SIST EN ISO 20184-2:2019
(Main)Molecular in vitro diagnostic examinations - Specifications for pre-examination processes for frozen tissue - Part 2: Isolated proteins (ISO 20184-2:2018)
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes for frozen tissue - Part 2: Isolated proteins (ISO 20184-2:2018)
This International Standard recommends the handling, documentation, storage and processing of frozen tissue specimens intended for the examination of extracted proteins during the pre-examination phase before a molecular assay is performed. This International Standard is applicable to molecular in vitro diagnostic examinations including laboratory developed tests performed by medical laboratories. It is also intended to be used by laboratory customers, in vitro diagnostics developers and manufacturers, but also pertains institutions and commercial organisations performing biomedical research, biobanks, and regulatory authorities.
Protein profiles and protein-protein interactions in tissues can change drastically before tissue collection (e.g., due to warm ischemia) and after tissue collection (e.g., due to cold ischemia). The changes are caused by e.g., gene induction, gene down regulation, protein degradation. Protein species amounts can change differently in different donors’ / patients’ tissues. The expression of genes can be influenced by the given treatment or intervention (surgery, biopsy), or drugs administered for anaesthesia or even treatment of concomitant disease as well as by the different environmental conditions after the tissue removal from the body.
Therefore, it is essential to take special measures to minimize the described protein profile changes and modifications within the tissue for subsequent examination.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in this document. In addition this document is not applicable to protein examination by immunohistochemistry.
NOTE International, national or regional regulations or requirements may also apply to specific topics covered in this International Standard.
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für präanalytische Prozesse für schockgefrorene Gewebeproben - Teil 2: Isolierte Proteine (ISO 20184-2:2018)
Diese Internationale Norm gibt Empfehlungen zur Handhabung, Dokumentation, Lagerung und Verarbeitung von aus gefrorenem Gewebe bestehenden und für die Untersuchung vorgesehenen isolierten Proteinen während der präanalytischen Phase vor Beginn der molekularen Analyse. Diese Internationale Norm ist anwendbar auf molekulare in-vitro-Diagnoseuntersuchungen, die von medizinisches Laboratorien und Laboratorien der molekularen Pathologie durchgeführt werden, die aus gefrorenem Gewebe isolierten Proteine auswerten. Sie hat außerdem den Zweck, von Kunden des Laboratoriums, Entwicklern der in-vitro-Diagnose und Herstellern sowie Institutionen und kommerziellen Organisationen, die biomedizinische Forschungen durchführen, und Biobanken und Arzneimittelagenturen verwendet zu werden.
Proteinprofile und Protein-Protein-Interaktionen in Geweben können sich vor der Probenahme (z. B. aufgrund von warmer Ischämie) und nach der Probenahme (z. B. aufgrund von kalter Ischämie) drastisch verändern. Die Veränderungen werden beispielsweise durch Geninduktion, die Herabregelung von Genen oder eine Protein-Degradation verursacht. Die Mengen der Proteinspezies können sich je nach Gewebespender/Patient unterschiedlich verändern. Die Genexpression kann durch die jeweilige Behandlung oder den Eingriff (Operation, Biopsie) oder die zur Anästhesie oder Behandlung von Begleiterkrankungen verabreichten Medikamente sowie abhängig von unterschiedlichen Umgebungsbedingungen nach der Gewebeentnahme aus dem Körper beeinflusst sein.
Daher ist es äußerst wichtig, dass besondere Maßnahmen getroffen werden, um die beschriebenen Proteinprofilveränderungen und -modifikationen im Gewebe für die anschließende Untersuchung möglichst gering zu halten.
Gewebe, die vor dem Gefriervorgang einer chemischen Vorbehandlung zur Stabilisierung unterzogen wurden, sind nicht durch dieses Dokument abgedeckt. Des Weiteren gilt dieses Dokument nicht für eine immunhistochemische Proteinuntersuchung.
ANMERKUNG Internationale, nationale oder regionale Regelungen bzw. Anforderungen können ebenfalls für bestimmte Themen in dieser Internationalen Norm gelten.
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus préanalytiques pour les tissus congelés - Partie 2: Protéines extraites (ISO 20184-2:2018)
Le présent document fournit des lignes directrices concernant la manipulation, la documentation, le stockage et le traitement de prélèvements de tissus congelés destinés à l'analyse des protéines extraites, durant la phase préanalytique précédant la réalisation d'un essai moléculaire.
Le présent document s'applique aux analyses de diagnostic moléculaire in vitro réalisées par des laboratoires de biologie médicale et des laboratoires de pathologie moléculaire qui évaluent les protéines extraites de tissus congelés. Il est également destiné à être utilisé par des clients de laboratoires, des développeurs et fabricants de l'industrie du diagnostic in vitro, ainsi que par des biobanques, des institutions et des organismes commerciaux spécialisés en recherche biomédicale, de même que des autorités de réglementation.
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 - 2. del: Izolirani proteini (ISO 20184-2:2018)
Ta mednarodni standard vsebuje priporočila za obravnavo, dokumentiranje, shranjevanje in obdelavo vzorcev zamrznjenih tkiv, namenjenih za preiskavo izvlečka proteinov med predpreiskovalno fazo, preden se izvede molekularni preskus. Ta mednarodni standard se uporablja za molekularne diagnostične preiskave in vitro, vključno z laboratorijsko razvitimi preskusi, ki jih izvajajo v medicinskih laboratorijih. Uporabljali naj bi ga tudi uporabniki laboratorijev, razvijalci in proizvajalci diagnostike in vitro, nanaša pa se tudi na institucije in komercialne organizacije, ki izvajajo biomedicinske raziskave, biobanke ter regulativne organe. Profili proteinov in interakcije protein-protein v tkivih se lahko pred zbiranjem tkiva (npr. zaradi tople ishemije) in po zbiranju tkiva (npr. zaradi hladne ishemije) zelo spremenijo. Spremembe so na primer posledica genske indukcije, znižanja izražanja gena, razgradnje proteina. Količine vrst proteinov se lahko različno spreminjajo pri tkivih različnih darovalcev/bolnikov. Na izražanje genov je mogoče vplivati z zdravljenjem ali posegom (operacija, biopsija), anestetiki ali celo z zdravljenjem sočasne bolezni kot tudi z različnimi okoljskimi pogoji po odstranitvi tkiva iz telesa. Zato je nujno treba sprejeti posebne ukrepe, da se zmanjšajo opisane spremembe profila proteina v tkivu za nadaljnje preiskave. Tkiva, ki so pred zamrzovanjem prestala predobdelavo za kemično stabilizacijo, niso zajeta v tem dokumentu. Ta dokument se ne uporablja za preiskave proteinov z imunohistokemijo. OPOMBA: Za določene teme, ki so zajete v tem mednarodnem standardu, lahko veljajo tudi mednarodni, nacionalni ali regionalni predpisi ali zahteve.
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 20184-2:2019
01-marec-2019
1DGRPHãþD
SIST-TS CEN/TS 16826-2:2015
0ROHNXODUQHGLDJQRVWLþQHSUHLVNDYHLQYLWUR6SHFLILNDFLMH]DSUHGSUHLVNRYDOQH
SURFHVH]D]DPU]QMHQDWNLYDGHO ,]ROLUDQLSURWHLQL ,62
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes
for frozen tissue - Part 2: Isolated proteins (ISO 20184-2:2018)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für
präanalytische Prozesse für schockgefrorene Gewebeproben - Teil 2: Isolierte Proteine
(ISO 20184-2:2018)
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus
préanalytiques pour les tissus congelés - Partie 2: Protéines extraites (ISO 20184-
2:2018)
Ta slovenski standard je istoveten z: EN ISO 20184-2:2018
ICS:
11.100.10 'LDJQRVWLþQLSUHVNXVQL In vitro diagnostic test
VLVWHPLLQYLWUR systems
SIST EN ISO 20184-2:2019 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 20184-2:2019
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SIST EN ISO 20184-2:2019
EN ISO 20184-2
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2018
EUROPÄISCHE NORM
ICS 11.100.10 Supersedes CEN/TS 16826-2:2015
English Version
Molecular in vitro diagnostic examinations - Specifications
for pre-examination processes for frozen tissue - Part 2:
Isolated proteins (ISO 20184-2:2018)
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 2: Protéines extraites schockgefrorene Gewebeproben - Teil 2: Isolierte
(ISO 20184-2:2018) Proteine (ISO 20184-2:2018)
This European Standard was approved by CEN on 30 September 2018.
This European Standard was corrected and reissued by the CEN-CENELEC Management Centre on 30 January 2019.
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, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATIO N
EUROPÄISCHES KOMITEE FÜR NORMUN G
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2018 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 20184-2:2018 E
worldwide for CEN national Members.
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SIST EN ISO 20184-2:2019
EN ISO 20184-2:2018 (E)
Contents Page
European foreword . 3
2
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SIST EN ISO 20184-2:2019
EN ISO 20184-2:2018 (E)
European foreword
This document (EN ISO 20184-2:2018) 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 June 2019, and conflicting national standards shall be
withdrawn at the latest by December 2021.
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 16826-2:2015.
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, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
Endorsement notice
The text of ISO 20184-2:2018 has been approved by CEN as EN ISO 20184-2:2018 without any
modification.
3
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SIST EN ISO 20184-2:2019
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SIST EN ISO 20184-2:2019
INTERNATIONAL ISO
STANDARD 20184-2
First edition
2018-11
Molecular in vitro diagnostic
examinations — Specifications for
pre-examination processes for frozen
tissue —
Part 2:
Isolated proteins
Analyses de diagnostic moléculaire in vitro — Spécifications relatives
aux processus préanalytiques pour les tissus congelés —
Partie 2: Protéines extraites
Reference number
ISO 20184-2:2018(E)
©
ISO 2018
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018
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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CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2018 – All rights reserved
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 4
5 Outside the laboratory . 5
5.1 Specimen collection . 5
5.1.1 General. 5
5.1.2 Information about the specimen donor/patient . 5
5.1.3 Information about the specimen . 6
5.1.4 Specimen processing . 6
5.2 Fresh tissue transport requirements . 6
5.2.1 General. 6
5.2.2 Preparations for the transport . 7
5.2.3 During transport . 7
6 Inside the laboratory . 7
6.1 Information about the reception of the specimen . 7
6.2 Evaluation of the pathology of the specimen and selection of the sample(s) . 7
6.3 Freezing of the specimen or sample(s) . 8
6.4 Storage requirements .10
6.5 Isolation of total protein .10
6.5.1 General.10
6.5.2 Using commercial kits .11
6.5.3 Using the laboratories own protocols .11
6.6 Quantity and quality assessment of isolated proteins .11
6.7 Storage of isolated total protein .12
Annex A (informative) Quantitative protein examination demonstrates changes of protein
amounts during cold ischemia .13
Bibliography .17
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(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.
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 2018 – All rights reserved
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(E)
Introduction
Molecular in vitro diagnostics, including molecular pathology, has enabled a significant progress in
medicine. Further progress is expected with new technologies analysing nucleic acids, proteins, and
metabolites in human tissues and body fluids. However, the profiles and/or integrity of these molecules
can change drastically during specimen collection, transport, storage, and processing thus making the
outcome from diagnostics or research unreliable or even impossible because the subsequent examination
assay will not determine the situation in the patient but an artificial molecular pattern generated during
the pre-examination process. Therefore, a standardization of the entire process from specimen collection
to the protein 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 protein examination in what is referred to as the pre-examination phase.
Protein profiles and protein–protein interactions in tissues can change drastically before, during (e.g.
due to warm ischemia) and after tissue collection (e.g. due to cold ischemia). The changes are caused
by e.g. gene induction, gene down regulation, protein degradation. Protein species amounts can change
differently in different donors’/patients’ tissues. The expression of genes can be influenced by the given
treatment or intervention (surgery, biopsy), or drugs administered for anaesthesia or even treatment of
concomitant disease as well as by the different environmental conditions after the tissue removal from
the body.
Therefore, it is essential to take special measures to minimize the described protein profile changes
and modifications within the tissue for subsequent examination.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in this
document. In addition this document is not applicable to protein examination by immunohistochemistry.
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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SIST EN ISO 20184-2:2019
INTERNATIONAL STANDARD ISO 20184-2:2018(E)
Molecular in vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 2:
Isolated proteins
1 Scope
This document gives guidelines on the handling, documentation, storage and processing of frozen
tissue specimens intended for the examination of isolated proteins during the pre-examination phase
before a molecular assay is performed.
This document is applicable to any molecular in vitro diagnostic examination performed by medical
laboratories and molecular pathology laboratories that evaluate proteins isolated from frozen tissue. It
is also intended to be used by laboratory customers, in vitro diagnostics developers and manufacturers,
biobanks, institutions and commercial organisations performing biomedical research, and regulatory
authorities.
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 15189:2012, Medical laboratories — Requirements for quality and competence
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. Tissues are heterogeneous and therefore cannot be
aliquoted.
Note 2 to entry: The definition is derived from the 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.
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(E)
3.2
ambient temperature
unregulated temperature of the surrounding air
3.3
analyte
component represented in the name of a measurable quantity
[SOURCE: ISO 17511:2003, 3.2]
3.4
analytical test performance
accuracy, precision, and sensitivity of a test to measure the analyte 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 stabilization or fixation
3.6
diagnosis
identification of a health or disease state from its signs and/or symptoms, where the diagnostic process
can involve examinations 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
3.7
examination
analytical test
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.
[SOURCE: ISO 15189:2012, 3.7, modified — The term and definition is used here without the original
notes.]
3.8
grossing
gross examination
inspection of pathology specimens with the bare eye to obtain diagnostic information, while being
processed for further microscopic examination
3.9
homogeneous
uniform in structure and composition
3.10
pre-examination processes
preanalytical phase
preanalytical workflow
processes that start, in chronological order, from the clinician’s request and include the examination
request, preparation and identification of the patient, collection of the primary sample(s), transportation
to and within the medical or pathology laboratory, isolation of analytes, and end when the analytical
examination begins
Note 1 to entry: The pre-examination phase includes preparative processes that influence the outcome of the
intended examination.
[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added and more detail was
included.]
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SIST EN ISO 20184-2:2019
ISO 20184-2:2018(E)
3.11
primary sample
specimen
discrete portion of a body fluid, breath, hair or tissue taken for examination, 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 is used here without the
original notes.]
3.12
protein
type of biological macromolecules composed of one or more chains with a defined sequence of amino
acids connected through peptide bonds
3.13
protein profile
amounts of the individual protein molecules that are present in a sample and that can be measured in
the absence of any losses, inhibition and interference
3.14
protein species
amounts of a chemically clearly-defined protein corresponding to one spot on a high-performance two-
dimensional gel electrophoresis pattern
[SOURCE: Jungblut et. al.1996]
3.15
PTM
post translational modifications
chemical alterations to a primary protein structure, often crucial for conferring biological activity on
a protein
[SOURCE: Encyclopedia of Psychopharmacology, 2010]
3.16
room temperature
temperature which is defined as 18 °C to 25 °C
Note 1 to entry: Local or national regulations can have different definitions.
3.17
sample
one or more parts taken from a primary sample
[SOURCE: ISO 15189:2012, 3.24, modified — The example was not taken over.]
3.18
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
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — The words “reference material” were replaced by
“sample material", “characteristic” has been replaced by “ability” and Note 1 to entry has been changed.]
Note 1 to entry: The analyte for the purpose of this document is isolated protein.
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ISO 20184-2:2018(E)
3.19
storage
prolonged interruption of the pre-analytical workflow of a sample or analyte respectively, or of their
derivatives e.g., stained sections or tissue blocks, under appropriate conditions in order to preserve
their properties
Note 1 to entry: Long-term storage typically occurs in laboratory archives or in biobanks.
3.20
validation
confirmation, throughout 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 where 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.
[SOURCE: ISO 9000:2015, 3.8.12, modified — Note 1 and Note 2 where 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;
— 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
3.23
workflow
series of activities necessary to complete a task
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 15189:2012, 4.2, 5.4.4, 5.4.6, or ISO/IEC 17020:2012, Clause 8 and 7.2. The requirements on
laboratory equipment, reagents, and consumables in accordance with ISO 15189:2012, 5.3 shall be
followed; ISO 15189:2012, 5.5.1.2 and 5.5.1.3, and ISO/IEC 17020:2012, 6.2 can also apply.
All steps of a diagnostic workflow can influence the final analytical test result. Thus, the entire
workflow including biomolecule stability and sample storage conditions shall be verified and validated.
Workflow steps which cannot always be controlled (e.g. warm ischemia) shall be documented. A risk
assessment of non-controllable workflow steps including their potential impact on the examination test
performance shall be performed and mitigation measures shall be established to enable the required
examination test performance.
The stability of the specific proteins to be examined and their posttranslational modifications (if
important for the assay) should be investigated throughout the complete pre-examination process
prior to the development and implementation of an examination test (e.g. by performing a time course
experiment or study; see also Annex A and Reference [8]).
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ISO 20184-2:2018(E)
Before tissues are stabilized by freezing, protein amounts, conformations and binding status can change
e.g. by protein degradation and altered synthesis following gene induction, gene down regulation, RNA
degradation, and changes of the biochemical pathway and energy status. These effects depend on the
duration of warm and cold ischemia and the ambient temperature before freezing. In addition, the
described effects can vary in different donors’/patients’ tissues.
Generally, the longer the duration of warm and cold ischemia and the higher the ambient temperature
before freezing the tissue specimen, the higher is the risk that changes in the protein profile can occur.
NOTE Prolonged cold ischemia durations result in changes of protein (e.g. cytokeratin 18) and
[8][9] [10]
phosphoprotein (e.g. phospho-p42/44) amounts . Keeping the specimen on wet-ice diminishes this effect .
Protein amounts as well as posttranslational modifications can also vary during the pre-examination phase,
depending on the origin and type of tissue, the underlying disease, the surgical procedure, the drug regimen,
and drugs administered for anaesthesia or treatment of concomitant disease and on the different environmental
conditions after the tissue removal from the body.
As warm ischemia cannot be easily standardized, its duration shall be documented. When it is not
possible to avoid cold ischemia, its duration shall be documented and temperatures of the specimen
container's surroundings shall be documented. Where the specimen is transported to another facility
for freezing, the transport duration shall be documented and the ambient conditions should also be
documented.
Safety regulations on transport and handling shall be followed (see ISO 15189:2012, 5.2.3 and 5.4.5,
and ISO 15190).
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.
If a commercial product is not used in accordance with the manufacturer’s instructions, responsibility
for its use and performance lies with the user.
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 intended
molecular examination (see also Clause 6) should be considered.
See also ISO 15189:2012, 5.4.4.
5.1.2 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 relevant health status of the specimen donor/patient (e.g. healthy, disease type, concomitant
disease, demographics [e.g. age and gender]);
b) the information about routine medic
...
SLOVENSKI STANDARD
oSIST prEN ISO 20184-2:2016
01-september-2016
0ROHNXODUQHGLDJQRVWLþQHSUHLVNDYHLQYLWUR6SHFLILNDFLMH]DSUHGSUHLVNRYDOQH
SURFHVH]D]DPU]QMHQDWNLYDGHO ,]ROLUDQLSURWHLQL ,62',6
Molecular in-vitro diagnostic examinations - Specifications for pre-examination processes
for frozen tissue - Part 2: Isolated proteins (ISO/DIS 20184-2:2016)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für
präanalytische Prozesse für schockgefrorene Gewebeproben - Teil 2: Isolierte Proteine
(ISO/DIS 20184-2:2016)
Examens de diagnostic moléculaire in vitro - Spécifications pour les processus
d'examens préliminaires des tissus congelés - Partie 2: Protéines isolées (ISO/DIS
20184-2:2016)
Ta slovenski standard je istoveten z: prEN ISO 20184-2
ICS:
11.100.10 'LDJQRVWLþQLSUHVNXVQL In vitro diagnostic test
VLVWHPLLQYLWUR systems
oSIST prEN ISO 20184-2:2016 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 20184-2:2016
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oSIST prEN ISO 20184-2:2016
DRAFT INTERNATIONAL STANDARD
ISO/DIS 20184-2
ISO/TC 212 Secretariat: ANSI
Voting begins on: Voting terminates on:
2016-06-28 2016-09-19
Molecular in-vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 2:
Isolated proteins
Titre manque
ICS: 11.100.10
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for
Standardization (ISO), and processed under the ISO lead mode of collaboration
as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member
bodies for a parallel five month enquiry.
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
To expedite distribution, this document is circulated as received from the
IN ADDITION TO THEIR EVALUATION AS
committee secretariat. ISO Central Secretariat work of editing and text
BEING ACCEPTABLE FOR INDUSTRIAL,
composition will be undertaken at publication stage.
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 20184-2:2016(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 2016
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ISO/DIS 20184-2:2016(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2016, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
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copyright@iso.org
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ii © ISO 2016 – All rights reserved
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ISO/DIS 20184-2:2016(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 4
5 Outside the laboratory . 5
5.1 Specimen collection . 5
5.1.1 Information about the specimen donor/patient . 5
5.1.2 Information about the specimen . 5
5.1.3 Specimen processing . 6
5.2 Fresh tissue transport requirements . 6
6 Inside the laboratory . 7
6.1 Information about the specimen receipt . 7
6.2 Evaluation of the pathology of the specimen and selection of the sample . 7
6.3 Cryo-storage of the specimen or sample . 8
6.3.1 The following steps shall be performed before, during and after the
freezing procedure: . 8
6.4 Storage requirements . 9
6.5 Isolation of total protein .10
6.5.1 General.10
6.5.2 Using commercial kits .10
6.5.3 Using the laboratories own protocols .10
6.6 Quantity and quality assessment of isolated proteins .10
6.7 Storage of isolated total protein .11
Annex A (informative) Quantitative protein examination demonstrates changes of protein
)
amounts during cold ischemia .12
Bibliography .16
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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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International
Standards adopted by the technical committees are circulated to the member bodies for voting.
Publication as an International Standard requires approval by at least 75 % of the member bodies
casting a vote.
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.
ISO 20184-2 was prepared by Technical Committee ISO/TC 212, Clinical laboratory testing and in vitro
diagnostic test systems.
ISO 20184 consists of the following parts, under the general title Molecular in vitro diagnostic
examinations — Specifications for pre-examination processes for frozen tissue:
— Part 1: Isolated RNA
— Part 2: Isolated proteins
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Introduction
Molecular in vitro diagnostics, including molecular pathology, has enabled a significant progress in
medicine. Further progress is expected by new technologies analyzing nucleic acids, proteins, and
metabolites in human tissues and body fluids. However, the profiles and/or integrity of these molecules
can change drastically during specimen collection, transport, storage, and processing thus making
the outcome from diagnostics or research unreliable or even impossible because the subsequent
examination assay will not determine the situation in the patient but an artificial molecular pattern
generated during the pre-examination process. Therefore, a standardization of the entire process from
specimen collection to the protein examination is needed. Studies have been undertaken to determine
the important influencing factors. This International Standard draws upon such work to codify and
standardize the steps for frozen tissue with regard to protein examination in what is referred to as the
pre-examination phase.
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oSIST prEN ISO 20184-2:2016
DRAFT INTERNATIONAL STANDARD ISO/DIS 20184-2:2016(E)
Molecular in-vitro diagnostic examinations —
Specifications for pre-examination processes for frozen
tissue —
Part 2:
Isolated proteins
1 Scope
This International Standard recommends the handling, documentation, storage and processing of
frozen tissue specimens intended for the examination of isolated proteins during the pre-examination
phase before a molecular assay is performed. This International Standard is applicable to any
molecular in vitro diagnostic examination performed by medical laboratories and molecular pathology
laboratories that evaluate proteins isolated from frozen tissue. It is also intended to be used by
laboratory customers, in vitro diagnostics developers and manufacturers, as well as institutions and
commercial organisations performing biomedical research, biobanks, and regulatory authorities.
Protein profiles and protein-protein interactions in tissues can change drastically before tissue
collection (e.g. due to warm ischemia) and after tissue collection (e.g. due to cold ischemia). The changes
are caused by e.g. gene induction, gene down regulation, protein degradation. Protein species amounts
can change differently in different donors’ / patients’ tissues. The expression of genes can be influenced
by the given treatment or intervention (surgery, biopsy), or drugs administered for anaesthesia or even
treatment of concomitant disease as well as by the different environmental conditions after the tissue
removal from the body.
Therefore, it is essential to take special measures to minimize the described protein profile changes
and modifications within the tissue for subsequent examination.
Tissues that have undergone chemical stabilization pre-treatment before freezing are not covered in this
document. In addition this document is not applicable to protein examination by immunohistochemistry.
NOTE International, national or regional regulations or requirements may also apply to specific topics
covered in this International Standard.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 15189:2012, Medical laboratories — Requirements for quality and competence
ISO 15190, Medical laboratories — Requirements for safety
ISO/IEC 17020:2012, 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 15189:2012 and the
following apply.
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3.1
ambient temperature
unregulated temperature of the surrounding air
3.2
analyte
component represented in the name of a measurable quantity (ISO 17511)
3.3
analytical test performance
the accuracy, precision, and sensitivity of a test to measure the analyte of interest
3.4
cold ischemia
condition after removal of the tissue from the body until its stabilization or fixation
3.5
diagnosis
identification of a disease from its signs and symptoms, where the diagnostic process can involve
examinations 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
3.6
examination
analytical phase
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.
[SOURCE: ISO 15189:2012, 3.7, modified — The term and definition is used here without the original
notes.]
3.7
grossing
gross examination
inspection of pathology specimens with the bare eye to obtain diagnostic information, while being
processed for further microscopic examination
3.8
homogeneous
uniform in structure and composition
3.9
pre-examination processes
preanalytical phase
preanalytical workflow
processes that start, in chronological order, from the clinician’s request and include the examination
request, preparation and identification of the patient, surgical procedure, collection of the primary
sample(s), temporary storage, transportation to and within the analytical laboratory, aliquotting,
retrieval, isolation of analytes, and end when the analytical examination begins
Note 1 to entry: The pre-examination phase includes preparative processes that influence the outcome of the
intended examination.
[SOURCE: ISO 15189:2012, 3.15, modified — An additional term was added and more details were
included.]
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3.10
primary sample
specimen
discrete portion of a body fluid, breath, hair or tissue taken for examination, 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 is used here without the
original notes.]
3.11
protein
type of biological macromolecules composed of one or more chains with a defined sequence of amino
acids connected through peptide bonds
3.12
protein profile
amounts of the individual protein molecules that are present in a sample and that can be measured in
the absence of any losses, inhibition and interference
3.13
protein species
amounts of a chemically clearly-defined protein corresponding to one spot on a high-performance two-
dimensional gel electrophoresis pattern
[4]
[SOURCE: Jungblut et. al.1996]
3.14
PTM
post translational modifications
chemical alterations to a primary protein structure, often crucial for conferring biological activity on
a protein
[5]
[SOURCE: Encyclopedia of Psychopharmacology, 2010]
3.15
sample
one or more parts taken from a primary sample
[SOURCE: ISO 15189:2012, 3.24, modified — The example was not taken over.]
3.16
room temperature
temperature which is defined as 18 °C to 25 °C for the purposes of this document
Note 1 to entry: Local or national regulations can have different definitions.
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
[SOURCE: ISO Guide 30:1992, 2.7]
Note 1 to entry: The analyte for the purpose of this document is extracted protein.
3.18
validation
confirmation, throughout 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.
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Note 2 to entry: Adapted from ISO 9000:2005, definition 3.8.5.
[SOURCE: ISO 15189:2012, 3.26]
3.19
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 9000:2005, 3.8.4]
3.20
warm ischemia
condition where the tissue is deprived of its normal blood supply containing oxygen and nutrients while
the tissue is in the body until the tissue is removed from the body
3.21
workflow
series of activities necessary to complete a task
4 General considerations
For general statements on medical laboratory quality management systems and in particular on
specimen collection and handling (including avoidance of cross contaminations) see ISO 15189:2012,
4.2, 5.4.4. The requirements on laboratory equipment, reagents, and consumables according to
ISO 15189:2012, 5.3 shall be followed; ISO 15189:2012, 5.5.1.2 and 5.5.1.3 can also apply.
All steps of a diagnostic workflow can influence the final examination test performance. Thus, the entire
workflow including biomolecule stability and sample storage conditions shall be verified and validated.
Workflow steps which cannot always be controlled (e.g. warm ischemia) shall be documented and their
impact on the examination test performance shall be investigated and mitigation measures shall be
established to enable the required examination test performance. In these cases, risk assessment is
recommended.
The stability of the specific proteins to be examined and their posttranslational modifications (if
important for the assay) should be investigated throughout the complete pre-examination process
prior to the development and implementation of an examination test.
Before tissues are stabilized by freezing; protein amounts, conformations and binding status can change
e.g. by protein degradation and altered synthesis following gene induction, gene down regulation, RNA
degradation, and changes of the biochemical pathway and energy status. These effects depend on the
duration of warm and cold ischemia times and the ambient temperature before freezing. In addition,
the described effects can vary in different donors’ / patients’ tissues.
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Generally, the longer the duration of warm and cold ischemia and the higher the ambient temperature
before freezing the tissue specimen, the higher is the risk that changes in the protein profile can occur.
NOTE Prolonged cold ischemia times result in changes of protein (e.g. cytokeratin 18) and phosphoprotein
[6] [7] [8]
(e.g. phospho-p42/44) amounts. , Keeping the specimen on wet-ice diminishes this effect. Protein
amounts as well as posttranslational modifications can also vary during the pre-examination phase, depending
on the origin and type of tissue, the underlying disease, the surgical procedure, the drug regimen, and drugs
administered for anaesthesia or treatment of concomitant disease and on the different environmental conditions
after the tissue removal from the body.
As warm ischemia cannot be easily standardized, its duration should be documented. When it is not
possible to avoid cold ischemia, its duration shall be documented and temperatures of the specimen
transport container’s surroundings should be documented. Where the specimen is transported to
another facility for freezing, the transport duration shall be documented and the ambient conditions
should also be documented.
Safety regulations on transport and handling shall be considered (see ISO 15189:2012, 5.2.3 and 5.4.5,
and ISO 15190).
During the whole pre-examination process precautions shall be taken to avoid cross contamination
between different samples, e.g. by using single-use material whenever feasible or appropriate cleaning
procedures between processing of different samples.
If a commercial product is not used in accordance with the manufacturers’ instructions, responsibility
for its use and performance lies with the user.
5 Outside the laboratory
5.1 Specimen collection
5.1.1 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 relevant health status of the specimen donor/patient (e.g. healthy, disease type, concomitant
disease, demographics (e.g. age and gender));
b) the 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 specimen donor/patient.
5.1.2 Information about the specimen
The documentation shall include, but is not limited to:
a) 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 fine-needle aspiration (FNA), or 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. fine-
needle aspiration (FNA), resection, biopsy device used for the collection);
c) the description of tissue type, tissue condition (e.g. diseased, unaffected by the disease) and organ
tissue of origin, including references to any marking applied in or outside the operating theatre
made by surgeon, radiologist or pathologist;
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d) the documentation steps described under 6.3, if freezing of the tissue is performed outside the
laboratory.
The documentation should also include the ID of the responsible person collecting the specimen.
5.1.3 Specimen processing
Tissues that need to be frozen for diagnostic purposes can originate from large tissue specimen (e.g.
operating theatre, post-mortem autopsy cutting room) or small tissue specimen like biopsies (e.g. FNA,
skin) or biopsies 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.
2. The freezing of the specimen or samples taken from the specimen can be performed outside the
laboratory or in the laboratory.
a) In case the specimen or sample is frozen outside the laboratory, proceed with 6.2 without delay.
Cold ischemia can influence the protein profile; therefore direct freezing should be preferred.
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).
Where the specimen was removed without the requirement of histopathological diagnosis; the
evaluation, selection and documentation of specimens may be done by other qualified persons
than pathologists.
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
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 establish a protocol for the transport
procedure of the tissue.
The following steps shall be performed:
1. the selection and use of collection containers and packages (e.g. cooling box, box for storing and
transportation, vacuum packaging) according to applicable transport regulations;
2. the selection and use of stabilization procedures (e.g. cooling methods) for transport;
NOTE Accidentally freezing and thawing the tissue (e.g. by using cool packs in a wrong manner) can lead to
protein degradation when the tissue thaws. It can also impact the morphological characterization.
3. the labelling of the collection container (e.g. registration-number, barcode, specimen type, quantity,
and organ tissue of origin) and additional documentation (information as specified in 5.1.1, 5.1.2,
and 5.1.3., 1. to 3.). If a single sample container contains several aliquots of the same specimen,
and the aliquots represent different features (e.g. tissue type, disease status, location) this shall be
documented.
Specimens should be transferred without delay into the transport container after the removal from the
body. The container should then be kept on wet-ice or at 2 °C to 8 °C in order to minimize protein profile
changes.
The temperatures of the collection container’s surroundings during cold ischemia (e.g. temperatures
in different rooms, transport) should be documented. If temperature cannot be measured, the
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temperature ranges should be estimated by classification as ambient temperature, room temperature,
or at 2 °C to 8 °C.
Temperature monitoring should be applied in a suitable manner.
If the specimen is not already frozen, it should be transported on wet-ice or at 2 °C to 8 °C without delay
in order to minimize the changes to the protein profile.
NOTE There is evidence that proteins in tissues can be stabilized in plastic bags under vacuum and when
kept at 0 °C to 4 C° during transport before the samples are frozen for biobanks or used for histopathological
[9]
evaluation.
The compliance with the protocol for the transport procedure shall be documented. Any deviations
from the protocol shall be described and documented.
6 Inside the laboratory
6.1 Information about the specimen receipt
The name of the person receiving the specimen shall be documented. The specimen arrival time and
conditions (e.g. labelling, transport conditions including temperature, tissue type and quantity of the
specimen, leaking/breaking of the container) of the received specimens shall be documented. Any
deviations from the established protocol for the transport procedure (see 5.2) shall be documented.
6.2 Evaluation of the pathology of the specimen and selection of the sample
The evaluation and documentation of the pathology of the specimen and the selection of the sample
from the specimen for further processing shall be done by or under supervision or responsibility of a
...
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