SIST EN ISO 10993-3:2015
(Main)Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2014)
Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2014)
This part of ISO 10993 specifies strategies for risk estimation, selection of hazard identification tests
and risk management, with respect to the possibility of the following potentially irreversible biological
effects arising as a result of exposure to medical devices:
— genotoxicity;
— carcinogenicity;
— reproductive and developmental toxicity.
This part of ISO 10993 is applicable when the need to evaluate a medical device for potential genotoxicity,
carcinogenicity, or reproductive toxicity has been established.
NOTE Guidance on selection of tests is provided in ISO 10993-1.
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität, Karzinogenität und Reproduktionstoxizität (ISO 10993-3:2014)
Dieser Teil der ISO 10993 beschreibt spezifische Strategien für die Gefahrenerkennung sowie Testverfahren
für Medizinprodukte für die nachfolgenden biologischen Aspekte:
- Genotoxizität,
- Karzinogenität und
- Reproduktions- und Entwicklungstoxizität.
Dieser Teil der ISO 10993 ist anwendbar, sobald die Notwendigkeit festgestellt wurde, ein Medizinprodukt auf
potenzielle Genotoxizität, Karzinogenität oder Reproduktionstoxizität zu untersuchen.
ANMERKUNG Richtlinien zur Auswahl der Prüfungen sind in der ISO 10993-1 enthalten.
Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:2014)
L'ISO 10993-3:2014 spécifie les stratégies pour l'estimation des risques, le choix des essais d'identification des risques et la gestion des risques, en fonction du risque d'apparition des effets biologiques potentiellement irréversibles suivants résultant de l'exposition à des dispositifs médicaux:
génotoxicité;
cancérogénicité;
toxicité sur la reproduction et le développement.
L'ISO 10993-3:2014 est applicable lorsque le besoin d'évaluer un dispositif médical dont le risque de génotoxicité, de cancérogénicité ou de toxicité sur la reproduction a été identifié.
Biološko ovrednotenje medicinskih pripomočkov - 3. del: Preskusi genske toksičnosti, kancerogenosti in toksičnosti za razmnoževanje (ISO 10993-3:2014)
Ta del standarda ISO 10993 določa strategije za oceno tveganja, izbiro preskusov za prepoznavanje nevarnosti
in upravljanje tveganja ob upoštevanju možnosti naslednjih potencialno nepovratnih bioloških
učinkov, ki so posledica izpostavljenosti medicinskim pripomočkom:
– genska toksičnost;
– kancerogenost;
– toksičnost za razmnoževanje in razvoj.
Ta del standarda ISO 10993 se uporablja, ko je ugotovljena potreba po ovrednotenju potencialne genske toksičnosti, kancerogenosti ali toksičnosti za razmnoževanje medicinskega pripomočka.
OPOMBA: Navodila za izbiro preskusov so zajeta v standardu ISO 10993-1.
General Information
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Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-3:2015
01-januar-2015
1DGRPHãþD
SIST EN ISO 10993-3:2009
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Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity
and reproductive toxicity (ISO 10993-3:2014)
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität,
Karzinogenität und Reproduktionstoxizität (ISO 10993-3:2014)
Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la
génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:2014)
Ta slovenski standard je istoveten z: EN ISO 10993-3:2014
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-3:2015 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-3:2015
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SIST EN ISO 10993-3:2015
EUROPEAN STANDARD
EN ISO 10993-3
NORME EUROPÉENNE
EUROPÄISCHE NORM
October 2014
ICS 11.100.20 Supersedes EN ISO 10993-3:2009
English Version
Biological evaluation of medical devices - Part 3: Tests for
genotoxicity, carcinogenicity and reproductive toxicity (ISO
10993-3:2014)
Évaluation biologique des dispositifs médicaux - Partie 3: Biologische Beurteilung von Medizinprodukten - Teil 3:
Essais concernant la génotoxicité, la cancérogénicité et la Prüfungen auf Gentoxizität, Karzinogenität und
toxicité sur la reproduction (ISO 10993-3:2014) Reproduktionstoxizität (ISO 10993-3:2014)
This European Standard was approved by CEN on 6 September 2014.
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, 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
© 2014 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-3:2014 E
worldwide for CEN national Members.
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SIST EN ISO 10993-3:2015
EN ISO 10993-3:2014 (E)
Contents Page
Foreword .3
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42 EEC on medical devices .4
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on active implantable medical devices .6
2
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SIST EN ISO 10993-3:2015
EN ISO 10993-3:2014 (E)
Foreword
This document (EN ISO 10993-3:2014) 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
evaluation of medical devices” the secretariat of which is held by NEN.
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 April 2015, and conflicting national standards shall be withdrawn at the
latest by April 2015.
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 10993-3:2009.
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 Directives.
For relationship with EU Directives, see informative Annex ZA and ZB, which are integral parts 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, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the United Kingdom.
Endorsement notice
The text of ISO 10993-3:2014 has been approved by CEN as EN ISO 10993-3:2014 without any modification.
3
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SIST EN ISO 10993-3:2015
EN ISO 10993-3:2014 (E)
Annex ZA
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42 EEC on medical devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 93/42 EEC on medical devices.
Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the 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.
Table ZA.1 — Correspondence between this European Standard and Directive 93/42/EEC on medical
devices
Essential Requirements (ERs) Clause(s)/sub-clause(s) of
Qualifying remarks/Notes
of Directive 93/42/EEC this EN
ER 7.1 is only partly covered by
ISO 10993-3, since the
standard does not provide
requirements on design and
manufacture. However, this
7.1 (First and second indent) 4, 5, 6 and 7
standard provides a means to
evaluate genotoxicity,
carcinogenicity or reproductive
toxicity risks associated with the
materials which are used.
ER 7.2 is not covered by
ISO 10993-3, since the
standard does not provide
requirements on design and
manufacture and does not
oblige to minimize risk.
However, this standard
7.2 4, 5, 6 and 7
provides a means to evaluate
genotoxicity, carcinogenicity or
reproductive toxicity. This
evaluation can be a preliminary
step for risk minimization. Other
forms of toxicity and
flammability are not dealt with in
this standard.
ER 7.5 is not covered by
ISO 10993-3, since the
standard does not provide
7.5 (First paragraph) 4, 5, 6 and 7 requirements on design,
manufacture and packaging
and does not oblige to minimize
risk.
4
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SIST EN ISO 10993-3:2015
EN ISO 10993-3:2014 (E)
However, this standard
provides a means to evaluate
genotoxicity, carcinogenicity or
reproductive toxicity. This
evaluation can be a preliminary
step for risk minimization. Other
forms of toxicity and
flammability 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 — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this standard.
5
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SIST EN ISO 10993-3:2015
EN ISO 10993-3:2014 (E)
Annex ZB
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on active implantable medical
devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 90/385 EEC on active implantable medical devices.
Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the 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.
Table ZB.1 — Correspondence between this European Standard and Directive 90/385/EEC on active
implantable medical devices
Essential Requirements (ERs) Clause(s)/sub-clause(s) of
Qualifying remarks/Notes
of Directive 90/385/EEC this EN
ER 9 is only partly covered by
, since the
ISO 10993-3
standard does not provide
requirements on design and
manufacture. However, this
9 (First and second indent) 4, 5, 6 and 7 standard provides a means to
assess genotoxicity,
carcinogenicity or reproductive
toxicity used in the manufacture
of medical devices. Other forms
of toxicity are not covered.
General Note: Presumption of conformity depends on also complying with all relevant clauses/subclauses of
ISO 10993-1.
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this standard.
6
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SIST EN ISO 10993-3:2015
INTERNATIONAL ISO
STANDARD 10993-3
Third edition
2014-10-01
Biological evaluation of medical
devices —
Part 3:
Tests for genotoxicity, carcinogenicity
and reproductive toxicity
Évaluation biologique des dispositifs médicaux —
Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la
toxicité sur la reproduction
Reference number
ISO 10993-3:2014(E)
©
ISO 2014
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2014
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
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Published in Switzerland
ii © ISO 2014 – All rights reserved
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(E)
Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Requirements for test strategies . 2
4.1 General . 2
4.2 Additional requirements for carcinogenicity testing . 3
4.3 Additional requirements for reproductive toxicity testing . 3
5 Genotoxicity tests . 4
5.1 General . 4
5.2 Test strategy . 4
5.3 Sample preparation . 6
6 Carcinogenicity tests . 7
6.1 General . 7
6.2 Evaluation strategy . 7
6.3 Sample preparation . 8
6.4 Test methods . 8
7 Reproductive and developmental toxicity tests . 9
7.1 General . 9
7.2 Test strategy . 9
7.3 Sample preparation .10
7.4 Test methods .10
8 Test report .11
Annex A (informative) Guidance on selecting an appropriate sample preparation procedure in
genotoxicity testing .12
Annex B (informative) Flowchart for follow-up evaluation .20
Annex C (informative) Rationale of test systems .21
Annex D (informative) Cell transformation test systems .23
Annex E (normative) Considerations for carcinogenicity studies performed as
implantation studies .24
Annex F (informative) In vitro tests for embryo toxicity.25
Bibliography .27
© ISO 2014 – All rights reserved iii
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(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. 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. 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.
The committee responsible for this document is ISO/TC 194.
This third edition of ISO 10993-3 cancels and replaces the second edition (ISO 10993-3:2003), which has
been technically revised.
The major technical changes are the following:
a) test strategy changed by inclusion of a in vivo test and a follow-up evaluation;
b) new Annex A ” Guidance on selecting an appropriate sample preparation procedure in genotoxicity
testing” included;
c) Inclusion of further in vitro and in vivo test for evaluating the genotoxic potential of medical devices;
d) new Annex B “Flowchart for follow-up evaluation” included;
e) Annex E changed to “Considerations for carcinogenicity studies performed as implantation studies”
and made normative;
f) new Annex F “In vitro tests for embryo toxicity” included.
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 process
— 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 skin sensitization
iv © ISO 2014 – All rights reserved
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(E)
— 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: 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]
The following part is under preparation:
— Part 33: Supplement to ISO 10993-3:— Guidance on tests to evaluate genotoxicity [Technical Report]
The following definitions apply in understanding how to implement an ISO International Standard and
other normative ISO deliverables (TS, PAS, IWA):
— “shall” indicates a requirement;
— “should” indicates a recommendation;
— “may” is used to indicate that something is permitted;
— “can” is used to indicate that something is possible, for example, that an organization or individual
is able to do something.
ISO/IEC Directives, Part 2 (sixth edition, 2011), 3.3.1, defines a requirement as an “expression in the
content of a document conveying criteria to be fulfilled if compliance with the document is to be claimed
and from which no deviation is permitted.”
ISO/IEC Directives, Part 2 (sixth edition, 2011), 3.3.2, defines a recommendation as an “expression in the
content of a document conveying that among several possibilities one is recommended as particularly
suitable, without mentioning or excluding others, or that a certain course of action is preferred but not
necessarily required, or that (in the negative form) a certain possibility or course of action is deprecated
but not prohibited.”
© ISO 2014 – All rights reserved v
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(E)
Introduction
The basis for biological evaluation of medical devices is often empirical and driven by the relevant
concerns for human safety. The risk of serious and irreversible effects, such as cancer or second generation
abnormalities, is of particular public concern. It is inherent in the provision of safe medical devices that
such risks be minimised to the greatest extent feasible. The assessment of mutagenic, carcinogenic and
reproductive hazards is an essential component of the control of these risks. Not all test methods for the
assessment of genotoxicity, carcinogenicity or reproductive toxicity are equally well developed, nor is
their validity well established for the testing of medical devices.
Significant issues with test sample size and preparation, scientific understanding of disease processes
and test validation can be cited as limitations of available methods. For example, the biological
significance of solid state carcinogenesis is poorly understood. It is expected that on-going scientific and
medical advances will improve our understanding of and approaches to these important toxicological
effects. At the time this document was prepared, the test methods proposed were those most acceptable.
Scientifically sound alternatives to the proposed testing may be acceptable insofar as they address
relevant matters of safety assessment.
In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful
assessment of expected human uses and potential interactions of the medical device with various
biological systems. These considerations will be particularly important in such areas as reproductive
and developmental toxicology.
This part of ISO 10993 presents test methods for the detection of specific biological hazards, and
strategies for the selection of tests, where appropriate, that will assist in hazard identification. Testing
is not always necessary or helpful in managing toxicological risks associated with exposure to medical
device materials but, where it is appropriate, it is important that maximum test sensitivity is achieved.
In view of the multitude of possible outcomes and the importance of factors such as extent of exposure,
species differences and mechanical or physical considerations, risk assessment have to be performed on
a case-by-case basis.
vi © ISO 2014 – All rights reserved
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SIST EN ISO 10993-3:2015
INTERNATIONAL STANDARD ISO 10993-3:2014(E)
Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive
toxicity
1 Scope
This part of ISO 10993 specifies strategies for risk estimation, selection of hazard identification tests
and risk management, with respect to the possibility of the following potentially irreversible biological
effects arising as a result of exposure to medical devices:
— genotoxicity;
— carcinogenicity;
— reproductive and developmental toxicity.
This part of ISO 10993 is applicable when the need to evaluate a medical device for potential genotoxicity,
carcinogenicity, or reproductive toxicity has been established.
NOTE Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
OECD 414, Prenatal Development Toxicity Study
OECD 415, One-Generation Reproduction Toxicity Study
OECD 416, Two-generation Reproduction Toxicity
OECD 421, Reproduction/Developmental Toxicity Screening Test
OECD 451, Carcinogenicity Studies
OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies
OECD 471, Bacterial Reverse Mutation Test
OECD 473, In vitro Mammalian Chromosome Aberration Test
© ISO 2014 – All rights reserved 1
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SIST EN ISO 10993-3:2015
ISO 10993-3:2014(E)
OECD 476, In vitro Mammalian Cell Gene Mutation Test
OECD 487, In Vitro Mammalian Cell Micronucleus Test
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.
3.1
carcinogenicity test
test to determine the carcinogenic potential of medical devices, materials, and/or extracts using multiple
exposures for a major portion of the life span of the test animal
3.2
energy-depositing medical device
device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation,
ionising radiation or ultrasound
Note 1 to entry: This does not include medical devices that deliver simple electrical current, such as electrocautery
medical devices, pacemakers or functional electrical stimulators.
3.3
genotoxicity test
test using mammalian or non-mammalian cells, bacteria, yeasts, fungi or whole animals to determine
whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused
by the test samples
3.4
maximum tolerated dose
MTD
maximum dose that a test animal can tolerate without any adverse effects
3.5
reproductive and developmental toxicity test
test to evaluate the potential effects of test samples on reproductive function, embryonic morphology
(teratogenicity), and prenatal and early postnatal development
3.6
test sample preparation
residual, extractables, leachables or biodegradable device materials that are resuspended in a vehicle
compatible with the test system
4 Requirements for test strategies
4.1 General
ISO 10993-1 indicates circumstances where the potential for genotoxicity, carcinogenicity and
reproductive toxicit
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-3:2013
01-april-2013
%LRORãNRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3UHVNXVLJHQVNH
WRNVLþQRVWLNDQFHURJHQRVWLLQWRNVLþQRVWL]DUD]PQRåHYDQMH ,62',6
Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity
and reproductive toxicity (ISO/DIS 10993-3:2013)
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität,
Karzinogenität und Reproduktionstoxizität (ISO/DIS 10993-3:2013)
Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la
génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO/DIS 10993-3:2013)
Ta slovenski standard je istoveten z: FprEN ISO 10993-3 rev
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-3:2013 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-3:2013
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oSIST prEN ISO 10993-3:2013
EUROPEAN STANDARD
DRAFT
FprEN ISO 10993-3 rev
NORME EUROPÉENNE
EUROPÄISCHE NORM
February 2013
ICS 11.100.20 Will supersede EN ISO 10993-3:2009
English Version
Biological evaluation of medical devices - Part 3: Tests for
genotoxicity, carcinogenicity and reproductive toxicity (ISO/FDIS
10993-3:2013)
Évaluation biologique des dispositifs médicaux - Partie 3: Biologische Beurteilung von Medizinprodukten - Teil 3:
Essais concernant la génotoxicité, la cancérogénicité et la Prüfungen auf Gentoxizität, Karzinogenität und
toxicité sur la reproduction (ISO/FDIS 10993-3:2013) Reproduktionstoxizität (ISO/FDIS 10993-3:2013)
This draft European Standard is submitted to CEN members for second parallel enquiry. It has been drawn up by the Technical Committee
CEN/TC 206.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN 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, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and United
Kingdom.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are aware and to
provide supporting documentation.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice and
shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2013 CEN All rights of exploitation in any form and by any means reserved Ref. No. FprEN ISO 10993-3 rev:2013: E
worldwide for CEN national Members.
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oSIST prEN ISO 10993-3:2013
prEN ISO 10993-3:2013 (E)
Contents Page
Foreword .3
2
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oSIST prEN ISO 10993-3:2013
prEN ISO 10993-3:2013 (E)
Foreword
This document (prEN ISO 10993-3:2013) has been prepared by Technical Committee ISO/TC 194 "Biological
evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206 “Biological evaluation
of medical devices” the secretariat of which is held by NEN.
This document is currently submitted to the second parallel Enquiry.
This document will supersede EN ISO 10993-3:2009.
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).
Endorsement notice
The text of ISO/DIS 10993-3:2013 has been approved by CEN as prEN ISO 10993-3:2013 without any
modification.
3
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oSIST prEN ISO 10993-3:2013
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oSIST prEN ISO 10993-3:2013
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-3.2
ISO/TC 194 Secretariat: DIN
Voting begins on Voting terminates on
2013-02-14 2013-04-14
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION • МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ • ORGANISATION INTERNATIONALE DE NORMALISATION
Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive toxicity
Évaluation biologique des dispositifs médicaux —
Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction
[Revision of second edition (ISO 10993-3:2003)]
ICS 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for Standardization (ISO), and
processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member bodies for a parallel
five-month enquiry.
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 formal vote in CEN.
To expedite distribution, this document is circulated as r eceived from the committee
secretariat. ISO Central Secretariat work of editing and text composition will be undertaken at
publication stage.
Pour accélérer la distribution, le présent document est distribué tel qu'il est parvenu du
secrétariat du comité. Le travail de rédaction et de composition de texte sera effectué au
Secrétariat central de l'ISO au stade de publication.
THIS DOCUMENT IS A DRAFT CIRCULATED FOR COMMENT AND APPROVAL. IT IS THEREFORE SUBJECT TO CHANGE AND MAY NOT BE
REFERRED TO AS AN INTERNATIONAL STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS BEING ACCEPTABLE FOR INDUSTRIAL, TECHNOLOGICAL, COMMERCIAL AND USER PURPOSES, DRAFT
INTERNATIONAL STANDARDS MAY ON OCCASION HAVE TO BE CONSIDERED IN THE LIGHT OF THEIR POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN NATIONAL REGULATIONS.
RECIPIENTS OF THIS DRAFT ARE INVITED TO SUBMIT, WITH THEIR COMMENTS, NOTIFICATION OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPORTING DOCUMENTATION.
© International Organization for Standardization, 2013
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
Copyright notice
This ISO document is a Draft International Standard and is copyright-protected by ISO. Except as permitted
under the applicable laws of the user’s country, neither this ISO draft nor any extract from it may be
reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic,
photocopying, recording or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
ii © ISO 2013 – All rights reserved
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
Contents Page
Foreword . v
Introduction . vii
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Requirements for test strategies . 3
4.1 General . 3
4.2 Additional requirements for carcinogenicity testing . 3
4.3 Additional requirements for reproductive toxicity testing . 4
5 Genotoxicity tests . 4
5.1 General . 4
5.2 Test strategy . 4
5.2.1 General . 4
5.2.2 In vitro test battery . 4
5.2.3 In vivo and in vitro test battery . 5
5.2.4 Follow-up evaluation . 5
5.3 Sample preparation . 7
6 Carcinogenicity tests . 7
6.1 General . 7
6.2 Evaluation strategy . 7
6.3 Sample preparation . 8
6.4 Test methods . 8
7 Reproductive and developmental toxicity tests . 9
7.1 General . 9
7.2 Test strategy . 9
7.3 Sample preparation . 10
7.4 Test methods . 10
8 Test report . 11
Annex A (informative) Rationale of test systems . 12
A.1 Genotoxicity tests . 12
A.2 Carcinogenicity tests . 13
A.3 Reproductive/developmental toxicity tests . 13
Annex B (informative) Cell transformation test systems . 14
Annex C (normative) Considerations for carcinogenicity studies performed as implantation
studies . 15
C.1 Foreign body carcinogenesis . 15
C.2 Animal welfare considerations . 15
C.3 Justification for carcinogenicity studies . 15
Annex D (informative) Guidance on selecting an appropriate sample preparation procedure in
genotoxicity testing . 16
D.1 General . 16
D.2 Device materials . 17
D.2.1 Low Molecular Weight Chemicals (LMWC) . 17
D.2.2 Polymers (including naturally occurring polymers) . 17
D.2.3 Inorganic materials: Wear debris from metals, alloys and ceramics . 18
D.3 Sample Preparation Methods . 18
© ISO 2012 – All rights reserved 3
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
D.3.1 Method A . 20
D.3.2 Method B . 20
D.3.3 Method C . 22
D.4 Additional guidance on special sample preparation procedures . 23
D.4.1 Biodegradable polymers . 23
D.4.2 Inorganic materials: Wear debris from metals, alloys and ceramics . 23
D.4.3 LMWC . 23
Annex E (informative) In vitro tests for embryotoxicity . 24
Bibliography . 25
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42 on medical devices . 33
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC . 34
4 © ISO 2012 – All rights reserved
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International
Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices and
by Technical Committee CEN/TC 206, Biological evaluation of medical devices in collaboration.
This third edition cancels and replaces the second edition (EN ISO 10993:2003), which has been technically
revised.
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 procedure
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
© ISO 2012 – All rights reserved 5
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
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]
6 © ISO 2012 – All rights reserved
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
Introduction
The basis for biological evaluation of medical devices is often empirical and driven by the relevant concerns for
human safety. The risk of serious and irreversible effects, such as cancer or second generation abnormalities,
is of particular public concern. It is inherent in the provision of safe medical devices that such risks be
minimised to the greatest extent feasible. The assessment of mutagenic, carcinogenic and reproductive
hazards is an essential component of the control of these risks. Not all test methods for the assessment of
genotoxicity, carcinogenicity or reproductive toxicity are equally well developed, nor is their validity well
established for the testing of medical devices.
Significant issues with test sample size and preparation, scientific understanding of disease processes and test
validation can be cited as limitations of available methods. For example, the biological significance of solid
state carcinogenesis is poorly understood. It is expected that ongoing scientific and medical advances will
improve our understanding of and approaches to these important toxicity test methods. At the time this
document was prepared, the test methods proposed were those most acceptable. Scientifically sound
alternatives to the proposed testing may be acceptable insofar as they address relevant matters of safety
assessment.
In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful
assessment of expected human uses and potential interactions of the medical device with various biological
systems. These considerations will be particularly important in such areas as reproductive and developmental
toxicology.
This part of ISO 10993 presents test methods for the detection of specific biological hazards, and strategies for
the selection of tests, where appropriate, that will assist in hazard identification. Testing is not always
necessary or helpful in hazard identification but, where it is appropriate, it is important that maximum test
sensitivity is achieved.
The interpretation of findings and their implications for human health effects are beyond the scope of this part
of ISO 10993. Because of the multitude of possible outcomes and the importance of factors such as extent of
exposure, species differences and mechanical or physical considerations, risk assessment has to be
performed on a case-by-case basis.
© ISO 2012 – All rights reserved 7
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oSIST prEN ISO 10993-3:2013
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oSIST prEN ISO 10993-3:2013
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-3.2
Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive toxicity
1 Scope
This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the
following biological aspects:
genotoxicity,
carcinogenicity and
reproductive and developmental toxicity.
This part of ISO 10993 is applicable when the need to evaluate a medical device for potential genotoxicity,
carcinogenicity, or reproductive toxicity has been established.
NOTE Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following referenced documents are indispensable for the application 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 procedure
ISO 10993-2, Biological evaluation of medical devices – Part 2: Animal welfare requirements
ISO 10993-6, Biological evaluation of medical devices – Part 6: Tests for local effects after implantation
ISO 10993-12, Biological evaluation of medical devices – Part 12: Sample preparation and reference
materials
ISO 10993-18, Biological evaluation of medical devices – Part 18: Chemical characterisation of materials
OECD 414, Prenatal Development Toxicity Study
OECD 415, One-Generation Reproduction Toxicity Study
OECD 416, Two-generation Reproduction Toxicity
OECD 421, Reproduction/Developmental Toxicity Screening Test
OECD 451, Carcinogenicity Studies
OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies
© ISO 2012 – All rights reserved 1
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
OECD 471, Bacterial Reverse Mutation Test
OECD 473, In vitro Mamalian Chromosome Aberration Test
OECD 474, Mammalian Erythrocyte Micronucleus Test
OECD 475, Mammalian Bone Marrow Chromosome Aberration Test
OECD 476, In vitro Mammalian Cell Gene Mutation Test
3 Terms and definitions
For the purposes of this part of ISO 10993, the definitions given in ISO 10993-1, ISO 10993-12 and the
following definitions apply.
3.1
carcinogenicity test
test to determine the carcinogenic potential of medical devices, materials, and/or extracts using multiple
exposures for a major portion of the life span of the test animal
NOTE 1 to entry These tests may be designed to examine simultaneously in a single study both chronic toxicity and
carcinogenicity . When chronic toxicity and carcinogenicity are to be evaluated in a single study, particular care needs to
be taken at the study design stage to ensure the dose groups are appropriate. This helps to prevent or minimise
premature mortality from chronic/cumulative systemic toxicity compromising the statistical evaluation of data derived
from animals surviving to the end of the study period (i.e. normal life-span).
3.2
energy-depositing medical device
device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation,
ionising radiation or ultrasound
NOTE 1 to entry This does not include medical devices that deliver simple electrical current, such as electrocautery
medical devices, pacemakers or functional electrical stimulators.
3.3
genotoxicity test
test using mammalian or non-mammalian cells, bacteria, yeasts, fungi or whole animals to determine
whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by
the test samples
3.4
maximum tolerated dose
MTD
maximum dose that a test animal can tolerate without any adverse effects
3.5
reproductive and developmental toxicity test
test to evaluate the potential effects of test samples on reproductive function, embryonic morphology
(teratogenicity), and prenatal and early postnatal development
3.6
test sample preparation
residual, extractables, leachables or (resorbable) device materials that are resuspended in a vehicle
compatible with the test system
2 © ISO 2012 – All rights reserved
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oSIST prEN ISO 10993-3:2013
ISO/DIS 10993-3.2
4 Requirements for test strategies
4.1 General
ISO 10993-1 indicates circumstances where the potential for genotoxicity, carcinogenicity and reproductive
toxicity is a relevant hazard for consideration in an overall biological safety evaluation. In determining if
genotoxicity, carcinogenicity and reproductive toxicity testing of the device is warranted an assessment of
risk shall address the following factors
the mechanistic basis of the toxic response under consideration, if available,
existing information relevant to the genotoxicity, carcinogenicity and reproductive toxicity evaluation of
the medical device,
the material has a long history of patient use (e.g., patient use is similar in terms of contact location and
duration however the toxicity endpoints should be monitored in the subject population), the final finished
medical device residuals are well characterized and the residuals do not express features that may be
of concern (e.g., structure-activity relationship, or previous demonstration of relevant outcomes),
device’s intended use,
exposure route,
patient population,
extent and duration of localized (at the site of implantation or use) and systemic exposure,
manufacturing process (e.g. cleaning solvents, leachates, monomers, processing aids, release agents),
causes of concerns (e.g. structure-activity relationship, previous demonstration of genotoxicity,
carcinogenicity and reproductivity in the product class),
degradation products or metabolites of the device material,
the anticipated impact of test results (or lack of testing) on risk management judgements,
the medical device does not change the type or increase the amount of residuals that the patient will be
exposed to, either through an increase in device exposure, or an increase in device size when
compared to an equivalent marketed device.
Testing shall be conducted on the final product (including sterilization if applicable), or representatives from
the final products, or materials processed in the same manner as the final product (including sterilization if
applicable). The decision to test, and the nature of the test sample, shall be justified and documented.
Testing may be warranted for additional states of the device such as, wear debris generated from the device
or materials that cure in situ (e.g. cements, adhesives and pre-polymer mi
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-3:2011
01-oktober-2011
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3UHVNXVLJHQVNH
WRNVLþQRVWLNDQFHURJHQRVWLLQWRNVLþQRVWL]DUD]PQRåHYDQMH ,62',6
Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity
and reproductive toxicity (ISO/DIS 10993-3:2011)
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität,
Karzinogenität und Reproduktionstoxizität (ISO/DIS 10993-3:2011)
Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la
génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO/DIS 10993-3:2011)
Ta slovenski standard je istoveten z: prEN ISO 10993-3
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-3:2011 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-3:2011
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oSIST prEN ISO 10993-3:2011
EUROPEAN STANDARD
DRAFT
prEN ISO 10993-3
NORME EUROPÉENNE
EUROPÄISCHE NORM
August 2011
ICS 11.100.20 Will supersede EN ISO 10993-3:2009
English Version
Biological evaluation of medical devices - Part 3: Tests for
genotoxicity, carcinogenicity and reproductive toxicity (ISO/DIS
10993-3:2011)
Évaluation biologique des dispositifs médicaux - Partie 3: Biologische Beurteilung von Medizinprodukten - Teil 3:
Essais concernant la génotoxicité, la cancérogénicité et la Prüfungen auf Gentoxizität, Karzinogenität und
toxicité sur la reproduction (ISO/DIS 10993-3:2011) Reproduktionstoxizität (ISO/DIS 10993-3:2011)
This draft European Standard is submitted to CEN members for parallel enquiry. It has been drawn up by the Technical Committee
CEN/TC 206.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN 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, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are aware and to
provide supporting documentation.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice and
shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2011 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN ISO 10993-3:2011: E
worldwide for CEN national Members.
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oSIST prEN ISO 10993-3:2011
prEN ISO 10993-3:2011 (E)
Contents Page
Foreword .3
2
---------------------- Page: 4 ----------------------
oSIST prEN ISO 10993-3:2011
prEN ISO 10993-3:2011 (E)
Foreword
This document (prEN ISO 10993-3:2011) has been prepared by Technical Committee ISO/TC 194 "Biological
evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206 “Biological evaluation
of medical devices” the secretariat of which is held by NEN.
This document is currently submitted to the parallel Enquiry.
This document will supersede EN ISO 10993-3:2009.
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).
Endorsement notice
The text of ISO/DIS 10993-3:2011 has been approved by CEN as a prEN ISO 10993-3:2011 without any
modification.
3
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oSIST prEN ISO 10993-3:2011
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oSIST prEN ISO 10993-3:2011
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-3
ISO/TC 194 Secretariat: DIN
Voting begins on Voting terminates on
2011-08-04 2012-01-04
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ ORGANISATION INTERNATIONALE DE NORMALISATION
Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive toxicity
Évaluation biologique des dispositifs médicaux —
Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction
[Revision of second edition (ISO 10993-3:2003)]
ICS 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for Standardization (ISO), and
processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member bodies for a parallel
five-month enquiry.
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 formal vote in CEN.
In accordance with the provisions of Council Resolution 15/1993 this document is circulated in
the English language only.
Conformément aux dispositions de la Résolution du Conseil 15/1993, ce document est distribué
en version anglaise seulement.
To expedite distribution, this document is circulated as received from the committee
secretariat. ISO Central Secretariat work of editing and text composition will be undertaken at
publication stage.
Pour accélérer la distribution, le présent document est distribué tel qu'il est parvenu du
secrétariat du comité. Le travail de rédaction et de composition de texte sera effectué au
Secrétariat central de l'ISO au stade de publication.
THIS DOCUMENT IS A DRAFT CIRCULATED FOR COMMENT AND APPROVAL. IT IS THEREFORE SUBJECT TO CHANGE AND MAY NOT BE
REFERRED TO AS AN INTERNATIONAL STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS BEING ACCEPTABLE FOR INDUSTRIAL, TECHNOLOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON OCCASION HAVE TO BE CONSIDERED IN THE LIGHT OF THEIR POTENTIAL TO BECOME
STANDARDS TO WHICH REFERENCE MAY BE MADE IN NATIONAL REGULATIONS.
RECIPIENTS OF THIS DRAFT ARE INVITED TO SUBMIT, WITH THEIR COMMENTS, NOTIFICATION OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPORTING DOCUMENTATION.
© International Organization for Standardization, 2011
---------------------- Page: 7 ----------------------
oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
Copyright notice
This ISO document is a Draft International Standard and is copyright-protected by ISO. Except as permitted
under the applicable laws of the user’s country, neither this ISO draft nor any extract from it may be
reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic,
photocopying, recording or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
ii © ISO 2011 – All rights reserved
---------------------- Page: 8 ----------------------
oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
Contents Page
Foreword .v
Introduction.vii
1 Scope.1
2 Normative references.1
3 Terms and definitions .2
4 Requirements for test strategies .3
4.1 General.3
4.2 Additional requirements for carcinogenicity testing.3
4.3 Additional requirements for reproductive toxicity testing.3
5 Genotoxicity tests.4
5.1 General.4
5.2 Test strategy.4
5.2.1 General.4
5.2.2 In vitro test battery .4
5.2.3 In vivo testing .5
5.2.4 Follow-up evaluation.5
5.3 Sample preparation.7
5.4 Test methods.7
5.4.1 General.7
6 Carcinogenicity tests.7
6.1 General.7
6.2 Evaluation strategy.7
6.3 Sample preparation.8
6.4 Test methods.8
7 Reproductive and developmental toxicity tests.9
7.1 General.9
7.2 Test strategy.9
7.3 Sample preparation.10
7.4 Test methods.10
8 Test report.11
Annex A (informative) Rationale of test systems .12
A.1 Genotoxicity tests.12
A.2 Carcinogenicity tests.13
A.3 Reproductive/developmental toxicity tests .13
Annex B (informative) Cell transformation test systems.14
Annex C (normative) Considerations for carcinogenicity studies performed as implantation
studies .15
C.1 Foreign body carcinogenesis .15
C.2 Animal welfare considerations.15
C.3 Justification for carcinogenicity studies .15
Annex D (normative) Guidance on selecting an appropriate sample preparation procedure in
genotoxicity testing.16
D.1 General.16
D.2 Device materials.17
D.2.1 Low Molecular Weight Chemicals (LMWC).17
D.2.2 Polymers (including naturally occurring polymers) .17
© ISO 2011 – All rights reserved 3
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oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
D.2.3 Inorganic materials: Wear debris from metals, alloys and ceramics.18
D.3 Sample Preparation Methods .18
D.3.1 Method A.19
D.3.2 Method B.20
D.3.3 Method C.22
D.4 Additional guidance on special sample preparation procedures.22
D.4.1 Biodegradable polymers.22
D.4.2 Inorganic materials: Wear debris from metals, alloys and ceramics.22
D.4.3 LMWC.22
Annex E (informative) Tests to evaluate genotoxicity.23
E.1 General.23
E.2 Selection of tests .23
E.3 Recommended tests.23
E.4 Use of in vitro tests to detect genotoxicity .24
E.5 Use of in vivo tests to detect genotoxicity.25
E.6 Bacterial reverse mutation assay.26
E.6.1 General.26
E.6.2 Preparations.26
E.6.3 Test conditions .28
E.6.4 Procedure.30
E.6.5 Data and reporting.31
E.7 In vitro mammalian chromosome aberration test .34
E.7.1 General.34
E.7.2 Preparations.34
E.7.3 Test conditions .35
E.7.4 Procedure.37
E.7.5 Data and reporting.38
E.8 In vitro mammalian cell gene mutation test using mouse lymphoma (L5178Y) cells .40
E.8.1 General.40
E.8.2 Preparations.41
E.8.3 Test conditions .42
E.8.4 Procedure.43
E.8.5 Data and reporting.45
E.9 Mammalian erythrocyte micronucleus test.48
E.9.1 General.48
E.9.2 Preparations.48
E.9.3 Test conditions .49
E.9.4 Procedure.50
E.9.5 Data and reporting.52
E.10 Chromosome aberration test (in vivo).54
E.10.1 General.54
E.10.2 Preparations.55
E.10.3 Test conditions .55
E.10.4 Procedure.56
E.10.5 Data and reporting.58
Annex F (informative) In vitro tests for embryotoxicity.61
Bibliography .62
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oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International
Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices and
by Technical Committee CEN/TC 206, Biological evaluation of medical devices in collaboration.
This third edition cancels and replaces the second edition (EN ISO 10993:2003), which has been technically
revised.
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 procedure
⎯ 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
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oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
⎯ 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]
6 © ISO 2011 – All rights reserved
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oSIST prEN ISO 10993-3:2011
ISO/DIS 10993-3
Introduction
The basis for biological evaluation of medical devices is often empirical and driven by the relevant concerns for
human safety. The risk of serious and irreversible effects, such as cancer or second generation abnormalities,
is of particular public concern. It is inherent in the provision of safe medical devices that such risks be
minimised to the greatest extent feasible. The assessment of mutagenic, carcinogenic and reproductive
hazards is an essential component of the control of these risks. Not all test methods for the assessment of
genotoxicity, carcinogenicity or reproductive toxicity are equally well developed, nor is their validity well
established for the testing of medical devices.
Significant issues with test sample size and preparation, scientific understanding of disease processes and test
validation can be cited as limitations of available methods. For example, the biological significance of solid
state carcinogenesis is poorly understood. It is expected that ongoing scientific and medical advances will
improve our understanding of and approaches to these important toxicity test methods. At the time this
document was prepared, the test methods proposed were those most acceptable. Scientifically sound
alternatives to the proposed testing may be acceptable insofar as they address relevant matters of safety
assessment.
In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful
assessment of expected human uses and potential interactions of the medical device with various biological
systems. These considerations will be particularly important in such areas as reproductive and developmental
toxicology.
This part of ISO 10993 presents test methods for the detection of specific biological hazards, and strategies for
the selection of tests, where appropriate, that will assist in hazard identification. Testing is not always
necessary or helpful in hazard identification but, where it is appropriate, it is important that maximum test
sensitivity is achieved.
The interpretation of findings and their implications for human health effects are beyond the scope of this part
of ISO 10993. Because of the multitude of possible outcomes and the importance of factors such as extent of
exposure, species differences and mechanical or physical considerations, risk assessment has to be
performed on a case-by-case basis.
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oSIST prEN ISO 10993-3:2011
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oSIST prEN ISO 10993-3:2011
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-3
Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive toxicity
1 Scope
This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the
following biological aspects:
⎯ genotoxicity,
⎯ carcinogenicity and
⎯ reproductive and developmental toxicity.
This part of ISO 10993 is applicable when the need to evaluate a medical device for potential genotoxicity,
carcinogenicity, or reproductive toxicity has been established.
NOTE Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following referenced documents are indispensable for the application 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 procedure
ISO 10993-2, Biological evaluation of medical devices – Part 2: Animal welfare requirements
ISO 10993-6, Biological evaluation of medical devices – Part 6: Tests for local effects after implantation
ISO 10993-12, Biological evaluation
...
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