HEPA and ULPA Filters

[
The Aseptic Core.
Coordinated by Ed White
HEPA and ULPA Filters
Ed White
“The Aseptic Core” discusses scientific and regulatory aspects of aseptic processing, with an emphasis on
aseptic formulation and filling. This column provides
practical advice to professionals involved in the qualification of aseptic processes and the myriad support processes involved. The primary objective for this column:
Useful information.
Reader comments, questions, and suggestions are
needed to help us meet our objective for this column.
Discussion topics and case studies related to aseptic processing submitted by readers are invited. Please e-mail
your suggestions to coordinating editor Susan Haigney
at [email protected].
KEY POINTS
The following key points are discussed in this article:
• High efficiency particulate air (HEPA) filters and ultralow penetration air (ULPA) filters are used in almost
every aseptic process
• HEPA filters have an efficiency of at least 99.97% for
0.3-micrometer particles. ULPA filters have an efficiency of at least 99.999%
• HEPA and ULPA filters consist of a filter frame, filter media, separators, bond material, and gasket
material
• HEPA and ULPA filters work by the sieve effect, inertial
impaction, interception, and diffusion
• Use of HEPA and ULPA filters in critical zones is mandated by US and international current good manufacturing practice (CGMP) regulations
• HEPA and ULPA filter testing generally includes verification of airflow velocity and installed filter leakage
testing
• HEPA and ULPA filter leak tests include the photometer method (most commonly used method) and the
discrete particle count method (used for specialized
For more Author
information,
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installations)
• HEPA and ULPA maintenance typically includes periodic replacement of pre-filters, monitoring of pressure
drop across the filters, periodic inspection of ductwork
upstream of the HEPA and ULPA filters, and periodic
inspection of gaskets and gel seals.
INTRODUCTION
HEPA and ULPA filters are found in every aseptic processing
facility. They are necessary for almost every aseptic process, yet few people think much about them. This column
provides an overview of HEPA and ULPA filters.
WHAT ARE HEPA AND ULPA FILTERS?
HEPA and ULPA filters are designations for specialized
filters designed to filter dry air with a rated efficiency of
99.97% or greater. They are not absolute filters, but instead
provide a rated reduction in particulate burden as verified
by a particulate challenge.
HEPA and ULPA filters consist of the following
components:
•F
ilter frame. The filter frame holds the filter media
in place, provides a rigid frame to promote uniform
air flow, and provides a surface for attachment of a
gasket or gel seal. Filter frames can be constructed of
many materials, including galvanized steel, stainless
steel, plywood, particle board, aluminum, or plastic.
Pharmaceutical HEPA filters are typically constructed
with an aluminum, stainless steel, or galvanized steel
(non-critical application) frame; some biosafety hoods
or laminar flow hoods may have plywood or particle
board frames.
•F
ilter media. The filter media is a fibrous material
typically constructed of randomly arranged and tightly
packed glass or ceramic fibers. The filter media is typically pleated to provide more filter surface area within
[
ABOUT THE AUTHOR
Ed White is a QA validation specialist at Baxter Healthcare Bioscience, Thousand Oaks, CA.
He may be reached at [email protected].
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Ed White, Coordinator.
a given space. Some ULPA filters are constructed of
expanded PTFE fluoropolymer (ePTFE). These filters
are typically used for specialized applications or in the
semiconductor industry, as they are incompatible with
polyalphaolefin (PAO).
•S
eparators. The separators are used to keep the pleats
apart, maximizing the effective filter area of the HEPA.
The separators can be constructed of corrugated aluminum or be of the “minipleat” design. In the minipleat
design, shown in Figure 1 and Figure 2, pleated filter
media is separated by strips of filter media or adhesive.
This design allows the media to be more closely packed
than in a HEPA filter with aluminum separators. The
majority of HEPA filters used in pharmaceutical facilities is of the minipleat design.
•B
ond material. The bond material is used to attach
the filter media to the filter frame. The bond material
may be made of several different adhesives, including
epoxy, silicone, and polyurethane.
•G
asket or gel seal. This ensures that air flows
through, rather than around, the filter media. Filters
may have gasket seals or gel seals, depending on the
installation type. Gaskets are either adhesive bonded
to the filter frame or are formed in place.
el seal filters have special channels into which siliG
cone or urethane gel is poured. When installed, the gel
channel mates with a knife edge installed in the ceiling
grid or filter module. A metal tab typically holds the
filter in place, allowing the knife edge to “float” in the
gel. It is important that the knife edge stays above the
bottom of the gel channel to ensure a positive seal.
Figure 3 illustrates a typical gel seal.
HEPA and ULPA filters only differ in their efficiency
ratings. HEPA stands for high efficiency particulate air
filter. A HEPA filter is capable of filtering out >99.97%
of particulate matter averaging 0.3 micrometers in diameter. ULPA stands for ultra-low penetration air filter. An
ULPA filter is capable of filtering >99.999% of particulate
matter at the most penetrating particle size (MPPS). For
most filters, including HEPA filters, the most penetrating particle size is in the range from 0.1 micrometers to
0.2 micrometers.
WHY USE HEPA FILTERS?
The use of HEPA filtration in critical areas is mandated
in the US Food and Drug Administration and international regulations for critical processing areas, including
the following:
• 21 CFR 211.42(c) (1) states, “There shall be separate
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or defined areas or such other control systems for the
firm’s operations as are necessary to prevent contamination or mix-ups during the course of the following
procedures: … (10) Aseptic processing, which includes
as appropriate: … (iii) An air supply filtered through
high-efficiency particulate air filters under positive
pressure, regardless of whether flow is laminar or
non-laminar…”
• 21 CFR 211.46(c) (2) states, “…Air filtration systems,
including pre-filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas…”
• The FDA aseptic processing guidance document (3)
states, “HEPA-filtered air should be supplied in critical
areas at a velocity sufficient to sweep particles away
from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be
justified and appropriate to maintain unidirectional
airflow and air quality under dynamic conditions
within the critical area.”
• EU GMP Annex 1 (4) states, “The manufacture of sterile
products should be carried out in clean areas, entry to
which should be through airlocks for personnel and/or
for equipment and materials. Clean areas should be
maintained to an appropriate cleanliness standard and
supplied with air, which has passed through filters of
an appropriate efficiency.”
The requirement for HEPA filtration of air entering aseptic process areas is critical to maintaining the cleanliness of
the aseptic processing environment and in maintaining the
sterility of aseptically processed products. Because there is
no additional bioburden reduction for aseptically processed
products, a single contamination event will compromise
the sterility of the product. By supplying HEPA-filtered air
to the aseptic processing area, the pharmaceutical manufacturer significantly reduces the probability of a contamination event. The aseptic processing guidance (3) document
summarizes this concept in the following statement:
“To maintain product sterility, it is essential that
the environment in which aseptic operations (e.g.,
equipment setup, filling) are conducted be controlled
and maintained at an appropriate quality. One aspect
of environmental quality is the particle content of
the air. Particles are significant because they can
enter a product as an extraneous contaminant, and
can also contaminate it biologically by acting as a
vehicle for microorganisms. Appropriately designed
air handling systems minimize particle content of
a critical area.”
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Figure 1: Typical minipleat filter construction.
Pleated filter media
Strip of filter media or
adhesive used to maintain
separation between pleats
Frame
Epoxy bond
Gasket
HOW DO HEPA FILTERS WORK?
Because of the filter media used, HEPA filters are more
analogous to depth filters than to membrane filters.
HEPA filters capture airborne particles through several
mechanisms including the sieve effect, impaction, interception, and diffusion, as follows:
•S
ieve effect. This effect occurs for large particles
(>5 micrometers in diameter). These particles are
just too large to fit through the open areas in the
filter media. Removal efficiency for large particles
due to the sieve effect is typically >99.9999%.
• I nertial impaction. Inertial impaction occurs as
particles are carried through the filter media by the
airstream. As the airstream shifts to flow around
fibers, inertia causes the particles carried by the
airstream to impact the fibers. This mechanism
typically occurs for particles in the 0.5 micrometer
to 5 micrometer range.
• I nterception. Smaller particles may be intercepted
by the fibers when they come within 1 particle diameter of a fiber when following the gas stream. This
mechanism can be effective because of the high
fiber density of HEPA and ULPA filter media. This
mechanism is effective in the 0.1 micrometer to 1
micrometer range.
• Brownian diffusion. Brownian diffusion occurs
with very fine particles that are small enough to be
affected by collision with the gas molecules in the
airstream. Brownian motion causes these particles
to move randomly within the airstream, increasing
the probability of the particles contacting a fiber.
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HEPA FILTER CLASSIFICATIONS
HEPA filters are classified by the Institute for Environmental Sciences and Technology (IEST) in their Recommended Practice IEST-RP-CC001 (5) HEPA and ULPA filter
classifications range from Type A to Type K, but not all of
these classifications are commonly used in the pharmaceutical industry. HEPA/ULPA filter types C, D, and F are
commonly used in the pharmaceutical industry. Type J
and type K filters may be used in ultraclean applications
such as filling isolators or aseptic compounding. EN1822
types H14 and U15 are commonly used in Europe. The
Table lists some common filter types used in the United
States and Europe and their ratings.
HEPA AND ULPA FILTER TESTING
HEPA and ULPA filters are typically tested as part of
certification of a cleanroom environment. Tests specific
to HEPA and ULPA filters only are discussed. Tests for
the larger cleanroom environment will be discussed in
an upcoming column. Tests specific to the HEPA and
ULPA filters include the following:
• Airflow velocity is mandatory for unidirectional
cleanrooms or clean zones, optional for non-unidirectional cleanrooms or clean zones
• Airflow volume is mandatory for unidirectional or
non-unidirectional cleanrooms or clean zones
• Installed filter system leakage test (ISO 14644-3,
Clause B.6) for all cleanrooms.
Airflow Velocity Test
For the airflow velocity test, the filter is checked for velocity at several points using an airflow velocity meter or
airflow hood. The filter is typically divided into a grid
of equal surface areas, not to exceed 4 ft2 or 0.4 m2. The
average velocity of each filter should be within the range
of 0.37 meters/second to 0.54 meters/second (0.45 m/s
±20%). The relative standard deviation (RSD) across
the filter bank (or filter for individual filter installations)
should be 15% or less. The RSD is calculated by dividing the standard deviation of the readings by the average
of the readings, and multiplying the result by 100. The
airflow velocity for a particular clean room may differ
and should be based on maintaining a proper airflow
over critical zones. Higher or lower velocities may be
appropriate, especially in specialized installations such
as isolators, depyrogenation tunnels, and depyrogenation ovens.
Airflow Volume Test
This test is typically performed using an electronic
micromanometer with an appropriate airflow hood.
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Ed White, Coordinator.
It can also be performed by multiplying the average
airflow velocity of the filter by the effective surface
area of the filter. The airflow volume of each filter is
measured using the hood (this may require multiple
measurements for larger filters), and the total volume
of air supplied by all of the filters in a room is divided
by the volume of the room to determine the number
of air changes per hour in the room.
Figure 2: Typical minipleat HEPA filter with gel seal.
Installed Filter Leakage Test
The installed filter leakage test may be performed using
one of two methods: the photometer method or the
discrete particle count method. In both methods, a
challenge aerosol is introduced upstream of the filter,
and the filter is scanned to detect leakage >0.01% of
the upstream concentration.
Installed Filter System Leakage Test—
Photometer Method
The photometer method is the most accepted method in
the pharmaceutical and biotech industries. In this method, an aerosol challenge, typically Polydisperse PAO, is
introduced upstream of the filter in such a way that the
challenge is uniformly distributed across the filter. An
upstream concentration is taken, and the aerosol generator
is adjusted to achieve a challenge level of approximately 10
µg/L to 90 µg/L. The aerosol photometer is adjusted to read
100% at the upstream concentration, and then it is used to
scan the filter. Any measurement >0.01% of the upstream
concentration is considered a designated leak, assuming
a photometer sampling rate of 1 cubic foot/minute (28.3
L/min). The leak may be repaired using silicone sealant
if the repair is less than 1.5 inch (3.8 cm) in any direction
and if the repairs cover less than 3% of the filter surface.
If either of these criteria is exceeded, the filter should be
replaced. Whether the filter is repaired or replaced, the leak
test should be repeated. The aseptic processing guidance
(3) states, “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 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.”
Installed Filter System Leakage Test—
Discrete Particle Count Method
The particle count method is little used in the pharmaceutical and biotech industries because of the somewhat greater
complexity of the test, and the greater acceptance of the
photometer method by regulatory agencies, especially FDA.
This method is widely used in the semiconductor industry
because of industry concerns about molecular contaminagxpandjv t.com
Figure 3: Typical gel seal installation.
Filter media
Ceiling grid
or filter
housing
Filter frame
Knife edge
Wing nut
Adhesive
Metal tab
Silicone or
urethane gel
Protective screen
Acorn nut
tion of silicon wafers with PAO. This method is generally
limited to specialized applications such as depyrogenation
tunnels and ovens where burn off of PAO after certification
procedure is a concern. Large installations of gel-seal filters
are also of concern because PAO can interact with gel seals
causing hardening or liquifaction of the gel-seal material.
This method can use polystyrene microspheres instead of
PAO, or may use PAO in much lower concentrations than
the photometer method.
In this method, a challenge aerosol consisting of polystyrene microspheres or PAO with a count median diameter
(CMD) between 0.1 µm and 0.3 µm is introduced upstream
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Table: IEST RP-CC001 and EN1822-1 filter classifications typically used for pharmaceutical
and biotech applications.
Filter
Type
Minimum %
Efficiency
Particle
Size μm
Integrity Test Method
Application
B
99.97%
0.3 MMD
Two flow leak test
HEPA filters for low classification areas
C
99.99%
0.3 MMD
Photometer-Polydisperse PAO
General use HEPA filters
General use HEPA filters; critical zone
filters; isolator applications; large
installations where hot aerosol
generators are needed
D
99.999%
0.3 MMD
Photometer-Polydisperse PAO
F
>99.999%
0.1-0.2 or
0.2-0.3
Particle count or photometerCritical zone filters; isolator applications;
Aerosol challenge may be
large installations where hot aerosol
polydisperse PAO or polystyrene
are needed
microspheres (polystyrene latex beads)
J
99.99%
0.1-0.2 or
0.2 to 0.3
Particle count or photometer-Polydisperse PAO
High airflow installations
K
99.995%
0.1-0.2 or
0.2 to 0.3
Particle count or photometerpolydisperse PAO
Critical zone filters; isolator applications;
large installations where hot aerosol
generators are needed
H14
(EN1822)
99.995%
MPPS
Photometer-polydisperse PAO
General use HEPA filters
U15
(EN1822)
99.9995%
MPPS
Photometer-polydisperse PAO
General use HEPA filters; critical zone
filters; isolator applications; large
installments where hot aerosol
generators are needed
*MMD: Mass Median Diameter; MPPS: Most Penetrating Particle Size; PAO: Polyalphaolefin
at a concentration of approximately 106 particles/ft 3.
Challenge concentration is measured using a particle
counter with an appropriate measuring range for the
particulate challenge. Because the particle counting
range is outside the operating range of the particle
counter, the sample must be diluted using a special
instrument that uses a capillary tube to provide a
precise and repeatable dilution factor. The particle
count is multiplied by the dilution factor to obtain
the concentration of the aerosol in particles/ft 3. The
downstream side of the filter is scanned with a particle
counter with a specialized probe. Any particle count
>0.01% of the upstream concentration is considered a
designated leak. In practice, any count >3 particles/ft 3
encountered during scanning should be verified by
a stationary scan.
IEST Recommended Practice IEST-RP-CC034.2 and
ISO 14644-3 give more detailed instructions on how
to perform the discrete particle count method and
the photometer method.
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HEPA FILTER MAINTENANCE AND
REPLACEMENT
Other than periodic recertification, HEPA filters require
little maintenance. The types of maintenance required
may include the following:
• Periodic replacement of pre-filters upstream of the
HEPA/ULPA filters prevents premature loading of
the HEPA/ULPA filters by reducing the particle load
reaching the filters.
• Monitoring of the pressure drop across the filters using
a differential pressure sensor. When the differential pressure reaches or exceeds the manufacturer’s
recommended pressure drop, the filters should be
replaced.
• Periodic inspection of the ductwork upstream of
the HEPA filter to ensure that there is no buildup of
particulate matter or debris that could damage the
HEPA filters.
• Periodic inspection, where possible, of gaskets or gel
seals for evidence of deterioration.
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Ed White, Coordinator.
VALIDATION IMPLICATIONS
It is impossible to validate a critical processing environment without ensuring that the supply air to the environment is properly filtered and that the filters have been
installed properly. The validation of HEPA and ULPA
filters should provide this assurance. The installation
qualification (IQ) should include proper installation of
the filters, including inspection of the associated equipment (e.g., prefilters, excessive particulate in ductwork,
etc.). Gel seals and gaskets should be inspected. Testing,
including pressure drop testing, should be conducted.
Requirements for the preventative maintenance program
are specified in the IQ. The operational qualification
(OQ) would include filter certification testing, including
airflow velocity, airflow volume, and system leakage. Filter
performance qualification (PQ) testing will be discussed
as part of qualifying the cleanroom environment in a
future column.
HEPA and ULPA filter testing is crucial to any validation
program, whether this testing is performed by the validation department, maintenance department, or an external
service. Review of the HEPA certification program should
be part of the initial qualification or requalification of an
aseptic environment. Qualification and requalification
of an aseptic processing environment will be covered in
the next issue of “The Aseptic Core.”
GLOSSARY
Aerosol photometer: Aerosol photometer is an instrument
that measures mass concentration of aerosols using the
forward light scattering principle.
Challenge aerosol: Aerosol generated from a selected
aerosol source material to be used as an upstream challenge for HEPA and ULPA filter leak testing.
Count median diameter (CMD): CMD is the median diameter of the numeric distribution of the challenge aerosol—50% of the particles in the challenge distribution are
larger than the CMD, and 50% of the particles are smaller
than the CMD.
Designated leak: A designated leak is a leak that should
be detectable during scanning of a filter. A leak greater
than or equal to 0.01% of the upstream concentration
(when using an aerosol photometer) or upstream particle
count (when using a discrete particle counter) should be
detectable.
Discrete particle counter (DPC): Discrete particle counter
is an instrument capable of counting and sizing individual
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airborne particles. This is the familiar cleanroom particle
counter. A DPC used for filter leak testing should be able
to count particles at 0.3 micrometers or greater.
HEPA (high efficiency particulate air) filter: A dry, extended media filter in a rigid frame, having a minimum
particle collection efficiency of 99.97% for 0.3 µm mass
median diameter particles of PAO.
Laskin nozzle aerosol generator: An aerosol generator
using a specialized nozzle (Laskin nozzle) to generate a
heterogeneous (polydisperse) aerosol from liquid PAO,
using compressed air as a source (compressed nitrogen
should be used for a hot aerosol generator). For smaller
installations, a “cold” aerosol generator that generates the
aerosol directly using a Laskin nozzle may be used. For
large installations, a “hot” generator that superheats the
vapor generated by the Laskin nozzles then re-condenses
the vapor as a cold polydisperse aerosol is used.
Mass median diameter (MMD): Mass median diameter is
the 50th percentile of the mass distribution of the aerosol.
Monodisperse aerosol: Monodisperse aerosol is one having a relatively narrow distribution of particle sizes. Polystyrene microspheres are an example of a monodisperse
aerosol.
Most penetrating particle size (MPPS): MPPS is the particle
size at which a HEPA or ULPA filter has its lowest efficiency.
The MPPS represents the worst-case filter challenge for
efficiency testing.
PAO: PAO stands for polyalphaolefin, which is a synthetic
oil commonly used in the pharmaceutical industry. A Polydisperse aerosol of PAO is commonly used as a challenge
material for leak testing of HEPA and ULPA filters.
Polydisperse aerosol: Polydisperse aerosol is one having a
broad distribution of particle sizes. An example of a Polydisperse aerosol is a PAO aerosol generated by a hot or
cold aerosol generator.
Polystyrene latex (PSL) beads: PSL beads are a uniform suspension of polystyrene microspheres in water, usually with
a small amount of surfactant to ensure stable dispersion of
the microspheres. PSL is used as an alternative challenge to
PAO when using the particle count method for leak testing
ULPA filters.
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The term “polystyrene latex beads” is somewhat misleading, as this material does not contain any natural rubber
latex. The term latex in this case refers to a stable, uniform
suspension of particles in an aqueous medium. Because of
the confusion between polystyrene latex and natural rubber
or plant-based latex, the term polystyrene microspheres is
becoming a common synonym for PSL.
Scanning: Method of testing for leaks in HEPA or ULPA filters. During a filter scan, an aerosol photometer or discrete
particle counter sampling probe is slowly moved across the
filter in a series of parallel overlapping strokes. The sampling
probe is typically kept about 1 inch away from the filter surface. When a potential leak is detected, the probe is held
stationary for a short period of time to verify the leak.
Standard leak penetration: Standard leak penetration is
the leak penetration measured by a stationary probe using
a particle counter or photometer with a flow rate of 1 cubic
foot per minute (28.3 liters per minute).
ULPA (ultra-low penetration air) filter: An ULPA filter is a
dry extended media filter in a rigid frame, with a minimum
particle-collection efficiency of 99.999%. Depending on the
filter, the particle-collection efficiency can be measured at
0.3 µm or at MPPS. ULPA filters can be used in most applications where HEPA filters are used.
REFERENCES
1.FDA, Code of Federal Regulations, Title 21—Food And Drugs,
“Chapter I—Food And Drug Administration, Department
Of Health And Human Services, Subchapter C—Drugs:
General, Part 211—Current Good Manufacturing Practice
For Finished Pharmaceuticals, Subpart C—Buildings and
Facilities, Sec. 211.42 Design and construction features,”
Revised as of April 1, 2008.
2.FDA, Code of Federal Regulations, Title 21—Food And Drugs,
“Chapter I—Food And Drug Administration, Department
Of Health And Human Services, Subchapter C—Drugs:
General, Part 211—Current Good Manufacturing Practice
For Finished Pharmaceuticals, Subpart C—Buildings and
Facilities, Sec. 211.46 Ventilation, air filtration, air heating
and cooling,” Revised as of April 1, 2008.
3.FDA, Guidance for Industry: Sterile Drug Products Produced by
Aseptic Processing–Current Good Manufacturing Practice, 2004.
4.European Commission: Enterprise and Industry Directorate-General, EudraLex—The Rules Governing Medicinal Prod-
54
Journal
of
Validation T echnology [Summer 2009]
ucts in the European Union—Volume 4—EU Guidelines to Good
Manufacturing Practice—Medicinal Products for Human and
Veterinary Use, “Annex 1: Manufacture of Sterile Medicinal
Products (corrected version),” 2008.
5.Institute of Environmental Sciences and Technology, Recommended Practice, IEST-RP-CC001, 2005. JVT
GENERAL REFERENCES
Institute of Environmental Sciences and Technology, IEST-RPCC001.4, “HEPA and ULPA Filters,” 2005.
IEST, IEST-RP-CC006.3, “Testing Cleanrooms,” 2004.
IEST, IEST-RP-CC007.2, “Testing ULPA Filters,” 2007.
IEST, IEST-RP-CC021.2, “Testing HEPA and ULPA Filter Media,”
2005.
IEST, IEST-RP-CC034.2, “HEPA and ULPA Filter Leak Tests,”
2005.
International Organization for Standardization (ISO). ISO
14644-1, “Cleanrooms and associated controlled environments, Part 1: Classification of Air Cleanliness,” 1999.
ISO, ISO 14644-2, “Cleanrooms and associated controlled environments–Part 2: Specifications for testing and monitoring
to prove continued compliance with ISO 14644-1,” 2000.
ISO, ISO 14644-3, “Cleanrooms and associated controlled environments–Part 3: Test Methods,” 2005.
European Committee for Standardization. EN 1822-1:1998:
High efficiency air filters (HEPA and ULPA) Part 1: Classification, performance testing, marking, 1998.
ARTICLE ACRONYM LISTING
CGMP
CMD
FDA
HEPA
IEST
Current Good Manufacturing Practice
Count Median Diameter
US Food and Drug Administration
High Efficiency Particulate Air
Institute for Environmental Sciences and
Technology
IQ
Installation Qualification
ISO
International Organization for Standardization
MMD Mass Median Diameter
MPPS Most Penetrating Particle Size
OQ
Operations Qualification
PAOPolyalphaolefin
PQ
Performance Qualification
RSD
Relative Standard Deviation
ULPA Ultra-Low Penetration Air
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