National foreword

This British Standard is the UK implementation of EN ISO 10993‑23:2021. It is identical to ISO 10993‑23:2021.

The UK participation in its preparation was entrusted to Technical Committee CH/194, Biological evaluation of medical devices.

A list of organizations represented on this committee can be obtained on request to its committee manager.

Contractual and legal considerations

This publication has been prepared in good faith, however no representation, warranty, assurance or undertaking (express or implied) is or will be made, and no responsibility or liability is or will be accepted by BSI in relation to the adequacy, accuracy, completeness or reasonableness of this publication. All and any such responsibility and liability is expressly disclaimed to the full extent permitted by the law.

This publication is provided as is, and is to be used at the recipient’s own risk.

The recipient is advised to consider seeking professional guidance with respect to its use of this publication.

This publication is not intended to constitute a contract. Users are responsible for its correct application.

This publication has been prepared under a mandate given to the European Standards Organizations by the European Commission and the European Free Trade Association and is intended to support essential requirements of the EU legislation detailed in the European foreword. Annex ZA/ZZ describes how the publication relates to the legislation.

For the Great Britain market (England, Scotland and Wales), if the UK Government has designated this publication for conformity with UKCA marking legislation and has not amended the essential requirements of that legislation, Annex ZA/ZZ and any references to EU law in the publication should be read in accordance with the designation as applying to UK legislation in the same way as to EU law. Further information on designated standards can be found at

www.bsigroup.com/standardsandregulation.

For the Northern Ireland market, UK law will continue to implement relevant EU law subject to periodic confirmation. References to EU legislation are therefore still valid.

More information on legislation can be found at www.gov.uk.

Compliance with a British Standard cannot confer immunity from legal obligations

This British Standard was published under the authority of the Standards Policy and Strategy Committee on 30 April 2021.

Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents).

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/TC 206, Biological and clinical evaluation of medical devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

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.

Introduction

This document assesses possible contact hazards from medical devices, which can produce 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.

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 if qualified for use with medical devices.

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 tests 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 (see ISO 10993‑1 and ISO 10993‑2).

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 reconstructed human epidermis (RhE) models^[³¹^]. The method was adapted for detection of irritant chemicals in medical device extracts. The results of a large round robin study that tested two types of RhE models showed that these models can also be used to detect the presence of irritant chemicals extracted from polymeric materials [polyvinylchloride (PVC) and silicone] commonly used in the manufacture of medical devices^[⁶^]. This method was found to be equally sensitive in the detection of low concentrations of some strong irritant compounds when compared to the human patch testing and intracutaneous rabbit test^[¹⁴^]. Therefore, a stepwise approach for irritant testing can start with the in vitro RhE model.

The developed and validated RhE models are appropriate to predict skin tissue irritation response. It is recommended to explore the use of other alternative in vitro models to assess the irritation potential for mucosal or eye epithelial applications.

It is intended that, for regulatory submission, these studies be conducted using GLP or ISO/IEC 17025 as applicable to the respective country and comply 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^[⁴⁰^] and the European Pharmacopoeia^[³⁹^]. 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.

Instructions are given in normative Annex A for the preparation of materials specifically in relation to the above tests. In normative Annex D several special in vivo irritation tests are described for application of medical devices in areas other than skin. In addition, normative Annex E provides information for conducting human skin irritation testing.

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 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.

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.

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 10993‑2.

This document includes:

pre-test considerations for irritation, including in silico and in vitro methods for dermal exposure;
details of in vitro and in vivoirritation test procedures;
key factors for the interpretation of the results.

2 Normative references

3 Terms and definitions

4 General principles — Step-wise approach

5 Pre-test considerations

5.1 General

5.2 Types of material

5.3 Information on chemical composition

6 In vitro irritation tests

6.1 General

6.2 In vitro reconstructed human epidermis model

6.3 Materials

6.4 Methods

6.5 Considerations for test performance

6.6 Application of the test sample and rinsing

6.7 MTT test for determination of RhE tissue viability after the exposure period

6.8 Test acceptance criteria

6.9 Data calculation steps

6.10 Data interpretation — Prediction model

6.11 Method documentation sheet

6.12 Test report

7 In vivo irritation tests

7.1 General

7.2 Animal irritation test by skin exposure

7.3 Animal irritation test by intracutaneous (intradermal) administration

8 Human skin irritation test

8.1 Introduction

8.2 Initial considerations

Bibliography

BS EN ISO 10993-23:2021

Biological evaluation of medical devices - Tests for irritation

Current, Under Review

Published:

30 Apr 2021