Biological evaluation of medical devices - Part 6: Tests for local effects after implantation (ISO 10993-6:2016)

ISO 10993-6:2016 specifies test methods for the assessment of the local effects after implantation of biomaterials intended for use in medical devices.
ISO 10993-6:2016 applies to materials that are
- solid and non-absorbable,
- non-solid, such as porous materials, liquids, gels, pastes, and particulates, and
- degradable and/or absorbable, which may be solid or non-solid.
The test sample is implanted into a site and animal species appropriate for the evaluation of the biological safety of the material. These implantation tests are not intended to evaluate or determine the performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 can also be applied to medical devices that are intended to be used topically in clinical indications where the surface or lining might have been breached, in order to evaluate local tissue responses.
The local effects are evaluated by a comparison of the tissue response caused by a test sample to that caused by control materials used in medical devices whose clinical acceptability and biocompatibility characteristics have been established. The objective of the test methods is to characterize the history and evolution of the tissue response after implantation of a medical device/biomaterial including final integration or absorption/degradation of the material. In particular for degradable/absorbable materials, the degradation characteristics of the material and the resulting tissue response should be determined.
ISO 10993-6:2016 does not deal with systemic toxicity, carcinogenicity, teratogenicity or mutagenicity. However, the long-term implantation studies intended for evaluation of local biological effects might provide insight into some of these properties. Systemic toxicity studies conducted by implantation might satisfy the requirements of this part of ISO 10993. When conducting combined studies for evaluating local effects and systemic effects, the requirements of both standards is to be fulfilled.

Biologische Beurteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach Implantationen (ISO 10993-6:2016)

Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets locaux après implantation (ISO 10993-6:2016)

ISO 10993-6:2016 spécifie les méthodes d'essai pour l'évaluation des effets locaux après une implantation de biomatériaux destinés à être utilisés dans des dispositifs médicaux.
ISO 10993-6:2016 s'applique aux matériaux qui sont
- solides et non absorbables,
- non solides, comme les matériaux poreux, liquides, en gel, pâteux et particulaires, et
- dégradables et/ou absorbables, qui peuvent être solides ou non solides.
L'échantillon d'essai est implanté dans un site et dans une espèce animale appropriés à l'évaluation de la sécurité biologique du matériau. Ces essais d'implantation ne sont pas destinés à évaluer ou à déterminer les performances de l'échantillon d'essai en matière de charge mécanique ou fonctionnelle. La présente partie de l'ISO 10993 peut également être appliquée à des dispositifs médicaux destinés à une utilisation topique dans des indications cliniques où la surface ou le revêtement pourrait perdre son intégrité, afin d'évaluer les réponses tissulaires locales.
Les effets locaux sont évalués par comparaison de la réponse tissulaire induite par un échantillon d'essai avec celle induite par des matériaux de contrôle utilisés dans des dispositifs médicaux dont les caractéristiques d'acceptabilité clinique et de biocompatibilité ont été établies. L'objectif des méthodes d'essai est de caractériser l'historique et l'évolution de la réponse tissulaire après l'implantation d'un dispositif médical ou biomatériau, y compris l'intégration finale ou l'absorption/dégradation du matériau. Particulièrement pour les matériaux dégradables/absorbables, il convient de déterminer les caractéristiques de dégradation du matériau et la réponse tissulaire résultante.
ISO 10993-6:2016 ne traite pas de la toxicité systémique, de la cancérogénicité, de la tératogénicité ou de la mutagénicité. Les études d'implantation à long terme destinées à l'évaluation des effets biologiques locaux pourraient, cependant, apporter des informations sur certaines de ces propriétés. Des études de toxicité systémique effectuées par implantation pourraient répondre aux exigences de la présente partie de l'ISO 10993. Lors de la réalisation d'études combinées pour l'évaluation des effets locaux et systémiques, les exigences des deux normes appliquées doivent être satisfaites.

Biološko ovrednotenje medicinskih pripomočkov - 6. del: Preskusi, povezani z lokalnimi učinki po implantaciji (ISO 10993-6:2016)

Ta del standarda ISO 10993 določa preskusne metode za oceno lokalnih učinkov po implantaciji biomaterialov, namenjenih za uporabo v medicinskih pripomočkih.
Ta del standarda ISO 10993 se uporablja za materiale, ki:
- so trdni in niso vpojni;
- niso trdni, npr. porozni materiali, tekočine, geli, paste in delci; ter
- so razgradljivi in/ali vpojni, ki so lahko trdni ali netrdni.
Preskusni vzorec je vsajen v mesto in živalsko vrsto, primerno za ovrednotenje
biološke varnosti materiala. Ti implantacijski preskusi niso namenjeni ovrednotenju ali določanju uspešnosti preskusnih vzorcev v smislu mehanske ali funkcionalne obremenitve. Ta del standarda ISO 10993 je mogoče uporabljati tudi za medicinske pripomočke, ki so namenjeni za lokalni nanos pri kliničnih indikacijah, pri katerih je površina ali sluznica morda predrta, za ovrednotenje odzivov lokalnega tkiva.
Lokalni učinki so ovrednoteni s primerjavo odziva tkiva, ki ga povzroči preskusni vzorec, in odziva, ki ga povzroči kontrolni material, ki se uporablja v medicinskih pripomočkih, katerih lastnosti klinične sprejemljivosti in biološke združljivosti so že bile ugotovljene. Namen preskusnih metod je opredelitev zgodovine in razvoja odzivov tkiva po implantaciji medicinskega pripomočka/biomateriala, vključno s končno integracijo ali absorpcijo/degradacijo materiala. Zlasti pri razgradljivih/vpojnih materialih je treba določiti degradacijske značilnosti materiala in posledični odziv tkiva.
Ta del standarda ISO 10993 ne zajema sistemske toksičnosti, kancerogenosti, teratogenosti ali mutagenosti. Kljub temu bi dolgoročne študije o implantaciji, namenjene ovrednotenju lokalnih bioloških učinkov, lahko zagotovile vpogled v nekatere od teh lastnosti. Študije o sistemski toksičnosti, opravljene z implantacijo, morda izpolnjujejo zahteve tega dela standarda ISO 10993. Pri izvajanju kombiniranih študij za ovrednotenje lokalnih in sistemskih učinkov, morajo biti izpolnjene zahteve obeh standardov.

General Information

Status
Published
Publication Date
13-Dec-2016
Current Stage
6060 - Definitive text made available (DAV) - Publishing
Due Date
14-Dec-2016
Completion Date
14-Dec-2016

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SLOVENSKI STANDARD
SIST EN ISO 10993-6:2017
01-februar-2017
1DGRPHãþD
SIST EN ISO 10993-6:2009
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO3UHVNXVLSRYH]DQL]
ORNDOQLPLXþLQNLSRLPSODQWDFLML ,62

Biological evaluation of medical devices - Part 6: Tests for local effects after implantation

(ISO 10993-6:2016)

Biologische Beurteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach

Implantationen (ISO 10993-6:2016)

Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets

locaux après implantation (ISO 10993-6:2016)
Ta slovenski standard je istoveten z: EN ISO 10993-6:2016
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-6:2017 en

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

---------------------- Page: 1 ----------------------
SIST EN ISO 10993-6:2017
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SIST EN ISO 10993-6:2017
EN ISO 10993-6
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2016
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-6:2009
English Version
Biological evaluation of medical devices - Part 6: Tests for
local effects after implantation (ISO 10993-6:2016)

Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil 6:

6: Essais concernant les effets locaux après Prüfungen auf lokale Effekte nach Implantationen (ISO

implantation (ISO 10993-6:2016) 10993-6:2016)
This European Standard was approved by CEN on 4 November 2016.

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

© 2016 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-6:2016 E

worldwide for CEN national Members.
---------------------- Page: 3 ----------------------
SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (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

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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
European foreword

This document (EN ISO 10993-6:2016) 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 June 2017, and conflicting national standards shall be

withdrawn at the latest by June 2017.

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 10993-6:2009.

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 10993-6:2016 has been approved by CEN as EN ISO 10993-6:2016 without any

modification.

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.
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)

Table 1 — Correlations between undated normative references and dated EN and ISO standards

Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
ISO 10993-4 EN ISO 10993-4:2009 ISO 10993-4:2002
ISO 10993-12 EN ISO 10993-12:2012 ISO 10993-12:2012
ISO 10993-16 EN ISO 10993-16:2010 ISO 10993-16:2010

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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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (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.
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)

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
This part of ISO 10993 specifies
test methods for the assessment
4, 5, 6 and Annex A, Annex B,
of the local effects after
7.1 (First and second indent)
Annex C and Annex D
implantation of biomaterials
intended for use in medical
devices.
These implantation tests are not
intended to evaluate or
4, 5, 6 and Annex A, Annex B,
determine the performance of
7.2
Annex C and Annex D
the test sample in terms of
mechanical or functional
loading.
This part of ISO 10993 does not
deal with systemic toxicity,
carcinogenicity, teratogenicity or
mutagenicity. However, the long-
term implantation studies
intended for evaluation of local
biological effects may provide
insight into some of these
properties. Systemic toxicity
studies conducted by
4, 5, 6 and Annex A, Annex B,
implantation may satisfy the
7.5 (First paragraph)
Annex C and Annex D
requirements of this part of
ISO 10993. When conducting
combined studies for evaluating
local effects and systemic effects,
the requirements of this part of
ISO 10993 and ISO 10993-11
shall be fulfilled.
For ER 7.1 (first and second
indent), flammability is not
covered

General Note: Presumption of conformity depends on also complying with all relevant

clauses/subclauses of ISO 10993-1.

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.
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (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.
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)

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) Remarks/Notes
Directive 90/385/EEC of this EN
This part of ISO 10993 specifies
test methods for the assessment of
the local effects after implantation
of biomaterials intended for use in
medical devices.
These implantation tests are not
intended to evaluate or determine
the performance of the test sample
in terms of mechanical or
functional loading.
This part of ISO 10993 does not
deal with systemic toxicity,
4, 5, 6 and Annex A,
carcinogenicity, teratogenicity or
9 (only first and second
Annex B, Annex C and
mutagenicity. However, the long-
indent)
Annex D
term implantation studies intended
for evaluation of local biological
effects may provide insight into
some of these properties. Systemic
toxicity studies conducted by
implantation may satisfy the
requirements of this part of
ISO 10993. When conducting
combined studies for evaluating
local effects and systemic effects,
the requirements of this part of
ISO 10993 and ISO 10993-11 shall
be fulfilled.

General Note: Presumption of conformity depends on also complying with all relevant

clauses/subclauses of ISO 10993-1.

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.
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SIST EN ISO 10993-6:2017
INTERNATIONAL ISO
STANDARD 10993-6
Third edition
2016-12-01
Biological evaluation of medical
devices —
Part 6:
Tests for local effects after
implantation
Évaluation biologique des dispositifs médicaux —
Partie 6: Essais concernant les effets locaux après implantation
Reference number
ISO 10993-6:2016(E)
ISO 2016
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2016, Published in Switzerland

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
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2016 – All rights reserved
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 2

4 Common provisions for implantation test methods ....................................................................................................... 2

5 Test methods, general aspects................................................................................................................................................................ 4

6 Test report ................................................................................................................................................................................................................... 9

6.1 General ........................................................................................................................................................................................................... 9

6.2 Test laboratory ........................................................................................................................................................................................ 9

6.3 Implant samples .................................................................................................................................................................................... 9

6.4 Animals and implantation ............................................................................................................................................................. 9

6.5 Retrieval and histological procedure ................................................................................................................................10

6.6 Macroscopic and microscopic evaluation .....................................................................................................................10

6.7 Final evaluation ...................................................................................................................................................................................10

Annex A (normative) Test methods for implantation in subcutaneous tissue ......................................................11

Annex B (normative) Test method for implantation in muscle .............................................................................................13

Annex C (normative) Test method for implantation in bone ...................................................................................................15

Annex D (normative) Test method for implantation in brain tissue ................................................................................18

Annex E (informative) Examples of evaluation of local biological effects after implantation ...............23

Bibliography .............................................................................................................................................................................................................................27

© ISO 2016 – All rights reserved iii
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
Foreword

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

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

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

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

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

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

electrotechnical standardization.

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

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

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

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

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

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

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

on the ISO list of patent declarations received (see www.iso.org/patents).

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

constitute an endorsement.

For an explanation on the meaning of ISO specific terms and expressions related to conformity

assessment, as well as information about ISO’s adherence to the WTO principles in the Technical

Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information

The committee responsible for this document is ISO/TC 194, Biological and clinical evaluation of medical

devices.

This third edition cancels and replaces the second edition (ISO 10993-6:2007), which has been

technically revised with the following changes:
a) addition of guidance on biological evaluation of absorbable medical devices;
b) new Annex D.

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 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
— 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

iv © ISO 2016 – All rights reserved
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)

— 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]

— Part 33: Guidance on tests to evaluate genotoxicity — Supplement to ISO 10993-3 [Technical Report]

The following parts are under preparation:
— Part 5: Tests for in vitro cytotoxicity
© ISO 2016 – All rights reserved v
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SIST EN ISO 10993-6:2017
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SIST EN ISO 10993-6:2017
INTERNATIONAL STANDARD ISO 10993-6:2016(E)
Biological evaluation of medical devices —
Part 6:
Tests for local effects after implantation
1 Scope

This part of ISO 10993 specifies test methods for the assessment of the local effects after implantation

of biomaterials intended for use in medical devices.
This part of ISO 10993 applies to materials that are
— solid and non-absorbable,

— non-solid, such as porous materials, liquids, gels, pastes, and particulates, and

— degradable and/or absorbable, which may be solid or non-solid.

The test sample is implanted into a site and animal species appropriate for the evaluation of the

biological safety of the material. These implantation tests are not intended to evaluate or determine the

performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 can

also be applied to medical devices that are intended to be used topically in clinical indications where

the surface or lining might have been breached, in order to evaluate local tissue responses.

The local effects are evaluated by a comparison of the tissue response caused by a test sample to that

caused by control materials used in medical devices whose clinical acceptability and biocompatibility

characteristics have been established. The objective of the test methods is to characterize the history

and evolution of the tissue response after implantation of a medical device/biomaterial including

final integration or absorption/degradation of the material. In particular for degradable/absorbable

materials, the degradation characteristics of the material and the resulting tissue response should be

determined.

This part of ISO 10993 does not deal with systemic toxicity, carcinogenicity, teratogenicity or

mutagenicity. However, the long-term implantation studies intended for evaluation of local biological

effects might provide insight into some of these properties. Systemic toxicity studies conducted by

implantation might satisfy the requirements of this part of ISO 10993. When conducting combined

studies for evaluating local effects and systemic effects, the requirements of both standards is to be

fulfilled.
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 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood

ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference

materials
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ISO 10993-6:2016(E)

ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for

degradation products and leachables
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-2,

ISO 10993-12, ISO 10993-16 and the following apply.
3.1
absorb/absorption

action of a non-endogenous (foreign) material or substance, or its decomposition products passing

through or being assimilated by cells and/or tissue over time
3.2
degradation
decomposition of a material
[SOURCE: ISO 10993-9:2009, 3.1]
3.3
degradation product

any intermediate or final by-product which results from the physical, metabolic, and/or chemical

decomposition of a material or substance
[SOURCE: ISO/TR 37137:2014, 2.2, modified]
3.4
degrade

to physically, metabolically, and/or chemically decompose a material or substance

[SOURCE: ISO/TR 37137:2014, 2.3]
3.5
biomaterial

material or substance intended to interface with biological systems to evaluate, treat, augment or

replace any tissue, organ or function of the body.
[SOURCE: European Society Biomaterials Conference II]
4 Common provisions for implantation test methods
4.1 General

It is important that the study be planned in sufficient detail such that all relevant information can be

extracted from the use of each animal and each study (see ISO 10993-2, ISO 10993-11 and ISO 10993-16).

All animal studies shall be performed in a facility approved by a nationally recognized organization and

in accordance with all appropriate regulations dealing with laboratory animal welfare to comply with

the requirements of ISO 10993-2. These studies shall be performed under good laboratory practices or

other recognized, quality assurance systems.

The provisions of this Clause shall apply to the test methods specified in Annex A, Annex B, Annex C,

and Annex D.
4.2 Preparation of samples for implantation

4.2.1 Test sample and reference or control material preparation shall be in accordance with ISO 10993-

12. The implant size and shape shall be documented and justified. Test samples for various implant sites

are described in Annex A, Annex B, Annex C, and Annex D. Physical characteristics (such as form, density,

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SIST EN ISO 10993-6:2017
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hardness, surface) can influence the character of the tissue response to the test material and shall be

recorded and taken into account when the response is characterized. Control articles should be matched

as closely as reasonably possible for physical characteristics.
4.2.2 Each im
...

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