Determination of particle size distribution -- Single particle light interaction methods

This document describes a calibration and verification method for a light extinction liquid-borne particle counter (LELPC), which is used to measure the size and particle number concentration of particles suspended in liquid. The light extinction method described in this document is based on single particle measurements. The typical size range of particles measured by this method is between 1 µm and 100 µm in particle size. The method is applicable to instruments used for the evaluation of the cleanliness of pharmaceutical products (e.g. injections, water for injections, infusions), as well as the measurement of number and size distribution of particles in various liquids. The following are within the scope of this document: — size setting error; — counting efficiency; — size resolution; — maximum particle number concentration; — sampling flow rate error; — sampling time error; — sampling volume error; — calibration interval; — reporting results from test and calibration.

Détermination de la distribution granulométrique -- Méthodes d'interaction lumineuse de particules uniques

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Status
Published
Publication Date
21-Nov-2019
Current Stage
6060 - International Standard published
Start Date
21-Oct-2019
Completion Date
22-Nov-2019
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INTERNATIONAL ISO
STANDARD 21501-3
Second edition
2019-11
Determination of particle size
distribution — Single particle light
interaction methods —
Part 3:
Light extinction liquid-borne particle
counter
Détermination de la distribution granulométrique — Méthodes
d'interaction lumineuse de particules uniques —
Partie 3: Compteur de particules en suspension dans un liquide par
extinction de la lumière
Reference number
ISO 21501-3:2019(E)
ISO 2019
---------------------- Page: 1 ----------------------
ISO 21501-3:2019(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2019

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

below or ISO’s member body in the country of the requester.
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Phone: +41 22 749 01 11
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Email: copyright@iso.org
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Published in Switzerland
ii © ISO 2019 – All rights reserved
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ISO 21501-3:2019(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Principle ........................................................................................................................................................................................................................ 3

5 Basic configuration ............................................................................................................................................................................................ 3

6 Requirements .......................................................................................................................................................................................................... 3

6.1 Size setting error ................................................................................................................................................................................... 3

6.2 Counting efficiency .............................................................................................................................................................................. 4

6.3 Size resolution ......................................................................................................................................................................................... 4

6.4 Maximum particle number concentration ...................................................................................................................... 4

6.5 Sampling flow rate error ................................................................................................................................................................ 4

6.6 Sampling time error ........................................................................................................................................................................... 4

6.7 Sampling volume error .................................................................................................................................................................... 4

6.8 Calibration interval ............................................................................................................................................................................. 4

6.9 Reporting of test and calibration results .......................................................................................................................... 4

7 Test and calibration procedures .......................................................................................................................................................... 5

7.1 Size setting .................................................................................................................................................................................................. 5

7.1.1 Evaluation of size setting error ........................................................................................................................... 5

7.1.2 Procedure of size setting ........................................................................................................................................... 5

7.2 Evaluation of counting efficiency ............................................................................................................................................ 8

7.3 Evaluation of size resolution ....................................................................................................................................................... 9

7.4 Estimation of coincidence loss at the maximum particle number concentration .....................10

7.5 Evaluation of sampling flow rate error ...........................................................................................................................11

7.6 Evaluation of sampling time error ......................................................................................................................................11

7.7 Evaluation of sampling volume error ...............................................................................................................................11

Annex A (informative) Size resolution .............................................................................................................................................................12

Annex B (informative) Procedure for evaluating the uncertainties of the results of the

performance tests ............................................................................................................................................................................................13

Bibliography .............................................................................................................................................................................................................................18

© ISO 2019 – All rights reserved iii
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ISO 21501-3:2019(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

Any trade name used in this document is information given for the convenience of users and does not

constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/

iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 24, Particle characterization including

sieving, Subcommittee SC 4, Particle characterization.

This second edition cancels and replaces the first edition (ISO 21501-3:2007), which has been

technically revised. The main changes from the previous edition are as follows:

— Clause 4 for “Principle” and Clause 5 for “Basic configuration” have been added;

— “size calibration” and “verification of size setting” have been combined as “size setting error” in the

requirements (Clause 6);

— “Test report” (3.10 in the previous edition) has been changed to 6.9 on “Reporting of test and

calibration results”;

— information about uncertainties has been enriched and is now the subject of Annex B.

A list of all parts in the ISO 21501 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
iv © ISO 2019 – All rights reserved
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ISO 21501-3:2019(E)
Introduction

Monitoring particle contamination levels is required in various fields, e.g. in the electronic industry, in

the pharmaceutical industry, in the manufacturing of precision machines and in medical operations.

Particle counters are useful instruments for monitoring particle contamination in liquid. The purpose

of this document is to provide a calibration procedure and verification method for particle counters, so

as to minimize the inaccuracy in the measurement result by a counter, as well as the differences in the

results measured by different instruments.
© ISO 2019 – All rights reserved v
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INTERNATIONAL STANDARD ISO 21501-3:2019(E)
Determination of particle size distribution — Single
particle light interaction methods —
Part 3:
Light extinction liquid-borne particle counter
1 Scope

This document describes a calibration and verification method for a light extinction liquid-borne

particle counter (LELPC), which is used to measure the size and particle number concentration of

particles suspended in liquid. The light extinction method described in this document is based on single

particle measurements. The typical size range of particles measured by this method is between 1 µm

and 100 µm in particle size.

The method is applicable to instruments used for the evaluation of the cleanliness of pharmaceutical

products (e.g. injections, water for injections, infusions), as well as the measurement of number and

size distribution of particles in various liquids.
The following are within the scope of this document:
— size setting error;
— counting efficiency;
— size resolution;
— maximum particle number concentration;
— sampling flow rate error;
— sampling time error;
— sampling volume error;
— calibration interval;
— reporting results from test and calibration.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at https:// www .iso .org/ obp
© ISO 2019 – All rights reserved 1
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ISO 21501-3:2019(E)
3.1
calibration particles

monodisperse spherical particles with a known mean particle size, e.g. polystyrene latex (PSL) particles,

where the certified size is traceable to the International System of Units (SI), a relative standard

uncertainty of the certified size is equal to or less than 2,5 %, a refractive index that is approximately

1,59 at the wavelength of 589 nm (sodium D line)

Note 1 to entry: For spherical particles, the particle size is equal to the diameter.

3.2
counting efficiency

ratio of the particle number concentration measured by a light extinction liquid-borne particle counter (3.3)

of a certified reference material (3.7) for particle number concentration to the certified value of the CRM

3.3
LELPC
light extinction liquid-borne particle counter

instrument that measures liquid-borne particle numbers by counting the pulses as the particles pass

through the sensing volume, as well as particle size by the attenuation of light

Note 1 to entry: The optical particle size measured by the LELPC is the light extinction equivalent particle size

and not the geometrical size.
3.4
PHA
pulse height analyser
instrument that analyses the distribution of pulse heights
3.5
size resolution

measure of the ability of an instrument to distinguish between particles of different sizes

3.6
coincidence loss

reduction of particle count caused by multiple particles passing simultaneously through the sensing

volume and/or by the finite processing time of the electronic system
3.7
CRM
certified reference material

particle suspension, typically polystyrene latex particles suspended

in pure water, sufficiently homogeneous and stable, characterized for the mean particle size and number

concentration by a metrologically valid procedure, accompanied by a reference material certificate

that provides the associated uncertainties for the traceable values, and a statement of metrological

traceability

Note 1 to entry: If no CRM standards are available, the use of a particle suspension characterised with

corresponding uncertainties for particle size and concentration is sufficient.
3.8
MPE
maximum permissible error
limit of error

extreme value of measurement error, with respect to a known reference quantity value, permitted by

specifications for a given measurement, measuring instrument, or measuring system

Note 1 to entry: This document uses decimal numbers for the requirements to MPEs to avoid confusions that may

arise when relative uncertainties of test results are reported in percent figures.

2 © ISO 2019 – All rights reserved
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ISO 21501-3:2019(E)
4 Principle

The measurement principle of the LELPC is based on detection of light extinction by a particle when the

particle passes through an incident light beam.

The particle size is determined from the attenuation of light, and the number of particles from the

number of light extinction pulses by individual particles.

More specifically, a sample liquid is drawn from the inlet of the LELPC at a constant flow rate, and

introduced to the sensing volume of the LELPC where a light beam is irradiated. When a particle

suspended in the sample liquid passes through the light beam, it attenuates the light, occurring a

light extinction pulse. The light extinction pulse is detected by a photo detector, and converted to an

electrical pulse. The electrical pulse height is proportional to the attenuation of light, and depends on

the optical system design, the electronic components used, and the light source. The attenuation of light

is dependent on the size, refractive index, and shape of the particle. In order to establish a relationship

between the electrical pulse height and the particle size, calibration of each LELPC with use of particles

having a well-defined size, refractive index, and shape is required.
5 Basic configuration

An LELPC is composed typically of a light source, a sample liquid supply/suction system, a sensing

volume, a photoelectric conversion device, a pulse height analyser, and a display (see Figure 1). Some

LELPCs do not contain a sample liquid supply/suction system and/or a display.

To make the particle size calibration possible, the LELPC should be constructed so that pulse height

distributions for calibration particles can be measured.
Figure 1 — Example of basic configuration of LELPC
6 Requirements
6.1 Size setting error

The MPE for size setting in the minimum detectable particle size and other sizes specified by the

manufacturer of an LELPC is 0,10 (corresponding to 10 % of the specified size).

Size setting shall be conducted before the LELPC is shipped from the manufacturer, and when the size

setting error is found not fulfilled in a periodic calibration.

A recommended procedure for size setting is described in 7.1.2. If other methods are used, their

uncertainty shall be evaluated and described.
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ISO 21501-3:2019(E)
6.2 Counting efficiency

The counting efficiency shall be within 0,80 to 1,20 [corresponding to (100 ± 20) %] when the test is

carried out by the method described in 7.2.
6.3 Size resolution

The size resolution shall be less than or equal to 0,10 (corresponding to 10 %) when the test is carried

out by the method described in 7.3.
6.4 Maximum particle number concentration

The maximum measurable particle number concentration shall be specified by the manufacturer. The

coincidence loss at the maximum particle number concentration of an LELPC shall be less than or equal

to 0,1 (corresponding to 10 %).

NOTE The probability of occurrence of coincidence loss increases with increasing particle number

concentration.
6.5 Sampling flow rate error

The MPE of the sampling flow rate shall be specified by the manufacturer. The user shall check that the

sampling flow rate is within the range specified by the manufacturer.

If the LELPC does not have a flow rate control system this subclause does not apply, however the

manufacturer shall specify the allowable flow rate range of the LELPC.
6.6 Sampling time error

The MPE in the duration of sampling time shall be 0,01 (corresponding to 1 %) of the preset value.

This subclause does not apply when the LELPC is not equipped with a sampling system.

This subclause does not apply when the LELPC is equipped with a volumetric sampling system.

6.7 Sampling volume error

The MPE of sampling volume shall be 0,05 (corresponding to 5 %) of the preset value.

This subclause does not apply when the LELPC is not equipped with a volumetric sampling system.

6.8 Calibration interval

The calibration of the LELPC should be conducted at an interval equal to or shorter than one year. The

requirements should be met during the calibration interval.
6.9 Reporting of test and calibration results
The report shall contain at least the following information:
a) date of test/calibration;
b) test/calibration particles used;
c) results for the parameters:
1) size setting error;
2) counting efficiency;
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ISO 21501-3:2019(E)
3) sampling flow rate error;
4) size resolution (with the particle size used);

d) threshold voltage values or channel of the built-in PHA corresponding to the size settings;

e) reference of the test/calibration method used (i.e. ISO 21501-3).

f) report/certificate identification, test/calibration location, title and identification of test/calibration

provider including signature and date;

g) identification of customer and device under test, including how output was obtained for counting

efficiency (e.g. analogue, display or digital output).
A calibration certificate shall furthermore include:

h) identification and — if possible — statement of metrological traceability of all reference equipment

and calibration particles used;

i) relevant environmental conditions (e.g. temperature, air pressure and humidity) under which the

calibration was performed;

j) a stated uncertainty for each result for the parameters 1 to 2 with reference to the calculation

method (e.g. ISO/IEC Guide 98-3) — Annex B gives a recommended procedure for evaluating the

uncertainty of the results of the performance tests.

NOTE Calibration certificates issued by ISO/IEC 17025 accredited laboratories and covering all result

...

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