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New Regulations Concerning
Airborne Particle Counters
(ISO 21501 and ISO 14644)
Bob Latimer, Tony Harrison
2008
Cleanrooms Worldwide eVent
Agenda
1.
2.
3.
4.
5.
6.
7.
8.
cGMP and EU GMP Guidelines
ISO 21501 Key Elements
What is ISO 21501 Replacing
Air Particle Sensors and Calibration – The Basics
Counting Efficiency
Resolution
Signal to Noise Ratio and False Count Rate
Summary
Copyright 2008 Hach Ultra Analytics – Page 2
Aseptic Pharmaceutical Manufacturing
• The cGMP and EU GMP guidelines specify
particle count limits based upon cleanroom
classifications such as Grade A, B, etc.
• Both EU GMP and cGMP reference ISO 14644-1
for determining cleanroom classification.
• The next revision of ISO 14644-1 will refer to
ISO21501-4, a calibration standard for air particle
counters, ratified February 2007.
• ISO 21501 already cross references back to
ISO 14644-1
ISO 21501-4 states – “Instruments that conform to this
part of ISO 21501 are used for the classification of air
cleanliness in cleanrooms and associated controlled
environments in accordance with ISO 14644-1”
Copyright 2008 Hach Ultra Analytics – Page 3
Calibration to ISO 21501 Key Elements
• Particle size calibration using PSL particles traceable to an
international standard and within a standard uncertainty
< =2.5%
• The use of a Pulse Height Analyzer (PHA) to determine
sensor response for each of the particle counters size
channels
• The intent is to improve the accuracy of particle count data
and improve instrument to instrument correlation
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ISO 21501 – Sub Documents
ISO 21501 describes the instruments and calibration
requirements.
• Part 2: Light scattering liquid-borne particle counter
• Part 3: Light extinction liquid-borne particle counter
• Part 4: Light scattering airborne particle counter for
clean spaces
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What Standards/Guidelines Existed
Prior to ISO 21501?
1997
•
JIS B 9921:1997
A Japanese standard which comprehensively deals
with OPC design performance, most notably in the
area of counting efficiency.
1998
•
ASTM F 328-98 (updated 2003)
“Standard Practice for Calibration of an Airborne
Particle Counter Using Mono-disperse Spherical
Particles” (Officially withdrawn 2007).
•
IEST-RP-CC014.1
“Calibration and Characterization of Optical
Airborne Particle Counters” (Provides actual
methods to perform the calibration).
•
ISO 21501
2006
2007
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ISO 21501 Compared to Existing Re-calibration
Calibration
Attribute
ISO 21501-4
IEST-RP-CC014.1
Flow Rate
3.7, 4.7
Size Calibration
3.1, 3.2, 4.1, 4.2, 4.3, Annex A
7, A2
Zero Count (False
3.5, 4.5, Annex D
Count Rate)
Counting
Effeciency (CNC)
3.3, 4.3, Annex B
Counting
Effeciency (OPC)
6, A1, B1, C1
8, A3
ASTM F 328-98
JIS B (9921): 1997
10.1
5.2.1 (6.3.1)
10.2
6.2
10.3
5.2.2 (6.3.2
9, 11, A4, B2, B3, C3
10.5
10, 11, A5, B3, C4
5.2.5 (6.3.5)
Coincidence Limit
3.6, 4.6
12, A6, C5
10.6
5.2.6 (6.3.6)
Resolution
3.4, 4.4, Annex C
13, A7
10.4
5.2.4 (6.3.4)
Sampling time
3.8, 4.8
5.2.7 (6.3.7
Response rate
3.9, 4.9, Annex E
5.2.3 (6.3.3)
Minimum content on ISO 21501 calibration certificate.
A key difference with ISO 21501 is that key calibration
attributes are incorporated within the scope of
instrument re-calibration.
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MET ONE Air Particle Counters and
ISO 21501 Calibration
MET ONE
Air Particle Counter
0.5µm and 5.0µm
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Optical Particle Sensor Configuration
Collection
Optics
Detection
Zone
Reflector
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Light Trap
Detecting Particles
Detector
v
Collection Optics
t
Light Trap
Laser Diode
Particle
Oscilloscope
Oscilloscope
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Pulse Height Analyser
The Pulse Height Analyzer (PHA)
When aOscilloscope
particle sensors
output is connected to an
oscilloscopes input the
particles appear as a
series of voltage pulses in
time. The amplitudes of
the pulses relate to the
amount of light energy
scattered by the particle
and are therefore related
to the sizes of the
particles.
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When the sensors
signal output is
connected to Pulse
Height Analyzer (PHA)
the particles appear as
a distribution with the xaxis being pulse height
and the y axis being
number of particles. The
above picture depicts a
typical room air sample.
The above picture
depicts a PHA response
to a mono-dispersed
challenge such as PSL
calibration spheres.
Calibrating Air Particle Counters:
NIST-traceable Particles
Example: 0.5µm
Mean size
498 nm +/- 5 nm
Std Deviation
7.9 nm
Nominal Diameter
500nm
Certified Mean Diameter
498nm +/- 5nm
Standard Deviation
7.9nm
C.V. (a.k.a. RSD)
1.6%
Std Dev
C.V. (RSD) =
490.1 498
x 100
Mean size
Size (nm)
NIST-traceable standard particles have normal size distribution.
Nominal size and CV are certified.
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Selecting the Correct Calibration Voltage
ISO 21501 requires that the PHA response to the PSL
spheres is interpreted as the median. This is the point where
an equal number of particles fall on each side of the
bisected distribution. For normal distributions the mode and
the median fall at the same point. This is not always the
case in particle counting where skewed or irregular
distributions are not uncommon.
The calibration voltage for a given PSL introduction
Copyright 2008 Hach Ultra Analytics – Page 13
median
mode
Calibrating Air Particle Counters:
Constructing the Calibration
Calibration Example
PSL Size (µm)
0.299
0.499
1.02
3.005
5.1
9.9
0.3 0.5 1.0
3.5
Peak (mV)
35.2
262
391
869.4
1736.3
5565.3
5.0
Calibration requires that a variety of different PSL sizes are run
and the median voltages are recorded.
Copyright 2008 Hach Ultra Analytics – Page 14
Voltage
Calibration of Air Particle Counters
3400 SN:
10000
Signal (mV)
1000
100
10
1
0.1
1
PSL Size (µm)
10
ISO 21501: Counting Efficiency
The particle concentration (C)
C.E. is the ratio:
displayed by particle counter
Concentration (Co) of particles
drawn into the inlet of an OPC
=
C
x 100 (%)
Co
• Counting efficiency has arguably been the biggest variable
impacting the accuracy of airborne counters.
• Counting efficiency refers to the ability of the instrument to
count particles at a specified size.
• ISO 21501 makes use of the specification for counting
efficiency that was defined in the JIS B 9921 standard.
Copyright 2008 Hach Ultra Analytics – Page 16
Counting Efficiency – ISO 21501 Comparison
to 100% Count Standard
N
UUT
ISO 21501 Limits
50% +/- 20% (30% to 70%)
NIST
Traceable
PSL
Challenge
Unit Under test
Noise
Channel 1 size (um)
N
Standard
NIST-traceable ‘100% Count standard’
Example: Channel 1. Set to recover
100% of the challenge PLS
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Noise Channel 1 set to 100% efficiency
for UUT channel 1 size
ISO 21501 and Counting Efficiency:
A Two Part Test
N
N
ISO 21501 Limits
50% +/- 20% (30% to 70%)
OPC smallest
specified size.
Noise
Channel 1 size (um)
The counting efficiency for PSL particles
of the UUT minimum measurable particle
size shall be within the range 30% to
70%
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At 1.5 x to 2 x the
particle counters minimum
specified size all particles
should be counted in the first
channel. ISO 21501 allowed
limits are 90% to 110%
Noise
Channel 1 size (um)
AND for PLS particles of 1.5 times or
over up to and including two times the
minimum measurable particle size
value, shall be 90% to 110%
ISO 21501: Resolution
N
0.3µm
0.5µm
Particle
size
• Resolution – The ability to differentiate between similarly sized particles
• Affected by instrument quality and alignment of the sensor optics
Copyright 2008 Hach Ultra Analytics – Page 19
Resolution – Why It Is Important
N
0.3µm
0.5µm
A particle sensor with poor resolution, such as the
one above, cannot reliably distinguish between
different sized particles.
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Particle
size
Resolution R% = CV(%) = RSD(%)
ISO 21501 requires that resolution be
calculated from +/- 1 standard deviation
from the median.
The higher of the two values for  (SD) is
selected.
Peak
(median)
61% of
peak
2- 2

√
P
R% =
1 1
XP
x 100 (%)
where
R

P
XP
D1 D D2
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Resolution
Observed SD in µm
PSL SD in mm
PSL Size in µm
ISO 21501: False Count Rate –
Affected by Signal to Noise Ratio
Noise
Signal
Peak to Valley Ratio
Channel 1
Channel 1
Note: ISO 21501 does not specify a minimum S:N ratio although False Count Rate
is (next slide). Peak to Valley is described although not specified. Hach Ultra
maintains an internal Peak to Valley specification of 2:1
Copyright 2008 Hach Ultra Analytics – Page 22
ISO 21501 False Count Rate
Zero count criteria per ISO-21501 (1 or less counts per 5 minutes)
95% UCL based on Poisson distribution
400
350
False Count
300
250
Above Blue
Line Fails
200
Below Blue
Line Passes
150
100
50
0
0
500
1000
1500
Total Sample Time (minutes)
2000
ISO 21501-4 Summary
ISO 21501-4 Parameters
Limit
Sampling flow rate (volumetric)
± 5%
Counting efficiency at channel 1
50% ± 20%
Counting efficiency at particle size 1.5 to 2 times channel 1
100% ± 10%
Particle size setting error
≤ 10%
Instrument resolution (at manufacturers specified size)
≤ 15%
Zero count test
≤ 1 count / 5 minutes
Maximum particle number concentration (manufacturer specified)
≤ 10%
Sampling time
± 1%
Response rate
≤ 0.5%
Calibration interval
≤ 1 year
Test Report Must Include as a Minimum:
Date of calibration
Particle sizes used for calibration
Flow rate
Size resolution
Counting efficiency
False count rate
Copyright 2008 Hach Ultra Analytics – Page 24
Hach Ultra and ISO 21501
• Hach Ultra has completed a full migration to ISO
21501 calibrations.
• Hach Ultra offers a complete line of ISO 21501
compliant air particle counters.
• Hach Ultra offers full ISO 21501 field and factory
calibration offerings designed to ensure accurate and
efficient service that goes beyond the instrument
– Certified Calibration Service Agreements with your choice of
either In-House and\or Service-at-your-Site options.
– Prescheduled calibration and preventative maintenance
services
Copyright 2008 Hach Ultra Analytics – Page 25
Hach Ultra and ISO 21501
Calibrations performed by Hach Ultra ISO 21501 certified
technicians
• 60 Global Direct Certified field technicians guarantees
prompt qualified support
– Hach Ultra technicians average over 8 years of Hach Ultra
calibration experience per associate
• 10 ISO 21501 capable factory service centers
– 1 US based ISO 9001:2000 certified factory service center
– 3 Strategically located US remote depot service centers to
support walk-in and close to customer depot support
– 5 European remote factory service centers
– 1 Asian remote factory service center
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Hach Ultra and ISO 21501
• Customer support available at
[email protected]
Copyright 2008 Hach Ultra Analytics – Page 27
Thank You
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