SIST EN ISO 20184-3:2021
(Main)Molecular in vitro diagnostic examinations - Specifications for pre-examination processes for frozen tissue - Part 3: Isolated DNA (ISO 20184-3:2021)
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes for frozen tissue - Part 3: Isolated DNA (ISO 20184-3:2021)
This document gives recommendations for the handling, documentation, storage and processing of frozen tissue specimens intended for the examination of isolated DNA during the pre-examination phase before a molecular examination is performed.
This document is applicable to any molecular in vitro diagnostic examination performed by medical laboratories and molecular pathology laboratories that evaluate DNA isolated from frozen tissue. It is also intended to be used by laboratory customers, in vitro diagnostics developers and manufacturers, biobanks, institutions and commercial organizations performing biomedical research, and regulatory authorities.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in this document.
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 gefrorene Gewebeproben - Teil 3: Isolierte DNA (ISO 20184-3:2021)
Dieses Dokument legt Anforderungen fest und gibt Empfehlungen zur Handhabung, Lagerung, Verarbeitung und Dokumentation von gefrorenen Gewebeproben, die für die DNA Untersuchung während der präanalytischen Phase vor Beginn der molekularen Untersuchung vorgesehen sind.
Dieses Dokument ist anwendbar auf molekulare in vitro diagnostische Untersuchungen, einschließlich im Laboratorium entwickelter Prüfungen, die von medizinischen Laboratorien und Laboratorien der molekularen Pathologie durchgeführt werden, die aus gefrorenem Gewebe isolierte DNA auswerten. Es ist außerdem dafür vorgesehen, von Kunden des Laboratoriums, Entwicklern und Herstellern von In vitro Diagnostika sowie Biobanken, Einrichtungen und kommerziellen Organisationen, die biomedizinische Forschungen durchführen, und Aufsichtsbehörden angewendet zu werden.
Gewebe, die vor dem Gefriervorgang einer chemischen Vorbehandlung zur Stabilisierung unterzogen wurden, sind nicht durch dieses Dokument abgedeckt.
ANMERKUNG Internationale, nationale oder regionale Bestimmungen bzw. Anforderungen können ebenfalls für bestimmte Themen in diesem Dokument gelten.
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus préanalytiques pour les tissus congelés - Partie 3: ADN extrait (ISO 20184-3:2021)
Le présent document spécifie des exigences et fournit des recommandations relatives à la manipulation, au stockage, au traitement et à la documentation de prélèvements de tissus congelés destinés à l’analyse de l’ADN durant la phase préanalytique précédant la réalisation d’une analyse moléculaire.
Le présent document s’applique aux analyses de diagnostic moléculaire in vitro, y compris les essais développés en laboratoires, réalisées par les laboratoires de biologie médicale et les laboratoires de pathologie moléculaire qui évaluent l’ADN extrait de tissus congelés. Il est également destiné à être utilisé par les clients de laboratoires, les développeurs et fabricants de l’industrie du diagnostic in vitro, ainsi que par les biobanques, les institutions et les organismes commerciaux spécialisés en recherche biomédicale et les autorités réglementaires.
Le cas des tissus ayant subi un prétraitement de stabilisation chimique avant la congélation n’est pas couvert par le présent document.
NOTE Des réglementations ou exigences internationales, nationales ou régionales peuvent également s’appliquer à des sujets spécifiques traités dans le présent document.
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne procese za zamrznjena tkiva - 3. del: Izolirana DNK (ISO 20184-3:2021)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 20184-3:2021
01-julij-2021
Nadomešča:
SIST-TS CEN/TS 16826-3:2018
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne
procese za zamrznjena tkiva - 3. del: Izolirana DNK (ISO 20184-3:2021)
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes
for frozen tissue - Part 3: Isolated DNA (ISO 20184-3:2021)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für
präanalytische Prozesse für gefrorene Gewebeproben - Teil 3: Isolierte DNA (ISO 20184-
3:2021)
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus
préanalytiques pour les tissus congelés - Partie 3: ADN extrait (ISO 20184-3:2021)
Ta slovenski standard je istoveten z: EN ISO 20184-3:2021
ICS:
11.100.10 Diagnostični preskusni In vitro diagnostic test
sistemi in vitro systems
SIST EN ISO 20184-3:2021 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 20184-3:2021
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SIST EN ISO 20184-3:2021
EN ISO 20184-3
EUROPEAN STANDARD
NORME EUROPÉENNE
May 2021
EUROPÄISCHE NORM
ICS 11.100.10 Supersedes CEN/TS 16826-3:2018
English Version
Molecular in vitro diagnostic examinations - Specifications
for pre-examination processes for frozen tissue - Part 3:
Isolated DNA (ISO 20184-3:2021)
Analyses de diagnostic moléculaire in vitro - Molekularanalytische in-vitro-diagnostische Verfahren
Spécifications relatives aux processus préanalytiques - Spezifikationen für präanalytische Prozesse für
pour les tissus congelés - Partie 3: ADN extrait (ISO gefrorene Gewebeproben - Teil 3: Isolierte DNA (ISO
20184-3:2021) 20184-3:2021)
This European Standard was approved by CEN on 9 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 20184-3:2021 E
worldwide for CEN national Members.
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SIST EN ISO 20184-3:2021
EN ISO 20184-3:2021 (E)
Contents Page
European foreword . 3
2
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SIST EN ISO 20184-3:2021
EN ISO 20184-3:2021 (E)
European foreword
This document (EN ISO 20184-3:2021) 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 November 2021, and conflicting national standards
shall be withdrawn at the latest by May 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 16826-3:2018.
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 20184-3:2021 has been approved by CEN as EN ISO 20184-3:2021 without any
modification.
3
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SIST EN ISO 20184-3:2021
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SIST EN ISO 20184-3:2021
INTERNATIONAL ISO
STANDARD 20184-3
First edition
2021-05
Molecular in vitro diagnostic
examinations — Specifications for
pre-examination processes for frozen
tissue —
Part 3:
Isolated DNA
Analyses de diagnostic moléculaire in vitro — Spécifications relatives
aux processus préanalytiques pour les tissus congelés —
Partie 3: ADN extrait
Reference number
ISO 20184-3:2021(E)
©
ISO 2021
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(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
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Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 5
5 Outside the laboratory . 6
5.1 Specimen collection . 6
5.1.1 General. 6
5.1.2 Information about the patient/specimen donor . 6
5.1.3 Information about the specimen . 6
5.1.4 Specimen processing . 6
5.2 Fresh tissue transport requirements . 7
5.2.1 General. 7
5.2.2 Preparations for the transport . 7
5.2.3 During transport . 8
6 Inside the laboratory . 8
6.1 Information about the reception of the specimen . 8
6.2 Evaluation of the pathology of the specimen and selection of the sample(s) . 8
6.3 Freezing of the specimen or sample(s) . 9
6.4 Storage requirements .11
6.5 DNA isolation .11
6.5.1 General.11
6.5.2 Using commercial kits .12
6.5.3 Using laboratory developed protocols .12
6.6 Quantity and quality assessment of isolated DNA .12
6.7 Storage of isolated DNA .13
Bibliography .14
© ISO 2021 – All rights reserved iii
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(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).
A list of all parts in the ISO 20184 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
iv © ISO 2021 – All rights reserved
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
Introduction
Molecular in vitro diagnostics, including molecular pathology, has enabled significant progress in
medicine. Further progress is expected with new technologies analysing nucleic acids, proteins, and
metabolites in human tissues and body fluids. However, integrity and profile of these molecules can
change during specimen collection, transport, storage, and processing. As a consequence the outcome
from diagnostics or research can become unreliable or even impossible because the subsequent
examination assay might not determine the real situation in the patient but instead, an artificial profile
which is generated during the pre-examination process.
DNA integrity in tissues can change during processing and storage. Modifications of the DNA molecules
can impact the validity and reliability of the examination test results. It is essential to take special
measures to minimize the described DNA changes and modifications for subsequent examination.
Therefore, a standardization of the entire process from specimen collection to DNA examination is
needed. Studies have been undertaken to determine the important influencing factors. This document
draws upon such work to codify and standardize the steps for frozen tissue with regard to DNA
examination in what is referred to as the pre-examination 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.
© ISO 2021 – All rights reserved v
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SIST EN ISO 20184-3:2021
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SIST EN ISO 20184-3:2021
INTERNATIONAL STANDARD ISO 20184-3:2021(E)
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 3:
Isolated DNA
1 Scope
This document specifies requirements and gives recommendations for the handling, storage,
processing, and documentation of frozen tissue specimens intended for DNA examination during the
pre-examination phase before a molecular examination is performed.
This document is applicable to molecular in vitro diagnostic examinations including laboratory
developed tests performed by medical laboratories and molecular pathology laboratories that
evaluate DNA isolated from frozen tissue. It is also intended to be used by laboratory customers, in
vitro diagnostics developers and manufacturers, biobanks, institutions and commercial organizations
performing biomedical research, and regulatory authorities.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in
this document.
NOTE International, national, or regional regulations or requirements can also apply to specific topics
covered in this document.
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
aliquot
portion of a larger amount of homogenous material, assumed to be taken with negligible sampling error
Note 1 to entry: The term is usually applied to fluids. Solid tissues are heterogeneous and therefore cannot be
aliquoted.
© ISO 2021 – All rights reserved 1
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
[SOURCE: Compendium of Chemical Terminology Gold Book. International Union of Pure and Applied
Chemistry. Version 2.3.3., 2014; the PAC, 1990,62,1193 (Nomenclature for sampling in analytical
chemistry (Recommendations 1990)) p. 1206; and the PAC 1990, 62, 2167 (Glossary of atmospheric
chemistry terms (Recommendations 1990)) p. 2173.]
3.2
ambient temperature
unregulated temperature of the surrounding air
3.3
analyte
component represented in the name of a measurable quantity
[SOURCE: ISO 17511:2020, 3.2, modified — The example was not taken over.]
3.4
analytical test performance
accuracy, precision, and sensitivity of a test to measure the analyte (3.3) of interest
Note 1 to entry: Other test performance characteristics such as robustness, repeatability can apply as well.
3.5
biobanking
process of acquisitioning and storing, together with some or all of the activities related to collection,
preparation, preservation, testing, analysing and distributing defined biological material as well as
related information and data
[SOURCE: ISO 20387:2018, 3.6]
3.6
cold ischemia
condition after removal of the tissue from the body until its stabilization or fixation
[SOURCE: ISO 20184-2:2018, 3.5]
3.7
diagnosis
identification of a health or disease state from its signs and/or symptoms, where the diagnostic process
can involve examinations (3.10) and tests for classification of an individual's condition into separate
and distinct categories or subclasses that allow medical decisions about treatment and prognosis to be
made
[SOURCE: ISO 20184-2:2018, 3.6]
3.8
DNA
deoxyribonucleic acid
polymer of deoxyribonucleotides occurring in a double-stranded (dsDNA) or single-stranded (ssDNA)
form
[SOURCE: ISO 22174:2005, 3.1.2]
3.9
DNase
deoxyribonuclease
enzyme that catalyzes the degradation of DNA (3.8) into smaller components
[SOURCE: ISO 20184-1:2018, 3.8]
2 © ISO 2021 – All rights reserved
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
3.10
examination
analytical test
set of operations with the object of determining the value or characteristics of a property
Note 1 to entry: Processes that start with the isolated analyte (3.3) and include all kinds of parameter testing or
chemical manipulation for quantitative or qualitative examination.
[SOURCE: ISO 15189:2012, 3.7, modified — Notes to entry 1 to 3 have been removed. Note 1 to entry has
been added and “analytical test” has been added as a preferred term.]
3.11
grossing
gross examination
inspection of pathology specimens with the bare eye to obtain diagnostic information, while being
processed for further microscopic examination (3.10)
[SOURCE: ISO 20184-1:2018, 3.10]
3.12
homogeneous
uniform in structure and composition
[SOURCE: ISO 20184-1:2018, 3.11]
3.13
interfering substance
endogenous substance of a specimen (3.18)/sample (3.17) or exogenous substance (e.g. stabilization
solution) that can alter an examination (3.10) result
[SOURCE: ISO 20184-1:2018, 3.12]
3.14
pre-examination process
preanalytical phase
preanalytical workflow
process that starts in chronological order, from the clinician’s request and include the examination
(3.10) request, preparation and identification of the patient, collection of the primary sample(s) (3.18),
transportation to and within the medical or pathology laboratory, isolation of analytes (3.3), and ends
when the analytical examination (3.10) begins
Note 1 to entry: The pre-examination phase includes preparative processes that influence the outcome of the
intended examination (3.10).
[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added and more detail was
included.]
3.15
proficiency test
evaluation of participant performance against pre-established criteria by means of inter-laboratory
comparisons
[SOURCE: ISO/IEC 17043:2010, 3.7, modified — The term and definition are used here without the
original notes.]
3.16
room temperature
for the purpose of this document, temperature in the range of 18 °C to 25 °C
Note 1 to entry: Local or national regulations can have different definitions.
[SOURCE: ISO 20184-1:2018, 3.19]
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
3.17
sample
one or more parts taken from a primary sample (3.19)
[SOURCE: ISO 15189:2012, 3.24, modified — The example was not taken over.]
3.18
specimen
primary sample
discrete portion of a body fluid, breath, hair or tissue taken for examination (3.10), study or analysis of
one or more quantities or properties assumed to apply for the whole
[SOURCE: ISO 20184-1:2018, 3.14]
3.19
stability
ability of a sample (3.17) 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 analyte (3.3) for the purpose of this document is DNA (3.7).
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — The words “reference material” were replaced by
“sample material”.]
3.20
storage
maintenance of biological material under defined and standardized conditions for the intended use
Note 1 to entry: Long-term storage typically occurs in laboratory archives or in biobanks.
3.21
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended
use or application have been fulfilled
Note 1 to entry: The term “validated” is used to designate the corresponding status.
[SOURCE: ISO 9000:2015, 3.8.13, modified — Note 1 and Note 3 were not taken over.]
3.22
verification
confirmation, through provision of objective evidence, that specified requirements have been fulfilled
Note 1 to entry: The term “verified” is used to designate the corresponding status.
Note 2 to entry: Confirmation can comprise activities such as:
— performing alternative calculations,
— comparing a new design specification with a similar proven design specification,
— undertaking tests and demonstrations, and
— reviewing documents prior to issue.
[SOURCE: ISO 9000:2015, 3.8.12, modified — Note 1 and Note 2 to entry have been deleted; Note 3 to
entry has been renumbered as Note 1 to entry; new Note 2 to entry has been added.]
4 © ISO 2021 – All rights reserved
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
3.23
warm ischemia
condition before the tissue is removed from the body, but where it is deprived of its normal blood supply
[SOURCE: ISO 20184-1:2018, 3.25]
Note 1 to entry: Disruption of normal blood supply varies significantly case by case. Therefore, warm ischemia
duration and its effects depend on individual cases and it also can depend on the anatomy of the arterial blood
supply.
3.24
workflow
series of activities necessary to complete a task
[SOURCE: ISO 20184-1:2018, 3.26 ]
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, ISO/IEC 17025 or ISO/IEC 17020. The requirements on laboratory equipment, reagents, and
consumables according to ISO 15189 shall be followed; ISO/IEC 17025 and ISO/IEC 17020 can also apply.
All steps of the pre-examination, examination and post-examination processes (i.e. the entire
workflow) can influence the diagnosis or research study results. Thus, this entire workflow shall be
specified, verified and validated during the development of the examination. This includes specifically
all pre-examination process steps such as the examination request, preparation and identification of
the patient, collection of the primary sample(s), transport to and within the medical laboratory, storage
and isolation of analytes. Workflow steps which cannot always be controlled (e.g. warm ischemia) shall
be documented.
In contrast to RNA or proteins, DNA in tissue is relatively stable during warm and cold ischemia.
Changes of DNA sequence or copy numbers (e.g. comparative genomic hybridization (CGH) profiles)
[9]
due to longer warm and cold ischemia durations are unknown . However, DNA methylation profiles
[10]
may change in response to ischemia . The duration until the specimen is frozen should be kept as
short as possible in order to avoid enzymatic degradation of DNA. The duration before freezing shall be
[9]
documented and the temperature before freezing should be documented .
During the design and development of a DNA based examination, 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.
Safety requirements on specimen transport and handling shall be considered as given in ISO 15189 and
ISO 15190. International, national, or regional regulations or requirements can also apply.
During the whole pre-examination process, precautions shall be taken to avoid cross contamination
between different specimens/samples, e.g. by using single-use material whenever feasible or
appropriate cleaning procedures between processing of different specimens/samples.
Where the examination manufacturer has specified instructions for pre-examination steps, these shall
be followed. When, for justified reasons (e.g. unmet patient needs), a commercial product is not used
in accordance to the manufacturer's instructions, responsibility for its validation, verification, use and
performance lies with the user.
For general considerations on specimen collection, transport, receipt, and handling, see ISO 20658 and
ISO 20387.
© ISO 2021 – All rights reserved 5
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SIST EN ISO 20184-3:2021
ISO 20184-3:2021(E)
5 Outside the laboratory
5.1 Specimen collection
5.1.1 General
Where the intended examination is known, its instructions for use including requirements for pre-
examination steps such as specimen collection shall be followed (see also Clause 6 and ISO 15189).
5.1.2 Information about the patient/specimen donor
The documentation shall include the identity of the patient/specimen donor, which can be in the form
of a code. The documentation shall be undertaken by the department collecting the specimen from the
patient and should include, but is not limited to:
a) the relevant health status of the patient/specimen donor (e.g. healthy, disease type, concomitant
disease and demographics (e.g. age and gender);
b) the relevant information about routine medical treatment and special treatment prior to tissue
collection (e.g. anaesthetics, medications, surgical or diagnostic procedures);
c) the appropriate consent from the patient/specimen donor.
5.1.3 Information about the specimen
The documentation shall include, but is not limited to:
a) if required for the examination, the start of ischemia within the body (warm ischemia) by
documentation of the ischemia-relevant vessel ligation/clamping time point (usually arterial
clamping time);
NOTE Not needed where small tissue biopsy resection for freezing is perfor
...
SLOVENSKI STANDARD
oSIST prEN ISO 20184-3:2020
01-oktober-2020
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne
procese za zamrznjena tkiva - 3. del: Izolirana DNK (ISO/DIS 20184-3:2020)
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes
for frozen tissue - Part 3: Isolated DNA (ISO/DIS 20184-3:2020)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für
präanalytische Prozesse für gefrorene Gewebeproben - Teil 3: Isolierte DNA (ISO/DIS
20184-3:2020)
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus
préanalytiques pour les tissus congelés - Partie 3: ADN isolé (ISO/DIS 20184-3:2020)
Ta slovenski standard je istoveten z: prEN ISO 20184-3
ICS:
11.100.10 Diagnostični preskusni In vitro diagnostic test
sistemi in vitro systems
oSIST prEN ISO 20184-3:2020 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 20184-3:2020
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oSIST prEN ISO 20184-3:2020
DRAFT INTERNATIONAL STANDARD
ISO/DIS 20184-3
ISO/TC 212 Secretariat: ANSI
Voting begins on: Voting terminates on:
2020-08-03 2020-10-26
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 3:
Isolated DNA
Analyses de diagnostic moléculaire in vitro — Spécifications relatives aux processus préanalytiques pour
les tissus congelés —
Partie 3: ADN extrait
ICS: 11.100.10
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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 . 5
5 Outside the laboratory . 5
5.1 Specimen collection . 5
5.1.1 General. 5
5.1.2 Information about the patient/specimen donor+ . 6
5.1.3 Information about the specimen . 6
5.1.4 Specimen processing . 6
5.2 Fresh tissue transport requirements . 7
5.2.1 General. 7
5.2.2 Preparations for the transport . 7
5.2.3 During transport . 7
6 Inside the laboratory . 8
6.1 Information about the reception of the specimen . 8
6.2 E valuation of the pathology of the specimen and selection of the sample(s) . 8
6.3 Freezing of the specimen or sample(s) . 9
6.4 Storage requirements .10
6.5 DNA isolation .11
6.5.1 General.11
6.5.2 Using commercial kits .11
6.5.3 Using laboratory developed protocols .11
6.6 Quantity and quality assessment of isolated DNA .12
6.7 Storage of isolated DNA .12
Bibliography .14
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
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This document was prepared by Technical Committee ISO/TC 212, Clinical laboratory testing and in
vitro diagnostic test systems.
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Introduction
Molecular in vitro diagnostics, including molecular pathology, has enabled significant progress in
medicine. Further progress is expected with new technologies analysing nucleic acids, proteins, and
metabolites in human tissues and body fluids. However, integrity of these molecules can change during
specimen collection, transport, storage, and processing.
Consequently making the outcome from diagnostics or research unreliable or even impossible
because the subsequent examination assay might not determine the real situation in the patient but
an artificial profile generated during the pre-examination process. Therefore, a standardization of the
entire process from specimen collection to DNA examination is needed. Studies have been undertaken
to determine the important influencing factors. This document draws upon such work to codify and
standardize the steps for frozen tissue with regard to DNA examination in what is referred to as the
pre-examination phase.
DNA integrity in tissues can change during processing and storage. Modifications of the DNA molecules
can impact the validity and reliability of the examination test results. Therefore, it is essential to
take special measures to minimize the described DNA changes and modifications for subsequent
examination.
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.
Further details can be found in the ISO/IEC Directives, Part 2.
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DRAFT INTERNATIONAL STANDARD ISO/DIS 20184-3:2020(E)
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 3:
Isolated DNA
1 Scope
This document gives requirements and recommendations for the handling, storage, processing, and
documentation of frozen tissue specimens intended for DNA examination during the pre-examination
phase before a molecular examination is performed.
This document is applicable to molecular in vitro diagnostic examinations including laboratory
developed tests performed by medical laboratories and molecular pathology laboratories that
evaluate DNA isolated from frozen tissue. It is also intended to be used by laboratory customers, in
vitro diagnostics developers and manufacturers, biobanks, institutions and commercial organizations
performing biomedical research, and regulatory authorities.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in
this document.
NOTE International, national, or regional regulations or requirements can also apply to specific topics
covered in this document.
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
ISO/IEC 17020, Conformity assessment — Requirements for the operation of various types of bodies
performing inspection
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/
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3.1
aliquot
portion of a larger amount of homogenous material, assumed to be taken with negligible sampling error
Note 1 to entry: The term is usually applied to fluids. Solid tissues are heterogeneous and therefore cannot be
aliquoted.
[SOURCE: Compendium of Chemical Terminology Gold Book. International Union of Pure and Applied
Chemistry. Version 2.3.3., 2014; the PAC, 1990,62,1193 (Nomenclature for sampling in analytical
chemistry (Recommendations 1990)) p. 1206; and the PAC 1990, 62, 2167 (Glossary of atmospheric
chemistry terms (Recommendations 1990)) p. 2173.]
3.2
ambient temperature
unregulated temperature of the surrounding air
3.3
analyte
component represented in the name of a measurable quantity
[16]
[SOURCE: ISO 17511:2003, 3.2, modified — The example was not taken over. ]
3.4
analytical test performance
accuracy, precision, and sensitivity of a test to measure the analyte (3.3) of interest
Note 1 to entry: Other test performance characteristics such as robustness, repeatability can apply as well.
3.5
cold ischemia
condition after removal of the tissue from the body until its stabilization or fixation
[19]
[SOURCE: ISO 20184-2:2018, 3.5 ]
3.6
diagnosis
can involve examinations (3.9) and tests for classification of an individual's condition into separate and
distinct categories or subclasses that allow medical decisions about treatment and prognosis to be made
[19]
[SOURCE: ISO 20184-2:2018, 3.6 ]
3.7
DNA
deoxyribonucleic acid
polymer of deoxyribonucleotides occurring in a double-stranded (dsDNA) or single-stranded
(ssDNA) form
[21]
[SOURCE: ISO 22174:2005, 3.1.2 ]
3.8
DNase
deoxyribonuclease
enzyme that catalyzes the degradation of DNA (3.7) into smaller components
[18]
[SOURCE: ISO 20184-1:2018, 3.8 ]
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3.9
examination
analytical test
set of operations with the object of determining the value or characteristics of a property
Note 1 to entry: Processes that start with the isolated analyte (3.3) and include all kinds of parameter testing or
chemical manipulation for quantitative or qualitative examination.
[SOURCE: ISO 15189:2012, 3.7, modified — Notes to entry 1 to 3 have been removed. Note 1 to entry has
been added and “analytical test” has been added as a preferred term.]
3.10
grossing
gross examination
inspection of pathology specimens with the bare eye to obtain diagnostic information, while being
processed for further microscopic examination (3.9)
[18]
[SOURCE: ISO 20184-1:2018, 3.10 ]
3.11
homogeneous
uniform in structure and composition
[18]
[SOURCE: ISO 20184-1:2018, 3.11 ]
3.12
interfering substance
endogenous substance of a specimen (3.14)/sample (3.17) or exogenous substance (e.g. stabilization
solution) that can alter an examination (3.9) result
[18]
[SOURCE: ISO 20184-1:2018, 3.12 ]
3.13
pre-examination process
preanalytical phase
preanalytical workflow
process that starts in chronological order, from the clinician’s request and include the examination
(3.9) request, preparation and identification of the patient, collection of the primary sample(s) (3.14),
transportation to and within the medical or pathology laboratory, isolation of analytes (3.3), and ends
when the analytical examination (3.9) begins
Note 1 to entry: The pre-examination phase includes preparative processes that influence the outcome of the
intended examination (3.9).
[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added and more detail was
included.]
3.14
primary sample
specimen
discrete portion of a body fluid, breath, hair or tissue taken for examination (3.9), study or analysis of
one or more quantities or properties assumed to apply for the whole
[18]
[SOURCE: ISO 20184-1:2018, 3.14 ]
3.15
proficiency test
evaluation of participant performance against pre-established criteria by means of inter-laboratory
comparisons
[SOURCE: ISO/IEC 17043:2010, 3.7, modified — The term and definition are used here without the
[23]
original notes. ]
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3.16
room temperature
temperature in the range of 18 °C to 25 °C
Note 1 to entry: Local or national regulations can have different definitions.
[18]
[SOURCE: ISO 20184-1:2018, 3.19 ]
3.17
sample
one or more parts taken from a primary sample (3.14)
[SOURCE: ISO 15189:2012, 3.24, modified — The example was not taken over.]
3.18
stability
ability of a sample (3.17) 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 analyte (3.3) for the purpose of this document is DNA (3.7).
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — The words “reference material” were replaced by
[24]
“sample material”. ]
3.19
storage
maintenance of biological material under defined and standardized conditions for the intended use
Note 1 to entry: Long-term storage typically occurs in laboratory archives or in biobanks.
3.20
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended
use or application have been fulfilled
Note 1 to entry: The term “validated” is used to designate the corresponding status.
[15]
[SOURCE: ISO 9000:2015, 3.8.13, modified — Note 1 and Note 3 were not taken over. ]
3.21
verification
confirmation, through provision of objective evidence, that specified requirements have been fulfilled
Note 1 to entry: The term “verified” is used to designate the corresponding status.
[15]
[SOURCE: ISO 9000:2015, 3.8.12, modified — Note 1 and Note 2 were not taken over. ]
Note 2 to entry: Confirmation can comprise activities such as:
— performing alternative calculations,
— comparing a new design specification with a similar proven design specification,
— undertaking tests and demonstrations, and
— reviewing documents prior to issue.
3.22
warm ischemia
condition before the tissue is removed from the body, but where it is deprived of its normal blood supply
[18]
[SOURCE: ISO 20184-1:2018, 3.25 ]
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3.23
workflow
series of activities necessary to complete a task
[18]
[SOURCE: ISO 20184-1:2018, 3.26 ]
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
[22]
ISO 15189, ISO/IEC 17025 or ISO/IEC 17020 . The requirements on laboratory equipment, reagents,
and consumables according to ISO 15189 shall be followed; ISO/IEC 17025 and ISO/IEC 17020 can also
[22]
apply .
All steps of the pre-examination, examination and post-examination processes (i.e. the entire
workflow) can influence the diagnosis or research study results. Thus, this entire workflow shall be
specified, verified and validated during the development of the examination. This includes specifically
all pre-examination process steps such as the examination request, preparation and identification of
the patient, collection of the primary sample(s), transport to and within the medical laboratory, storage
and isolation of analytes. Workflow steps which cannot always be controlled (e.g. warm ischemia) shall
be documented.
In contrast to RNA or proteins, DNA in tissue is relatively stable during warm and cold ischemia.
Changes of DNA sequence or copy numbers (e.g. comparative genomic hybridization (CGH) profiles)
[1]
due to longer warm and cold ischemia durations are unknown . However, DNA methylation patterns
[2]
may change in response to ischemia . The duration until the specimen is frozen should be kept as
short as possible in order to avoid enzymatic degradation of DNA. The duration before freezing shall be
[1]
documented and the temperature before freezing should be documented .
During the design and development of a DNA based examination, 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.
Safety requirements on specimen transport and handling shall be considered (see ISO 15189 and
ISO 15190). International, national, or regional regulations or requirements can also apply.
During the whole pre-examination process, precautions shall be taken to avoid cross contamination
between different specimens/samples, e.g. by using single-use material whenever feasible or
appropriate cleaning procedures between processing of different specimens/samples.
Where the examination manufacturer has specified instructions for pre-examination steps, these shall
be followed. When, for justified reasons (e.g. unmet patient needs), a commercial product is not used
in accordance to the manufacturer's instructions, responsibility for its validation, verification, use and
performance lies with the user.
For general considerations on specimen collection, transport, receipt, and handling, see ISO 20658 and
ISO 20387.
5 Outside the laboratory
5.1 Specimen collection
5.1.1 General
For the collection of the specimen, the requirements (e.g. disease condition, specimen size) for the
intended molecular examination (see also Clause 6) should be considered.
See also ISO 15189.
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5.1.2 Information about the patient/specimen donor+
The documentation shall include the ID of the patient/specimen donor, which can be in the form of a
code. The documentation should include, but is not limited to:
a) the relevant health status of the patient/specimen donor (e.g. healthy, disease type, concomitant
disease and demographics (e.g. age and gender);
b) the relevant information about routine medical treatment and special treatment prior to tissue
collection (e.g. anaesthetics, medications, surgical or diagnostic procedures);
c) the appropriate consent from the patient/specimen donor.
5.1.3 Information about the specimen
The documentation shall include, but is not limited to:
a) if required for the examination, the start of ischemia within the body (warm ischemia) by
documentation of the ischemia-relevant vessel ligation/clamping time point (usually arterial
clamping time);
NOTE Not needed where small tissue biopsy resection for freezing is performed.
b) the time and date when tissue is removed from the body and the method of removal (e.g. core-
needle biopsy, resection, biopsy device used for the collection);
c) the description of tissue type and origin, tissue condition (e.g. diseased, unaffected by the disease),
including references to any marking applied in or outside the operating theatre made by surgeon,
radiologist or pathologist;
If the freezing of the tissue is performed outside the laboratory, the documentation steps described
under 6.2, where pathology evaluation is required, and 6.3 shall be performed.
The documentation should also include the ID of the responsible person collecting the specimen, this
can be in the form of a code.
5.1.4 Specimen processing
Tissues that need to be frozen for diagnostic purposes can originate from a large specimen or can be
small specimens e.g. biopsies taken by endoscopy or taken from patients during a surgical procedure
where fast frozen section diagnosis is required.
1) Any additions or modifications to the specimen after removal from the body (e.g. labelling for the
orientation of the specimen (e.g. ink-marking, stitches, incision(s)) shall be documented.
Where a pathology diagnosis is required on the specimen, sampling shall be performed by or under
supervision or guidance of a medically qualified (e.g. board certified) pathologist (see 6.2) and
these personnel should be aware of all examinations for the specimen to ensure proper handling.
Where the specimen was removed without the requirement of pathology diagnosis, the evaluation,
selection and documentation of specimens may be done by other qualified persons than
pathologists.
[17]
2) Formalin fixation can have a negative impact on DNA based examinations (see ISO 20166-3) .
Frozen tissue samples are therefore preferred depending on the specific analytical examination.
[18]
Where both DNA and RNA are intended to be examined, see ISO 20184-1 .
3) [18]. Freezing can be performed outside the laboratory or inside the laboratory under the direction
or supervision of a pathologist.
Cold ischemia can influence the DNA pattern (e.g. fragmentation); therefore, immediate freezing
according to 6.3.2 should be preferred.
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a) In case the specimen or sample is frozen outside the laboratory, proceed with 6.2 without delay.
b) In case the specimen or sample is frozen inside the laboratory, fresh tissue specimens need to
be transported to the laboratory. The steps described under 5.2 for fresh tissue transport shall
be performed without delay.
5.2 Fresh tissue transport requirements
5.2.1 General
Where transport of the specimen or sample to the laboratory is required for freezing, the laboratory
in partnership with the clinical or surgery department shall provide instructions for the transport
procedure of the specimen.
5.2.2 Preparations for the transport
The following steps shall be performed:
a) the selection and use of containers and packages (e.g. cooling box, box for storing and transportation,
vacuum packaging);
NOTE 1 This will be in accordance with applicable transport regulations.
b) the selection and use of stabilization procedures (e.g. cooling methods) for transport;
NOTE 2 Accidentally freezing of the fresh tissue (e.g. by using cool packs incorrectly) can lead to DNA
degradation when the tissue thaws. It can also impact the morphological characterization.
c) the labelling of the container (e.g. registration-number, barcode, specimen type, quantity, and
organ tissue of origin) and additional documentation (information as specified in 5.1.2, 5.1.3, 5.1.4,
and 5.2.2, a) to b)).
A single container may only contain several specimens, if these specimens come from the same location
(i.e. similar or corresponding anatomical or histological organ parts) and have the same macroscopic
features such as tissue type and disease status (e.g. inflammation, tumour and necrosis).
NOTE 3 Specimens that have the
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