SIST EN ISO 10993-23:2021
(Main)Biological evaluation of medical devices - Part 23: Tests for irritation (ISO 10993-23:2021)
Biological evaluation of medical devices - Part 23: Tests for irritation (ISO 10993-23:2021)
This document specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation by using an in vitro reconstructed human epidermis model.
Biologische Beurteilung von Medizinprodukten - Teil 23: Prüfungen auf Irritation (ISO 10993-23:2021)
Dieses Dokument legt das Verfahren für die Bewertung von Medizinprodukten und ihren Bestandteilen hinsichtlich ihres Potentials, eine Irritation hervorzurufen, fest. Die Prüfungen wurden so entwickelt, dass das Irritationspotential von Medizinprodukten, ihren Werkstoffen oder Extrakten nach ISO 10993 1 und ISO 10993 2 vorhergesagt und klassifiziert werden kann.
Dieses Dokument beinhaltet:
— vor der Prüfung durchzuführende Überlegungen hinsichtlich einer Irritation, einschließlich In silico und In vitro-Verfahren zur dermalen Exposition;
— Einzelheiten zur Durchführung von In vitro und In vivo-Irritationsprüfungen;
— Schlüsselfaktoren für die Interpretation der Ergebnisse.
Évaluation biologique des dispositifs médicaux - Partie 23: Essais d'irritation (ISO 10993-23:2021)
Le présent document spécifie le mode opératoire pour l'évaluation du potentiel des dispositifs médicaux et de leurs matériaux constitutifs à provoquer une irritation. Les essais sont conçus pour prédire et classer le potentiel d'irritation des dispositifs médicaux, des matériaux ou de leurs extraits conformément à l'ISO 10993‑1 et à l'ISO 10993‑2.
Le présent document comprend :
— les considérations préalables à la réalisation des essais d'irritation, y compris des méthodes in silico et in vitro d'exposition cutanée ;
— les informations détaillées relatives aux modes opératoires d'essai d'irritation in vitro et in vivo ;
— les facteurs clés pour l'interprétation des résultats.
Biološko ovrednotenje medicinskih pripomočkov - 23. del: Preskusi draženja (ISO 10993-23:2021)
General Information
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-23:2021
01-julij-2021
Biološko ovrednotenje medicinskih pripomočkov - 23. del: Preskusi draženja (ISO
10993-23:2021)
Biological evaluation of medical devices - Part 23: Tests for irritation (ISO 10993-
23:2021)
Biologische Beurteilung von Medizinprodukten - Teil 23: Prüfungen auf Irritation (ISO
10993-23:2021)
Évaluation biologique des dispositifs médicaux - Partie 23: Essais d'irritation (ISO 10993-
23:2021)
Ta slovenski standard je istoveten z: EN ISO 10993-23:2021
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
SIST EN ISO 10993-23:2021 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-23:2021
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SIST EN ISO 10993-23:2021
EN ISO 10993-23
EUROPEAN STANDARD
NORME EUROPÉENNE
March 2021
EUROPÄISCHE NORM
ICS 11.100.20
English Version
Biological evaluation of medical devices - Part 23: Tests for
irritation (ISO 10993-23:2021)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
23: Essais d'irritation (ISO 10993-23:2021, Version 23: Prüfungen auf Irritation (ISO 10993-23:2021)
corrigée inclus 2021-02)
This European Standard was approved by CEN on 1 October 2020.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2021 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-23:2021 E
worldwide for CEN national Members.
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 5
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 7
Annex ZC (informative) Relationship between this European standard and the General
Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered. 9
2
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
European foreword
This document (EN ISO 10993-23:2021) 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 September 2021, and conflicting national standards
shall be withdrawn at the latest by September 2021.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directive(s).
For the relationship with EU Directive(s) see informative Annex ZA, ZB and ZC, which are integral parts
of this document.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
3
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
Table — Correlations between undated normative references and dated EN and ISO standards
Equivalent dated standard
Normative references as listed in
Clause 2 of the ISO standard
EN ISO or IEC
a
ISO 10993-1 EN ISO 10993-1:2021 ISO 10993-1:2018
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
a
ISO 10993-9 EN ISO 10993-9:2021 ISO 10993-9:2019
a
ISO 10993-12 EN ISO 10993-12:2021 ISO 10993-12:2020
ISO 10993-13 EN ISO 10993-13:2010 ISO 10993-13:2010
ISO 10993-14 EN ISO 10993-14:2001 ISO 10993-14:2009
a
ISO 10993-15 EN ISO 10993-15:2021 ISO 10993-15:2019
a
ISO 10993-18 EN ISO 10993-18:2021 ISO 10993-18:2020
ISO 14155 EN ISO 14155:2020 ISO 14155:2020
a
Under preparation at European level.
NOTE 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 14971:2012.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the
United Kingdom.
Endorsement notice
The text of ISO 10993-23:2021 has been approved by CEN as EN ISO 10993-23:2021 without any
modification.
4
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/sub-clause(s) of
Remarks/Notes
Directive 93/42/EEC this EN
ER 7.1 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture. However, this standard
provides a means to assess potential
4, 5, 6, 7, 8 and Annex A, D
irritancy induced by chemical and/or
7.1 (First and second indent)
and E
physical properties of substances used
in the manufacture of medical devices.
Other forms of toxicity and
flammability are not covered.
ER 7.2 is only partly covered by this
standard, since the standard does not
provide requirements on design,
4, 5, 6, 7, 8 and Annex A, D
7.2
manufacture and packaging and does
and E
not oblige to minimize risk. However,
this standard provides a means to
assess irritancy to contaminants and
5
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
residues in medical devices.
ER 7.5 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture. However, this standard
provides a means to assess irritancy to
4, 5, 6, 7, 8 and Annex A, D
substances leaking from medical
7.5 (First paragraph)
and E
devices. This evaluation can be a
preliminary step for risk minimization.
Other forms of toxicity are not dealt
with in this standard.
General Note: Presumption of conformity depends on also complying with the relevant parts of the ISO 10993
series.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
6
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active
implantable medical devices [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 90/385/EEC this EN
ER 9 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture.
However, this standard provides a
4, 5, 6, 7, 8 and Annex A, D
9 (only first and second indent) means to assess potential irritancy
and E
induced by chemical and/or physical
properties of substances used in the
manufacture of medical devices.
Other forms of toxicity and
flammability are not covered.
General Note: Presumption of conformity depends on also complying with the relevant parts of the ISO 10993
series.
7
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
8
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
Annex ZC
(informative)
Relationship between this European standard and the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered
This European standard has been prepared under a Commission’s standardisation request 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].
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 ZC.1 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.
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 This Annex ZC is based on normative references according to the table of references in the European
Foreword, replacing the references in the core text.
NOTE 4 When a General Safety and Performance Requirement does not appear in Table ZC.1, it means that it is
not addressed by this European Standard.
Table ZC.1 — Correspondence between this European Standard and
Annex I of Regulation (EU) 2017/745 [OJ L 117]
General Safety and Performance
Clause(s)/sub-clause(s) of
Requirements of Regulation Remarks/Notes
this EN
(EU) 2017/745
10.1 is only partly covered by EN ISO
10993-23, since the standard does not
provide requirements on design and
manufacture. However, this standard
provides a means to assess potential
irritancy induced by chemical and/or
10.1 a), b), g) and h) 4, 5, 6, 7, 8 and Annex A, D and E
physical properties of substances used
in the manufacture of medical devices.
Other forms of toxicity and flammability
(10.1 a) and b) are not covered.
9
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SIST EN ISO 10993-23:2021
EN ISO 10993-23:2021 (E)
10.2 is only partly covered by this
standard, since the standard does not
provide requirements on design,
manufacture and packaging and does
10.2 4, 5, 6, 7, 8 and Annex A, D and E
not oblige to minimize risk. However,
this standard provides a means to
assess irritancy to contaminants and
residues in medical devices.
10.4.1 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture. However, this standard
provides a means to assess irritancy to
10.4.1 (First paragraph, first
substances leaking from medical
4, 5, 6, 7, 8 and Annex A, D and E
sentence)
devices. This evaluation can be a
preliminary step for risk minimization.
Other forms of toxicity are not dealt
with in this standard.
General Note: Presumption of conformity depends on also complying with the relevant parts of the ISO 10993
series.
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.
10
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SIST EN ISO 10993-23:2021
INTERNATIONAL ISO
STANDARD 10993-23
First edition
2021-01
Biological evaluation of medical
devices —
Part 23:
Tests for irritation
Évaluation biologique des dispositifs médicaux —
Partie 23: Essais d'irritation
Reference number
ISO 10993-23:2021(E)
©
ISO 2021
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SIST EN ISO 10993-23:2021
ISO 10993-23:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
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SIST EN ISO 10993-23:2021
ISO 10993-23:2021(E)
Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General principles — Step-wise approach . 3
5 Pre-test considerations . 4
5.1 General . 4
5.2 Types of material. 5
5.2.1 Initial considerations . 5
5.2.2 Ceramics, metals and alloys . 5
5.2.3 Polymers . 5
5.2.4 Biologically derived materials . 5
5.3 Information on chemical composition . 5
5.3.1 General. 5
5.3.2 Existing data sources . 5
6 In vitro irritation tests . 6
6.1 General . 6
6.2 In vitro reconstructed human epidermis model . 6
6.2.1 Test system — Reconstructed human epidermis model . 6
6.2.2 Principle of the method . 6
6.2.3 Prediction model. 7
6.3 Materials . 8
6.3.1 Reconstructed human epidermis models — Product description . 8
6.3.2 Preparation of medical device extracts . 8
6.4 Methods . 9
6.4.1 General. 9
6.4.2 Test procedure . 9
6.4.3 Media and end point solutions .10
6.4.4 Test sample and control preparation .10
6.5 Considerations for test performance .11
6.5.1 Receipt of the reconstructed human epidermis tissues.11
6.5.2 Preparation and pre-incubation .11
6.6 Application of the test sample and rinsing .11
6.6.1 General.11
6.6.2 Preparation .12
6.6.3 Test extract and controls exposure .12
6.7 MTT test for determination of RhE tissue viability after the exposure period .13
6.7.1 MTT incubation and Isopropanol extraction .13
6.7.2 Absorbance measurements .13
6.8 Test acceptance criteria .14
6.9 Data calculation steps .14
6.9.1 General.14
6.9.2 Isopropanol background control for OD in RhE assay .14
6.9.3 Negative DPBS or PBS treated controls .14
6.9.4 Positive control . .14
6.9.5 Tested extract and VC samples (TTs) .15
6.10 Data interpretation — Prediction model .15
6.11 Method documentation sheet .15
6.12 Test report .16
7 In vivo irritation tests .16
7.1 General .16
© ISO 2021 – All rights reserved iii
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SIST EN ISO 10993-23:2021
ISO 10993-23:2021(E)
7.2 Animal irritation test by skin exposure .17
7.2.1 Principle .
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-23:2019
01-julij-2019
Biološko ovrednotenje medicinskih pripomočkov - 23. del: Preskusi draženja
(ISO/DIS 10993-23:2019)
Biological evaluation of medical devices - Part 23: Tests for irritation (ISO/DIS 10993-
23:2019)
Biologische Beurteilung von Medizinprodukten - Teil 23: Prüfungen auf Irritation
(ISO/DIS 10993-23:2019)
Évaluation biologique des dispositifs médicaux - Partie 23: Essais d'irritation (ISO/DIS
10993-23:2019)
Ta slovenski standard je istoveten z: prEN ISO 10993-23
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
oSIST prEN ISO 10993-23:2019 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-23:2019
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oSIST prEN ISO 10993-23:2019
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-23
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2019-05-08 2019-07-31
Biological evaluation of medical devices —
Part 23:
Tests for irritation
ICS: 11.100.20
THIS DOCUMENT IS A DRAFT CIRCULATED
This document is circulated as received from the committee secretariat.
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
ISO/CEN PARALLEL PROCESSING
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
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-23:2019(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2019
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oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(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
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2019 – All rights reserved
---------------------- Page: 4 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)
Contents Page
Foreword .v
Introduction .vii
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General principles — Step-wise approach . 3
5 Pretest considerations . 4
5.1 General . 4
5.2 Types of material. 4
5.2.1 Initial considerations . 4
5.2.2 Ceramics, metals and alloys . 5
5.2.3 Polymers . 5
5.2.4 Biologically derived materials . 5
5.3 Information on chemical composition . 5
5.3.1 General. 5
5.3.2 Existing data sources . 5
6 In vitro irritation tests . 6
6.1 General . 6
6.2 In vitro reconstructed human epidermis (RhE) model. . 6
6.2.1 Test system — Reconstructed human epidermis (RhE) model . 6
6.2.2 Principle of the method . 6
6.2.3 Prediction Model (PM) . 7
6.3 Materials . 8
6.3.1 Reconstructed human epidermis (RhE) models — Product Description . 8
6.3.2 Preparation of medical device extracts . 8
6.4 Methods . 9
6.4.1 Test procedure . 9
6.4.2 Media and end point solutions .10
6.4.3 Test sample and control preparation .10
6.5 Considerations for test performance .11
6.5.1 Receipt of the RhE tissues .11
6.6 Application of the Test Sample and Rinsing .11
6.6.1 General.11
6.6.2 Preparation .11
6.6.3 Test extract and controls exposure .12
6.7 MTT test for determination of RhE tissue viability after the exposure period .12
6.7.1 MTT measurement .12
6.7.2 Absorbance measurements .13
6.8 Test acceptance criteria .13
6.9 Data calculation steps .14
6.10 Data interpretation – Prediction model .14
6.11 Quality assurance and archiving .15
6.12 Method documentation sheet (MDS) . .15
6.13 Test report .15
7 In vivo irritation tests .16
7.1 General .16
7.2 Animal irritation test by skin exposure .16
7.2.1 Principle .16
7.2.2 Test materials .16
7.2.3 Animals and husbandry .17
7.2.4 Test procedure .17
7.2.5 Observation of animals . .19
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7.2.6 Evaluation of results .19
7.2.7 Test report .20
7.3 Animal irritation test by intracutaneous (intradermal) administration.21
7.3.1 Introduction .21
7.3.2 Exclusion from test .21
7.3.3 Test sample .21
7.3.4 Animals and husbandry .21
7.3.5 Test procedure .21
7.3.6 Observation of animals . .22
7.3.7 Evaluation of results .23
7.3.8 Test report .23
8 Human skin irritation test .24
8.1 Introduction .24
8.2 Initial considerations .24
Annex A (normative) Preparation of materials for irritation testing .25
Annex B (informative) Test method check list for in vitro irritation testing using
reconstructed human epidermis (RhE) models .27
Annex C (informative) Example of method documentation sheet (MDS) for reconstructed
human epidermis (RhE) models .29
Annex D (normative) Special irritation tests .35
Annex E (normative) Human skin irritation test .50
Annex F (informative) Background information on irritation tests .54
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered .56
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered .58
Annex ZC (informative) Relationship between this European standard and the General
Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered . .60
Bibliography .62
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation 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.
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.
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European Foreword
The following referenced documents are indispensable for the application of this document. For undated
references, the latest edition of the referenced document (including any amendments) applies. For dated
references, only the edition cited applies. However, for any use of this standard ‘within the meaning of
Annex ZA’, the user should always check that any referenced document has not been superseded and
that its relevant contents can still be considered the generally acknowledged state-of-art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
Table — Correlations between undated normative references and dated EN and ISO standards
Equivalent dated standard
Normative references as listed in
Clause 2 of the ISO standard
EN ISO or IEC
ISO 10993-1 EN ISO 10993-1:2019 ISO 10993-1:2018
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
a a
ISO 10993-9 EN ISO 10993-9:2019 ISO 10993-9:2019
ISO 10993-12 EN ISO 10993-12:2012 ISO 10993-12:2012
ISO 10993-13 EN ISO 10993-13:2010 ISO 10993-13:2010
ISO 10993-14 EN ISO 10993-14:2001 ISO 10993-14:2009
a a
ISO 10993-15 EN ISO 10993-15:2019 ISO 10993-15:2019
a a
ISO 10993-18 EN ISO 10993-18:2019 ISO 10993-18:2019
a a
ISO 14155 EN ISO 14155:2019 ISO 14155:2019
a
Under preparation. Documents are at final stage and have to be submitted to ISO/CS for FDIS vote.
NOTE 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 14971:2012.
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Introduction
This document assesses possible contact hazards from medical devices, which can produce skin,
mucosal, and eye irritation.
Some materials that are included in medical devices have been tested, and their skin or mucosal
irritation potential has been demonstrated. Other materials and their chemical components have not
been tested and can induce adverse effects when in contact with human tissue. The manufacturer is
thus obliged to evaluate each device for potential adverse effects prior to marketing.
Traditionally, tests in small animals have been performed prior to testing on humans to help predict
human responses. More recently, in vitro tests as well as human tests have been added as adjuncts
or alternatives. For skin irritation testing of neat chemicals in vitro tests were developed using
[32]
reconstructed human epidermis (RhE) models . The method was adapted for detection of irritant
chemicals in medical device extracts. The results of a large round robin study showed that some RhE
models can also be used to detect the presence of irritant chemicals extracted from polymeric materials
[5]
(polyvinylchloride (PVC) and silicone) commonly used in the manufacture of medical devices .
Irritation responses at other locations/tissues are generally not predicted by this RhE model though
other in vitro models are available (e.g. mucosal or eye epithelial models) that might be used if qualified
for use with medical devices.
It is intended that these studies be conducted using Good Laboratory Practice, or an equivalent
quality system, that complies with regulations related to animal welfare. Statistical analysis of data is
recommended and can be used whenever appropriate.
This document is intended for use by professionals, appropriately qualified by training and experience,
who are able to interpret its requirements and judge the outcomes of the evaluation for each medical
device, taking into consideration all the factors relevant to the device, its intended use and the current
knowledge of the medical device provided by review of the scientific literature and previous clinical
experience.
The tests included in this document are important tools for the development of safe products, provided
that they are executed and interpreted by trained personnel.
This document is based on numerous standards and guidelines, including OECD Test Guidelines (TG),
U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for
the selection and conduct of tests enabling evaluation of irritation responses relevant to the safety of
medical materials and devices.
The irritation potential of a medical device or its components can be predicted either by an in vivo
animal irritation test or by an in vitro irritation test using a reconstructed human epidermis (RhE)
as a model. ISO 10993-2 describes animal welfare aspects for performing animal studies for the
biological evaluation of medical devices thereby also emphasizing the 3R’s for replacement, reduction,
and refinement of animal studies. This document describes tests to determine the irritancy of medical
devices, materials or their extracts either by in vitro or in vivo tests. In vitro tests have preference over
in vivo tests when appropriately validated and providing equally relevant information to that obtained
from in vivo tests (ISO 10993-1, ISO 10993-2). A stepwise approach would be to start irritant testing
with the in vitro RhE model. When indicated either for confirmation or further categorization of the
irritant activity in vivo animal tests, followed by human irritant tests might be considered.
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DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-23:2019(E)
Biological evaluation of medical devices —
Part 23:
Tests for irritation
1 Scope
This document specifies the procedure for the assessment of medical devices and their constituent
materials with regard to their potential to produce irritation. The tests are designed to predict and
classify the irritation potential of medical devices, materials or their extracts according to ISO 10993-1
and ISO 10993-12.
This document includes:
— pre-test considerations for irritation, including in silico and in vitro methods for dermal exposure;
— details of in vitro and in vivo irritation test procedures;
— key factors for the interpretation of the results.
Instructions are given in Annex A for the preparation of materials specifically in relation to the above
tests. In Annex D several special in vivo irritation tests are described for application of medical devices
in areas other than skin. In addition, Annex E provides information for conducting human skin irritation
testing.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
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
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 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
degradation products from metals and alloys
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice
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3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http: //www .electropedia .org/
— ISO Online browsing platform: available at http: //www .iso .org/obp
3.1
blank test solution
blank
solution prepared in the same way as the sample measuring solution but so that it does not contain the
analyte to be determined
[SOURCE: ISO 10136-1:1993, 3.8]
3.2
dose
dosage
amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area
Note 1 to entry: The terms are often used interchangeably (more commonly dosage).
3.3
erythema
reddening of the skin or mucous membrane
3.4
eschar
scab or discoloured slough of skin
3.5
extract
liquid or suspension that results from exposing a test or control material to an extraction vehicle under
controlled conditions
3.6
irritant
agent that produces irritation
3.7
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a
substance/material
Note 1 to entry: Skin irritation is a reversible reaction and is mainly characterized by local erythema (redness)
and swelling of the skin.
3.8
necrosis
cell death as a direct result of irreversible changes caused by injury or disease
Note 1 to entry: One should be aware that tissue repair will occur either resulting in complete functional
restoration or resulting in scar formation.
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