New Regulations Concerning Airborne Particle Counters (ISO 21501 and ISO 14644) Bob Latimer, Tony Harrison 2008 Cleanrooms Worldwide eVent.

New Regulations Concerning Airborne Particle Counters (ISO 21501 and ISO 14644)

Bob Latimer, Tony Harrison2008

Cleanrooms Worldwide eVent

Copyright 2008 Hach Ultra Analytics – Page 2

Agenda

1. cGMP and EU GMP Guidelines

2. ISO 21501 Key Elements

3. What is ISO 21501 Replacing

4. Air Particle Sensors and Calibration – The Basics

5. Counting Efficiency

6. Resolution

7. Signal to Noise Ratio and False Count Rate

8. Summary


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”


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


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


What Standards/Guidelines ExistedPrior to ISO 21501?

• JIS B 9921:1997A Japanese standard which comprehensively deals with OPC design performance, most notably in the area of counting efficiency.

• 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Counter Using Mono-disperse Spherical Particles” (Officially withdrawn 2007).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

1997

1998

2006

2007


ISO 21501 Compared to Existing Re-calibrationCalibration Attribute ISO 21501-4 IEST-RP-CC014.1 ASTM F 328-98 JIS B (9921): 1997

Flow Rate 3.7, 4.7 6, A1, B1, C1 10.1 5.2.1 (6.3.1)

Size Calibration 3.1, 3.2, 4.1, 4.2, 4.3, Annex A7, A2 10.2 6.2

Zero Count (False Count Rate)

3.5, 4.5, Annex D 8, A3 10.3 5.2.2 (6.3.2

Counting Effeciency (CNC)

9, 11, A4, B2, B3, C3

Counting Effeciency (OPC)

10, 11, A5, B3, C4

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)

3.3, 4.3, Annex B 5.2.5 (6.3.5)10.5

A key difference with ISO 21501 is that key calibration attributes are incorporated within the scope of instrument re-calibration.

Minimum content on ISO 21501 calibration certificate.


MET ONE Air Particle Counters and ISO 21501 Calibration

MET ONE

Air Particle Counter

0.5µm and 5.0µm


Optical Particle Sensor Configuration

Light Trap

Collection Optics

Reflector

Detection Zone


Laser Diode

Detector

Collection Optics

Particle

Light Trap

Detecting Particles

t

v

Oscilloscope Pulse Height AnalyserOscilloscopeOscilloscope


The Pulse Height Analyzer (PHA)

OscilloscopeOscilloscopeWhen a 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.

When the sensors signal output is connected to Pulse Height Analyzer (PHA) the particles appear as a distribution with the x-axis 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

Mean size498 nm +/- 5 nm

Std Deviation7.9 nm

Size (nm)

NIST-traceable standard particles have normal size distribution.Nominal size and CV are certified.

Nominal Diameter 500nm

Certified Mean Diameter 498nm +/- 5nm

Standard Deviation 7.9nm

C.V. (a.k.a. RSD) 1.6%

Example: 0.5µm

498490.1

C.V. (RSD) =Std Dev

Mean size x 100


Selecting the Correct Calibration Voltage

The calibration voltage for a given PSL introduction

mode

median

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.


Calibrating Air Particle Counters: Constructing the Calibration

Voltage

Calibration requires that a variety of different PSL sizes are run and the median voltages are recorded.

PSL Size (µm) Peak (mV)0.299 35.20.499 2621.02 391

3.005 869.45.1 1736.39.9 5565.3

0.3 0.5 1.0 3.5 5.0

Calibration Example

Calibration of Air Particle Counters

3400 SN:

1

10

100

1000

10000

0.1 1 10

PSL Size (µm)

Sig

na

l (m

V)


ISO 21501: Counting Efficiency

= x 100 (%)

C

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.

The particle concentration (C)

displayed by particle counter Concentration (Co) of particles drawn into the inlet of an OPC

C.E. is the ratio:


Channel 1 size (um)Noise

N

Counting Efficiency – ISO 21501 Comparison to 100% Count Standard

Channel 1 set to 100% efficiency for UUT channel 1 size

Noise

N

Unit Under test

NIST-traceable ‘100% Count standard’ Example: Channel 1. Set to recover 100% of the challenge PLS

ISO 21501 Limits

50% +/- 20% (30% to 70%)

UUT

Standard

NIST Traceable

PSL Challenge


The counting efficiency for PSL particles of the UUT minimum measurable particle size shall be within the range 30% to 70%

ISO 21501 Limits50% +/- 20% (30% to 70%)

Channel 1 size (um)

OPC smallest specified size.

Noise

N

ISO 21501 and Counting Efficiency: A Two Part Test

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%

Channel 1 size (um)Noise

N

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

Particle size0.3µm

• Resolution – The ability to differentiate between similarly sized particles

• Affected by instrument quality and alignment of the sensor optics

0.5µm


Resolution – Why It Is Important

N

Particle size0.3µm

A particle sensor with poor resolution, such as the one above, cannot reliably distinguish between different sized particles.

0.5µm


1 1

D1 D2D

Peak(median)

61% of peak

ISO 21501 requires that resolution be calculated from +/- 1 standard deviation from the median.

The higher of the two values for (SD) is selected.

Resolution R% = CV(%) = RSD(%)

R% = x 100 (%)

2 - P 2

XPwhere

R Resolution

Observed SD in µm P PSL SD in m

XP PSL Size in µm

√


ISO 21501: False Count Rate – Affected by Signal to Noise Ratio

Channel 1

Peak to Valley Ratio

Noise

Channel 1Note: 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

Signal

ISO 21501 False Count RateZero count criteria per ISO-21501 (1 or less counts per 5 minutes)

95% UCL based on Poisson distribution

0

50

100

150

200

250

300

350

400

0 500 1000 1500 2000

Total Sample Time (minutes)

Fa

lse

Co

un

t Above Blue Line Fails

Below Blue Line Passes


ISO 21501-4 SummaryISO 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


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



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



• Customer support available at [email protected]


Thank You

New Regulations Concerning Airborne Particle Counters (ISO 21501 and ISO 14644) Bob Latimer, Tony Harrison 2008 Cleanrooms Worldwide eVent.

Documents

hach ultra analytics

airborne particle counters

calibration standard

air particle sensors

calibration met

revision of iso

calibration certificate

calibration example