ISO and USA Cleanroom Standards

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 Cleanroom Control
ISO 14644 >>> ENVIRONMENT <<< FS 209E

Verification
focuses on
Environment

PROCESS PEOPLE
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 Cleanroom Control
ENVIRONMENT

Monitoring
focuses on
• PROCESS
• PEOPLE

PROCESS PEOPLE
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 Cleanroom Control
ENVIRONMENT

ISO 14644-1, -2
Verification
FS 209 E

GMP, cGMP
FDA Guidelines Monitoring
ISO 14644-3

PROCESS PEOPLE
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 Recent ISO Documents related to cleanrooms
ISO Document Title Status

ISO-14644-1 Classification of Air Cleanliness Active

ISO-14644-2 Cleanroom Testing for Compliance Active

Methods for Evaluating & Measuring Cleanrooms &

ISO-14644-3 Draft
Associated Controlled Environments

ISO-14644-4 Cleanroom Design & Construction Active

ISO-14644-5 Cleanroom Operations Draft

ISO-14644-6 Terms, Definitions & Units Draft

ISO-14644-7 Enhanced Clean Devices Draft

ISO-14644-8 Molecular Contamination Draft

ISO-14698-1 Biocontamination: Control General Principles Active

ISO-14698-2 Biocontamination: Evaluation & Interpretation of Data Active

Biocontamination: Methodology for Measuring Efficiency

ISO-14698-3 Active
of Cleaning Inert Surfaces

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 Cleanroom Verification
Initial and periodic certification
– Federal Standard 209E
– ISO 14644-1, -2
Three states
– As-built
– At Rest
– Operational / Dynamic
Averaging of Data from all positions

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 Verification: FS209E and ISO 14644-1
Define Cleanroom classes

Establish minimum sampling volumes

– purpose: gather a sample volume with theoretically at least 20
particles to help with statistical validity of sample

Establish minimum number of points to classify area, based

on statistical criteria

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 Verification: ISO 14644-1
ISO 14644-1 FED STD 209E ISO 14644-1 adds
ISO Class English Metric
– 2 “ultra-clean” classes
1
• ISO Class 1
2
• ISO Class 2
3 1 M1.5 – 1 “very dirty” class
4 10 M2.5 • ISO Class 9
5 100 M3.5 Total of 9 classes
6 1,000 M4.5 Counts / cubic meter
7 10,000 M5.5 Must specify room status
– “as-built” / “at rest” / “in operation
8 100,000 M6.5

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 Verification: ISO 14644-1
CLASS Number of Particles per Cubic Meter by Micrometer Size

0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um

ISO 1 10 2

ISO 2 100 24 10 4

ISO 3 1,000 237 102 35 8

ISO 4 10,000 2,370 1,020 352 83

FS 209E ISO 5 100,000 23,700 10,200 3,520 832 29

Class 100
ISO 6 1,000,000 237,000 102,000 35,200 8,320 293

ISO 7 352,000 83,200 2,930

ISO 8 3,520,000 832,000 29,300

ISO 9 35,200,000 8,320,000 293,000

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 Verification: ISO 14644-1 versus FS 209E
Parameter FS 209E ISO 14644-1

2.83 liter 2.0 liter

Minimum sample volume
(0.1 cubic foot) (0.07 cubic foot)

Minimum sample time not specified 1 minute

Minimum number of
1 1
samples at each location

Note: Typical sample volume may be larger than minimum listed above especially for
smaller size particles in very clean areas (better than ISO Class 5 or FS 209E Class 100)

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 Verification: Number of points required
ISO Class 5 FS Class 100

250

200

150

100

50

0
50 100 150 200 250 300 350 400 450 500
Floor Area in square meters
Generally, ISO 14644-1 and -2 require fewer number of sample positions because the
number is calculated by taking the square root of the floor area in square meters.

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 Verification: Number of points required
ISO Class 7 FS Class 10K

60

50

40

30

20

10

0
50 100 150 200 250 300 350 400 450 500
Floor Area in square meters
Generally, ISO 14644-1 and -2 require fewer number of sample positions because the
number is calculated by taking the square root of the floor area in square meters.
Because this Class is non-unidirectional or turbulent, FS 209E requires fewer points.

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 Continued Compliance: ISO 14644-2
Schedule of Tests to Demonstrate Continuing Compliance

Maximum Time
Test Parameter Class Test Procedure
Interval

Particle Count
<= ISO 5 24
6 Months
ISO 14644-1
Test Annex A
> ISO 5 12months
Months

Important
Air Pressure note: If Particle counts and Differential
All Classes 12 Months
ISO 14644-1
Difference Annex B5
Pressure are monitored continuously (for
example, by a Facility Monitoring System) then
ISO 14644-1
Airflow
the MaximumAllTime Classes
Interval12for
Months
re-certification
Annex B4
can be extended to 24 months.

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 FDA (monitoring) vs. 209E and ISO
FDA or GMP focus: parameters during operation
– dynamic or “in operation”
– potential effect on product is critical issue

but Verification is normally done during idle time

– infrequent but thorough check of the environment
– “as-built”
– “at rest”

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 Key Points regarding FDA and cleanrooms
FDA does not rely on or require FS 209E
Verification is different than Monitoring
FDA: process verification by media fill
FDA: operation control by monitoring
For monitoring, no standard specifies exactly
– the number of positions in fill room or others areas
– the placement of sample positions in an area

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 Cleanroom monitoring
Monitoring is intended to insure that the product
exposure is controlled within limits
because
even with a good environment . . .

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 People as Contamination
5 to 10 million cells per day

2300 micro-organisms per

square cm

Filter efficiency of clothing is

highly variable

. . . People and Process can

contaminate the Product.

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 Cleanroom Monitoring
In Operation or Dynamic Only
Relates to Process and Product Quality
Data needed for Product Release
Average only count data from same location
– each point must be below limit on the average
– but not necessarily each sample
– may be OK to delay ALERT or ACTION until 3rd or 5th
consecutive high reading

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 FDA prohibits averaging across positions
“A” “B”
for 2 positions in ISO
Class 5 (FS 209E
Class 100) ...
125 3
119 8
120 12
364 >> 121 FDA 8 << 23
says
65
“No !”
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 ISO Regulations
ISO 14644-1 Cleanroom Design (“new 209E”)
will eventually replace FS209E, even in USA (3 - 5 years)

EU GMP Annex I - Sterile Products

requires monitoring of 5 um particles as well as 0.5 um

ISO 13408 “Aseptic Guidelines”

very similar to FDA version for liquid filling

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 End:
ISO and USA Cleanroom Standards

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