kSIST FprEN ISO 10993-23:2020

Biological evaluation of medical devices - Part 23: Tests for irritation (ISO/FDIS 10993-23:2020)

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/DIS 10993-23:2019)

Dieses Dokument legt das Verfahren für die Beurteilung 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/DIS 10993-23:2019)

Biološko ovrednotenje medicinskih pripomočkov - 23. del: Preskusi draženja (ISO/FDIS 10993-23:2020)

Standards Content (sample)

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.

---------------------- Page: 1 ----------------------
oSIST prEN ISO 10993-23:2019
---------------------- Page: 2 ----------------------
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
---------------------- Page: 3 ----------------------
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: [phone]
Fax: [phone]
Email: [e-mail]
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

© ISO 2019 – All rights reserved iii
---------------------- Page: 5 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)

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

iv © ISO 2019 – All rights reserved
---------------------- Page: 6 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso.o rg/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.
© ISO 2019 – All rights reserved v
---------------------- Page: 7 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)
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

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.
vi © ISO 2019 – All rights reserved
---------------------- Page: 8 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)
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.

© ISO 2019 – All rights reserved vii
---------------------- Page: 9 ----------------------
oSIST prEN ISO 10993-23:2019
---------------------- Page: 10 ----------------------
oSIST prEN ISO 10993-23:2019
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

© ISO 2019 – All rights reserved 1
---------------------- Page: 11 ----------------------
oSIST prEN ISO 10993-23:2019
ISO/DIS 10993-23:2019(E)
3 Terms a nd definiti ons
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.
2 © ISO 2019 – All rights reserved
---------------------- Page: 12 -
...