Molecular in vitro diagnostic examinations - Specifications for pre-examination processes in metabolomics in urine, venous blood serum and plasma (ISO 23118:2021)

This document covers the preanalytical phase and recommends the handling, documentation and processing of urine, venous blood plasma and serum intended for metabolomics analysis.
The document is applicable to metabolomics examinations and is of importance to biomedical laboratories, customers of laboratories, in vitro diagnostics developers and manufacturers, institutions and companies performing biomedical research, biobanks, and regulatory authorities. The adoption of the described procedures for the preanalytical phase make it possible to compare and evaluate the results obtained from metabolic profiling analysis.
NOTE International, national or regional regulations or requirements can also apply to specific topics covered in this document.

Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für präanalytische Prozesse für Metabolomuntersuchungen in Urin, venösem Blutserum und -plasma (ISO 23118:2021)

Dieses Dokument legt die Anforderungen fest an die Handhabung, Dokumentation und Verarbeitung von für die Metabolomanalyse vorgesehenem Urin, venösem Blutplasma und -serum während der präanalytischen Phase. Dieses Dokument gilt für Metabolomuntersuchungen und kann von biomedizinischen Laboren, Kunden dieser Labore, Entwicklern und Herstellern von In-vitro-Diagnostika, Einrichtungen und kommerziellen Organisationen, die in der biomedizinischen Forschung tätig sind, Biobanken und Aufsichtsbehörden angewendet werden.

Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus préanalytiques pour l'analyse du métabolome dans l'urine et le sang veineux (sérum et plasma) (ISO 23118:2021)

Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne procese metabolomike v urinu, serumu in plazmi venske krvi (ISO 23118:2021)

General Information

Status
Published
Public Enquiry End Date
14-Sep-2020
Publication Date
29-Jun-2021
Technical Committee
Current Stage
6060 - National Implementation/Publication (Adopted Project)
Start Date
11-Jun-2021
Due Date
16-Aug-2021
Completion Date
30-Jun-2021

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SLOVENSKI STANDARD
SIST EN ISO 23118:2021
01-september-2021
Nadomešča:
SIST-TS CEN/TS 16945:2016
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne
procese metabolomike v urinu, serumu in plazmi venske krvi (ISO 23118:2021)

Molecular in vitro diagnostic examinations - Specifications for pre-examination processes

in metabolomics in urine, venous blood serum and plasma (ISO 23118:2021)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für

präanalytische Prozesse für Metabolomuntersuchungen in Urin, venösem Blutserum und

-plasma (ISO 23118:2021)

Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus

préanalytiques pour l'analyse du métabolome dans l'urine et le sang veineux (sérum et

plasma) (ISO 23118:2021)
Ta slovenski standard je istoveten z: EN ISO 23118:2021
ICS:
11.100.10 Diagnostični preskusni In vitro diagnostic test
sistemi in vitro systems
SIST EN ISO 23118:2021 en,fr,de

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

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SIST EN ISO 23118:2021
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SIST EN ISO 23118:2021
EN ISO 23118
EUROPEAN STANDARD
NORME EUROPÉENNE
June 2021
EUROPÄISCHE NORM
ICS 11.100.10 Supersedes CEN/TS 16945:2016
English Version
Molecular in vitro diagnostic examinations - Specifications
for pre-examination processes in metabolomics in urine,
venous blood serum and plasma (ISO 23118:2021)

Analyses de diagnostic moléculaire in vitro - Molekularanalytische in-vitro-diagnostische Verfahren

Spécifications relatives aux processus préanalytiques - Spezifikationen für präanalytische Prozesse für

pour l'analyse du métabolome dans l'urine et le sang Metabolomuntersuchungen in Urin, venösem

veineux (sérum et plasma) (ISO 23118:2021) Blutserum und -plasma (ISO 23118:2021)

This European Standard was approved by CEN on 20 May 2021.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this

European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references

concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN

member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by

translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management

Centre has the same status as the official versions.

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

© 2021 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 23118:2021 E

worldwide for CEN national Members.
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SIST EN ISO 23118:2021
EN ISO 23118:2021 (E)
Contents Page

European foreword ....................................................................................................................................................... 3

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SIST EN ISO 23118:2021
EN ISO 23118:2021 (E)
European foreword

This document (EN ISO 23118:2021) has been prepared by Technical Committee ISO/TC 212 "Clinical

laboratory testing and in vitro diagnostic test systems" in collaboration with Technical Committee

CEN/TC 140 “In vitro diagnostic medical devices” the secretariat of which is held by DIN.

This European Standard shall be given the status of a national standard, either by publication of an

identical text or by endorsement, at the latest by December 2021, and conflicting national standards

shall be withdrawn at the latest by June 2024.

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 16945:2016.

According to the CEN-CENELEC Internal Regulations, the national standards organizations of the

following countries are bound to implement this European Standard: 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.
Endorsement notice

The text of ISO 23118:2021 has been approved by CEN as EN ISO 23118:2021 without any modification.

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SIST EN ISO 23118:2021
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SIST EN ISO 23118:2021
INTERNATIONAL ISO
STANDARD 23118
First edition
2021-05
Molecular in vitro diagnostic
examinations — Specifications
for pre-examination processes in
metabolomics in urine, venous blood
serum and plasma
Analyses de diagnostic moléculaire in vitro — Spécifications relatives
aux processus préanalytiques pour l'analyse du métabolome dans
l'urine et le sang veineux (sérum et plasma)
Reference number
ISO 23118:2021(E)
ISO 2021
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SIST EN ISO 23118:2021
ISO 23118:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021

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.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
---------------------- Page: 8 ----------------------
SIST EN ISO 23118:2021
ISO 23118:2021(E)
Contents Page

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

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

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

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

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

4 General considerations .................................................................................................................................................................................. 3

5 Urine .................................................................................................................................................................................................................................. 4

5.1 Outside the laboratory ..................................................................................................................................................................... 4

5.1.1 Urine collection ................................................................................................................................................................. 4

5.1.2 Transport requirements ............................................................................................................................................ 5

5.2 Inside the laboratory ......................................................................................................................................................................... 5

5.2.1 Specimen reception ....................................................................................................................................................... 5

5.2.2 Storage requirements .................................................................................................................................................. 6

5.2.3 Urine sample processing ........................................................................................................................................... 6

5.2.4 Long-term storage requirements for urine samples......................................................................... 6

5.2.5 Urine thawing ..................................................................................................................................................................... 6

6 Blood ................................................................................................................................................................................................................................. 7

6.1 Outside the laboratory ..................................................................................................................................................................... 7

6.1.1 Primary collection .......................................................................................................................................................... 7

6.1.2 Transport of pre-processed specimens to laboratory ..................................................................... 8

6.2 Inside the laboratory ......................................................................................................................................................................... 8

6.2.1 Specimen reception ....................................................................................................................................................... 8

6.2.2 Sample processing .......................................................................................................................................................... 9

6.2.3 Transport of processed samples to a laboratory for metabolomics analysis

or transport to a biobank ......................................................................................................................................... 9

6.2.4 Long-term storage requirements ...................................................................................................................... 9

6.2.5 Serum and plasma thawing and use ............................................................................................................10

Annex A (informative) Instability of the metabolome.....................................................................................................................11

Bibliography .............................................................................................................................................................................................................................17

© ISO 2021 – All rights reserved iii
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SIST EN ISO 23118:2021
ISO 23118:2021(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 212, Clinical laboratory testing and in

vitro diagnostic test systems, in collaboration with the European Committee for Standardization (CEN)

Technical Committee CEN/TC 140, In vitro diagnostic medical devices, in accordance with the Agreement

on technical cooperation between ISO and CEN (Vienna Agreement).

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 2021 – All rights reserved
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SIST EN ISO 23118:2021
ISO 23118:2021(E)
Introduction

Metabolomics is the "-omic" science that deals with the characterization of the metabolome, in turn

defined as the whole set of small molecules (molecular mass <2 000 Da) in a certain biological system

[1]

such as a cell, a tissue, an organ, or an entire organism . The analyses are mainly performed via two

major analytical techniques, namely mass spectrometry (MS) and nuclear magnetic resonance (NMR)

[2][3][4]

. The former has a sensitivity that can be as low as picomolar, requires sample separation and

multiple experimental runs targeted to specific classes of compounds. The latter measures metabolites

present at concentration above 1 µM and is mainly used for untargeted analyses, where all metabolites

above the detection limit are observed simultaneously, independent of their chemical nature, without

any separation procedure.

The metabolome is dynamic and quite sensitive to perturbations. The metabolome can change

drastically during primary sample collection, transport, storage, and processing. As a result, the

outcome from the diagnostic and research measurements could become an unreliable representation

of the specific targeted physiological state or point in time, but instead describes an artificial profile

generated during the pre-examination process. Pre-analytical variations have been identified to

originate from two main sources:
a) enzymatic activity in the samples, mainly related to the presence of cells;

b) chemical reactions (e.g. redox reactions) among metabolites or between metabolites and oxygen,

see References [5] to [11].

Moreover, the analyses can be influenced by the use of additives or by the introduction of contaminants,

and therefore the selection of appropriate collection tubes and plasticware is also a critical aspect of

the pre-examination phase.

Studies have been undertaken to establish the best pre-examination procedures in terms of

maintenance of the original sample metabolome by identifying the critical steps and parameters

affecting the metabolome composition. Additionally, standardization of the entire pre-examination

workflow is needed to ensure comparability in multicentre studies. At the present state of the art, there

are no defined pre-examination procedures for metabolomic samples. As a consequence, the procedures

adopted by the various centres differentially influence the metabolome of the samples, making their

comparison unreliable. The adoption of the present requirements for the pre-examination phase make

it possible to compare and evaluate the results obtained from metabolic analysis.

This document draws upon such studies to codify and standardize the steps for urine, serum and

plasma metabolomics analysis in what is referred to as the pre-analytical phase.
© ISO 2021 – All rights reserved v
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SIST EN ISO 23118:2021
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SIST EN ISO 23118:2021
INTERNATIONAL STANDARD ISO 23118:2021(E)
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes in
metabolomics in urine, venous blood serum and plasma
1 Scope

This document specifies requirements and gives recommendations for the handling, documentation

and processing of urine, venous blood plasma and serum intended for metabolomics analysis in the pre-

examination processes. This document is applicable to metabolomics examinations and can be used by

biomedical laboratories, customers of laboratories, in vitro diagnostics developers and manufacturers,

institutions and companies performing biomedical research, biobanks, and regulatory authorities.

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 15189, Medical laboratories — Requirements for quality and competence
ISO 15190, Medical laboratories — Requirements for safety
3  Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 15189 and the following apply.

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

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
biofluid

biological fluid which can be excreted (such as urine or sweat), secreted (such as breast milk, saliva

or bile), obtained with a needle (such as blood or cerebrospinal fluid), or produced as a result of a

pathological process (such as blister or cyst fluid)
3.2
examination

set of operations having the object of determining the value or characteristics of a property

Note 1 to entry: Processes that start with the isolated analyte and include all kinds of parameter testing or

chemical manipulation for quantitative or qualitative examination.

Note 2 to entry: For metabolomic analysis, analyte isolation is not necessarily required.

[SOURCE: ISO 20166-1:2018, 3.10, modified — admitted term “analytical test” has been deleted and

Note 2 entry has been added.]
3.3
fasting
abstinence from any solid or liquid food excluding water for at least 8 hours
© ISO 2021 – All rights reserved 1
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SIST EN ISO 23118:2021
ISO 23118:2021(E)
3.4
mass spectrometry

method used to analyse chemical compounds on the basis of their mass to charge ratio

3.5
metabolic profiling

use of analytical platforms to simultaneously measure the ensemble of metabolites (3.6) in biological

systems that can be measured by the employed (or selected) technique
EXAMPLE Examples for such techniques are NMR and MS.
3.6
metabolites

small molecules (≤ 2 000 Da) that are intermediates and/or products of metabolism of the host

organisms, of its microflora, deriving from food, drinks, drugs or pollutants.
Note 1 to entry: For further information see Reference [1].
3.7
metabolome

complete set of metabolites (3.6) to be found within an organism or a biological sample

Note 1 to entry: For further information see Reference [1]
3.8
metabolomics

comprehensive analysis of the metabolome (3.7) of a biological specimen (3.14) (e.g., organism, cell,

tissue or biofluids (3.1))
3.9
MS-based metabolomics

use of mass spectrometry (3.4) to measure metabolites (3.6) in biological samples

3.10
nuclear magnetic resonance spectroscopy
NMR

method based on the selective absorption of high frequency radio waves by atomic nuclei subjected to a

stationary magnetic field
Note 1 to entry: NMR provides chemical and structural properties of molecules.
3.11
NMR-based metabolomics

use of NMR spectroscopy (3.10) to measure metabolites (3.6) in biological samples

3.12
plasma
liquid part of unclotted blood
Note 1 to entry: Plasma samples can contain anti-coagulants.
3.13
pre-examination processes
preanalytical phase
preanalytical workflow

processes that start, in chronological order, from the clinician’s request and include the examination

(3.2) request, preparation and identification of the patient, collection of the primary sample(s),

temporary storage, transportation to and within the analytical laboratory, aliquoting, retrieval

Note 1 to entry: The preanalytical phase can include preparative processes that can influence the outcome of the

intended examination (3.2).
2 © ISO 2021 – All rights reserved
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SIST EN ISO 23118:2021
ISO 23118:2021(E)

[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added, and more details were

included.]
3.14
primary sample
specimen

discrete portion of a body fluid, breath, hair or tissue taken for examination (3.2), study or analysis of

one or more quantities or properties assumed to apply for the whole

[SOURCE: ISO 15189:2012, 3.16, modified — The term and definition are used here without the original

notes.]
3.15
room temperature
temperature which is defined as 18 °C to 25 °C for the purpose of this document
3.16
serum
liquid that can be separated from clotted blood
3.17
stability

characteristic of a reference material, when stored under specified conditions, to maintain a specified

property value within specified limits for a specified period of time

[SOURCE: ISO Guide 30:2015, 2.1.15 — The term and definition are used here without the original note.]

4 General considerations

For general statements on medical laboratory quality management systems and in particular on

specimen collection, reception, and handling (including avoidance of cross contaminations) see

ISO 15189 or ISO/IEC 17020. The requirements on laboratory equipment, reagents, and consumables

according to ISO 15189 shall be followed; ISO/IEC 17020 can also apply.

All steps of a diagnostic workflow can influence the final analytical test result and a risk assessment

shall be performed (see also ISO 14971). Mitigation measures for eliminating or reducing identified risks

shall be established where required for ensuring the performance of the examination. It shall especially

be investigated and ensured that the metabolites intended to be analysed are not compromised in a

manner impacting the examination performance. This can be done, e.g. by applying the intended

examination to specimens/samples which underwent time course studies reflecting the individual pre-

examination process steps such as transport and storage and by implementing measures to prevent or

reduce impacts by the identified pre-analytical variables.

In the absence of suitable specimen stabilization technologies, regarding the metabolome, the specimen

collection shall be carried out in hospital premises or institutions where there are immediate suitable

biofluid processing procedures available.

Specifically, for specimens intended to be analysed by metabolomics, the following steps shall be

considered:
a) patient pre-treatment (fasting, therapy, etc.);
b) the specimen collection from the patient;

c) the selection of collection containers and packages (e.g. collection tubes, cooling box, box for storing

and transportation);

d) the selection of stabilization procedures (e.g. any compounds added for stabilizing the specimen);

e) the recording of any additions or modifications to the specimen;
© ISO 2021 – All rights reserved 3
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SIST EN ISO 23118:2021
ISO 23118:2021(E)
f) the recording of types and quantity as well as description of specimens.

Safety requirements for facilities, transport and handling shall be considered in accordance with

ISO 15189 and ISO 15190. WHO Guidelines for the Safe Transport of Infectious Substances and

[14]
Diagnostic Specimens should be followed.
5 Urine
5.1 Outside the laboratory
5.1.1 Urine collection
5.1.1.1 General

For the collection of the specimen the requirements (e.g. disease condition, specimen size) for the

intended molecular examination shall be considered.
See also ISO 15189.
5.1.1.2 Information about the specimen donor/patient

The documentation shall include the ID of the specimen donor/patient, which can be in the form of a

code.
The documentation should include, but is not limited to:

a) the health status and relevant lifestyle factors of the urine donor [e.g. healthy, disease type,

concomitant disease(s)];
b) demographics (e.g., age, sex);

c) the information about medical treatment and any treatment prior to urine collection (e.g.

anaesthetics, medications, diagnostic procedures);

d) the collection time, including information about fasting, previous activities.

e) the appropriate consent from the specimen donor/patient.
5.1.1.3 Selection and labelling of collection containers
The laboratory shall define the container intended for urine collection.

Additives are usually not used, because they can interfere with the analytical method. If they are

required for specific purposes, their impact on the analytical performance and outcome shall be

analysed. Some additives in collection tubes could present a risk to patients (e.g. toxic or corrosive).

For the labelling (specimen identification) of the urine collection tube a routine procedure (see also

ISO 15189) or a procedure with additional information (e.g. 2D-barcode) shall be used.

5.1.1.4 Urine collection and reception from the specimen donor
5.1.1.4.1 General

Instruction for the urine collection shall be given to the donor, including any safety measures that need

to be followed while handling collection containers containing harmful additives. All urine collection

4 © ISO 2021 – All rights reserved
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SIST EN ISO 23118:2021
ISO 23118:2021(E)

devices should be checked for compatibility with metabolomics, e.g. avoiding any interference with the

metabolomics profile.

NOTE For non-toilet-trained children, the most popular non-invasive method used is the clean catch, which

National Institute for Health and Clinical Excellence (NICE), 2007 defines as a gold standard. This involves

catching a sample by holding a sterile specimen bottle in the urine stream. Urine collection bags and urine

collection pads can also be used to collect urine. NICE suggests urine collection pads as the next best option to

clean catch.

The first midstream urine of the morning should be collected after a minimum of 8 h fasting. Drinking

can influence urine metabolite concentrations. This requires a normalization. Specify, if collected at

different times, or for 24 h collection. Any variations to instructions shall be validated. Fasting enables

to perform the metabolomics analysis of urine where donors are synchronized having similar metabolic

conditions. Research or dedicated analytical tests can require different patient conditions.

A sufficient volume of urine shall be collected according to the requirements of the preanalytical

preparation steps and the analytical test.

Any clinical procedure affecting the specimen collection shall be documented. The total collected

volume shall be documented.

5.1.1.4.2 Information on the urine specimen and storage requirements at the urine collection

site

As metabolic profiles can change after urine collection and can thereby affect the validity and reliability

of the analytical test result, the documentation on the primary urine specimen shall include the time

and date of urine collection.

The whole urine specimen should be kept refrigerated at 2 °C to 8 °C for a maximum of 2 h and shall not

be frozen prior to centrifugation and/or filtration to avoid cell disruption upon ice crystal formation,

unless specified differently by the analytical test.

The allowed urine specimen total storage duration includes the time for storage at the point of urine

collection, transportation to the testing laboratory and further storage at the testing laboratory or

other institutions.
5.1.2 Tr
...

SLOVENSKI STANDARD
oSIST prEN ISO 23118:2020
01-september-2020
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne
procese metabolomike v urinu, serumu in plazmi venske krvi (ISO/DIS 23118:2020)

Molecular in vitro diagnostic examinations - Specifications for pre-examination processes

in metabolomics in urine, venous blood serum and plasma (ISO/DIS 23118:2020)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für

präanalytische Prozesse für Metabolomuntersuchungen in Urin, venösem Blutserum und

–plasma (ISO/DIS 23118:2020)

Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus

préanalytiques pour l'analyse du métabolome dans l'urine et le sang veineux (sérum et

plasma) (ISO/DIS 23118:2020)
Ta slovenski standard je istoveten z: prEN ISO 23118
ICS:
11.100.10 Diagnostični preskusni In vitro diagnostic test
sistemi in vitro systems
oSIST prEN ISO 23118:2020 en,fr,de

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

---------------------- Page: 1 ----------------------
oSIST prEN ISO 23118:2020
---------------------- Page: 2 ----------------------
oSIST prEN ISO 23118:2020
DRAFT INTERNATIONAL STANDARD
ISO/DIS 23118
ISO/TC 212 Secretariat: ANSI
Voting begins on: Voting terminates on:
2020-07-13 2020-10-05
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes in
metabolomics in urine, venous blood serum and plasma
ICS: 11.100.10
THIS DOCUMENT IS A DRAFT CIRCULATED
This document is circulated as received from the committee secretariat.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
ISO/CEN PARALLEL PROCESSING
BEING ACCEPTABLE FOR INDUSTRIAL,
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 23118:2020(E)
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. ISO 2020
---------------------- Page: 3 ----------------------
oSIST prEN ISO 23118:2020
ISO/DIS 23118:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

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.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
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Contents Page

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

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

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

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

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

4 General Considerations ................................................................................................................................................................................. 3

5 Urine .................................................................................................................................................................................................................................. 4

5.1 Outside the laboratory ..................................................................................................................................................................... 4

5.1.1 Urine collection ................................................................................................................................................................. 4

5.1.2 Transport requirements ............................................................................................................................................ 5

5.2 Inside the laboratory ......................................................................................................................................................................... 5

5.2.1 Specimen reception ....................................................................................................................................................... 5

5.2.2 Storage requirements .................................................................................................................................................. 6

5.2.3 Urine sample processing ........................................................................................................................................... 6

5.2.4 Long-term storage requirements for urine samples......................................................................... 6

5.2.5 Urine thawing ..................................................................................................................................................................... 6

6 Blood ................................................................................................................................................................................................................................. 7

6.1 Outside the laboratory ..................................................................................................................................................................... 7

6.1.1 Primary collection .......................................................................................................................................................... 7

6.1.2 Transport of pre-processed specimens to laboratory ..................................................................... 8

6.2 Inside the laboratory ......................................................................................................................................................................... 8

6.2.1 Specimen reception ....................................................................................................................................................... 8

6.2.2 Sample processing .......................................................................................................................................................... 9

6.2.3 Transport of processed samples to a laboratory for metabolomics analysis

or transport to a biobank ......................................................................................................................................... 9

6.2.4 Long-term storage requirements ...................................................................................................................... 9

6.2.5 Serum and plasma thawing and use ............................................................................................................10

Annex A (informative) Instability of the metabolome.....................................................................................................................11

Bibliography .............................................................................................................................................................................................................................17

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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 212, Clinical laboratory testing and in

vitro diagnostic test systems.

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
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Introduction

Metabolomics is the -omic science that deals with the characterization of the metabolome, in turn

defined as the whole set of small molecules (molecular mass < 2000) in a certain biological system such

as a cell, a tissue, an organ, or an entire organism [3]. The analyses are mainly performed via two major

analytical techniques, namely mass spectrometry (MS) and nuclear magnetic resonance (NMR) [4-6].

The former has a sensitivity that can be as low as picomolar, requires sample separation and multiple

experimental runs targeted to specific classes of compounds. The latter measures metabolites present

at concentration above 1 µM and is mainly used for untargeted analyses, where all metabolites above

the detection limit are observed simultaneously, independent of their chemical nature, without any

separation procedure.

The metabolome is dynamic and quite sensitive to perturbations. The metabolome can change

drastically during primary sample collection, transport, storage, and processing. As a result, the

outcome from the diagnostic and research measurements may become an unreliable representation

of the specific targeted physiological state or point in time, but instead describes an artificial profile

generated during the pre-examination process. Pre-analytical variations have been identified to

originate from two main sources: i) can result from enzymatic activity in the samples, mainly related

to the presence of cells; ii)can result from chemical reactions (e.g. redox reactions) among metabolites

or between metabolites and oxygen [7-13]. Moreover, the analyses can be influenced by the use of

additives or by the introduction of contaminants, and therefore the selection of appropriate collection

tubes and plasticware is also a critical aspect of the pre-examination phase.

Studies have been undertaken to establish the best pre-examination procedures in terms of maintenance

of the original sample metabolome by identifying the critical steps and parameters affecting the

metabolome composition. Additionally, standardization of the entire pre-examination workflow is

needed to ensure comparability in multicenter studies. At the present state of the art, there are no

defined pre-examination procedures for metabolomic samples. As a consequence, the procedures

adopted by the various centers differentially influence the metabolome of the samples, making their

comparison unreliable The adoption of the present requirements for the pre-examination phase make

it possible to compare and evaluate the results obtained from metabolic analysis.

This document draws upon such studies to codify and standardize the steps for urine, serum and

plasma metabolomics analysis in what is referred to as the pre-analytical phase.
In this document, the following verbal forms are used:
— “shall” indicates a requirement;
— “should” indicates a recommendation;
— “may” indicates a permission;
— “can” indicates a possibility or a capability.
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DRAFT INTERNATIONAL STANDARD ISO/DIS 23118:2020(E)
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes in
metabolomics in urine, venous blood serum and plasma
1 Scope

This document specifies requirements for the handling, documentation and processing of urine, venous

blood plasma and serum intended for metabolomics analysis in the pre-examination processes. This

document is applicable to metabolomics examinations and can be used by biomedical laboratories,

customers of laboratories, in vitro diagnostics developers and manufacturers, institutions and

companies performing biomedical research, biobanks, and regulatory authorities.
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 15189, Medical laboratories — Requirements for quality and competence
ISO 15190, Medical laboratories — Requirements for safety
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 15189 and the following apply.

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

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
biofluid

biological fluid which can be excreted (such as urine or sweat), secreted (such as breast milk, saliva

or bile), obtained with a needle (such as blood or cerebrospinal fluid), or produced as a result of a

pathological process (such as blister or cyst fluid)
3.2
examination

set of operations having the object of determining the value or characteristics of a property

Note 1 to entry: Processes that start with the isolated analyte and include all kinds of parameter testing or

chemical manipulation for quantitative or qualitative examination.

Note 2 to entry: For metabolomic analysis, analyte isolation is not necessarily required.

[SOURCE: ISO 20166-1:2018, 3.10, modified — admitted term “analytical test” has been deleted and

Note 2 entry has been added.]
3.3
fasting
abstinence from any solid or liquid food excluding water for at least 8 hours
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3.4
mass spectrometry

method used to analyse chemical compounds on the basis of their mass to charge ratio

3.5
metabolic profiling

use of analytical platforms to simultaneously measure the ensemble of metabolites (3.6) in biological

systems that can be measured by the employed (or selected) technique
EXAMPLE Examples for such techniques are NMR and MS.
3.6
metabolites

small molecules (≤ 2000 Da) that are intermediates and/or products of metabolism of the host

organisms, of its microflora, deriving from food, drinks, drugs or pollutants.
Note 1 to entry: For further information see Bibliography [3].
3.7
metabolome

complete set of metabolites (3.6) to be found within an organism or a biological sample

Note 1 to entry: For further information see Bibliography [3].
3.8
metabolomics

comprehensive analysis of the metabolome (3.7) of a biological specimen (3.14) (e.g., organism, cell,

tissue or biofluids (3.1))
3.9
MS-based metabolomics

use of mass spectrometry (3.4) to measure metabolites (3.6) in biological samples

3.10
nuclear magnetic resonance spectroscopy
NMR

method based on the selective absorption of high frequency radio waves by atomic nuclei subjected to a

stationary magnetic field.
Note 1 to entry: NMR provides chemical and structural properties of molecules.
3.11
NMR-based metabolomics
use of NMR spectroscopy to measure metabolites (3.6) in biological samples
3.12
plasma
liquid part of unclotted blood
Note 1 to entry: Plasma samples can contain anti-coagulants.
3.13
pre-examination processes
preanalytical phase
preanalytical workflow

processes that start, in chronological order, from the clinician’s request and include the examination

(3.2) request, preparation and identification of the patient, collection of the primary sample(s),

temporary storage, transportation to and within the analytical laboratory, aliquoting, retrieval

Note 1 to entry: The preanalytical phase can include preparative processes that can influence the outcome of the

intended examination (3.2).
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[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added, and more details were

included.]
3.14
primary sample
specimen

discrete portion of a body fluid, breath, hair or tissue taken for examination (3.2), study or analysis of

one or more quantities or properties assumed to apply for the whole

[SOURCE: ISO 15189:2012, 3.16, modified — The term and definition are used here without the

original notes.]
3.15
room temperature
temperature which is defined as 18 °C to 25 °C for the purpose of this document.
3.16
serum
liquid that can be separated from clotted blood
3.17
stability

ability of a sample material, when stored under specified conditions, to maintain a stated property

value within specified limits for a specified period of time

Note 1 to entry: The analytes for the purpose of this document are metabolites (3.6).

[SOURCE: ISO Guide 30:1992, 2.7]
4 General Considerations

For general statements on medical laboratory quality management systems and in particular on specimen

collection, reception, and handling (including avoidance of cross contaminations) see ISO 15189or

ISO/IEC 17020:2012, 8 and 7.2. The requirements on laboratory equipment, reagents, and consumables

according to ISO 15189 shall be followed; ISO 15189, and ISO/IEC 17020:2012, 6.2 can also apply.

All steps of a diagnostic workflow can influence the final analytical test result and a risk assessment

shall be performed (see also ISO 14971). Mitigation measures for eliminating or reducing identified risks

shall be established where required for ensuring the performance of the examination. It shall especially

be investigated and ensured that the metabolites intended to be analysed are not compromised in a

manner impacting the examination performance. This can be done, e.g. by applying the intended

examination to specimens/samples which underwent time course studies reflecting the individual pre-

examination process steps such as transport and storage and by implementing measures to prevent or

reduce impacts by the identified pre-analytical variables.

In the absence of suitable specimen stabilization technologies, regarding the metabolome, the specimen

collection shall be carried out in hospital premises or institutions where there are immediate suitable

biofluid processing procedures available.

Specifically for specimens intended to be analysed by metabolomics, the following steps shall be

considered:
a) patient pretreatment (fasting, therapy, etc.);
b) the specimen collection from the patient;

c) the selection of collection containers and packages (e.g. collection tubes, cooling box, box for storing

and transportation);

d) the selection of stabilization procedures (e.g. any compounds added for stabilizing the specimen);

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e) the recording of any additions or modifications to the specimen;
f) the recording of types and quantity as well as description of specimens.

Safety requirements for facilities, transport and handling shall be considered (see ISO 15189 and

ISO 15190). WHO Guidelines for the Safe Transport of Infectious Substances and Diagnostic Specimens

(https:// www .who .int/ csr/ emc97 _3 .pdf) should be followed.
5 Urine
5.1 Outside the laboratory
5.1.1 Urine collection
5.1.1.1 General

For the collection of the specimen the requirements (e.g. disease condition, specimen size) for the

intended molecular examination shall be considered.
See also ISO 15189.
5.1.1.2 Information about the specimen donor/patient

The documentation shall include the ID of the specimen donor/patient, which can be in the form of a code.

The documentation should include, but is not limited to:

a) the health status and relevant lifestyle factors of the urine donor [e.g. healthy, disease type,

concomitant disease(s)];
b) demographics (e.g., age, sex);

c) the information about medical treatment and any treatment prior to urine collection (e.g.

anaesthetics, medications, diagnostic procedures);

d) the collection time, including information about fasting, previous activities.

e) the appropriate consent from the specimen donor/patient.
5.1.1.3 Selection and labelling of collection containers
The laboratory shall define the container intended for urine collection.

Additives are usually not used, because they can interfere with the analytical method. If they are

required, for specific purposes their impact on the analytical performance and outcome shall be

analysed. Some additives in collection tubes could present a risk to patients (e.g. toxic or corrosive).

For the labelling (specimen identification) of the urine collection tube a routine procedure (see also

ISO 15189) or a procedure with additional information (e.g. 2D-barcode) shall be used.

5.1.1.4 Urine collection and reception from the specimen donor

Instruction for the urine collection shall be given to the donor, including any safety measures that need

to be followed while handling collection containers containing harmful additives. All urine collection

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devices should be checked for compatibility with metabolomics, e.g. avoiding any interference with the

metabolomics profile.

NOTE For non-toilet-trained children, the most popular non-invasive method used is the clean catch, which

National Institute for Health and Clinical Excellence (NICE), 2007 defines as a gold standard. This involves

catching a sample by holding a sterile specimen bottle in the urine stream. Urine collection bags and urine

collection pads can also be used to collect urine. NICE suggests urine collection pads as the next best option to

clean catch.

The first midstream urine of the morning should be collected after a minimum of 8 h fasting. Drinking

can influence urine metabolite concentrations. This requires a normalization. Specify, if collected at

different times, or for 24-h collection. Any variations to instructions shall be validated. Fasting enables

to perform the metabolomics analysis of urine where donors are synchronized having similar metabolic

conditions. Research or dedicated analytical tests can require different patient conditions.

A sufficient volume of urine shall be collected according to the requirements of the preanalytical

preparation steps and the analytical test.

Any clinical procedure affecting the specimen collection shall be documented. The total collected

volume shall be documented.

5.1.1.4.1 Information on the urine specimen and storage requirements at the urine

collection site

As metabolic profiles can change after urine collection and can thereby affect the validity and reliability

of the analytical test result, the documentation on the primary urine specimen shall include the time

and date of urine collection.

The whole urine specimen should be kept refrigerated at 2 °C to 8 °C for a maximum of 2 h and shall not

be frozen prior to centrifugation and/or filtration to avoid cell disruption upon ice crystal formation,

unless specified differently by the analytical test.

The allowed urine specimen total storage duration includes the time for storage at the point of urine

collection, transportation to the testing laboratory and further storage at the testing laboratory or

other institutions.
5.1.2 Transport requirements

During transport, the specimen should be kept cool (temperature range 2 °C to 8 °C).

Appropriate measures shall be taken to secure temperature specifications and to reduce time for the

delivery, which should be completed within 2 h from collection.

The compliance with the protocol for the transport procedure shall be documented. Any deviations

from the protocol shall be described and documented.

WHO Guidelines for the Safe Transport of Infectious Substances and Diagnostic Specimens (https://

www .who .int/ csr/ emc97 _3 .pdf) should be followed.
5.2 Inside the laboratory
5.2.1 Specimen reception

The urine specimen reception time and conditions (e.g. labelling, transport conditions, volume, leaking

and precipitation) of the received specimens shall be documented. Nonconformities of labelling,

transport conditions and urine volume differences to specifications described for the urine collection

or specimen preparation requirements shall be documented.
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Where there are nonconformities in transport conditions, overall storage and transport time or urine

volume that could affect the validity and reliability of the analytical test result [9-11], a new specimen

should be obtained.

If required for the analytical test, specimen properties should be assessed (e.g. pH-value, creatinine

concentration, blood and/or bacterial contaminations).
5.2.2 Storage requirements

The storage temperature and time interval between specimen receipt and sample processing for urine

shall be documented.
The storage temperature should be according to 5.1.1.5.

The urine specimen total storage duration shall include the time for storage at the urine collection

site (5.1.1.5), transportation to the laboratory (5.1.2) and further storage at the laboratory or other

institutions.

Some examinations need special urine storage/archiving conditions. Manufacturers’/providers’

instructions shall be followed. Appropriate measures shall be taken to ensure compliance with

temperature recommendations.
5.2.3 Urine sample processing

Centrifugation (recommended: 1 000 g to 3 000 g for 5 min at 2 °C to 8 °C) followed by filtration (e.g.

with a 0.20 μm cut-off filter) to remove particulate matter and cells.
Alternatively, only filtration can be used and documented.

Filter material and devices shall be proven neither to absorb nor to release metabolites or interfere

with their analyses.

NOTE The above mentioned centrifugation/filtration is important to avoid cell disruption that would

contaminate the specimen [9-11].
Alternative processing procedures shall be validated.
5.2.4 Long-term storage requirements for urine samples

The temperature and durations between sample receipt, sample processing and freezing of the

processed sample shall be documented.

If the processed sample is intended to be stored frozen, the impact on the metabolomics analyses should

be validated. The processed sample should be aliquoted into cryo-vials in the suitable volume needed

for the metabolic profile testing. The minimum aliquot volume is determined by the analytical test. The

vials shall be tested to avoid sample contamination (e.g. from phthalates).

Before freezing, cells should be removed, following section (5.2.3). Controlled-rate freezing via slow

programmable coolin
...

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