SIST EN ISO 10993-15:2023
(Main)Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15:2019)
Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15:2019)
This document specifies general requirements for the design of tests for identifying and quantifying
degradation products from final metallic medical devices or corresponding material samples finished
as ready for clinical use.
This document is applicable only to those degradation products generated by chemical alteration of the
final metallic device in an in vitro degradation test. Because of the nature of in vitro tests, the test results
approximate the in vivo behaviour of the implant or material. The described chemical methodologies
are a means to generate degradation products for further assessments.
This document is applicable to both materials designed to degrade in the body as well as materials that
are not intended to degrade.
This document is not applicable to evaluation of degradation which occurs by purely mechanical
processes; methodologies for the production of this type of degradation product are described in
specific product standards, where available.
NOTE Purely mechanical degradation causes mostly particulate matter. Although this is excluded from the
scope of this document, such degradation products can evoke a biological response and can undergo biological
evaluation as described in other parts of ISO 10993.
Because of the wide range of metallic materials used in medical devices, no specific analytical
techniques are identified for quantifying the degradation products. The identification of trace elements
(<10–6 w/w) contained in the specific metal or alloy is not addressed in this document, nor are specific
requirements for acceptable levels of degradation products provided in this document.
This document excludes the biological activity of the degradation products. (See instead the applicable
clauses of ISO 10993-1 and ISO 10993-17).
Biologische Beurteilung von Medizinprodukten - Teil 15: Qualitativer und quantitativer Nachweis von Abbauprodukten aus Metallen und Legierungen (ISO 10993-15:2019)
Dieses Dokument legt allgemeine Anforderungen zur Konzeption von Prüfungen für den qualitativen und quantitativen Nachweis von Abbauprodukten von fertigen Medizinprodukten aus Metall oder entsprechenden Werkstoffproben im Endzustand fest, die zur klinischen Anwendung bereit sind.
Dieses Dokument ist nur auf solche Abbauprodukte anwendbar, die durch eine chemische Veränderung des fertigen Metallproduktes in einer In vitro Prüfung erzeugt werden. Aufgrund der Natur dieser In vitro Prüfungen entsprechen die Prüfergebnisse in etwa dem In vivo Verhalten des Implantats oder des Werkstoffs. Die beschriebenen chemischen Verfahren sind ein Mittel, um Abbauprodukte für weitere Bewertungen zu erzeugen.
Dieses Dokument ist anwendbar sowohl auf Materialien, die dafür vorgesehen sind, vom Körper abgebaut zu werden, als auch auf solche, bei denen das nicht vorgesehen ist.
Dieses Dokument gilt nicht für eine Beurteilung des Abbaus durch rein mechanische Prozesse. Methoden zur Generierung dieser Art von Abbauprodukten sind, falls vorhanden, in den spezifischen Produktnormen beschrieben.
ANMERKUNG Rein mechanischer Abbau verursacht meist partikelförmiges Material. Obwohl dieses aus dem Anwendungsbereich dieses Dokuments ausgeschlossen ist, können solche Abbauprodukte eine biologische Reaktion hervorrufen und einer biologischen Beurteilung, wie in anderen Teilen der ISO 10993 beschrieben, unterzogen werden.
In Anbetracht des breiten Spektrums an metallischen Werkstoffen, die für Medizinprodukte verwendet werden, werden keine spezifischen analytischen Verfahren zum quantitativen Nachweis der Abbauprodukte festgelegt. Der Nachweis von Spurenelementen (< 10−6 w/w), die in bestimmten Metallen oder Legierungen vorhanden sind, wird in diesem Dokument nicht beschrieben. Ebenso legt dieses Dokument keine spezifischen Anforderungen für akzeptierbare Toleranzwerte von Abbauprodukten fest.
Dieses Dokument beschreibt nicht die biologische Aktivität der Abbauprodukte. (Hierzu wird auf die anwendbaren Abschnitte von ISO 10993 1 und ISO 10993 17 verwiesen.)
Évaluation biologique des dispositifs médicaux - Partie 15: Identification et quantification des produits de dégradation issus des métaux et alliages (ISO 10993-15:2019)
Le présent document spécifie les exigences générales pour la conception des essais d'identification et de quantification des produits de dégradation issus de dispositifs médicaux métalliques finaux ou d'échantillons des matériaux correspondants prêts pour une utilisation clinique.
Le présent document ne s'applique qu'aux produits de dégradation créés par une modification chimique du dispositif métallique final et au moyen d'un essai de dégradation in vitro. En raison de la nature des essais in vitro, les résultats d'essai donnent une approximation du comportement in vivo de l'implant ou du matériau. En raison du caractère accéléré de ces essais, la méthodologie chimique décrite est un moyen de générer des produits de dégradation en vue d'analyses ultérieures.
Le présent document s'applique aux matériaux conçus pour se dégrader dans le corps, ainsi qu'aux matériaux qui ne sont pas conçus pour se dégrader.
Le présent document n'est pas applicable à l'évaluation de la dégradation qui se produit uniquement suite à des processus mécaniques; les méthodologies de génération de ce type de produit de dégradation sont décrites, le cas échéant, dans les normes des produits considérés.
NOTE La dégradation purement mécanique donne principalement de la matière sous forme de particules. Bien qu'ils n'entrent pas dans le domaine d'application du présent document, de tels produits de dégradation peuvent entraîner une réponse biologique et peuvent subir une évaluation biologique telle que celle décrite dans les autres parties de l'ISO 10993.
En raison de la grande variété des matériaux métalliques utilisés dans la fabrication des dispositifs médicaux, la présente partie de l'ISO 10993 n'indique aucune technique d'analyse spécifique pour la quantification des produits de dégradation. Le présent document ne traite pas de l'identification d'éléments à l'état de trace (< 10−6 w/w) contenus dans le métal ou l'alliage analysé. Il ne fournit aucune exigence spécifique relative aux niveaux admissibles de produits de dégradation.
Le présent document ne couvre pas l'activité biologique des produits de dégradation (pour cela, voir les articles correspondants de l'ISO 10993-1 et de l'ISO 10993-17).
Biološko ovrednotenje medicinskih pripomočkov - 15. del: Identifikacija in ugotavljanje količine razgradnih produktov iz kovin in zlitin (ISO 10993-15:2019)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-15:2023
01-september-2023
Nadomešča:
SIST EN ISO 10993-15:2009
Biološko ovrednotenje medicinskih pripomočkov - 15. del: Identifikacija in
ugotavljanje količine razgradnih produktov iz kovin in zlitin (ISO 10993-15:2019)
Biological evaluation of medical devices - Part 15: Identification and quantification of
degradation products from metals and alloys (ISO 10993-15:2019)
Biologische Beurteilung von Medizinprodukten - Teil 15: Qualitativer und quantitativer
Nachweis von Abbauprodukten aus Metallen und Legierungen (ISO 10993-15:2019)
Évaluation biologique des dispositifs médicaux - Partie 15: Identification et quantification
des produits de dégradation issus des métaux et alliages (ISO 10993-15:2019)
Ta slovenski standard je istoveten z: EN ISO 10993-15:2023
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
SIST EN ISO 10993-15:2023 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-15:2023
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SIST EN ISO 10993-15:2023
EN ISO 10993-15
EUROPEAN STANDARD
NORME EUROPÉENNE
May 2023
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-15:2009
English Version
Biological evaluation of medical devices - Part 15:
Identification and quantification of degradation products
from metals and alloys (ISO 10993-15:2019)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
15: Identification et quantification des produits de 15: Qualitativer und quantitativer Nachweis von
dégradation issus des métaux et alliages (ISO 10993- Abbauprodukten aus Metallen und Legierungen (ISO
15:2019) 10993-15:2019)
This European Standard was approved by CEN on 19 April 2023.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2023 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-15:2023 E
worldwide for CEN national Members.
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SIST EN ISO 10993-15:2023
EN ISO 10993-15:2023 (E)
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard the General Safety
and Performance Requirements of Regulation (EU) 2017/745 aimed to be covered . 4
2
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SIST EN ISO 10993-15:2023
EN ISO 10993-15:2023 (E)
European foreword
This document (EN ISO 10993-15:2023) 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 2023, and conflicting national standards
shall be withdrawn at the latest by November 2023.
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 EN ISO 10993-15:2009.
This document has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of EU
Directive(s) / Regulation(s).
For the relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.
Any feedback and questions on this document should be directed to the users’ national standards
body/national committee. A complete listing of these bodies can be found on the CEN website.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the
United Kingdom.
Endorsement notice
The text of ISO 10993-15:2019 has been approved by CEN as EN ISO 10993-15:2023 without any
modification.
3
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SIST EN ISO 10993-15:2023
EN ISO 10993-15:2023 (E)
Annex ZA
(informative)
Relationship between this European Standard the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered
This European standard has been prepared under M/575 to provide one voluntary means of
conforming to the General Safety and Performance Requirements of Regulation (EU) 2017/745 of 5
April 2017 concerning medical devices [OJ L 117] and to system or process requirements including
those relating to quality management systems, risk management, post-market surveillance systems,
clinical investigations, clinical evaluation or post-market clinical follow-up.
Once this standard is cited in the Official Journal of the European Union under that Regulation,
compliance with the normative clauses of this standard given in Table ZA.1 and application of the
edition of the normatively referenced standards as given in Table ZA.2 confers, within the limits of the
scope of this standard, a presumption of conformity with the corresponding General Safety and
Performance Requirements of that Regulation, and associated EFTA Regulations.
Where a definition in this harmonised standard differs from a definition of the same term set out in
Regulation (EU) 2017/745, the differences shall be indicated in the Annex Z. For the purpose of using
this standard in support of the requirements set out in Regulation (EU) 2017/745, the definitions set
out in this Regulation prevail.
Where the European standard is an adoption of an International Standard, the scope of this document
can differ from the scope of the European Regulation that it supports. As the scope of the applicable
regulatory requirements differ from nation to nation and region to region the standard can only
support European regulatory requirements to the extent of the scope of the European Regulation for
medical devices ((EU) 2017/745).
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 Regulation (EU) 2017/745. This means that risks have to be
‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’,
‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as
possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance
Requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety
and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.
NOTE 3 When a General Safety and Performance Requirement does not appear in Table ZA.1, it means that it is
not addressed by this European Standard.
4
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SIST EN ISO 10993-15:2023
EN ISO 10993-15:2023 (E)
Table ZA.1 — Correspondence between this European Standard and Annex I of
Regulation (EU) 2017/745 [OJ L 117] and to system or process requirements including those relating
to quality management systems, risk management, post-market surveillance systems, clinical
investigations, clinical evaluation or post-market clinical follow-up
General Safety and
Clause(s) / sub-
Performance
clause(s)
Requirements of Remarks / Notes
Regulation (EU)
of this EN
2017/745
10.1 a), b), c) and h) 10.1 a), b), c) and h) are only partly covered by ISO
10993-15, since the standard does not provide
requirements on design and manufacture.
However, this part of ISO 10993 provides
considerations on how to plan a degradation study
of metallic materials intended for use in medical
devices in order to obtain quantitative degradation
data as a basis for the safety evaluation of a medical
4, 6 and 7
device.
Therefore, this standard provides a means to
evaluate degradation risks associated with the
metallic materials which are used.
These tests are not intended to evaluate or
determine the performance of the test sample in
terms of mechanical or functional loading.
For 10.1 a), flammability is not covered.
NOTE 4 This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2019/A11:2021.
General Note: Presumption of conformity depends on also complying with the relevant parts of the ISO 10993
series.
Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this
Annex ZA
Column 1 Column 2 International Column 3 Column 4
Reference in Standard Edition
Title Corresponding European
Clause 2
Standard Edition
ISO 3585 ISO 3585:1998 Borosilicate glass 3.3 - None
Properties
For applicable standard
edition see Column 2
ISO 3696 ISO 3696:1987 Water for analytical EN ISO 3696:1995
laboratory use - Specification
and test methods
ISO 8044 ISO 8044:2020 Corrosion of metals and alloys EN ISO 8044:2020
- Vocabulary
ISO 10993-1 ISO 10993-1:2018 Biological evaluation of EN ISO 10993-1:2020
medical devices - Part 1:
5
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SIST EN ISO 10993-15:2023
EN ISO 10993-15:2023 (E)
Column 1 Column 2 International Column 3 Column 4
Reference in Standard Edition
Title Corresponding European
Clause 2
Standard Edition
Evaluation and testing within
a risk management process
ISO 10993-9 ISO 10993-9:2019 Biological evaluation of EN ISO 10993-9:2021
medical devices - Part 9:
Framework for identification
and quantification of potential
degradation products
ISO 10993-12 ISO 10993-12:2021 Biological evaluation of EN ISO 10993-12:2021
medical devices - Part 12:
Sample preparation and
reference materials
ISO 10993-13 ISO 10993-13:2010 Biological evaluation of EN ISO 10993-13:2010
medical devices - Part 13:
Identification and
quantification of degradation
products from polymeric
medical devices
ISO 10993-14 ISO 10993-14:2001 Biological evaluation of EN ISO 10993-14:2009
medical devices - Part 14:
Identification and
quantification of degradation
products from ceramics
ISO 10993-16 ISO 10993-16:2017 Biological evaluation of EN ISO 10993-16:2017
medical devices - Part 16:
Toxicokinetic study design for
degradation products and
leachables
The documents listed in the Column 1 of table ZA.2, in whole or in part, are normatively referenced in
this document, i.e. are indispensable for its application. The achievement of the presumption of
conformity is subject to the application of the edition of Standards as listed in Column 4 or, if no
European Standard Edition exists, the International Standard Edition given in Column 2 of table ZA.2.
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 product(s) falling within the scope of
this standard.
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SIST EN ISO 10993-15:2023
INTERNATIONAL ISO
STANDARD 10993-15
Second edition
2019-11
Biological evaluation of medical
devices —
Part 15:
Identification and quantification of
degradation products from metals
and alloys
Évaluation biologique des dispositifs médicaux —
Partie 15: Identification et quantification des produits de dégradation
issus des métaux et alliages
Reference number
ISO 10993-15:2019(E)
©
ISO 2019
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SIST EN ISO 10993-15:2023
ISO 10993-15:2019(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2019
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
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Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2019 – All rights reserved
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SIST EN ISO 10993-15:2023
ISO 10993-15:2019(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Degradation test methods . 3
4.1 General . 3
4.2 Prerequisites . 3
5 Reagent and sample preparation . 4
5.1 Sample documentation . 4
5.2 Test solution (electrolyte) . 4
5.3 Preparation of test samples . 4
5.3.1 Test samples. 4
5.3.2 Sampling. 4
5.3.3 Sample shape . 4
5.3.4 Sample surface condition . 5
6 Electrochemical tests . 5
6.1 Apparatus . 5
6.2 Sample preparation . 5
6.3 Test conditions . 5
6.4 Potentiodynamic measurements . . 6
6.5 Potentiostatic measurements . 8
7 Immersion test . 9
7.1 Apparatus . 9
7.2 Sample preparation . 9
7.3 Immersion test procedure . 9
8 Analysis .10
9 Test report .10
Annex A (informative) Electrolytes for the electrochemical tests .12
Annex B (informative) Schematic diagram of the electrochemical measuring circuit .13
Annex C (informative) Schematic drawing of an electrolytic cell .14
Bibliography .15
© ISO 2019 – All rights reserved iii
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SIST EN ISO 10993-15:2023
ISO 10993-15:2019(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 194, Biological and clinical evaluation of
medical devices.
This second edition cancels and replaces the first edition (ISO 10993-15:2000), which has been
technically revised.
The main changes compared to the previous edition are as follows:
a) the document now considers materials designed to degrade in the body as well as materials that
are not intended to degrade;
b) the information on test methods has been amended to consider nanomaterials and relevant
material specific standards;
c) the test solution (electrolyte) has been specified more;
d) the sample shape has been specified more;
e) the immersion test procedure has been expanded;
f) the status of Annex C in the previous edition has been changed and now included as Annex A.
A list of all parts in the ISO 10993 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 2019 – All rights reserved
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SIST EN ISO 10993-15:2023
ISO 10993-15:2019(E)
Introduction
One of the potential health hazards resulting from medical devices can be due to the interactions of
their electrochemically induced degradation products with the biological system. Therefore, the
evaluation of potential degradation products from metallic materials by methods suitable for testing
the electrochemical behaviour of these materials is a necessary step in the biological performance
testing of materials.
The body environment typically contains cations of sodium, potassium, calcium, and magnesium, and
anions of chloride, bicarbonate, phosphate, and organic acids generally in concentrations between
–3 –3
2 × 10 mol/l and 150 × 10 mol/l. A range of organic molecules such as proteins, enzymes, and
lipoproteins are also present, but their concentrations can vary to a great extent. Earlier studies
assumed that organic molecules did not exert a significant influence on the degradation of metallic
implants, but newer investigations indicate that implant–tissue interactions should be taken into
account. Depending on a particular product or application, altering the pH of the testing environment
may also need to be considered.
In such biological environments, metallic materials may undergo a certain degradation, and the
different degradation products can interact with the biological system in different ways. Therefore, the
identification and quantification of these degradation products is an important step in evaluating the
biological performance of medical devices.
© ISO 2019 – All rights reserved v
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SIST EN ISO 10993-15:2023
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SIST EN ISO 10993-15:2023
INTERNATIONAL STANDARD ISO 10993-15:2019(E)
Biological evaluation of medical devices —
Part 15:
Identification and quantification of degradation products
from metals and alloys
1 Scope
This document specifies general requirements for the design of tests for identifying and quantifying
degradation products from final metallic medical devices or corresponding material samples finished
as ready for clinical use.
This document is applicable only to those degradation products generated by chemical alteration of the
final metallic device in an in vitro degradation test. Because of the nature of in vitro tests, the test results
approximate the in vivo behaviour of the implant or material. The described chemical methodologies
are a means to generate degradation products for further assessments.
This document is applicable to both materials designed to degrade in the body as well as materials that
are not intended to degrade.
This document is not applicable to evaluation of degradation which occurs by purely mechanical
processes; methodologies for the production of this type of degradation product are described in
specific product standards, where available.
NOTE Purely mechanical degradation causes mostly particulate matter. Although this is excluded from the
scope of this document, such degradation products can evoke a biological response and can undergo biological
evaluation as described in other parts of ISO 10993.
Because of the wide range of metallic materials used in medical devices, no specific analytical
techniques are identified for quantifying the degradation products. The identification of trace elements
–6
(<10 w/w) contained in the specific metal or alloy is not addressed in this document, nor are specific
requirements for acceptable levels of degradation products provided in this document.
This document excludes the biological activity of the degradation products. (See instead the applicable
clauses of ISO 10993-1 and ISO 10993-17).
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 3585, Borosilicate glass 3.3 — Properties
ISO 3696, Water for analytical laboratory use — Specification and test methods
ISO 8044, Corrosion of metals and alloys — Basic terms and definitions
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
© ISO 2019 – All rights reserved 1
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SIST EN ISO 10993-15:2023
ISO 10993-15:2019(E)
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 8044, ISO 10993-1,
ISO 10993-9, ISO 10993-12 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
alloy
material composed of a metallic element with one or more addition(s) of other metallic and/o
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Biological evaluation of medical devices - Part 15: Identification and quantification of
degradation products from metals and alloys (ISO/DIS 10993-15:2018)
Biologische Beurteilung von Medizinprodukten - Teil 15: Qualitativer und quantitativer
Nachweis von Abbauprodukten aus Metallen und Legierungen (ISO/DIS 10993-15:2018)
Évaluation biologique des dispositifs médicaux - Partie 15: Identification et quantification
des produits de dégradation issus des métaux et alliages (ISO/DIS 10993-15:2018)
Ta slovenski standard je istoveten z: prEN ISO 10993-15
ICS:
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PHGLFLQVNLKSULSRPRþNRY medical devices
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oSIST prEN ISO 10993-15:2018
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oSIST prEN ISO 10993-15:2018
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-15
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2018-04-24 2018-07-17
Biological evaluation of medical devices —
Part 15:
Identification and quantification of degradation products
from metals and alloys
Évaluation biologique des dispositifs médicaux —
Partie 15: Identification et quantification des produits de dégradation issus des métaux et alliages
ICS: 11.100.20
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ISO/DIS 10993-15:2018(E)
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TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
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©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2018
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oSIST prEN ISO 10993-15:2018
ISO/DIS 10993-15:2018(E)
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© ISO 2018
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oSIST prEN ISO 10993-15:2018
ISO/DIS 10993-15:2018(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Degradation test methods . 2
4.1 General . 2
4.2 Prerequisites . 3
5 Reagent and sample preparation . 3
5.1 Sample documentation . 3
5.2 Test solution (electrolyte) . 3
5.3 Preparation of test samples . 4
5.3.1 Test samples. 4
5.3.2 Sampling. 4
5.3.3 Sample shape . 4
5.3.4 Sample surface condition . 4
6 Electrochemical tests . 4
6.1 Apparatus . 4
6.2 Sample preparation . 5
6.3 Test conditions . 5
6.4 Potentiodynamic measurements . . 5
6.5 Potentiostatic measurements . 7
7 Immersion test . 7
7.1 Apparatus . 7
7.2 Sample preparation . 8
7.3 Immersion test procedure . 8
8 Analysis . 9
9 Test report . 9
Annex A (normative) Electrolytes for the electrochemical tests .10
Annex B (informative) Schematic diagram of the electrochemical measuring circuit .11
Annex C (informative) Schematic drawing of an electrolytic cell .12
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered .14
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered .15
Annex ZC (informative) Relationship between this European Standard and the general
health and safety requirements of Regulation (EU) 2017/745 on medical devices
aimed to be covered .17
Bibliography .18
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oSIST prEN ISO 10993-15:2018
ISO/DIS 10993-15:2018(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 on 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: www .iso .org/ iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
This second edition cancels and replaces the first edition (ISO 10993-15:2000), which has been
technically revised.
The main changes compared to the previous edition are as follows:
a) document now considers materials designed to degrade in the body as well as materials that are
not intended to degrade;
b) information on test methods amended to consider nanomaterials and relevant material specific
standards;
c) test solution (electrolyte) more specified;
d) sample shape more specified;
e) immersion test procedure expanded;
f) Annex C changed to normative and now Annex A.
A list of all parts in the ISO 10993- series can be found on the ISO website.
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oSIST prEN ISO 10993-15:2018
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Introduction
One of the potential health hazards resulting from medical devices may be due to the interactions
of their electrochemically induced degradation products with the biological system. Therefore, the
evaluation of potential degradation products from metallic materials by methods suitable for testing
the electrochemical behavior of these materials is a necessary step in the biological performance
testing of materials.
The body environment typically contains cations of sodium, potassium, calcium, and magnesium, and
anions of chloride, bicarbonate, phosphate, and organic acids generally in concentrations between 2 x 10
–3 mol and 150 x 10 –3 mol. A range of organic molecules such as proteins, enzymes, and lipoproteins is
also present, but their concentrations may vary to a great extent. Earlier studies assumed that organic
molecules did not exert a significant influence on the degradation of metallic implants, but newer
investigations indicate that implant–protein interactions should be taken into account. Depending on
a particular product or application, altering the pH of the testing environment may also need to be
considered.
In such biological environments, metallic materials may undergo a certain degradation, and the
different degradation products may interact with the biological system in different ways. Therefore,
the identification and quantification of these degradation products is an important step in evaluating
the biological performance of medical devices.
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oSIST prEN ISO 10993-15:2018
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-15:2018(E)
Biological evaluation of medical devices —
Part 15:
Identification and quantification of degradation products
from metals and alloys
1 Scope
This document provides guidance on general requirements for the design of tests for identifying and
quantifying degradation products from final metallic medical devices or corresponding material
samples finished as ready for clinical use.
This document is applicable only to those degradation products generated by chemical alteration of the
final metallic device in an in vitro accelerated degradation test. Because of the accelerated nature of
these tests, the test results may not reflect the implant or material behavior in the body. The described
chemical methodologies are a means to generate degradation products for further assessments.
This document considers both materials designed to degrade in the body as well as materials that are
not intended to degrade.
This document is not applicable to degradation products induced by applied mechanical stress.
Mechanically induced degradation, such as wear, can be covered in the appropriate product-specific
standard. Where product-group standards provide applicable product-specific methodologies for the
identification and quantification of degradation products, those standards should be considered.
Because of the wide range of metallic materials used in medical devices, no specific analytical
techniques are identified for quantifying the degradation products. The identification of trace elements
–6
(< 10 w/w) contained in the specific metal or alloy is not addressed in this part of ISO 10993, nor are
specific requirements for acceptable levels of degradation products provided in this part of ISO 10993.
This document does not address the biological activity of the degradation products; see instead the
applicable clauses of ISO 10993-1 and ISO 10993-17.
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 3585, Borosilicate glass 3.3 — Properties
ISO 3696, Water for analytical laboratory use — Specification and test methods
ISO 8044, Corrosion of metals and alloys — Basic terms and definitions
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
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ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 8044, ISO 10993-1,
ISO 10993-9, 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 https:// www .iso .org/ obp
3.1
alloy
material composed of a metallic element with one or more addition(s) of other metallic and/or non-
metallic elements
3.2
electrolyte
solution containing ions with the capacity to conduct electric current
3.3
open-circuit potential
potential of an electrode measured with respect to a reference electrode or another electrode when no
current flows to or from it
3.4
passive limit potential
E
a
electrode potential of the positive limit of the passive range
Note 1 to entry: See Figure 1.
3.5
breakdown potential
E
p
critical electrode potential above which localized or transpassive corrosion is found to occur
Note 1 to entry: See Figure 1.
4 Degradation test methods
4.1 General
To identify and quantify degradation products from metals and alloys in medical devices, a combination
of two procedures is described. The choice of test procedure shall be justified according to the function
of the medical device.
The first procedure described is a combination of a potentiodynamic test and a potentiostatic test. The
second procedure described is an immersion test.
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The potentiodynamic test is used to determine the general electrochemical behavior of the material
under consideration and to determine certain specific points (E and E ) on the potential/current
a p
density curve.
The immersion test is used to chemically degrade the test material to generate degradation products to
be analyzed.
If there is the possibility of the loss of a coating from a metallic substrate due to degradation, the
potential degradation products from the substrate material shall be considered, as well as the
coating itself. In addition, if a metallic substrate coated with a non-metallic material is to be tested,
the requirements of ISO 10993-13 and/or ISO 10993-14 shall be considered in order to determine the
potential degradation products of the coating.
The identified and quantified degradation products form the basis for evaluation of biological response
and, if appropriate, toxicokinetic studies in accordance with ISO 10993-16.
For those medical devices composed of or containing nanoscale materials, and for those instances where
metallic degradation products are within the nanoscale size range (approximately 1 nm to 100 nm), the
user is referred to ISO 10993-22 when creating their risk assessment documents.
If the medical device is made using a metal or metal alloy designed to be absorbed by the body, the
user is directed to relevant material specific standards (see bibliography) for methods and specific
considerations (e.g. electrolyte, atmosphere, etc.) appropriate for this class of materials.
4.2 Prerequisites
The rates of electrochemical degradation reactions are sensitive to small variations in test conditions,
instrumentation, sample conditions, and preparation. Therefore, electrochemical degradation testing
shall be carried out in an appropriately equipped laboratory by experienced and qualified personnel.
This includes proper maintenance and calibration of the test equipment. The methods and operating
conditions of the equipment shall also be validated.
Fulfillment of electrochemical test conditions for stability, warm-up time, etc., can be demonstrated by
[1]
conformance to.
5 Reagent and sample preparation
5.1 Sample documentation
The general composition of the material(s) under test shall be documented.
5.2 Test solution (electrolyte)
The test solution (electrolyte) to be used shall be appropriate for the intended use of the medical device.
All chemicals shall be of analytical grade and dissolved in water of grade 2 in accordance with ISO 3696.
The first choice for the electrolyte shall be an aqueous solution of 0,9 % sodium chloride.
Dependent on the composition and corrosion mechanism of the metal or alloy being tested, other
electrolytes may be used, such as artificial saliva or artificial plasma. Examples of electrolyte
compositions are given in Annex A, but other more material and physiologically relevant electrolyte
solutions and test conditions may be utilized. Possible effect of implant–protein interactions should be
taken into account.
NOTE Formulations for artificial sweat, gastrointestinal fluids, and lung fluids have been used [see
Bibliography].
In the test report, the choice of electrolyte shall be justified. If other than an aqueous solution of 0,9 %
sodium chloride is used, the pH of the electrolyte shall be specified.
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5.3 Preparation of test samples
5.3.1 Test samples
The sensitivity of chemical degradation testing is related to variation in material composition, to
material processing, and to surface-finishing procedures. The sampling procedure, sample shape,
and surface preparation are critical. In addition, confined spaces can result in crevice corrosion and
defects in coatings can cause pit corrosion, which shall be taken into consideration. The samples shall
be representative of the final devices.
5.3.2 Sampling
For each chemical test, at least two test samples shall be prepared as specified in ISO 10993-12. If
substantial deviations in the test results are found, the reasons for the deviation shall be determined,
and more samples shall be tested.
If the metallic sample has anisotropic properties due to manufacturing conditions, tests involving
single-surface exposure should include samples cut parallel to both the transverse and longitudinal
manufacturing directions.
5.3.3 Sample shape
Standard samples, either circular- or rectangular-section bars or flat coupons, or one single free
surface, may be used for degradation testing if they are prepared in a manner comparable to the final
medical device. Samples of actual device components may be of any shape and condition; however, the
testing shall be carried out under well-controlled conditions which shall be reported.
The surface area of the sample exposed to the electrolyte shall be determined to +/- 10% of the total
geometrical area to assure an accurate and repeatable determination of the degradation rates.
If representative samples are used, consideration shall be made regarding whether the differences
between the representative sample and the final medical device or component could affect the results
of the test. Testing of representative samples instead of the final medical device shall be supported by a
description of any differences between the representative sample and the final device. The report shall
contain a detailed rationale for why each difference is not expected to alter the biocompatibility of the
final device.
5.3.4 Sample surface condition
Since the surface condition of a material may affect its electrochemical behavior, the surface condition of
the test sample shall be identical to the final medical device and shall be described in the test report. For
comparing test results of different materials, the surface condition of the test samples shall be the same.
6 Electrochemical tests
6.1 Apparatus
Test cells of borosilicate glass, in appropriate sizes, in accordance with ISO 3585, with a means of
controlling the bath temperature within ± 1 °C.
-9 –1
Scanning potentiostat with a potential range ± 2 V and a current output range from 10 A to 10 A.
11
Potential-measuring instrument with a high input impedance (>10 Ω) and a sensitivity and
accuracy to detect a change of 1 mV over a potential range between ± 2 V.
Current-measuring instrument capable of measuring a current to ± 1 % of the absolute value over a
-9 –1
current range between 10 A and 10 A.
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Working electrode (test sample).
Counter-electrode(s) such as platinum (grid, plate, or wire) or vitreous carbon with an area at least 10
times that of the working electrode.
Reference electrode.
pH-meter with a sensitivity of ± 0,1.
A schematic diagram of the electrochemical measurement circuit which may be used as a system with
variable potential is given in Annex B.
A schematic drawing of an electrolytic cell is given in Annex C.
6.2 Sample preparation
Mount the test sample in a watertight electrode holder so that only the test surface is in contact with
the electrolyte. Take care to avoid the creation of conditions where crevice corrosion can occur due to
the formation of a crevice between the mounting and the sample. Before testing, clean the specimen
ultrasonically for 10 min to 15 min in ethanol, carefully rinse with water of grade 2 in accordance with
ISO 3696, and immediately transfer into the test cell.
6.3 Test conditions
Fill the test cell with the test solution (electrolyte). If the electrochemical behavior is temperature
sensitive in the range of 10 °C to 50 °C, maintain the electrolyte cell at (37 ± 1) °C. Reduce the oxygen level
3 –1
in the electrolyte by bubbling oxygen-free nitrogen or argon at a rate of approximately 100 cm ▪min
for not less than 30 min prior to the start of the test. The electrolyte shall be agitated either by the
bubbling gas or mechanical means to avoid concentration gradients. If gas agitation is used, take care
not to have any gas bubbles adhering to the active test surface.
Magnetic stirrers often interfere with electrochemical test cells. If they are used, their effect on the test
cell shall be determined as part of the validation of test equipment (see 4.2).
6.4 Potentiodynamic measurements
Measure the open-circuit potential not less than 2 h after the immersion of the working electrode. This
potential shall be the starting potential for potentiodynamic measurements. The sweep rate shall be
–1
1,0 mV▪s , except in tests where the sweep rate has little effect, where the test may be accelerated by
–1
increasing the sweep rate to 10 mV▪s . Record the potential/current density curve up to a maximum
–2
of 2 000 mV or a maximum current density of 1,0 mA▪cm , whichever comes first, to evaluate the
transpassive range of the sample (see Figure 1). To ensure consistency, reverse the scan and continue
–2
back at least to the open-circuit potential. Then repeat the test back to 2 000 mV or 1,0 mA▪cm . If
the curves are not reproducible, then continue cycling 5 to 10 times. If consistent potential/current
density curves are not achieved after 5 to 10 cycles, investigate possible causes such as test set- up,
electrode function, innate material properties, etc. The log current density/potential curves should also
be recorded (see Figure 2). Record the breakdown potential (E ) from the last cycle taken (see Figure 1).
p
Noble metals may b
...
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