PhEn-602
Notes # 4
J. Manfredi
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Basic definitions
Clean Room: A room in which the
concentration of airborne particles is
controlled and contains one or more clean
zones
Clean Zone: A defined space in which the
concentration of airborne particles is
controlled to meet a specified airborne
particulate class.
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Federal Standard 209E (FS-209E)
provides Clean Room Classes
Rooms classified based on number of
particles > 0.5 micron per cubic foot
Class descriptions still in use today.
FS 209E is concerned about the
following particle sizes, in microns:
0.1, 0.2, 0.3, 0.5, 5.0
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Types of Contaminants
Viable
Particulates
Non-Viable
Particulates
Pharmaceutical Facility Design
Spring 2009
Controlled Environments Types of Contaminants
Non-viable Particulates
Metal specks, fiber from clothing
Obtained from: Equipment, people, tools
Viable (micro-organisms)
Bacteria
Yeast, molds
Obtained from: People, outside air, water,
equipment, tools, excipients, active
ingredients
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Sources of particulate generation
Internal:
Personnel
Normally the highest source of contamination
Process
Air conditioning system
Introduction of raw materials
Introduction of equipment and materials
External
Outside air
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Some interesting facts:
Visible indoor air particles constitute only about 10% of particles
present in indoor air.
It may be possible to see particles as small as 10 microns
It may be possible to see particles as small as 10 microns under
favorable conditions.
The majority of harmful particles are 3 microns or less in size.
Particles of 1 micron or less adhere to surfaces by molecular
adhesion. Scrubbing is generally the only way to remove them.
Larger particles tend to settle out of the atmosphere due to
weight.
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Some more interesting facts:
Smaller, "respirable" particles remain virtually
suspended in the air until breathed in.
Approximately 98-99% of all particles by count are in
the size range of 5 microns or less. These particles
tend to remain in suspension or settle out so slowly.
From: www.peakpureair.com/particlesize.htm
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
Common items and their respective
particle sizes:
Microns
Eye of a needle
1,230
Human Hair
40 300
Oil Smoke
0.03 to 1
Bacteria
0.3 to 20
Pollens
10 to 1,000
Coal Dust
1 to 100
Beach sand
100 to 2,000
Mold spores
0.5 to 20
Tobacco smoke
0.01 to 1
Typical Atmospheric 0.001 to 30
Dust
Pharmaceutical Facility Design
Spring 2009
Clean Rooms and Controlled Environments
25 Microns
Dust
0.5 Microns
Other
contaminants
100
Microns
Human Hair
Pharmaceutical Facility Design
Spring 2009
10
Personnel Largest Source of
Contamination
People are huge sources of contamination - the
biggest source of viable and non-viable
contamination
Each adult loses about 6 - 14 grams of dead
skin material every day
Each person loses a complete layer of skin
about every four days - equivalent to
10,000,000 particles per day!
Ordinary walking movements emit about
10,000 particles per minute.
Pharmaceutical Facility Design
Spring 2009
11
Personnel Largest Source of Contamination
Particle Generation Rate
Particles/second
Walkin
g in No
rm al C
lothes
105
Walkin
g in Cle
a n r oo m
g a rm e n
ts
104
10
C a re f u
lly Walk
ing in G
oo d C l
e an ro o
m garm
ents
100
0.1
0.2
0.3
Particle size
0.5
Pharmaceutical Facility Design
Spring 2009
1.0
12
Clean Rooms and Controlled Environments
Occupancy state of the cleanroom:
As-Built:
As constructed, with no
equipment or personnel in room
At-Rest: Equipment in room, but no
personnel
Operational: (also called In-Operation)
Personnel and equipment in room, under
normal operations
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic Guidelines 1987
Requires pharmaceutical companies to use the FS209E classifications for aseptic manufacturing.
Non-viable particle levels must meet the FS 209E
classes.
Concerned only with the in-operation condition.
Concerned only with particles greater than or equal to
0.5 microns.
Contains limits for viable particles also to be
discussed later.
Website: www.fda.gov/cder/guidance /old027fn.pdf
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic Guidelines 1987
Controlled Area:
A controlled area is one in which unsterilized drug
product, in-process materials or containers/closures
are prepared.. acceptable air quality if it has a percubic-foot particle count of not more than 100,000 in
a size range of 0.5 micron and larger (Class 100,000)
when measured in the vicinity of the exposed articles
during periods of activity.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic Guidelines 1987
Critical Area:
A critical area is one in which the sterilized
drug product, containers, and closures are
exposed to environmental
conditions.acceptable air quality of Class
100 in a size range of 0.5 micron or larger
when measured no more than 1 ft away
from work site
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic guidelines: section 4, Buildings and
Facilities: Clean area control parameters should be
supported by microbiological and particle data obtained
during qualification studies. Initial cleanroom
qualification includes, in part, an assessment of air quality
under as-built, static conditions. It is important for area
qualification and classification to place most emphasis on
data generated under dynamic conditions (i.e., with
personnel present, equipment in place, and operations
ongoing). An adequate aseptic processing facility
monitoring program also will assess conformance with
specified clean area classifications under dynamic
conditions on a routine basis.
Pharmaceutical Facility Design
Spring 2009
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FDA Aseptic Guide Class of Clean Room
Supporting Clean Areas
Supporting clean areas can have various classifications and
functions. Many support areas function as zones in which
nonsterile components, formulated products, in-process
materials, equipment, and container/closures are prepared,
held, or transferred. These environments are soundly
designed when they minimize the level of particle
contaminants in the final product and control the
microbiological content (bioburden) of articles and
components that are subsequently sterilized.
Pharmaceutical Facility Design
Spring 2009
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FDA Aseptic Guide Class of Clean Room
Supporting Clean Areas
The nature of the activities conducted in a supporting
clean area determines its classification. FDA recommends
that the area immediately adjacent to the aseptic
processing line meet, at a minimum, Class 10,000 (ISO 7)
standards under dynamic conditions. Manufacturers can
also classify this area as Class 1,000 (ISO 6) or maintain
the entire aseptic filling room at Class 100 (ISO 5). An
area classified at a Class 100,000 (ISO 8) air cleanliness
level is appropriate for less critical activities (e.g.,
equipment cleaning).
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic Guidelines as mentioned:
Originally published in 1987
Revised - September 2004
Guidance for Industry Sterile Drug Products Produced by
Aseptic Processing
http://www.fda.gov/cder/guidance/5882fnl.htm
These are Guidelines not regulations
(21 CFR 210 and 211 are regulations/law).
However, as far as manufacturers are concerned, they are as
important as the law, since it represents FDAs current thinking and
expectations.
Section IV: Buildings and Facilities
*important guidelines re: aseptic facility design
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Federal Standard 209E Cleanroom
Classes
Class
Max. # Particles/ft3
(English) of a size 0.5 m
1
1
10
10
100
100
1,000
1,000
10,000
10,000
100,000
100,000
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
The development of ISO standards:
Before 2000 each country developed its own
cleanroom standards
US followed Federal Standard 209E
Several European Countries assembled as
part of CEN - Committee for European
Normalization - to standardize cleanroom
standards CEN standards were initiated
Prior agreement between ISO and CEN
ISO standards would take precedence
Pharmaceutical Facility Design
Spring 2009
22
Clean Rooms and Controlled Environments
Cleanroom Standards:
FS 209E - The traditional cleanroom
standard for all industries.
Obsolete as of November 2001,
replaced by ISO standards
FS 209E still being used by many..
Industry currently uses both 209E and
ISO classifications in the design of
todays cleanroom, but 209E will
eventually fade-away
Pharmaceutical Facility Design
Spring 2009
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Cancellation of FED-STD-209E
The U.S. General Services Administration (GSA) released a Notice of Cancellation for FED-STD-209E, Airborne
Particulate Cleanliness Classes in Cleanrooms and Clean Zones, on November 29, 2001. (Please note that the
IEST address changed after the issuance of the notice. The new address is 5005 Newport Drive, Suite 506,
Rolling Meadows, IL 60008-3841.)
The Notice of Cancellation is based on the recommendation by IEST Working Group CC100 that FED-STD-209E
no longer be maintained. The IEST, assigned by the GSA as the Preparing Activity organization for FED-STD209E, has recommended that International Standard ISO 14644, Cleanrooms and controlled environmentsPart 1: Classification of air cleanliness, and Part 2: Specifications for testing and monitoring to prove continued
compliance with ISO 14644-1, supersede FED-STD-209E.
ISO 14644-1 and 14644-2 are two parts of a multi-part group of ISO Standards developed by ISO Technical
Committee 209 (ISO/TC 209). All ISO/TC 209 Standards may be ordered online through IEST. Click here to
enter the IEST Publications Store.
NOTICE OF CANCELLATION
FED-STD-209 NOTICE 1
November 29, 2001
FEDERAL STANDARD
AIRBORNE PARTICULATE CLEANLINESS CLASSES
IN CLEANROOMS AND CLEAN ZONES
Federal Standard 209E dated September 11, 1992 is hereby canceled and
superseded by International Organization for Standardization (ISO)
Standards. International Standards for Cleanrooms and associated
controlled environments, ISO 14644-1 Part 1: Classification of air
cleanliness; and ISO 14644-2 Part 2: Specifications for testing and
monitoring to prove continued compliance with ISO 14644-1.
Application for copies of ISO Standards 14644-1 Part 1, and 14644-2 Part
2; may be addressed to the Institute of Environmental Sciences and
Technology (IEST), 940 East Northwest Highway, Mount Prospect, IL
60056-3444. Phone: 847-255-1561, Fax: 847-255-1699, Web site:
www.iest.org, E-mail: [email protected].
Preparing Activity: GSA-FSS
FSC 3694
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
ISO Technical Committee 209 was formed
(no relation to FS 209 which was to be
superceded)
Each country sent their delegates to the
committee meetings
First meeting in 1993
Scope: To develop a set of international
standards which standardize equipment,
facilities and operational methods for
cleanrooms and associated controlled
environments
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Scope included defining operational limits,
procedural limits and testing attributes to
minimize micro-contamination.
Over 36 countries were involved
US Team consisted of representatives from
industry, consultants, cleanroom
manufacturers, IEST, FDA
IEST: Institute of Environmental Sciences
and Testing
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Eight ISO standards originally conceived
14644-1
14644-2
14644-3
14644-4
14644-5
14644-6
14644-8
Classification of Air Cleanliness Approved
Specifications for Testing and Monitoring
to Ensure Continued Compliance with ISO
14644-1 Approved
Metrology and Test Methods
Design, Construction and Start-up
Operation
Terms and Definitions (dictionary) 14644-7
Separative enclosures (clean air hoods,
gloveboxes, isolators, mini environments)
Molecular Contamination
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
ISO Standards: 14644-1 and 14644-2 most
important of all standards
Part 1: Classification of air cleanliness
Gives the airborne particle limits for different standards
of cleanrooms. It also gives the methods that should be used
to measure the airborne particles when testing a cleanroom to
determine its class.
Part 2: Specifications for testing and monitoring to prove
continued compliance with ISO 14644-1
Gives information, including time intervals, for testing a
cleanroom to show that it still complies with the ISO 14644-1
standard.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
ISO Standards:
Part 3: Metrology and test methods
Gives a description of the test methods that should be used to test the
cleanroom to show that it is working correctly.
Part 4: Design, construction, and startup
Gives general guidance as to how a cleanroom should be designed,
constructed and made ready for handing over to the user.
Part 5: Operation
Gives general advice on how to run a cleanroom.
Part 6: Terms and definitions
A collection of all the definitions of terms used in the ISO cleanroom
standards.
Part 7: Separative enclosures (clean air hoods, gloveboxes, isolator,
mini environments)
Gives information on clean air devices such as isolators and minienvironments
Part 8: Molecular contamination
Gives information on gaseous contamination in cleanrooms.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Must classify each clean room in terms of:
ISO
class
Occupancy
Particle
state
Size
e.g.: ISO Class 5 as-built at 0.2 and
0.5 micrometers
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
ISO 14644-1 gives a method to classify
cleanrooms. The classification is based on
the following equation:
Cn=10N(0.1/D)2.08
Cn is the maximum permitted concentration (in particles/m of air) of airborne
particles that are equal to, or larger, than the considered particle size.
Cn is rounded to the nearest whole number, using no more than three
significant figures.
N is the ISO classification number, which shall not exceed the value of 9.
Intermediate ISO classification numbers may be specified, with 0.1 the smallest
permitted increment of N.
D is the considered particle size in mm.
0.1 is a constant with a dimension of mm.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled
Environments Cleanroom Standards
FS 209E - US Federal Standard 209E
ISO - International Standards Organization the
NEW standards very important
IEST- Institute of Environmental Sciences and
Testing
FDA Aseptic Guidelines
EU - European Union GMPs
USP - United States Pharmacopeia
Pharmaceutical Facility Design
Spring 2009
32
Clean Rooms and Controlled
Environments Cleanroom Standards
Pharmaceutical
Regulatory/Guidance
Documents
General Standards
ISO
STANDARDS
14644-1
14644-2
FDA
ASEPTIC
GUIDELINES
USP
US
FS 209 E
IEST
(EU)
European
Union
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Major issues addressed in the next few weeks:
Understand differences between FDA Aseptic
Guidelines and EU Requirements
Understand differences between FS 209E and ISO
14644-1
Perform basic particle distribution calculations to
verify class
Be able to relate manufacturing process to the
Class of Clean Room, both for FDA and EU
requirements.
Pharmaceutical Facility Design
Spring 2009
34
Clean Rooms and Controlled Environments
Unit of measure for particle size:
Metric: Micron.same as micrometer,
1 micron=10-6 meters.
Denoted as: Micron: m
1inch=25,400 microns
1/16 of an inch=1,587 microns
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FDA Aseptic Guidelines
Important Notes:
FDA Aseptic guidelines do not allow averaging at a sampling site!
Each discrete sample must be below the class limit.
This is important, since you can pass ISO and FS 209E, and not
meet FDA requirement.
FDA aseptic guidelines still reference the FS 209E classes, as well
as the ISO classes. They are allowing manufacturers too use
either system for cleanroom certification.
The Pharmaceutical Industry does not typically use Class 1 or
Class 10 rooms. These designations are commonly used in the
semiconductor industry.
Pharmaceutical Facility Design
Spring 2009
36
Clean Rooms and Controlled Environments
Federal Standard 209E Cleanroom
Classes with metric designations
Class
(English)
# Particles/ft3
0.5 m
M 1.5
M 2.5
10
10
M 3.5
100
100
M 4.5
1,000
1,000
M 5.5
10,000
10,000
M 6.5
100,000
100,000
SI Class
Pharmaceutical Facility Design
Spring 2009
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FS 209E and other particle size limits
Pharmaceutical Facility Design
Spring 2009
38
Clean Rooms and Controlled Environments
ISO Classes- Particles per Cubic Meter
CLASS
0.1m
ISO 1
ISO 2
ISO 3
ISO 4
ISO 5
ISO 6
ISO 7
ISO 8
ISO 9
0.2m
PARTICLE SIZE
0.3m 0.5m
1m
10
2
100
24
10
1,000
237
102
10,000
2,370
1,020
100,000 23,700 10,200
1,000,000 237,000 102,000
4
35
352
3,520
35,200
352,000
3,520,000
35,200,000
Pharmaceutical Facility Design
Spring 2009
5m
8
83
832
29
8,320
293
83,200
2,930
832,000 29,300
8,320,000 293,000
39
Clean Rooms and Controlled Environments
Pharmaceutical:
A controlled* area where personnel are required to
be in a minimal amount of gowning. (e.g.: Packing
hall). Typical gowning consists of coat, hat and
shoe covers
*controlled term is used generically. It is different from the
controlled area referenced in the 1987 Aseptic guidelines.
Pharmaceutical with local monitoring:
A pharmaceutical area that has at least some
portions designed as Class 100,000 at rest.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Pharmaceutical also called
Controlled Not Classified
Often designed as EU Grade D
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Unclassified area:
self explanatory.typical of general access
areas, mechanical rooms,etc.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
US Pharmacopeia (USP) Considerations:
Classification of clean rooms and other
controlled environments is based on Federal
Standard 209E.
Pharmaceutical and Medical Device
manufacturers have adopted the classifications:
Class 100, Class 10,000 and Class 100,000
These classes are now represented by
M3.5, M5.5, M6.5.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
USP Considerations
Pharmaceutical industry deals with class
M3.5 and above.
Higher cleanliness levels are typically
used in the electronics industry.
Classes are based on in-operation or
dynamic mode.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
USP Considerations
Although there is no direct relationship
established between the 209E controlled
environment, it is generally accepted by
scientists that airborne microorganisms in
controlled environments can influence the
microbiological quality of the intermediate or
final products manufactured..
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
USP Considerations
Monitoring of total particulate count in controlled
environments, even with the use of electronic
instrumentation on a continuous basis, does not
provide information on the microbiological content
of the environment... While airborne
microorganisms are not free-floating or single cells,
they frequently associate with particles of 10 to 20
m. Particulate counts as well as microbial counts
within controlled environments vary with the sampling
location and the activities being conducted during
sampling.
Pharmaceutical Facility Design
Spring 2009
46
Clean Rooms and Controlled Environments
For the Pharmaceutical Industry in the US, the
primary document to follow is the FDA Aseptic
Guidelines
For the European community, the EU GMPs provide
requirements for cleanroomswell discuss this in
more detail later
Both the FDA and EU GMPs requirements are
consistent with the classes represented in FS 209E
and ISO standards
For the US, the USP also contains requirements for
controlled environments/clean rooms
Latest USP publication: #31
Pharmaceutical Facility Design
Spring 2009
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Controlled Environments
How do we reduce the level of contaminants?
Airborne particles are HEPA filtered
Contact parts are cleaned and sterilized
Use of steam sterilization or irradiation of components
Water purification systems are installed
Limit aseptic core interventions
Sterile filter the bulk solution (product)
Wear clean room garments - limit shedding..follow proper
aseptic techniques.very important.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Unidirectional Flow: Also called Laminar Flow
airflow having generally parallel
streamlines, operating in a single direction,
and with uniform velocity over its cross
section. For example:
VERTICAL
UNIDIRECTIONAL
FLOW
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Non-unidirectional Flow: Also called mixedflow or turbulent flow airflow which is not
unidirectional. For example:
NON-UNIDIRECTIONAL FLOW
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
ISO vs FS209E: key differences
Three new classes were introduced; ISO Class 1 and Class 2,
both of which are cleaner than FS 209E Class 1, & ISO Class 9.
For the most part, ISO Class 3 through 8 are very similar to FS
209E Class 1 through 100,000.
ISO added the 1.0 micron particle size
ISO generally requires fewer sampling locations than FS 209E
With ISO, number of sample locations is based on clean room
area, whereas FS 209E it is based on Class, size of clean room,
and whether or not unidirectional flow is present
ISO has a minimum 1 minute sample time, FS 209E does not.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Common items: ISO Standard 14644-1 & 2
and FS 209E
No fewer than two sample locations
If less than 10 samples are taken, then use statistical methods.
Minimum sample volume and time is also dictated in each
standard
Averaging particle readings at a site is allowed. Two rules:
Acceptable as longs as average at each site is below the class limit.
Average of all sites should not exceed class limit, adjusted to 95%
upper confidence intervalnormal distribution assumed.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FS 209E & ISO Standard 14644-1 & 2
Note that the number of sampling locations is the minimum
required.
Its often easier to sample a room at 10 or more locations,
rather than going through the statistical analysis
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
Common items - ISO Standard 14644-1 & 2 and FS 209E
If less than 10 samples are taken, then use of
statistical methods is required.
Averaging particle readings at a site is allowed.
Two rules:
Acceptable as longs as average at each site is below the
class limit.
The 95% UCL (Upper Confidence Level) of the averages
of all sites should not exceed the class limit.
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
FS 209E & ISO Standard 14644-1 & 2
Sampling height is within 1 foot of equipment work surface
area
If no equipment present, typically 40 aff. is used
(aff.= above finished floor)
Note that the number of sampling locations is the minimum
required.
Its often easier to sample a room at 10 or more locations,
rather than going through the statistical analysis
Pharmaceutical Facility Design
Spring 2009
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Clean Rooms and Controlled Environments
European Union Guide to Good
Manufacturing Practices (EU cGMP)
Formal title: The Rules Governing Medicinal
Products in the European Union. Volume 4.
Good Manufacturing Practices Medicinal
Products for Human and Veterinary Use
Establishes four grades: Grade A, B, C, D
Each grade has limits for viable and nonviable particulates
Pharmaceutical Facility Design
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