, Title 21Food And Drugs, ARTICLE ACRONYM LISTING
Chapter IFood And Drug Administration, Department CGMP Current Good Manufacturing Practice
Of Health And Human Services, Subchapter CDrugs: CMD Count Median Diameter
General, Part 211Current Good Manufacturing Practice FDA US Food and Drug Administration
For Finished Pharmaceuticals, Subpart CBuildings and HEPA High Efficiency Particulate Air
Facilities, Sec. 211.42 Design and construction features, IEST Institute for Environmental Sciences and
Revised as of April 1, 2008. Technology
2. FDA, Code of Federal Regulations, Title 21Food And Drugs, IQ Installation Qualification
Chapter IFood And Drug Administration, Department ISO International Organization for Standardization
Of Health And Human Services, Subchapter CDrugs: MMD Mass Median Diameter
General, Part 211Current Good Manufacturing Practice MPPS Most Penetrating Particle Size
For Finished Pharmaceuticals, Subpart CBuildings and OQ Operations Qualification
Facilities, Sec. 211.46 Ventilation, air filtration, air heating PAO Polyalphaolefin
and cooling, Revised as of April 1, 2008. PQ Performance Qualification
3. FDA, Guidance for Industry: Sterile Drug Products Produced by RSD Relative Standard Deviation
Aseptic ProcessingCurrent Good Manufacturing Practice, 2004. ULPA Ultra-Low Penetration Air
4. European Commission: Enterprise and Industry Director-
ate-General, EudraLexThe Rules Governing Medicinal Prod-