[
The Aseptic Core.
Coordinated by Ed White
Cleanroom Design,
Construction, and Qualification
Ed White
“The Aseptic Core” discusses scientific and regulatory aspects of aseptic processing with an emphasis on
aseptic formulation and filling. This column has been
developed to provide practical advice to professionals
involved in the qualification of aseptic processes and
the myriad support processes involved.
Reader comments, questions, and suggestions are
needed to help us meet our objective for this column.
Please e-mail your suggestions to journal coordinating
editor Susan Haigney at [email protected].
KEY POINTS
The following key points are discussed in this article:
• Construction and qualification of a new aseptic processing area is a complex project involving multiple
disciplines
• Good upfront strategic planning is critical for an
effective qualification effort. All involved disciplines should be involved in planning for an aseptic
facility.
• Construction and qualification of a new aseptic processing facility can be divided into several phases:
planning, design, construction, commissioning, qualification, submission, and project closeout.
• Detailed design reviews should be performed on
vendor design documents. These reviews should be
repeated for any design changes.
• The US Food and Drug Administration’s aseptic
processing guideline, the European Commission’s
GMP Annex 1, and International Organization for
Standardization (ISO) 14644-4 can serve as useful
references during design reviews
• Cleanrooms are generally designed using a pressure
cascade that maintains a minimum differential pressure of 10–15 Pascal positive to adjacent areas of lower
classification
For more Author
information,
go to
gxpandjvt.com/bios
30
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• Cleanrooms and aseptic complexes should be designed
for optimum flow of material, equipment, personnel,
and waste streams so that raw materials and waste
streams cannot cross over finished goods, personnel
cannot move from less clean to cleaner areas without
gowning, clean and dirty equipment cannot mix, and
multiple products are segregated
• Cleanroom classification is performed per the ISO
14644 series of standards
• Some cleanroom reclassification activities can be
satisfied with routine monitoring data.
INTRODUCTION
In this issue, we move from the topic of high efficiency
particulate air (HEPA) filters to the larger topic of cleanroom design and classification. The construction of a
new cleanroom is a complex project, involving multiple
disciplines and extending over several years. As this topic
is quite complex, this article gives a broad overview of the
topic, with a focus on the design process and cleanroom
classification. Future articles in this column will give more
detail to specific qualification activities.
CLEANROOM DESIGN, CONSTRUCTION,
AND QUALIFICATION PROCESS
A typical cleanroom or aseptic facility design and construction process can be divided into several phases: planning,
design, construction, commissioning, and qualification.
On completion of the qualification phase, a submission is
prepared and submitted to one or more regulatory agencies
for approval. On receipt of approval, the facility enters
an operational phase in which product is manufactured
for sale and routine quality controls are in place. Figure
1 shows a flow chart of a typical facility design, commissioning, and qualification process.
[
ABOUT THE AUTHOR
Ed White is a senior principal validation engineer at Baxter Healthcare in Thousand Oaks, California.
He may be reached by e-mail at [email protected].
of
Validation T echnology [Autumn 2009]
iv thome.com
Ed White, Coordinator.
Figure 1: Facility design, commissioning, and qualification process.
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The Aseptic Core.
Planning Phase
Because of the cost, duration, and complexity of a cleanroom construction project, some form of project management is typically used. The planning phase for a cleanroom construction project should include definition of
costs, timelines and deliverables, and identification of
constraints and risks. Careful attention should be taken
in the planning phase, as effective planning can make the
difference between a project that is delivered on time and
on budget and meeting strict quality standards compared
to one that is late, over budget, and fails to meet quality
standards. Involving all involved disciplines, including manufacturing, engineering, quality, validation,
environmental monitoring, cleaning, sterilization, etc.,
will make it more likely that the critical requirements
are captured in the planning stage, reducing additions
to the cleanroom design that increase the cost and duration of the project.
Design Phase
The first phase covered in this flow chart is the design
phase, which begins with the preparation of formal process and product requirements. These requirements
should answer the following questions:
• Will the facility be dedicated to a single product or
will it be a multiproduct facility?
• Will the product(s) include any lyophilized products,
any moisture-sensitive products, or any oxygensensitive or light sensitive products?
• Are any of the products temperature-sensitive?
• Do any of the products have special containment
requirements, such as cytoxic products?
• How will the product(s) be presented to the consumer
(e.g., vials, syringes, ampoules, cartridges, etc.)? Are
any devices included in the presentations that will
require additional equipment in the cleanroom?
• Can the products be terminally sterilized or must
they be aseptically filled?
• Do the processes require dedicated or disposable
equipment, or can equipment be shared between
some products with appropriate precautions? Consideration should be given to whether the product
dosage is low enough to cause concern with cleaning validation.
The project team working on the product and process
definitions will need to answer many more questions
than the examples presented. The product and process
definitions should lead to user requirements specifications (URS) for the equipment, utilities, and facilities
that are included in the project. These requirements
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will give generic requirements for the equipment, utilities, and facilities that are detailed enough to prepare
more detailed specifications. The URS should focus
on what should be done, not how it is done, as follows.
For example:
• The cleanroom should be designed to provide a
Grade A environment over all filling and closing
equipment and should be at least 15 Pascal positive
to any area of lower classification. Sufficient space
should be provided for aseptic filling and stoppering
equipment, as well as associated conveyors, and for
transfer of sterilized vials from a depyrogenation
tunnel located external to the cleanroom. Sufficient
Grade B space should be provided in the cleanroom
for production operators and for environmental
monitoring operations; or
• The filler shall be capable of aseptically filling and
closing vials from 5 mL to 20 mL at consistent speeds
from 15,000 vials per hour for 5 mL vials to 7,500
vials per hour for 20 mL vials. The filler will be
capable of fully or partially inserting 20 mm stoppers
into the vials at these speeds. The filler will automatically check-weigh the vials so that each filling
head is checked at least once every 15 minutes. The
filler will be capable of displaying actual fill weights
and control charts of the fill weights, and will be
capable of exporting the fill weight data through a
standard data interface.
Once the URS is complete, the preliminary risk assessment should be performed to identify risks that need
to be addressed in the design, and a preliminary design
should be prepared (typically by an architectural and
engineering [A&E] firm). A preliminary design review
should be performed on the preliminary design to ensure
that the user requirements are met, and that the design
complies with current good manufacturing practice
(CGMP) requirements, as outlined in the appropriate
reference such as the US Food and Drug Association’s
aseptic processing guideline (1) or the European (EU)
GMP Annex 1 (2). The International Organization for
Standardization (ISO) Standard 14644-4 (3) is also a
useful reference for preliminary design review. After the
preliminary design has been reviewed and approved,
the A&E firm will prepare a request for quotes, which
the various vendors and contractors will use to prepare
basis of design and quotation documents. Once the
vendors and contractors have been selected, functional
specifications are typically written for the equipment and
utilities (functional specifications can be written as part
of the bid package in some cases). Functional specificaiv thome.com
Ed White, Coordinator.
tions are used by the vendors to prepare detailed design
specifications that undergo a detailed design review and
design qualification in which the vendor design is reviewed
to ensure it meets user requirements and the appropriate CGMP requirements. The design review should be
updated if any design changes are implemented after the
detailed design is approved.
Construction Phase
Once the detailed design reviews are complete the project
moves to the construction phase, in which the facilities,
utilities, and equipment are built. This phase uses standard construction management techniques for the facilities, utilities, and equipment. Special attention should
be given to items such as welded piping such as waterfor-injection (WFI) piping, and cleanroom construction
during this phase. The construction phase concludes
when the equipment, facilities, and equipment are constructed and installed. Equipment typically undergoes a
factory acceptance test (FAT) before it is shipped. An FAT is
intended to verify that the equipment meets its approved
design specifications and functional specifications before
it ships. The contract with the vendor typically specifies
that successful completion of an FAT is required before the
equipment may ship. An FAT is typically executed using
an FAT protocol that is approved by representatives from
the vendor and customer. Once the FAT is approved, the
equipment may ship and may be installed at the customer
site. A site acceptance test (SAT) may be performed once
the equipment is installed in the cleanroom to ensure that
the equipment has been installed properly.
Commissioning Phase
Once the construction phase is complete, the project moves
into the commissioning phase. In this phase, the equipment, utilities, and facility are tested to ensure they meet
design specifications, functional specifications, and user
requirements. The commissioning phase differs from the
subsequent qualification phase in that a less formal change
management system is typically in place during commissioning, allowing changes to be made and documented
with lower levels of approval than would be necessary
during the qualification phase. Typical activities that
occur during the commissioning phase may include the
following:
• Redlining of equipment, facility, and utility drawings
to ensure they reflect the actual systems as installed
• Verification of field interconnects, if not performed
as part of a site acceptance test
• Verification that equipment and utilities operate as
designed
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• Verification of materials of construction for equipment, utilities, and cleanrooms, if not verified during
the construction phase
• Cycle development for various component, equipment, and material preparation processes such as
steam sterilization processes, clean-in-place and
steam-in-place, closure washing, siliconization (if
necessary) and sterilization processes, depyrogenation processes, sterile filtration, etc.
• Preparation of forms and procedures for equipment,
facilities, and utilities, and many other activities
• Air balancing of the facility to ensure proper air flows
and pressure cascades. This is typically done by professional air balancing firms that are certified by the
National Environmental Balancing Bureau (NEBB).
The commissioning phase is typically closed out by a
formal commissioning report, which evaluates whether
the equipment, utilities, and facilities are properly installed
and properly operating, and whether or not the equipment, facilities, or utilities are ready for qualification.
Qualification Phase
The qualification phase begins with completion of commissioning of the equipment, facilities, and utilities and
continues through aseptic process simulations (media
fills) and process validation (conformance) runs. Some
installation qualification (IQ) activities, such as verification of piping, wiring, or materials of construction,
may begin in the commissioning phase or even in the
construction phase, continuing into the qualification
phase. Operational qualification (OQ) and performance
qualification (PQ) activities are almost totally contained
in the qualification phase, although some OQ activities
may be performed during commissioning if no changes are
made to the equipment subsequent to the OQ activities.
It is in the qualification phase that cleanroom certification
activities are typically performed.
Submission Phase
The submission phase consists of the preparation of
regulatory submissions once qualification activities are
completed. These submissions are sent for approval to
one or more regulatory agencies. Any product manufactured during the submission phase is held pending
approval of the submission.
Operational Phase
Once approval is received, the cleanroom can be considered to be operational. Product being held pending
submission may be released, assuming it meets its predetermined specifications.
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The Aseptic Core.
POINTS TO CONSIDER FOR CLEANROOM
DESIGN
There is not a single “right” way to construct an aseptic
processing facility or cleanroom, as each should be
designed to accommodate the processes and products
contained in the cleanroom. There are, however,
general principles of design that should be followed
in constructing a cleanroom or aseptic processing
facility. Many points to consider can be found in ISO
14644-4, the FDA aseptic processing guideline, and
in EU Annex 1. I highly recommend these references.
The following points should be considered:
• Floors, walls, and ceilings should be constructed of materials that are smooth, hard, and easy
to clean. Transitions between floors and walls
should be designed with a smooth transition
(coved) to allow for easy cleaning.
• Temperature and humidity controls in cleanrooms
and supporting areas should be sufficient to maintain operator comfort when gowned and maintain adequate humidity for the process. Consider
humidity and temperature loads from operating
equipment such as autoclaves, CIP/SIP, etc., when
designing temperature and humidity controls.
• Cleanrooms should be designed to facilitate personnel, equipment, and material flows to prevent
microbial contamination of sterilized or sanitized
equipment and facilities, sterilized components,
and sterile filtered drug product. Personnel
should enter the cleanroom through gowning
facilities. Equipment and materials should either
enter through sterilization or depyrogenation
equipment or through airlocks using a validated
sanitization procedure. Multiproduct facilities
should be designed to eliminate or minimize
instances where product streams cross.
• Pay careful attention to locations of return ducts
in Grade A/B rooms, as they can affect the unidirectional airflow over critical processing zones.
• Investing in a computational flow dynamics
(CFD) analysis of the cleanroom design may be
worthwhile, as this can reveal unforeseen problems in the design. CFD analysis will require
accurate representation of the equipment as
installed, accurate locations of HEPA filters and
returns, and accurate estimates of supply volumes
of the HEPA filters.
• The cleanroom should be positive by at least 10-15
Pascal to all surrounding zones of lower classification. This is accomplished by a cascade-type
design, in which the cleanroom is surrounded
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by areas of lower classification, which are then
surrounded by areas of even lower classification,
eventually leading to an external unclassified
area. Illustration of the cleanliness cascade concept is shown in Figure 2.
• When setting up pressure monitoring in an existing building monitoring system (BMS) or when
installing a new BMS, consider where the reference area for differential pressures is located. It
is important that a stable reference point is used
to ensure good control of differential pressures.
Referencing one clean zone to another clean zone
can be problematic, as it can cause fluctuations in
one clean zone to cascade to other clean zones.
CLEANROOM QUALIFICATION
Qualification of an aseptic processing facility is a
complex project including qualification of the cleanrooms in the facility, IQ/OQ/PQ of the equipment and
utilities in the facility, airflow visualization studies,
personnel training and qualification, aseptic process
simulations, process validation, conformance runs,
and other validation activities. This article focuses on
the activities involved in certification and qualification of the cleanroom itself.
Installation Qualification
Installation qualification activities for a new cleanroom typically include the following items:
• Verification that the materials of construction
are as specified (e.g., Epoxy Terrazzo flooring,
smooth hard walls compatible with cleaning
chemicals such as phenolic compounds or sodium
hypochlorite, etc.)
• Verification of adequate lighting (typically defined
in user requirements) at work height
• Verification of appropriate installation of air handling units and ductwork or laminar flow units
• Verification that air handling ductwork has been
adequately cleaned. This is very important, as
improperly cleaned ductwork can cause HEPA
leaks in some cases.
• Verification that the specified HEPA or ultra-low
particulate air (ULPA) filters have been installed
and installed properly
• Verification of location and size of returns
• Verification of instrumentation type, location,
and installation
• Verification of installation of air handling units
or laminar flow units.
iv thome.com
Ed White, Coordinator.
Figure 2: Cleanroom cleanliness cascade (adapted from ISO 14644-4).
Operational Qualification
Operational qualification for a clean room might include
the following:
• Verification of proper operation of air handling units,
humidifiers and dehumidifiers, duct heaters, smoke
alarms, dampers, and other controls
• Verification of proper operation of the building management system (BMS) or other control system for
the cleanroom
• Measurement of vibration and noise in the
cleanroom
• Cleanroom classification activities.
Cleanroom Qualification
Classification of a cleanroom is typically performed
according to ISO 14644-1 and its supporting documents.
Typical activities involved in classification of a cleanroom
include the following:
• Certification of HEPA filters, as discussed in the
previous column.
• Measurement of airflow velocity and airflow volume.
For Grade A areas, airflow velocity is measured using
an anemometer or micromanometer at several points
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across each filter. The average velocity for each filter
may be multiplied by the average velocity for that
filter to obtain an airflow volume for that filter. The
airflow volume for each filter is added to the airflow
volume of the other filters to obtain the total air supply volume for a room. Outside of Grade A areas,
airflow volume is typically measured directly using
a device such as a flow hood. The volume readings
for each filter are summed to provide the total supply
volume for the room.
• Air changes per hour are calculated by dividing
the supply volume in cubic feet or cubic meters
per hour by the room volume in cubic feet or
cubic meters. The FDA aseptic processing guideline recommends a minimum of 20 air changes/hour for class 100,000 (ISO 8) cleanrooms,
with significantly higher rates for cleanrooms
with lower particulate classifications, as follows:
Example 1: A 30-ft by 35-ft component preparation
area with a 10-ft ceiling height is supplied by nine
HEPA filters, each with an average supply velocity of
520 ft/min. The air changes per hour are calculated
as follows:
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The Aseptic Core.
Table: EU grades and equivalent ISO classes.
Non-viable particulate (particles/m3)
At rest
In operation
EU
grade
ISO Class
0.5 μm
5.0 μm
0.5 μm
5.0 μm
The local zone for high-risk
operations (e.g., filling zone),
stopper bowls, open ampoules
and vials, making aseptic
connections.
A
4.8
3520
20
3520
20
For aseptic preparation and
filling, this is the background
environment for the grade A zone.
B
5 at rest, 7 in
operation
3520
29
352,000
2900
Clean areas for carrying out less
critical stages in the manufacture
of sterile products.
C
7 at rest, 8 in
operation
352,000
2900
3,520,000
29,000
Clean areas for carrying out less
critical stages in the manufacture
of sterile products.
D
8 at rest, not
defined in operation
3,520,000
29,000
Not defined
Not defined
Activities
a.Supply volume = 520 ft3/min x 9 filters x 60
min/hr = 280,800 ft3/h
b.Room volume = 30 ft x 35 ft x 10 ft = 10,500
ft3
c.Air Changes/Hour = Supply Volume/Room
Volume = 280,800 ft3/h / 10,500 ft3 = 26.7 Air
Changes/Hour.
Example 2: An aseptic filling room measures 10m
x 4.5m x3m, and is supplied by 24 HEPA filters,
each supplying an average volume of 0.28 m3/s at
a velocity 0.45 m/s, as follows:
a.Supply Volume = 0.28 m3/s x 3600 s/h x 24
filters = 24,192 m3/h
b.Room Volume = 15 m x 4.5 m x 3 m = 202.5
m3
c.Air Changes/Hour = Supply Volume/Room
Volume = 24,192 m3/h / 202.5 m3 = 119.5 Air
Changes/Hour.
• Measurement of differential pressures between
rooms. This is typically accomplished using an
electronic micromanometer or differential pressure
gauge. Differential pressures are measured between
reference points in the higher-pressure room and
the lower pressure room. Generally, cleaner areas
should be 10–15 Pascal (0.04–0.06 inches of water
column) positive to less clean areas. Figure 3 shows
a pressure cascade in a typical cleanroom.
• Particulate classification is performed per ISO 146441 and its associated documents, using a standard
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discrete particle counter (DPC). Each room in the
complex should be verified as meeting the ISO
Class or EU Grade for the activities performed in
that room.
he Table lists the activities and associated cleanroom
T
grades in a typical cleanroom. As shown in the Table,
the EU Grade and associated ISO Class recommended
by FDA are equivalent except for EU Grade A, which
recommends a lower particle limit for the 5.0 µm
particle size class (20 particles/m3) than the limit
for the same particle size class in ISO 14644-1 (29
particles/m3).
I personally prefer certifying to the EU limits, as these
limits are more stringent than the ISO limits; a clean
zone certified to EU grade A will automatically meet
ISO class 5 requirements—the other limits are identical to the equivalent ISO class. One drawback to the
EU classification scheme is that EU does not allow for
sequential sampling in Grade A zones. EU Annex 1
requires that at least 1 cubic meter is sampled at each
site during classification activities.
The minimum number of sampling point locations
in each cleanroom is determined using the formula
NL= A1/2; where NL = the minimum number of sampling point locations, rounded up to a whole number,
and A1/2 = the area of the cleanroom or clean zone in
square meters. Once the number of sample sites is
determined, the room should be examined to determine which points within the cleanroom should be
tested. Special attention should be given to points
iv thome.com
Ed White, Coordinator.
Figure 3: Pressure cascade in typical cleanroom complex.
in the room where returns are located, and points
where critical operations are occurring, and to
points where particle ingress could occur, such as
portals between adjoining rooms. Example 3 shows
the calculation of the number of sample sites for a
filling room containing both EU Grade A and EU
Grade B zones.
xample 3. An aseptic filling room containing
E
Grade A and B zones is to be classified. The overall
room size is 11.4 m by 15.2 m, with a Grade A zone
4.6 m x 15.2 m (see Figure 4).
The area of the Grade A zone is 4.6 m x 15.2 m, or
69.9 square meters. Using the formula NL= A1/2 ,
the minimum number of sampling locations in the
Grade A zone is determined to be nine sampling
locations.
The Grade B area is (11.4–4.6) m x 15.2 m, or 103.4
square meters. Using the formula NL= A1/2, the minimum number of sampling locations is determined
to be 11 sampling locations.
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F or the Grade A zone, critical sites such as the portal
to the capping room, stopper hopper, conveyor belt,
filling needles, in feed turntable, and operator stations
are selected as the sampling locations, as follows:
a.For the Grade B zone, the sampling sites were
evenly distributed throughout each side of the
room, with an additional sampling site at the
double door leading to the room.
b.A 1 m3 air sample was taken at each Grade A
location using a discrete particle counter (we
have a 100 liter per minute counter)
c.Smaller air samples (100 liters per site) were
taken in the grade B zones, using the sequential sampling procedure listed in ISO 14644-1,
Appendix F.
d.All samples were taken in the “At Rest” condition, as this was an initial qualification of the
room. “In Operation” samples were taken at
a later phase in the validation project, during
performance qualification studies. The “In
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The Aseptic Core.
Figure 4: Sampling locations for Grade A/B cleanroom.
Operation” samples were taken using the same
procedure as the “At Rest” samples, excepting
that a full complement of operators were in the
room and all equipment was operating per normal procedures. “In Operation” samples were
taken during practice runs for aseptic process
simulations (Media Fills).
• Airflow visualization. This is performed in all Grade
A processing areas to demonstrate that the airflow is
appropriate for aseptic processing. Airflow visualization will be the topic of an upcoming column.
CONTINUING CLEANROOM COMPLIANCE
One final item to discuss is the periodic tasks for demonstrating continued compliance of a cleanroom with ISO
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14644 standards. These tasks include the following:
• HEPA filter leak testing: every 6 months for ISO
Class 5 and lower classifications, every 12 months
for classifications >ISO 5
• Particle classification: every 6 months for ISO 5 and
lower, every 12 months for >ISO 5
• Airflow volume or airflow velocity: every 12
months
• Air pressure difference: every 12 months.
Because of the routine particle counts in operational
conditions, verification of the classification of a cleanroom is usually performed under “at rest” conditions.
Retrospective review of in operation particle counts may
be used to demonstrate compliance under “in operation”
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Ed White, Coordinator.
conditions. Review and trending of viable and non-viable
particle counts should be part of a quality system for any
aseptic processing facility. Air pressure difference can also
be satisfied by review and trending of routine monitoring results—most building monitoring systems have
the capability of trending differential pressures. With
“in operaton” particle counts and differential pressures
satisfied by routine data, periodic recertification activities
are limited to HEPA filter leak testing, “at rest” particle
counts, and airflow volume or airflow velocity.
VALIDATION IMPLICATIONS
This column has discussed the cleanroom qualification
process through the classification phase. At this point,
the cleanroom is far from “validated.” The additional
validation tasks will be discussed in future columns.
REFERENCES
1.US Food and Drug Administration, Guidance for Industry:
Sterile Drug Products Produced by Aseptic Processing—Current
Good Manufacturing Practice, 2004.
2.European Commission: Enterprise and Industry Directorate-General, EudraLex–The Rules Governing Medicinal Products 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.
3.International Organization for Standardization (ISO),
ISO14644-4, Cleanrooms and Associated Controlled Environments–Part 4: Design, Construction and Startup, 2001.
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ADDITIONAL REFERENCES
ISO, ISO 14644-1, Cleanrooms and Associated Controlled Environment–Part 1: Classification of Air Cleanliness, 1999.
ISO, ISO 14644-2, Cleanrooms and Associated Controlled Environment–Part 2: Specifications for testing and monitoring
to prove continued compliance with ISO 14644-1, 2000.
ISO, ISO 14644-3, Cleanrooms and Associated Controlled Environment–Part 3: Test Methods, 2005. JVT
ARTICLE ACRONYM LISTING
A&E
BMS
CFD
CGMP
DPC
EU
FAT
FDA
HEPA
NEBB
IQ
ISO
Architectural and Engineering
Building Monitoring System
Computational Flow Dynamics
Current Good Manufacturing Practice
Discrete Particle Counter
European Commission
Factory Acceptance Test
US Food and Drug Administration
High Efficiency Particulate Air
National Environmental Balancing Bureau
Installation Qualification
International Organization for
Standardization
OQ
Operational Qualification
PQ
Performance Qualification
SAT
Site Acceptance Test
ULPA Ultra-Low Particulate Air
URS
User Requirements Specification
WFIWater-for-Injection
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