Guideline for the validation of physico-chemical analytical methods

This Technical Specification describes an approach for the validation of physico-chemical analytical methods for environmental matrices.
The guidance in this document addresses two different validation approaches, in increasing order of complexity. These are:
a)   method development and validation at the level of single laboratories (intra-laboratory validation);
b)   method validation at the level of several laboratories (between-laboratory or inter-laboratory validation), with a focus on methods that are sufficiently mature and robust to be applied not only by a few expert laboratories but by laboratories operating at the routine level.
The concept of these two approaches is strictly hierarchical, i.e. a method shall fulfil all criteria of the first level before it can enter the validation protocol of the second level.
This Technical Specification is applicable to the validation of a broad range of quantitative physico-chemical analytical methods for the analysis of water (including surface water, groundwater, waste water, and sediment). Analytical methods for other environmental matrices, like soil, sludge, waste, and biota can be validated in the same way. It is intended either for analytical methods aiming at substances that have recently become of interest or for test methods applying recently developed technologies.
The minimal requirements that are indispensable for the characterization of the fitness for purpose of an analytical method are: selectivity, precision, bias and measurement uncertainty. The aim of validation is to prove that these requirements are met.

Anleitung zur Validierung physikalisch-chemischer Analysenverfahren

Lignes directrices pour la validation des méthodes d'analyse physico-chimiques

Le présent document décrit une approche de validation des méthodes d’analyse physico-chimiques destinées aux matrices solides environnementales et à l’eau.
Les recommandations du présent document concernent la description initiale de la méthode et deux approches de validation différentes, par ordre croissant de complexité. Ces approches sont les suivantes :
a)   développement de méthodes, si la méthode est développée par le laboratoire, ou conditions d’adoption, si la méthode est un protocole normalisé adopté par le laboratoire ;
b)   validation de la méthode au niveau de laboratoires individuels (validation intralaboratoire) ;
c)   validation des méthodes au niveau de plusieurs laboratoires (validation interlaboratoires), en se concentrant sur les méthodes suffisamment abouties et robustes pour être appliquées par quelques laboratoires experts, mais aussi par des laboratoires de routine.
Le concept est strictement hiérarchisé, c’est-à-dire qu’une méthode doit remplir tous les critères de validation intralaboratoire avant de pouvoir passer au protocole de validation interlaboratoires.
Le présent document est applicable à la validation d’un large éventail de méthodes d’essai physico chimiques quantitatives destinées à l’analyse de l’eau (y compris l’eau potable, les eaux de surface, les eaux souterraines, les eaux usées et l’eau de mer), ainsi qu’à des matrices environnementales solides, telles que du sol, de la boue, des déchets liquides et solides, des sédiments et le biote. Il s’adresse à des protocoles normalisés adoptés par un laboratoire et soit à des méthodes d’essai visant des substances qui ont suscité un intérêt récent, soit à des méthodes d’essai qui appliquent des technologies récemment mises au point.
Les exigences minimales indispensables à la caractérisation de l’adéquation à l’objectif prévu d’une méthode d’analyse sont la sélectivité, la fidélité, la justesse, les caractéristiques de performance et l’incertitude de mesure. La validation a pour objectif de prouver que ces exigences sont satisfaites.
Après les définitions (Article 3) et la description des principes (Article 4), le présent document fournit une boîte à outils décrivant les caractéristiques de performance pertinentes dans le processus de validation.
Les Articles 7 et 8 se concentrent sur le processus de validation intralaboratoire (V1) et l’Article 9 sur le processus de validation interlaboratoires (V2). Les Articles 7 et 8 décrivent en grande partie les mêmes processus, mais se distinguent par l’approche permettant d’établir la LOQ.
La consignation des résultats des études de validation est abordée dans l’Article 10.

Smernica za validacijo fizikalno-kemijskih analiznih metod

General Information

Status
Published
Public Enquiry End Date
01-Oct-2020
Publication Date
08-Mar-2021
Technical Committee
Current Stage
6060 - National Implementation/Publication (Adopted Project)
Start Date
05-Jan-2021
Due Date
12-Mar-2021
Completion Date
09-Mar-2021

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SLOVENSKI STANDARD
SIST-TS CEN/TS 16800:2021
01-april-2021
Nadomešča:
SIST-TS CEN/TS 16800:2016
Smernica za validacijo fizikalno-kemijskih analiznih metod
Guideline for the validation of physico-chemical analytical methods
Anleitung zur Validierung physikalisch-chemischer Analysenverfahren
Lignes directrices pour la validation des méthodes d'analyse physico-chimiques
Ta slovenski standard je istoveten z: CEN/TS 16800:2020
ICS:
13.060.50 Preiskava vode na kemične Examination of water for
snovi chemical substances
13.080.10 Kemijske značilnosti tal Chemical characteristics of
soils
SIST-TS CEN/TS 16800:2021 en

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST-TS CEN/TS 16800:2021
CEN/TS 16800
TECHNICAL SPECIFICATION
SPÉCIFICATION TECHNIQUE
December 2020
TECHNISCHE SPEZIFIKATION
ICS 13.060.50 Supersedes CEN/TS 16800:2015
English Version
Guideline for the validation of physico-chemical analytical
methods

Lignes directrices pour la validation des méthodes Anleitung zur Validierung physikalisch-chemischer

d'analyse physico-chimiques Analysenverfahren

This Technical Specification (CEN/TS) was approved by CEN on 9 November 2020 for provisional application.

The period of validity of this CEN/TS is limited initially to three years. After two years the members of CEN will be requested to

submit their comments, particularly on the question whether the CEN/TS can be converted into a European Standard.

CEN members are required to announce the existence of this CEN/TS in the same way as for an EN and to make the CEN/TS

available promptly at national level in an appropriate form. It is permissible to keep conflicting national standards in force (in

parallel to the CEN/TS) until the final decision about the possible conversion of the CEN/TS into an EN is reached.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,

Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,

Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and

United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

© 2020 CEN All rights of exploitation in any form and by any means reserved Ref. No. CEN/TS 16800:2020 E

worldwide for CEN national Members.
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CEN/TS 16800:2020 (E)
Contents Page

European foreword ....................................................................................................................................................... 4

Introduction .................................................................................................................................................................... 5

1 Scope .................................................................................................................................................................... 6

2 Normative references .................................................................................................................................... 6

3 Terms and definitions ................................................................................................................................... 7

4 Principle .......................................................................................................................................................... 14

5 Characterization toolbox: performance characteristics ................................................................ 16

5.1 Introduction ................................................................................................................................................... 16

5.2 Characteristics .............................................................................................................................................. 16

5.2.1 Selectivity ........................................................................................................................................................ 16

5.2.2 Sensitivity ....................................................................................................................................................... 17

5.2.3 Robustness...................................................................................................................................................... 17

5.2.4 Trueness .......................................................................................................................................................... 17

5.2.5 Precision .......................................................................................................................................................... 19

5.2.6 Limit values .................................................................................................................................................... 19

5.2.7 Calibration ...................................................................................................................................................... 20

5.2.8 Application range ......................................................................................................................................... 20

5.2.9 Measurement uncertainty ........................................................................................................................ 20

6 Method development .................................................................................................................................. 21

7 Intra-laboratory validation (V1) – option 1, basic procedure ..................................................... 23

7.1 General ............................................................................................................................................................. 23

7.1.1 Validation 1 .................................................................................................................................................... 23

7.1.2 Adoption of a standardized method ...................................................................................................... 23

7.1.3 Extension of the application domain of an intra-laboratory validated method ................... 23

7.1.4 Complete in-house development ............................................................................................................ 23

7.2 Intra-laboratory performance characteristics .................................................................................. 24

7.2.1 General ............................................................................................................................................................. 24

7.2.2 Trueness .......................................................................................................................................................... 24

7.2.3 Precision .......................................................................................................................................................... 24

7.2.4 LOD, LOQ .......................................................................................................................................................... 25

7.2.5 Measurement uncertainty ........................................................................................................................ 26

8 Intra-laboratory validation (V1) – option 2, including verification of the LOQ ..................... 26

8.1 General ............................................................................................................................................................. 26

8.2 LOQ-V ................................................................................................................................................................ 26

9 Interlaboratory validation 2 (V2) .......................................................................................................... 27

9.1 General ............................................................................................................................................................. 27

9.2 Procedure........................................................................................................................................................ 28

9.2.1 Participating laboratories......................................................................................................................... 28

9.2.2 Materials: selection, preparation and pre-testing of samples ..................................................... 29

9.2.3 Replicates ........................................................................................................................................................ 30

9.2.4 Characteristics of the inter-laboratory study .................................................................................... 30

9.2.5 Assigned values ............................................................................................................................................. 30

9.2.6 Statistical evaluation and calculation of the results ........................................................................ 31

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10 Validation report .......................................................................................................................................... 32

10.1 General ............................................................................................................................................................. 32

10.2 Module A: Test method definition, documentation and general requirements .................... 32

10.3 Module B: Applicability domain validation ......................................................................................... 33

10.4 Module C: Intra-laboratory performance ............................................................................................ 33

10.5 Inter-laboratory validation ....................................................................................................................... 33

10.5.1 General ............................................................................................................................................................. 33

10.5.2 Documentation, publication and standardization ............................................................................ 34

Annex A (normative) Intra-laboratory validation ........................................................................................... 35

A.1 Module A: Test method definition, documentation and general requirements .................... 35

A.2 Module B: Application range and pre-validation .............................................................................. 38

Annex B (normative) Module C: Intra-laboratory performance ................................................................ 40

Annex C (normative) Module D: Requirements on the study for inter-laboratory validation ........ 41

Annex D (informative) Structure and content of a validation study documentation (V2) ................ 44

Annex E (informative) Robustness testing by systematic variation of influencing factors .............. 49

E.1 Design of experiment [21], [22] ................................................................................................................ 49

E.2 Calculation....................................................................................................................................................... 50

Annex F (informative) Protocol for spiking of solid matrices ..................................................................... 51

Bibliography ................................................................................................................................................................. 52

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CEN/TS 16800:2020 (E)
European foreword

This document (CEN/TS 16800:2020) has been prepared by Technical Committee CEN/TC 444

“Environmental characterization of solid matrices”, the secretariat of which is held by NEN.

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

patent rights. CEN shall not be held responsible for identifying any or all such patent rights.

This document supersedes CEN/TS 16800:2015.
The main changes compared to the previous edition are listed below:

— the scope has been extended from water only to water and environmental solid matrices, thus the

document has been modified accordingly;

— a protocol for spiking of solid matrices has been added in an informative annex.

According to the CEN/CENELEC Internal Regulations, the national standards organisations of the

following countries are bound to announce this Technical Specification: Austria, Belgium, Bulgaria,

Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,

Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of

North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United

Kingdom.
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Introduction

Environmental monitoring of chemical substances is increasingly carried out within a European

framework, and there is concern about the comparability of data at the European level. Methods used for

the monitoring of substances with recent interest have often not been properly validated either in-house

(i.e. within a single laboratory) or at the international level.

These issues may be addressed by adopting a harmonized approach towards method development and

validation. The main objective of this document is to provide a common European approach to the

validation of chemical methods for the respective monitoring of chemical substances in a broad range of

matrices. Although the development of this approach was triggered by the needs for monitoring of

emerging pollutants, it is of general nature and can be applied to the measurement of the concentration

of a wide range of substances in a variety of matrices.

This guidance considers the different requirements for the level of method maturity and validation at

different stages of the investigation or regulation of chemical substances.
This protocol will guide the user through the following steps:

— classification of existing methods with respect to their status towards validation, and the selection of

the appropriate validation approach;

— development of a method to extend its application; for example, if a method for determining a

required target compound in a selected matrix is available, but is not suitable for the same compound

in a different matrix of interest;

— the validation procedures to be undertaken to effectively demonstrate the validation status of a

selected method according to the approach adopted.

To agree on the use of one method, or several similar methods, in a trans-border or a multi-metrological

context, and allow comparison of the results reported by several data producers on the same location

(water quality measured on both bank of the same river, or soil composition measured on both sides of a

border, or continuity of quality assessment of waste after measurement provider, e.g.), the procedure of

establishing the LOQ of the measurement method must be clearly published.
The LOQ may result of:

— statistical evaluation of repeated measurements of a blank sample or a sample with a low

concentration of the compound of interest (LOQ);

— experimental verification with a spike matched matrix that the LOQ meets accuracy validation

criteria (LOQ-V).

Many (national and international) standards currently contain in their scope a statement like “this

method is applicable from a concentration level of xx µg/l or yy mg/kg dry matter”, without any

statement how this concentration level was established. When the limit of quantification is evaluated

(LOQ) or verified (LOQ-V) using the procedure of this guideline, there is a possibility that it does not meet

the lower limit of the claimed range.

Also, the LOQ and LOQ-V might be different depending on the analytical method. Therefore, if criteria are

set to the LOQ of a method, it is necessary to clarify if LOQ or LOQ-V is meant.
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1 Scope

This document describes an approach for the validation of physico-chemical analytical methods for

environmental solid matrices and water.

The guidance in this document addresses the initial description of the method and two different

validation approaches, in increasing order of complexity. These are:

a) method development, if the method is developed by the laboratory, or conditions of adoption, if the

method is a standardized protocol adopted by the laboratory;

b) validation at the level of single laboratories (within-laboratory validation);

c) method validation at the level of several laboratories (between-laboratory or inter-laboratory

validation), with a focus on methods that are sufficiently mature and robust to be applied not only by

a few expert laboratories but by laboratories operating at the routine level.

The concept is strictly hierarchical, i.e. a method shall fulfil all criteria of within-laboratory validation

before it can enter the validation protocol of the between-laboratory.

This document is applicable to the validation of a broad range of quantitative physico-chemical test

methods for the analysis of water (including drinking water, surface water, groundwater, waste water,

marine water), and of solid environmental matrices, such as soil, sludge, liquid and solid waste, sediment

and biota. It is intended for standardized protocols adopted by a laboratory, and either for test methods

aiming at substances that have recently become of interest or for test methods applying recently

developed technologies.

The minimal requirements that are indispensable for the characterization of the fitness for the intended

purpose of an analytical method are: selectivity, precision, trueness, performances characteristics and

measurement uncertainty. The aim of validation is to prove that these requirements are met.

In this document after the definitions (Clause 3) and description of the principles (Clause 4) a toolbox is

given describing the relevant performance characteristics in the validation process.

Clause 7 and 8 focus on the within laboratory validation process (V1) and Clause 9 on the interlaboratory

validation process (V2). Clause 7 and 8 describe largely the same processes, but differ in approach for

establishing the LOQ.
Reporting of the results of the validation studies is addressed in Clause 10.
2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO/IEC Guide 99:2007, International vocabulary of metrology — Basic and general concepts and

associated terms (VIM)
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3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO/IEC Guide 99:2007 (VIM) and

the following apply.
3.1
accepted reference value

value that serves as an agreed-upon reference for comparison, and which is derived as:

a) a theoretical or established value, based on scientific principles;

b) an assigned or certified value, based on experimental work of some national or international

organization;

c) a consensus or certified value, based on collaborative experimental work under the auspices of a

scientific or engineering group;

d) when a), b) and c) are not available, the expectation of the (measurable) quantity, i.e. the mean of a

specified population of measurements
[SOURCE: ISO 3534-2:2006, definition 3.2.7]
3.2
accuracy
closeness of agreement between a test result and the accepted reference value

Note 1 to entry: The term accuracy, when applied to a set of test results, involves a combination of random

components (usually expressed by a precision measure) and a common systematic error or bias component (usually

expressed by a measure for trueness).

Note 2 to entry: The technical term “accuracy” should not be confused with the term ‘trueness’ (see definition of

“trueness”).
[SOURCE: ISO 3534-2:2006, definition 3.3.1]
3.3
analyte
substance to be analysed (chemical species or physical parameter)
Note 1 to entry: The quantity of an analyte is the measurand (3.15).
3.4
bias

difference between the expectation of a test result or measurement result and a true value

Note 1 to entry: Bias is the total systematic error as contrasted to random error. There may be one or more

systematic error components contributing to the bias. A larger systematic difference from the accepted reference

value is reflected by a larger bias value.

Note 2 to entry: The bias of a measuring instrument is normally estimated by averaging the error of indication

over an appropriate number of repeated measurements. The error of indication is the: “indication of a measuring

instrument minus a true value of the corresponding input quantity”.

Note 3 to entry: In practice, accepted reference value is substituted for the true value.

[SOURCE: ISO 3534-2:2006, definition 3.3.2]
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3.5
blank
sample or test scheme without the analyte known to produce the measured signal

Note 1 to entry: Use of various types of blanks enable assessment of which proportion of the measured signal is

attributable to the measurand and which proportion to other causes. Various types of blank are available (see

definition of Reagent Blank and Sample Blank).
3.6
calibration

operation that, under specified conditions, in a first step, establishes a relation between the quantity

values with measurement uncertainties provided by measurement standards and corresponding

indications with associated measurement uncertainties and, in a second step, uses this information to

establish a relation for obtaining a measurement result from an indication

Note 1 to entry: A calibration may be expressed by a statement, calibration function, calibration diagram,

calibration curve, or calibration table. In some cases, it may consist of an additive or multiplicative correction of the

indication with associated measurement uncertainty.

Note 2 to entry: Calibration should not be confused with adjustment of a measuring system, often mistakenly

called “self-calibration”, nor with verification of calibration.
[SOURCE: ISO/IEC Guide 99:2007, definition 2.39]
3.7
certified reference material
CRM

reference material, accompanied by documentation issued by an authoritative body and providing one

or more specified property values with associated uncertainties and traceabilities, using valid procedures

[SOURCE: ISO/IEC Guide 99:2007, definition 5.14]
3.8
fitness for purpose

degree to which data produced by a measurement process enables a user to make technically and

administratively correct decisions for a stated purpose
3.9
intermediate precision
precision under intermediate precision conditions
[SOURCE: ISO 3534-2:2006, definition 3.3.15]
3.10
intermediate precision conditions

conditions where test results or measurement results are obtained with the same method, on identical

test/measurement items in the same test or measurement facility, under some different operating

conditions

Note 1 to entry: There are four elements to the operating condition: time, calibration, operator and equipment.

[SOURCE: ISO 3534-2:2006, definition 3.3.16 and ISO 11352:2012, definition 3.10]
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3.11
limit of detection
LOD

measured quantity value, obtained by a given measurement procedure, for which the probability of

falsely claiming the absence of a component in a material is β, given a probability α of falsely claiming its

presence
Note 1 to entry: IUPAC recommends default values for α and β equal to 0,05.
Note 2 to entry: The abbreviation LOD is sometimes used.
Note 3 to entry: The term “sensitivity” is discouraged for ‘detection limit’.

Note 4 to entry: The LOD is the lowest concentration of measurand in a sample that can be detected, but not

necessarily quantitated under the stated conditions of the test.
[SOURCE: ISO/IEC Guide 99:2007, definition 4.18]
3.12
limit of quantification
LOQ

lowest concentration of a measurand that can be determined with acceptable precision under the stated

conditions of the test

Note 1 to entry: as such defined, LOQ is based on evaluation of precision. This does not encompass neither any

eventual bias, nor laboratory measurement uncertainty at LOQ level.
3.13
Verified LOQ
LOQ-V

lowest concentration of a measurand that can be determined with acceptable accuracy under the stated

conditions of the test

Note 1 entry: LOQ-V is based on the check of a defined level of accuracy of the method at LOQ-V level. Bias and

precision have been considered to verify LOQ-V
3.14
reporting limit

specific concentration at or above the limit of quantification that is reported to the client with a certain

degree of confidence

Note 1 to entry: The reporting limit is often defined on a project-specific basis. If the reporting limit is set below

the limit of quantification by the client, method modification is required
[SOURCE: ISO/TS 13530:2009, 4.4.7]
3.15
linearity

ability of the method to obtain test results proportional to the concentration of measurand

Note 1 to entry: The linear range is by inference the range of measurand concentrations over which the method

gives test results proportional to the concentration of the measurand.
[SOURCE: EURACHEM Guide]
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CEN/TS 16800:2020 (E)
3.16
measurand
quantity intended to be measured

Note 1 to entry: The specification of a measurand requires knowledge of the kind of quantity, description of the

state of the phenomenon, body, or substance carrying the quantity, including any relevant component, and the

chemical entities involved.

Note 2 to entry: In chemistry, “analyte”, or the name of a substance or compound, are terms sometimes used for

“measurand”. This usage is erroneous because these terms do not refer to quantities.

[SOURCE: ISO/IEC Guide 99:2007, definition 2.3]
3.17
measurement

process of experimentally obtaining one or more quantity values that can reasonably be attributed to a

quantity
[SOURCE: ISO/IEC Guide 99:2007, definition 2.1]
3.18
measurement uncertainty

non-negative parameter characterizing the dispersion of the quantity values being attributed to a

measurand, based on the information used
[SOURCE: ISO/IEC Guide 99:2007, definition 2.26]
3.19
outlier

member of a set of values which is inconsistent with the other members of that set

Note 1 to entry: ISO 5725-2 specifies the statistical tests and the significance level to be used to identify outliers

in trueness and precision experiments.
[SOURCE: ISO 5725-1:1994, definition 3.21]
3.20
precision

closeness of agreement between independent test results obtained under stipulated conditions

Note 1 to entry: Precision depends only on the distribution of random errors and does not relate to the true value

or the specified value.

Note 2 to entry: The measure of precision is usually expressed in terms of imprecision and computed as a

standard deviation of the test results. Less precision is reflected by a larger standard deviation.

Note 3 to entry: “Independent test results” means results obtained in a manner not influenced by any previous

result on the same or similar test object. Quantitative measures of precision depend critically on the stipulated

conditions. Repeatability and reproducibility conditions are particular sets of extreme conditions.

[SOURCE: ISO 3534-2:2006, definition 3.3.4]
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3.21
proficiency testing

evaluation of participant performance against pre-established criteria by means of interlaboratory

comparisons
[SOURCE: EN ISO/IEC 17043:2010, definition 3.7]
3.22
quality assurance

part of quality management focused on providing confidence that quality requirements will be fulfilled

Note 1 to entry: A major part of quality assurance is quality control.
[SOURCE: EN ISO 9000:2015, definition 3.3.6]
3.23
quality control
part of quality management focused on fulfilling quality requirements
[SOURCE: EN ISO 9000:2015, definition 3.3.7]
3.24
quantity
property of a phenomenon, body, or substance, wher
...

SLOVENSKI STANDARD
kSIST-TS FprCEN/TS 16800:2020
01-september-2020
Smernica za validacijo fizikalno-kemijskih analiznih metod
Guideline for the validation of physico-chemical analytical methods
Anleitung zur Validierung physikalisch-chemischer Analysenverfahren
Lignes directrices pour la validation des méthodes d'analyse physico-chimiques
Ta slovenski standard je istoveten z: FprCEN/TS 16800
ICS:
13.060.50 Preiskava vode na kemične Examination of water for
snovi chemical substances
13.080.10 Kemijske značilnosti tal Chemical characteristics of
soils
kSIST-TS FprCEN/TS 16800:2020 en,fr,de

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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kSIST-TS FprCEN/TS 16800:2020
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kSIST-TS FprCEN/TS 16800:2020
FINAL DRAFT
TECHNICAL SPECIFICATION
FprCEN/TS 16800
SPÉCIFICATION TECHNIQUE
TECHNISCHE SPEZIFIKATION
June 2020
ICS Will supersede CEN/TS 16800:2015
English Version
Guideline for the validation of physico-chemical analytical
methods

Lignes directrices pour la validation des méthodes Anleitung zur Validierung physikalisch-chemischer

d'analyse physico-chimiques Analysenverfahren

This draft Technical Specification is submitted to CEN members for Vote. It has been drawn up by the Technical Committee

CEN/TC 444.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,

Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,

Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and

United Kingdom.

Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are

aware and to provide supporting documentation.

Warning : This document is not a Technical Specification. It is distributed for review and comments. It is subject to change

without notice and shall not be referred to as a Technical Specification.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

© 2020 CEN All rights of exploitation in any form and by any means reserved Ref. No. FprCEN/TS 16800:2020 E

worldwide for CEN national Members.
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Contents Page

European foreword ....................................................................................................................................................... 4

Introduction .................................................................................................................................................................... 5

1 Scope .................................................................................................................................................................... 6

2 Normative references .................................................................................................................................... 6

3 Terms and definitions ................................................................................................................................... 7

4 Principle .......................................................................................................................................................... 14

5 Characterization toolbox: performance characteristics ................................................................ 15

5.1 Introduction ................................................................................................................................................... 15

5.2 Characteristics .............................................................................................................................................. 16

5.2.1 Selectivity ........................................................................................................................................................ 16

5.2.2 Sensitivity ....................................................................................................................................................... 16

5.2.3 Robustness...................................................................................................................................................... 16

5.2.4 Trueness .......................................................................................................................................................... 17

5.2.5 Precision .......................................................................................................................................................... 18

5.2.6 Limit values .................................................................................................................................................... 18

5.2.7 Calibration ...................................................................................................................................................... 19

5.2.8 Application range ......................................................................................................................................... 20

5.2.9 Measurement uncertainty ........................................................................................................................ 20

6 Method development .................................................................................................................................. 20

7 Intra-laboratory validation (V1) – option 1, basic procedure ..................................................... 22

7.1 General ............................................................................................................................................................. 22

7.1.1 Validation 1 .................................................................................................................................................... 22

7.1.2 Adoption of a standardized method ...................................................................................................... 22

7.1.3 Extension of the application domain of an intra-laboratory validated method ................... 22

7.1.4 Complete in-house development ............................................................................................................ 23

7.2 Intra-laboratory performance characteristics .................................................................................. 23

7.2.1 General ............................................................................................................................................................. 23

7.2.2 Trueness .......................................................................................................................................................... 23

7.2.3 Precision .......................................................................................................................................................... 23

7.2.4 LOD, LOQ .......................................................................................................................................................... 25

7.2.5 Measurement uncertainty ........................................................................................................................ 25

8 Intra-laboratory validation (V1) – option 2, including verification of the LOQ ..................... 25

8.1 General ............................................................................................................................................................. 25

8.2 LOQ-V ................................................................................................................................................................ 25

9 Interlaboratory Validation 2 (V2) .......................................................................................................... 27

9.1 General ............................................................................................................................................................. 27

9.2 Procedure........................................................................................................................................................ 27

9.2.1 Participating laboratories......................................................................................................................... 27

9.2.2 Materials: selection, preparation and pre-testing of samples ..................................................... 28

9.2.3 Replicates ........................................................................................................................................................ 29

9.2.4 Characteristics of the inter-laboratory study .................................................................................... 29

9.2.5 Assigned values ............................................................................................................................................. 30

9.2.6 Statistical evaluation and calculation of the results ........................................................................ 30

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10 Validation report .......................................................................................................................................... 31

10.1 General ............................................................................................................................................................. 31

10.2 Module A: Test method definition, documentation and general requirements .................... 32

10.3 Module B: Applicability domain validation ......................................................................................... 32

10.4 Module C: Intra-laboratory performance ............................................................................................ 33

10.5 Inter-Laboratory Validation ..................................................................................................................... 33

10.5.1 General ............................................................................................................................................................. 33

10.5.2 Documentation, publication and standardization ............................................................................ 34

Annex A (normative) Intra-laboratory validation ........................................................................................... 35

A.1 Module A: Test method definition, documentation and general requirements .................... 35

A.2 Module B: Application range and pre-validation .............................................................................. 38

Annex B (normative) Module C: Intra-laboratory performance ................................................................ 40

Annex C (normative) Module D: Requirements on the study for inter-laboratory validation ........ 41

Annex D (informative) Structure and content of a validation study documentation (V2) ................ 44

Annex E (informative) Robustness testing by systematic variation of influencing factors .............. 49

E.1 Design of experiment [21], [22] ............................................................................................................... 49

E.2 Calculation....................................................................................................................................................... 49

Annex F (informative) Protocol for spiking of solid matrices ..................................................................... 51

Bibliography ................................................................................................................................................................. 52

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European foreword

This document (FprCEN/TS 16800:2019) has been prepared by Technical Committee CEN/TC 444 “Test

methods for environmental characterization of solid matrices”, the secretariat of which is held by NEN.

This document is currently submitted to the Vote on TR.
This document will supersede CEN/TR 16800:2008.

Its scope was enlarged to cover environmental solid matrices (soil, sediment, solid and liquid waste,

biowaste and sludge), and water.
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Introduction

Environmental monitoring of chemical substances is increasingly carried out within a European

framework, and there is concern about the comparability of data at the European level. Methods used for

the monitoring of substances with recent interest have often not been properly validated either in-house

(i.e. within a single laboratory) or at the international level.

These issues may be addressed by adopting a harmonized approach towards method development and

validation. The main objective of this document is to provide a common European approach to the

validation of chemical methods for the respective monitoring of chemical substances in a broad range of

matrices. Although the development of this approach was triggered by the needs for monitoring of

emerging pollutants, it is of general nature and can be applied to the measurement of the concentration

of a wide range of substances in a variety of matrices.

This guidance considers the different requirements for the level of method maturity and validation at

different stages of the investigation or regulation of chemical substances.
This protocol will guide the user through the following steps:

— classification of existing methods with respect to their status towards validation, and the selection of

the appropriate validation approach;

— development of a method to extend its application; for example, if a method for determining a

required target compound in a selected matrix is available, but is not suitable for the same compound

in a different matrix of interest;

— the validation procedures to be undertaken to effectively demonstrate the validation status of a

selected method according to the approach adopted.

To agree on the use of one method, or several similar methods, in a trans-border or a multi-metrological

context, and allow comparison of the results reported by several data producers on the same location

(water quality measured on both bank of the same river, or soil composition measured on both sides of a

border, or continuity of quality assessment of waste after measurement provider, e.g.), the procedure of

establishing the LOQ of the measurement method must be clearly published.
The LOQ may result of:

— Statistical evaluation of repeated measurements of a blank sample or a sample with a low

concentration of the compound of interest (LOQ)

— experimental verification with a spike matched matrix that the LOQ meets accuracy validation

criteria (LOQ-V).

Many (national and international) standards currently contain in their scope a statement like “this

method is applicable from a concentration level of xx µg/l or yy mg/kg dry matter”, without any

statement how this concentration level was established. When the limit of quantification is evaluated

(LOQ) or verified (LOQ-V) using the procedure of this guideline, there is a possibility that it does not

meet the lower limit of the claimed range.

Also, the LOQ and LOQ-V might be different depending on the analytical method. Therefore, if criteria

are set to the LOQ of a method, it is necessary to clarify if LOQ or LOQ-V is meant.

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1 Scope

This document describes an approach for the validation of physico-chemical analytical methods for

environmental solid matrices and water.

The guidance in this document addresses the initial description of the method and two different

validation approaches, in increasing order of complexity. These are:

a) method development, if the method is developed by the laboratory, or conditions of adoption, if the

method is a standardized protocol adopted by the laboratory

b) validation at the level of single laboratories (within-laboratory validation);

c) method validation at the level of several laboratories (between-laboratory or inter-laboratory

validation), with a focus on methods that are sufficiently mature and robust to be applied not only by

a few expert laboratories but by laboratories operating at the routine level.

The concept is strictly hierarchical, i.e. a method shall fulfil all criteria of within-laboratory validation

before it can enter the validation protocol of the between-laboratory.

This document is applicable to the validation of a broad range of quantitative physico-chemical test

methods for the analysis of water (including drinking water, surface water, groundwater, waste water,

marine water), and of solid environmental matrices, such as soil, sludge, liquid and solid waste, sediment

and biota. It is intended for standardized protocols adopted by a laboratory, and either for test methods

aiming at substances that have recently become of interest or for test methods applying recently

developed technologies.

The minimal requirements that are indispensable for the characterization of the fitness for the intended

purpose of an analytical method are: selectivity, precision, trueness, performances characteristics and

measurement uncertainty. The aim of validation is to prove that these requirements are met.

In this document after the definitions (Clause 3) and description of the principles (Clause 4) a toolbox is

given describing the relevant performance characteristics in the validation process.

Clause 7 and 8 focus on the within laboratory validation process (V1) and Clause 9 on the interlaboratory

validation process (V2). Clause 7 and 8 describe largely the same processes, but differ in approach for

establishing the LOQ.
Reporting of the results of the validation studies is addressed in Clause 10.
2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO/IEC Guide 99:2007, International vocabulary of metrology — Basic and general concepts and

associated terms (VIM)
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3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO/IEC Guide 99:2007 (VIM) and

the following apply.
3.1
accepted reference value

value that serves as an agreed-upon reference for comparison, and which is derived as:

a) a theoretical or established value, based on scientific principles;

b) an assigned or certified value, based on experimental work of some national or international

organization;

c) a consensus or certified value, based on collaborative experimental work under the auspices of a

scientific or engineering group;

d) when a), b) and c) are not available, the expectation of the (measurable) quantity, i.e. the mean of a

specified population of measurements
[SOURCE: ISO 3534-2:2006, definition 3.2.7]
3.2
accuracy
closeness of agreement between a test result and the accepted reference value

Note 1 to entry: The term accuracy, when applied to a set of test results, involves a combination of random

components (usually expressed by a precision measure) and a common systematic error or bias component (usually

expressed by a measure for trueness).

Note 2 to entry: The technical term “accuracy” should not be confused with the term ‘trueness’ (see definition of

“trueness”).
[SOURCE: ISO 3534-2:2006, definition 3.3.1]
3.3
analyte
substance to be analysed (chemical species or physical parameter)
Note 1 to entry: The quantity of an analyte is the measurand (3.15).
3.4
bias

difference between the expectation of a test result or measurement result and a true value

Note 1 to entry: Bias is the total systematic error as contrasted to random error. There may be one or more

systematic error components contributing to the bias. A larger systematic difference from the accepted reference

value is reflected by a larger bias value.

Note 2 to entry: The bias of a measuring instrument is normally estimated by averaging the error of indication

over an appropriate number of repeated measurements. The error of indication is the: “indication of a measuring

instrument minus a true value of the corresponding input quantity”.

Note 3 to entry: In practice, accepted reference value is substituted for the true value.

[SOURCE: ISO 3534-2:2006, definition 3.3.2]
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3.5
blank
sample or test scheme without the analyte known to produce the measured signal

Note 1 to entry: Use of various types of blanks enable assessment of which proportion of the measured signal is

attributable to the measurand and which proportion to other causes. Various types of blank are available (see

definition of Reagent Blank and Sample Blank).
3.6
calibration

operation that, under specified conditions, in a first step, establishes a relation between the quantity

values with measurement uncertainties provided by measurement standards and corresponding

indications with associated measurement uncertainties and, in a second step, uses this information to

establish a relation for obtaining a measurement result from an indication

Note 1 to entry: A calibration may be expressed by a statement, calibration function, calibration diagram,

calibration curve, or calibration table. In some cases, it may consist of an additive or multiplicative correction of the

indication with associated measurement uncertainty.

Note 2 to entry: Calibration should not be confused with adjustment of a measuring system, often mistakenly

called “self-calibration”, nor with verification of calibration.
[SOURCE: ISO/IEC Guide 99:2007, definition 2.39]
3.7
certified reference material
CRM

reference material, accompanied by documentation issued by an authoritative body and providing one

or more specified property values with associated uncertainties and traceabilities, using valid procedures

[SOURCE: ISO/IEC Guide 99:2007, definition 5.14]
3.8
fitness for purpose

degree to which data produced by a measurement process enables a user to make technically and

administratively correct decisions for a stated purpose
3.9
intermediate precision
precision under intermediate precision conditions
[SOURCE: ISO 3534-2:2006, definition 3.3.15]
3.10
intermediate precision conditions

conditions where test results or measurement results are obtained with the same method, on identical

test/measurement items in the same test or measurement facility, under some different operating

conditions

Note 1 to entry: There are four elements to the operating condition: time, calibration, operator and equipment.

[SOURCE: ISO 3534-2:2006, definition 3.3.16 and ISO 11352:2012, definition 3.10]
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3.11
limit of detection
LOD

measured quantity value, obtained by a given measurement procedure, for which the probability of

falsely claiming the absence of a component in a material is β, given a probability α of falsely claiming its

presence
Note 1 to entry: IUPAC recommends default values for α and β equal to 0,05.
Note 2 to entry: The abbreviation LOD is sometimes used.
Note 3 to entry: The term “sensitivity” is discouraged for ‘detection limit’.

Note 4 to entry: The LOD is the lowest concentration of measurand in a sample that can be detected, but not

necessarily quantitated under the stated conditions of the test.
[SOURCE: ISO/IEC Guide 99:2007, definition 4.18]
3.12
limit of quantitation
LOQ

lowest concentration of a measurand that can be determined with acceptable precision under the stated

conditions of the test

Note 1 to entry: as such defined, LOQ is based on evaluation of precision. This does not encompass neither any

eventual bias, nor laboratory measurement uncertainty at LOQ level.
3.13
Verified LOQ
LOQ-V

lowest concentration of a measurand that can be determined with acceptable accuracy under the stated

conditions of the test

Note 1 entry: LOQ-V is based on the check of a defined level of accuracy of the method at LOQ-V level.

Bias and precision have been considered to verify LOQ-V
3.14
reporting limit

specific concentration at or above the limit of quantification that is reported to the client with a certain

degree of confidence

Note 1 to entry: The reporting limit is often defined on a project-specific basis. If the reporting limit is set below

the limit of quantification by the client, method modification is required
[SOURCE: ISO/TS 13530:2009, 4.4.7]
3.15
linearity

ability of the method to obtain test results proportional to the concentration of measurand

Note 1 to entry: The linear range is by inference the range of measurand concentrations over which the method

gives test results proportional to the concentration of the measurand.
[SOURCE: EURACHEM Guide]
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3.16
measurand
quantity intended to be measured

Note 1 to entry: The specification of a measurand requires knowledge of the kind of quantity, description of the

state of the phenomenon, body, or substance carrying the quantity, including any relevant component, and the

chemical entities involved.

Note 2 to entry: In chemistry, “analyte”, or the name of a substance or compound, are terms sometimes used for

“measurand”. This usage is erroneous because these terms do not refer to quantities.

[SOURCE: ISO/IEC Guide 99:2007, definition 2.3]
3.17
measurement

process of experimentally obtaining one or more quantity values that can reasonably be attributed to a

quantity
[SOURCE: ISO/IEC Guide 99:2007, definition 2.1]
3.18
measurement uncertainty

non-negative parameter characterizing the dispersion of the quantity values being attributed to a

measurand, based on the information used
[SOURCE: ISO/IEC Guide 99:2007, definition 2.26]
3.19
outlier

member of a set of values which is inconsistent with the other members of that set

Note 1 to entry: ISO 5725-2 specifies the statistical tests and the significance level to be used to identify outliers

in trueness and precision experiments.
[SOURCE: ISO 5725-1:1994, definition 3.21]
3.20
precision

closeness of agreement between independent test results obtained under stipulated conditions

Note 1 to entry: Precision depends only on the distribution of random errors and does not relate to the true value

or the specified value.

Note 2 to entry: The measure of precision is usually expressed in terms of imprecision and computed as a

standard deviation of the test results. Less precision is reflected by a larger standard deviation.

Note 3 to entry: “Independent test results“ means results obtained in a manner not influenced by any previous

result on the same or similar test object. Quantitative measures of precision depend critically on the stipulated

conditions. Repeatability and reproducibility conditions are particular sets of extreme conditions.

[SOURCE: ISO 3534-2:2006, definition 3.3.4]
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3.21
proficiency testing

evaluation of participant performance against pre-established criteria by means of interlaboratory

comparisons
[SOURCE: EN ISO/IEC 17043:2010, definition 3.7]
3.22
quality assurance

part of quality management focused on providing confidence that quality requirements will be fulfilled

Note 1 to entry: A major part of quality assurance is quality control.
[SOURCE: EN ISO 9000:2015, definition 3.3.6]
3.23
quality control
part of quality management focused on fulfilling quality requirements
[SOURCE: EN ISO 9000:2015, definition 3.3.7]
3.24
quantity

property of a phenomenon, body, or substance, where the property has a magnitude that can be

expressed as a number and a reference
[SOURCE: ISO/IEC Guide 99:2007, definition 1.1]
3.25
working range

interval, being experimentally established and statistically proved by the calibration of the method,

between the lowest and highest quantity possibly measured by the method

Note 1 to entry: The lowest possible limit of a working range is the limit of quantification of an analytical method.

3.26
reagent blank

all reagents used during the analytical process (including solvents used for extraction or dissolution) are

analysed in isolation in order to check whether they contribute to the measurement signal

Note 1 to entry: The measurement signal arising from the measurand can then be corrected accordingly.

3.27
Analytical recovery

extent to which a known, added quantity of analyte (3.3) in a sample can be measured by an analytical

system
Note 1 to entry: Recovery is calculat
...

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