SIST EN ISO 10993-4:2017
(Main)Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2017)
Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2017)
This document specifies general requirements for evaluating the interactions of medical devices
with blood.
It describes
a) a classification of medical devices that are intended for use in contact with blood, based on the
intended use and duration of contact as defined in ISO 10993-1,
b) the fundamental principles governing the evaluation of the interaction of devices with blood,
c) the rationale for structured selection of tests according to specific categories, together with the
principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and
precision of tests for evaluating interactions of devices with blood. This document describes biological
evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a
specific device.
The changes in this document do not indicate that testing conducted according to prior versions of
this document is invalid. For marketed devices with a history of safe clinical use, additional testing
according to this revision is not recommended.
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur Wechselwirkung mit Blut (ISO 10993-4:2017)
Évaluation biologique des dispositifs médicaux - Partie 4: Choix des essais pour les interactions avec le sang (ISO 10993-4:2017)
ISO 10993-4:2017 spécifie des exigences générales pour l'évaluation des interactions des dispositifs médicaux avec le sang.
Il décrit les éléments suivants:
a) une classification des dispositifs médicaux destinés à être en contact avec le sang lors de leur utilisation, classification fondée sur l'utilisation prévue et la durée du contact définies dans l'ISO 10993‑1;
b) les principes fondamentaux qui gouvernent l'évaluation de l'interaction des dispositifs avec le sang;
c) la justification du choix des essais retenus selon les catégories, ainsi que les principes et la base scientifique de ces essais.
Les exigences détaillées pour les essais ne peuvent pas être spécifiées en raison de limites de connaissance et de précision des essais relatifs à l'évaluation des interactions des dispositifs avec le sang. Le présent document décrit l'évaluation biologique en termes généraux et il se peut qu'il ne fournisse pas nécessairement des préconisations suffisantes concernant les méthodes d'essai relatives à un dispositif spécifique.
Les modifications apportées au présent document ne signifient pas que les essais réalisés selon les versions précédentes sont invalides. Pour les dispositifs commercialisés dont l'utilisation clinique sûre est établie, il n'est pas recommandé de réaliser des essais supplémentaires selon la présente révision.
Biološko ovrednotenje medicinskih pripomočkov - 4. del: Izbira preskusov za ugotavljanje interakcij s krvjo (ISO 10993-4:2017)
Ta dokument določa splošne zahteve za ovrednotenje interakcij medicinskih pripomočkov s krvjo.
Opisuje:
a) razvrstitev medicinskih pripomočkov, namenjenih za uporabo v stiku s krvjo, na podlagi predvidene uporabe in trajanja stika, kot je opredeljeno v standardu ISO 10993-1;
b) temeljna načela za ovrednotenje interakcije pripomočkov s krvjo;
c) utemeljitev strukturirane izbire preskusov v skladu s posebnimi kategorijami skupaj z načeli in znanstveno osnovo teh preskusov.
Podrobnih zahtev za preskušanje ni mogoče določiti zaradi omejitev pri poznavanju in natančnosti preskusov za ovrednotenje interakcij pripomočkov s krvjo. Ta dokument opisuje biološko ovrednotenje s splošnimi izrazi in morda ne podaja zadostnih smernic za preskusne metode za določen pripomoček.
Spremembe v tem dokumentu ne pomenijo, da so preskusi, opravljeni v skladu s prejšnjimi različicami tega dokumenta, neveljavni. Za tržene pripomočke z zgodovino varne klinične uporabe dodatno preskušanje v skladu s to revizijo ni priporočeno.
General Information
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Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-4:2017
01-september-2017
1DGRPHãþD
SIST EN ISO 10993-4:2009
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Biological evaluation of medical devices - Part 4: Selection of tests for interactions with
blood (ISO 10993-4:2017)
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur
Wechselwirkung mit Blut (ISO 10993-4:2017)
Évaluation biologique des dispositifs médicaux - Partie 4: Choix des essais pour les
interactions avec le sang (ISO 10993-4:2017)
Ta slovenski standard je istoveten z: EN ISO 10993-4:2017
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-4:2017 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-4:2017
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SIST EN ISO 10993-4:2017
EN ISO 10993-4
EUROPEAN STANDARD
NORME EUROPÉENNE
May 2017
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-4:2009
English Version
Biological evaluation of medical devices - Part 4: Selection
of tests for interactions with blood (ISO 10993-4:2017)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil 4:
4: Choix des essais pour les interactions avec le sang Auswahl von Prüfungen zur Wechselwirkung mit Blut
(ISO 10993-4:2017) (ISO 10993-4:2017)
This European Standard was approved by CEN on 23 February 2017.
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 NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2017 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-4:2017 E
worldwide for CEN national Members.
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 4
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 6
2
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
European foreword
This document (EN ISO 10993-4:2017) has been prepared by Technical Committee ISO/TC 194
“Biological and clinical evaluation of medical devices” in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of 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 2017, and conflicting national standards
shall be withdrawn at the latest by November 2017.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent
rights.
This document supersedes EN ISO 10993-4:2009.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directive(s).
For relationship with EU Directive(s), see informative Annex ZA and Annex ZB, which is an integral part
of this document.
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 10993-4:2017 has been approved by CEN as EN ISO 10993-4:2017 without any
modification.
3
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 93/42/EEC of this EN
ER 7.1 (first indent) is partly
covered by ISO 10993-4, since the
standard does not provide
requirements on design and
6.1 and A.1, B.1, C.1, D.1 manufacture. However, this
7.1 (First indent)
and E.1 standard provides a means to
evaluate the interactions of medical
devices with blood. Other forms of
toxicity and flammability are not
dealt with in this standard.
4
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
ER 7.1 (second indent) is partly
covered by ISO 10993-4, since the
standard does not provide
requirements on design and
manufacture. However, this
6.1 and A.1, B.1, C.1, D.1 standard provides a means to
7.1 (Second indent)
and E.1 evaluate the interactions of medical
devices with blood. Other forms of
toxicity are not dealt with in this
standard. This evaluation can be a
preliminary step for risk
minimization.
ER 7.2 is partly covered by
ISO 10993-4, since the standard
does not provide requirements on
design, manufacture and packaging.
6.1 and A.1, B.1, C.1, D.1
7.2 However, this standard provides a
and E.1
means to assess the interactions of
medical devices with blood to
contaminants and residues in
medical devices.
ER 7.5 is partly covered by
ISO 10993-4, since the standard
does not provide requirements on
6.1 and A.1, B.1, C.1, D.1 design and manufacture. However,
7.5
and E.1 this standard provides a means to
evaluate interactions of substances
leaking from medical devices with
blood.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of this
standard.
5
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active
implantable medical devices [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 90/385/EEC of this EN
ER 9 (first indent) is partly covered
by ISO 10993-4, since the standard
does not provide requirements on
design and manufacture. These
haemocompatibility tests are not
intended to evaluate or determine
the performance of the test sample
6.1 and A.1, B.1, C.1, D.1
9 (first indent)
in terms of mechanical or
and E.1
functional loading. However, this
part of ISO 10993 specifies test
methods for the assessment of the
interaction with blood with
medical devices or biomaterials
intended for use in medical
devices. Other forms of toxicity are
6
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SIST EN ISO 10993-4:2017
EN ISO 10993-4:2017 (E)
not dealt with in this standard.
ER 9 (second indent) is partly
covered by ISO 10993-4, since the
standard does not provide
requirements on design and
6.1 and A.1, B.1, C.1, D.1 manufacture. However, this
9 (second indent)
and E.1 standard provides a means to
evaluate the interactions of
medical devices with blood. Other
forms of toxicity are not dealt with
in this standard.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of this
standard.
7
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SIST EN ISO 10993-4:2017
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SIST EN ISO 10993-4:2017
INTERNATIONAL ISO
STANDARD 10993-4
Third edition
2017-04
Biological evaluation of medical
devices —
Part 4:
Selection of tests for interactions
with blood
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
Reference number
ISO 10993-4:2017(E)
©
ISO 2017
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, 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.
ISO copyright office
Ch. de Blandonnet 8 • CP 401
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Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2017 – All rights reserved
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(E)
Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Abbreviated terms . 4
5 Types of devices in contact with blood (as categorized in ISO 10993-1) .5
5.1 Non-blood-contact devices . 5
5.2 External communicating devices . 5
5.2.1 General. 5
5.2.2 External communicating devices that serve as an indirect blood path . 5
5.2.3 External communicating devices directly contacting circulating blood . 5
5.3 Implant devices . 6
6 Characterization of blood interactions . 6
6.1 General requirements . 6
6.2 Categories of tests and blood interactions .12
6.2.1 Recommended tests for interactions of devices with blood .12
6.2.2 Non-contact devices .13
6.2.3 External communicating devices and implant devices.13
6.2.4 Limitations .13
6.3 Types of tests .13
6.3.1 In vitro tests .13
6.3.2 Ex vivo tests .14
6.3.3 In vivo tests .14
Annex A (informative) Preclinical evaluation of cardiovascular devices and prostheses .16
Annex B (informative) Recommended laboratory tests — Principles, scientific basis
and interpretation .21
Annex C (informative) Thrombosis — Methods for in vivo testing .32
Annex D (informative) Haematology/haemolysis — Methods for testing — Evaluation of
haemolytic properties of medical devices and medical device materials .39
Annex E (informative) Complement — Methods for testing .46
Annex F (informative) Less common laboratory tests .49
Annex G (informative) Tests which are not recommended .53
Bibliography .55
© ISO 2017 – All rights reserved iii
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(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 on 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 the following
URL: w w w . i s o .org/ iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
This third edition cancels and replaces the second edition (ISO 10993-4:2002), which has been
technically revised.
It also incorporates the Amendment ISO 10993-4:2002/Amd 1:2006.
The following changes were made:
a) some definitions have been revised and new definitions have been added;
b) Tables 1 and 2 have been consolidated into a single new Table 1 with test categories and headers
reorganized to emphasize and include material and mechanical-induced haemolysis testing and in
vitro and in vivo testing for assessment of risk for thrombosis;
c) Tables 3 and 4 have been consolidated into a single new Table 2 with a simplified list of suggested
and most common tests;
d) Annex B has been updated to cover only the most common practiced tests for assessing blood
interactions;
e) Annex C has been added to cover the topic of in vivo thrombosis and methods for testing;
f) Annex D, which was Annex C in the previous edition, has been updated and now includes added
information on mechanically-induced haemolysis;
g) Annex E has been added to cover the topic of complement testing and best test method practices;
h) Annexes F and G have been added to present the less common tests used to assess interactions with
blood and the tests that are not recommended for preclinical assessment of medical device blood
interaction, respectively. Many of these methods were previously included in Annex B;
iv © ISO 2017 – All rights reserved
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(E)
i) subtle language refinements can be found throughout the revised document;
j) the Bibliography has been reorganized by common subjects of interest and updated with additional
and more current references.
© ISO 2017 – All rights reserved v
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(E)
Introduction
The selection and design of test methods for the interactions of medical devices with blood should take
into consideration device design, materials, clinical utility, usage environment and risk benefit. This
level of specificity can only be covered in vertical standards.
The initial source for developing this document was the publication, Guidelines for blood/material
[14]
interactions, Report of the National Heart, Lung, and Blood Institute chapters 9 and 10. This
[15]
publication was subsequently revised .
vi © ISO 2017 – All rights reserved
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SIST EN ISO 10993-4:2017
INTERNATIONAL STANDARD ISO 10993-4:2017(E)
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with blood
1 Scope
This document specifies general requirements for evaluating the interactions of medical devices
with blood.
It describes
a) a classification of medical devices that are intended for use in contact with blood, based on the
intended use and duration of contact as defined in ISO 10993-1,
b) the fundamental principles governing the evaluation of the interaction of devices with blood,
c) the rationale for structured selection of tests according to specific categories, together with the
principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and
precision of tests for evaluating interactions of devices with blood. This document describes biological
evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a
specific device.
The changes in this document do not indicate that testing conducted according to prior versions of
this document is invalid. For marketed devices with a history of safe clinical use, additional testing
according to this revision is not recommended.
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 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and
the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
© ISO 2017 – All rights reserved 1
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SIST EN ISO 10993-4:2017
ISO 10993-4:2017(E)
3.1
anticoagulant
agent which prevents or delays blood coagulation
EXAMPLE Heparin, ethylenediaminetetraacetic acid (EDTA), sodium citrate.
3.2
blood/device interaction
interaction between blood or a blood component and a device
3.3
coagulation
phenomenon that results from activation of the clotting (coagulation) factor cascade
Note 1 to entry: Factors of the coagulation cascade and fibrinolytic systems can be measured following exposure
to devices either in vitro or in vivo.
3.4
complement system
part of the innate immune system consisting of over 30 distinct plasma proteins, including enzymes,
cofactors, and cellular receptors which may be involved in the promotion of thrombosis
Note 1 to entry: Effector molecules produced from complement components are possible components in the
phenomena of inflammation, phagocytosis and cell lysis. Complement activation related to immunotoxicity,
hypersensitivity and generation of anaphylatoxins is not covered in this document. (See ISO/TR 10993-20.)
Note 2 to entry: The focus in this document is complement activation as it can promote and accelerate haemolysis,
platelet and leukocyte activation and thrombosis on device material surfaces. (See also Annex E on complement
activation.)
3.5
direct blood contact
term used when the device or device material comes into physical contact with blood or blood
constituents
3.6
embolization
process whereby a blood thrombus, or foreign object, is carried in the bloodstream and which may
become lodged and cause obstructed blood flow downstream
3.7
ex vivo test system
term applied to a test system that shunts blood directly from a human subject or test animal into a test
chamber located outside the body
Note 1 to entry: If using an animal model, the blood may be shunted directly back into the animal (recirculating)
or collected in test tubes for evaluation (single pass). In either case, the test chamber is located outside the body.
3.8
haematology
study of blood that includes quantification of cellular and plasma components of the blood
3.9
haematocrit
ratio of the volume of erythrocytes to
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-4:2016
01-februar-2016
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Biological evaluation of medical devices - Part 4: Selection of tests for interactions with
blood (ISO/DIS 10993-4:2015)
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur
Wechselwirkung mit Blut (ISO 10993-4:2002, einschließlich ¿nderung 1:2006)
Évaluation biologique des dispositifs médicaux - Partie 4: Choix des essais pour les
interactions avec le sang (ISO/DIS 10993-4:2015)
Ta slovenski standard je istoveten z: prEN ISO 10993-4
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-4:2016 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-4:2016
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oSIST prEN ISO 10993-4:2016
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-4
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2015-11-26 2016-02-26
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with blood
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
ICS: 11.100.20
ISO/CEN PARALLEL PROCESSING
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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.
Should this draft be accepted, a final draft, established on the basis of comments
received, will be submitted to a parallel two-month approval vote in ISO and
THIS DOCUMENT IS A DRAFT CIRCULATED
formal vote in CEN.
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THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
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IN ADDITION TO THEIR EVALUATION AS
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ISO/DIS 10993-4:2015(E)
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NOTIFICATION OF ANY RELEVANT PATENT
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©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2015
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oSIST prEN ISO 10993-4:2016
ISO/DIS 10993-4:2015(E)
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© ISO 2015, Published in Switzerland
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ii © ISO 2015 – All rights reserved
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oSIST prEN ISO 10993-4:2016
ISO/DIS 10993-4
Contents Page
Foreword . vi
Introduction . viii
1 Scope .1
2 Normative references .1
3 Terms and definitions .1
4 Abbreviated terms .4
5 Types of devices in contact with blood (as categorized in ISO 10993-1:2009) .5
5.1 Non-blood-contact devices .5
5.2 External communicating devices .5
5.2.1 General .5
6 Characterization of blood interactions .7
6.1 General requirements .7
6.2 Categories of tests and blood interactions . 12
6.2.1 Recommended tests for interactions of devices with blood . 12
6.2.2 Non-contact devices . 13
6.2.3 External communicating devices and Implant devices . 13
6.2.4 Limitations . 13
6.3 Types of tests . 14
6.3.1 In vitro tests . 14
6.3.2 Ex vivo tests . 14
6.3.3 In vivo tests . 14
Annex A (informative) Preclinical evaluation of cardiovascular devices and prostheses . 16
A.1 General considerations . 16
A.1.1 Background . 16
A.1.2 Classification . 16
A.1.3 Advantages and limitations of animal models . 17
A.1.4 Advantages and limitations of in vitro models . 17
A.1.5 Test protocols for animal testing . 18
A.2 Cannulae used for direct vascular access, and cannulae used for indirect access . 18
A.3 Catheters and guide wires . 19
A.4 Extracorporeal blood oxygenators, haemodialysis/haemofiltration devices, donor
and therapeutic apheresis equipment, devices for adsorption of specific substances
from blood . 19
A.5 Ventricular-assist devices and total artificial hearts . 20
A.6 Heart valve prostheses . 20
A.7 Vascular grafts . 20
A.8 IVC filters, stents and stented grafts . 21
Annex B (informative) Recommended laboratory tests — principles, scientific basis and
interpretation . 22
B.1 General considerations . 22
B.1.1 Background . 22
B.1.2 In vitro vs. ex vivo vs. in vivo testing . 22
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B.2 Thrombosis . 23
B.2.1 Gross analysis - Retrieval and examination of device and autopsy of distal organs . 23
B.2.2 Percentage occlusion, surface area covered by thrombus, and thrombus-free surface
area . 23
B.2.3 Light microscopy . 23
B.2.4 Scanning electron microscopy (SEM). 24
B.3 In vitro hemocompatibility . 24
B.3.1 Haemolysis – Methods for Testing . 24
B.3.2 Coagulation – Methods for Testing . 24
B.3.3 Platelets – Methods for Testing . 27
B.3.4 Hematology – Methods for Testing . 29
B.3.5 Complement system – Methods for Testing for C3a and SC5b-9 . 29
B.4 Methodology considerations for testing of plasma factors specific to coagulation,
platelet and leucocyte activation, and complement activation, using ELISA (or other
similar) techniques . 30
B.4.1 General . 30
B.4.2 General assay methods and documentation . 31
B.4.3 Attachments . 32
Annex C (informative) Thrombosis — Methods for in vivo testing . 33
C.1 General considerations . 33
C.2 In vivo implant study of final device in pre-clinical animal study . 33
C.3 In vivo non-anticoagulated venous implant (NAVI) and anticoagulated venous
implant (AVI) thrombogenicity tests . 34
Annex D (informative) Haematology/haemolysis — Methods for testing — Evaluation of
haemolytic properties of medical devices and medical device materials . 39
D.1 General considerations . 39
D.2 Causes of haemolysis . 39
D.2.1 Osmotic pressure (osmotic pressure-induced haemolysis) . 39
D.2.2 Mechanical forces (mechanically-induced haemolysis) . 39
D.2.3 Biochemical factors ( material-induced haemolysis) . 40
D.3 Clinical significance of haemolysis . 40
D.3.1 Toxic effects. 40
D.3.2 Thrombosis and anemia . 40
D.4 Determining a pass/fail assessment for haemolysis . 40
D.5 Haemolysis testing — general considerations . 41
D.5.1 Methods . 41
D.5.2 Blood and blood component preservation . 43
D.5.3 Protection of employees handling blood . 44
D.5.4 Blood collection (phlebotomy) . 44
D.5.5 Species selection . 45
D.5.6 Evaluation of haemolysis – in vitro, ex vivo and in vivo exposure to blood or blood
components . 45
D.5.7 Direct contact versus indirect methods . 45
Annex E (informative) Complement — Methods for testing . 46
E.1 Background information . 46
E.2 Complement activation tests and documentation (suggested to consider in reporting
complement test results for scientific or regulatory purposes) . 47
Annex F (informative) Less common laboratory tests. 49
F.1 General . 49
F.2 Thrombosis . 49
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F.2.1 Flow reduction . 49
F.2.2 Gravimetric analysis (thrombus mass) . 49
F.2.3 Pressure drop across device . 50
F.2.4 Adsorbed protein analysis (via antibody binding). 50
F.2.5 Imaging techniques – angiography, intravascular ultrasound, Doppler ultrasound,
CT and MRI . 50
F.3 Coagulation . 50
F.3.1 Thrombin generation assay using chromogenic substrates . 50
F.3.2 Fibrinogen and fibrin degradation products (FDP) . 50
F.3.3 D-dimer . 50
F.4 Platelets . 51
F.4.1 Platelet adhesion assessments . 51
F.4.2 Platelet microparticle formation . 51
F.4.3 Gamma imaging of radiolabelled platelets. 51
F.5 Hematology . 51
F.5.1 Leucocyte state and morphology . 51
F.5.2 Blood cell adhesion assessments . 51
F.5.3 Platelet leucocyte complexes (PLCs) . 52
F.6 Complement system . 52
F.6.1 Complement activation assessment of C5a . 52
Annex G (informative) Tests which are not recommended. 53
G.1 General . 53
G.2 Coagulation . 53
G.2.1 APTT (activated prothrombin time), PT (prothrombin time), and TT and (thrombin
time) . 53
G.3 Platelets . 53
G.3.1 Platelet aggregation . 53
G.3.2 Template bleeding time . 54
G.3.3 Platelet lifespan . 54
G.4 Hematology . 54
G.4.1 Reticulocyte count . 54
G.5 Complement system . 54
G.5.1 Complement activation assessment of Bb, iC3b, CH-50, C3 convertase, C5 convertase . 54
Bibliography . 55
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national
standards bodies (ISO member bodies). The work of preparing International Standards is normally
carried out through ISO technical committees. Each member body interested in a subject for which a
technical committee has been established has the right to be represented on that committee.
International organizations, governmental and non-governmental, in liaison with ISO, also take part in
the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all
matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO's adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 194, Biological and clinical evaluation of
medical devices.
This third edition cancels and replaces the second edition (ISO 10993-4:2007, ISO 10993-4: A1:2009),
which has been technically revised.
The major technical changes are the following:
a) some definitions have been revised and new definitions have been added;
b) Original Tables 1 and 2 have been consolidated into a single new Table 1 with test categories
and headers reorganized to emphasize and include (1) material and mechanical-induced
haemolysis testing and (2) in vitro and in vivo testing for assessment of risk for thrombosis;
c) Original Tables 3 and 4 have been consolidated into a single new Table 2 with a simplified list
of suggested and most common tests;
d) Annex B has been updated to cover only the most common practiced tests for assessing blood
interactions;
e) A new Annex C has been added to cover the topic of in vivo thrombosis and methods for testing;
f) Annex D, previously Annex C Evaluation of the haemolytic properties of medical devices and
their components, has been updated and now includes added information on mechanically-
induced haemolysis;
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g) New Annex E has been added to cover the topic of Complement testing and best test method
practices;
h) New Annexes F and Annex G are added to present the less common tests used to assess
interactions with blood, and, tests not used in preclinical assessment of medical device blood
interaction, respectively. Many of these methods were previously included in Annex B;
i) Subtle language refinements can be found throughout the revised document;
j) The Bibliography has been reorganized by common subjects of interest and updated with
additional and more current references.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical
devices:
— Part 1: Evaluation and testing within a risk management system
— Part 2: Animal welfare requirements
— Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
— Part 4: Selection of tests for interactions with blood
— Part 5: Tests for in vitro cytotoxicity
— Part 6: Tests for local effects after implantation
— Part 7: Ethylene oxide sterilization residuals
— Part 9: Framework for identification and quantification of potential degradation products
— Part 10: Tests for irritation and delayed-type hypersensitivity
— Part 11: Tests for systemic toxicity
— Part 12: Sample preparation and reference materials
— Part 13: Identification and quantification of degradation products from polymeric medical devices
— Part 14: Identification and quantification of degradation products from ceramics
— Part 15: Identification and quantification of degradation products from metals and alloys
— Part 16: Toxicokinetic study design for degradation products and leachables
— Part 17: Method for the establishment of allowable limits for leachable substances
— Part 18: Chemical characterization of materials
— Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
specification]
— Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical
specification]
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Introduction
The selection and design of test methods for the interactions of medical devices with blood should take
into consideration device design, materials, clinical utility, usage environment and risk benefit. This
level of specificity can only be covered in vertical standards.
The initial source for developing this part of ISO 10993 was the publication, Guidelines for
blood/material interactions, Report of the National Heart, Lung, and Blood Institute [16]; chapters 9 and
10. This publication has since been revised [17].
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DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-4
Biological evaluation of medical devices — Part 4: Selection of
tests for interactions with blood
1 Scope
This part of ISO 10993 specifies general requirements for evaluating the interactions of medical devices
with blood.
It describes
a) a classification of medical devices that are intended for use in contact with blood, based on the
intended use and duration of contact as defined in ISO 10993-1,
b) the fundamental principles governing the evaluation of the interaction of devices with blood,
c) the rationale for structured selection of tests according to specific categories, together with the
principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and
precision of tests for interactions of devices with blood. This part of ISO 10993 describes biological
evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a
specific device.
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 am
...
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