SIST EN ISO 23118:2021

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.

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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,
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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

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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
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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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oSIST prEN ISO 23118:2020
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
MS
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
...