oSIST prEN 10993-9:2018

Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products (ISO/DIS 10993-9:2018)

This document provides general principles for the systematic evaluation of the potential and observed degradation of medical devices through the design and performance of in vitro degradation studies. Information obtained from these studies can be used in the biological evaluation described in the ISO 10993 series.
This document is applicable to both materials designed to degrade in the body as well as materials that are not intended to degrade.
This document is not applicable to:
a) the evaluation of degradation which occurs by purely mechanical processes; methodologies for the production of this type of degradation product are described in specific product standards, where available;
NOTE Purely mechanical degradation causes mostly particulate matter. Although this is excluded from the scope of this document, such degradation products can evoke a biological response and can undergo biological evaluation as described in other parts of ISO 10993.
b) leachable components which are not degradation products;
c) medical devices or components that do not contact the patient's body directly or indirectly.

Biologische Beurteilung von Medizinprodukten - Teil 9: Rahmen zur Identifizierung und Quantifizierung von möglichen Abbauprodukten (ISO/DIS 10993-9:2018)

Dieses Dokument beschreibt allgemeine Prinzipien zur systematischen Beurteilung von möglichem und beobachtetem Abbau bei Medizinprodukten durch Planung und Durchführung von In vitro Abbaustudien. Informationen, die aus diesen Studien resultieren, können für die in der Normenreihe ISO 10993 beschriebene biologische Beurteilung verwendet werden.
Dieses Dokument gilt sowohl für Materialien, die dafür vorgesehen sind, vom Körper abgebaut zu werden, als auch für solche, bei denen das nicht vorgesehen ist.
Dieses Dokument gilt nicht für:
a)   die Beurteilung des Abbaus durch rein mechanische Prozesse. Methoden zur Generierung dieser Art von Abbauprodukten sind, falls vorhanden, in den spezifischen Produktnormen beschrieben;
ANMERKUNG   Rein mechanischer Abbau verursacht meist Feinstaub. Obwohl dieser aus dem Anwendungsbereich dieses Dokuments ausgeschlossen ist, können solche Abbauprodukte eine biologische Reaktion hervorrufen und können daher einer biologischen Beurteilung, wie in anderen Teilen der ISO 10993 beschrieben, unterzogen werden.
b)   herauslösbare Komponenten, die keine Abbauprodukte sind;
c)   Medizinprodukte oder deren Komponenten, die weder direkt noch indirekt mit dem Körper des Patienten in Berührung kommen.

Évaluation biologique des dispositifs médicaux - Partie 9: Cadre pour l'identification et la quantification des produits potentiels de dégradation (ISO/DIS 10993-9:2018)

Le présent document donne les principes généraux pour l'évaluation systématique de la dégradation potentielle et observée des dispositifs médicaux, à travers la conception et l'exécution des études de dégradation in vitro. Les informations obtenues dans le cadre de ces études peuvent servir aux évaluations biologiques décrites dans la série de normes ISO 10993.
Le présent document s'applique aux matériaux conçus pour se dégrader dans le corps, ainsi qu'aux matériaux qui ne sont pas conçus pour se dégrader.
Le présent document ne s'applique pas:
a) à l'évaluation de la dégradation qui se produit uniquement suite à des processus mécaniques; les méthodologies de génération de ce type de produit de dégradation sont décrites, le cas échéant, dans les normes des produits considérés;
NOTE La dégradation purement mécanique donne principalement de la matière sous forme de particules. Bien qu'ils n'entrent pas dans le domaine d'application du présent document, de tels produits de dégradation peuvent entraîner une réponse biologique et peuvent être soumis à une évaluation biologique telle que celle décrite dans les autres parties de l' ISO 10993.
b) aux composants relargables qui ne sont pas des produits de dégradation;
c) aux dispositifs médicaux ou composants qui ne sont pas directement ou indirectement en contact avec le corps du patient.

Biološko ovrednotenje medicinskih pripomočkov - 9. del: Okvirni sistem za prepoznavanje in ugotavljanje količine morebitnih razgradnih produktov (ISO/DIS 10993-9:2018)

General Information

• Status: Not Published
• Public Enquiry End Date: 19-Jun-2018
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 4020 - Public enquire (PE) (Adopted Project)
• Start Date: 04-May-2018
• Due Date: 21-Sep-2018
• Completion Date: 27-Jun-2018
• Directive: 2007/47/EC - Directive 2007/47/EC of the European Parliament and of the council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market
• Directive: 90/385/EEC - 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
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/BC/CEN/89/9 - Joint Standardization request to CEN/CENELEC concerning harmonized standards relating to horizontal aspects in the field of medical devices
• Ref Project: FprEN ISO 10993-9 - Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products (ISO/FDIS 10993-9:2019)

RELATIONS

• Revised: SIST EN ISO 10993-9:2010 - Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products (ISO 10993-9:2009)
• Effective Date: 01-Jun-2018

Standards Content (sample)

SLOVENSKI STANDARD
oSIST prEN 10993-9:2018
01-junij-2018
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO2NYLUQLVLVWHP]D
SUHSR]QDYDQMHLQXJRWDYOMDQMHNROLþLQHPRUHELWQLKUD]JUDGQLKSURGXNWRY,62',6


Biological evaluation of medical devices - Part 9: Framework for identification and

quantification of potential degradation products (ISO/DIS 10993-9:2018)

Biologische Beurteilung von Medizinprodukten - Teil 9: Rahmen zur Identifizierung und

Quantifizierung von möglichen Abbauprodukten (ISO/DIS 10993-9:2018)

Évaluation biologique des dispositifs médicaux - Partie 9: Cadre pour l'identification et la

quantification des produits potentiels de dégradation (ISO/DIS 10993-9:2018)
Ta slovenski standard je istoveten z: prEN ISO 10993-9
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN 10993-9:2018 en,fr,de

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

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oSIST prEN 10993-9:2018
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oSIST prEN 10993-9:2018
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-9
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2018-04-24 2018-07-17
Biological evaluation of medical devices —
Part 9:
Framework for identification and quantification of
potential degradation products
Évaluation biologique des dispositifs médicaux —

Partie 9: Cadre pour l'identification et la quantification des produits potentiels de dégradation

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 10993-9:2018(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 2018
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ISO/DIS 10993-9:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018

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
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Phone: [phone]
Fax: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii © ISO 2018 – All rights reserved
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Contents Page

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

Introduction ..................................................................................................................................................................................................................................v

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

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

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

4 Principles for design of degradation studies .......................................................................................................................... 2

4.1 General ........................................................................................................................................................................................................... 2

4.2 Preliminary considerations .......................................................................................................................................................... 3

4.3 Study design .............................................................................................................................................................................................. 3

4.4 Characterization of degradation products from medical devices ............................................................... 4

5 Study report ............................................................................................................................................................................................................... 4

Annex A (normative) Consideration of the need for degradation studies ....................................................................5

Annex B (informative) Degradation study considerations ............................................................................................................ 7

Annex ZA (informative) Relationship between this European Standard and the essential

requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered ....................................................10

Annex ZB (informative) Relationship between this European Standard and the essential

requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered ................................................11

Annex ZC (informative) Relationship between this European Standard and the general

health and safety requirements of Regulation (EU) 2017/745 on medical devices

aimed to be covered .......................................................................................................................................................................................13

Bibliography .............................................................................................................................................................................................................................15

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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 on 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 the following URL: www .iso .org/ iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of

medical devices.

This third edition cancels and replaces the second edition (ISO 10993-9:2009), which has been

technically revised.
The main changes compared to the previous edition are as follows:
a) biodegradation changed to degradation;

b) information on test methods amended to consider nanomaterials and relevant material specific

standards;
A list of all parts in the ISO 10993- series can be found on the ISO website.
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Introduction

This document is intended to present the general principles on which the specific material investigations

to identify and quantify degradation products described in ISO 10993-13 (polymers), ISO 10993-14

(ceramics) and ISO 10993-15 (metals and alloys) are based.

Information obtained from these studies is intended to be used in the biological evaluations described

in the remaining parts of ISO 10993.

The materials used to construct medical devices can form degradation products when exposed to the

biological environment, and in the body these products might behave differently to the bulk material.

Mechanical wear, which is not in scope of this standard, causes mostly particulate debris, whereas the

release of substances from surfaces due to leaching, chemical breakdown of structures or corrosion

can lead to free ions or to different kinds of reaction products in the form of organic or inorganic

compounds.

The degradation products can be either reactive or stable and without biochemical reaction with their

environment. Accumulations of substantial quantities of stable degradation products can, however,

have physical effects on the surrounding tissues. Degradation products might remain at the location

of their generation or might be transported within the biological environment by various mechanisms.

The level of biological tolerability of degradation products depends on their nature and concentration,

and should be primarily assessed through clinical experience and focused studies. For theoretically

possible, new and/or unknown degradation products, relevant testing is necessary. For well-described

and clinically accepted degradation products, further investigation need not be necessary.

Note that the safety and efficacy of a medical device can be compromised as a result of any unintended

or premature degradation, which should be considered in the risk management of the device.

This document can be applied to the degradation of materials used in any kind of product that falls

within the definition of “medical device” in ISO 10993-1, even if such products are subject to different

regulations from those applying to medical devices, e.g. the scaffold in a tissue engineered medical

product, or a carrier matrix to deliver drugs or biologics.
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oSIST prEN 10993-9:2018
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-9:2018(E)
Biological evaluation of medical devices —
Part 9:
Framework for identification and quantification of
potential degradation products
1 Scope

This document provides general principles for the systematic evaluation of the potential and observed

degradation of medical devices through the design and performance of in vitro degradation studies.

Information obtained from these studies can be used in the biological evaluation described in the

ISO 10993- series.

This document considers both materials designed to degrade in the body as well as materials that are

not intended to degrade.
This document is not applicable to:

a) evaluation of degradation which occurs by purely mechanical processes; methodologies for the

production of this type of degradation product are described in specific product standards, where

available;

NOTE Purely mechanical degradation causes mostly particulate matter. Although this is excluded from

the scope of this document, such degradation products can evoke a biological response and thus need to

undergo biological evaluation as described in other parts of ISO 10993.
b) leachable components which are not degradation products;

c) medical devices or components that do not contact the patient's body directly or indirectly.

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 10993-13, 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 13781, Implants for surgery — Homopolymers, copolymers and blends on poly(lactide) — In vitro

degradation testing

ISO/TR 10993-22, Biological evaluation of medical devices — Part 22: Guidance on nanomaterials

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3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following 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 https:// www .iso .org/ obp
3.1
degradation
decomposition of a material
3.2
absorb

action of a non-endogenous (foreign) material or substance passing through or being assimilated by

cells and/or tissue over time
3.3
leachable

substances that can be released from a medical device or material during clinical use

3.4
corrosion
attack on metallic materials by chemical or electrochemical reactions

Note 1 to entry: The term is sometimes used in a general sense for the deterioration of other materials but is in

this part of ISO 10993 reserved for metallic materials.
3.5
substance
single chemical element or compound, or a complex structure of compounds
3.6
device component
one of the different parts of which a device is composed
3.7
degradation product

particle or chemical compound that is derived from the chemical breakdown of the original material

3.8
service environment

anatomical location for the intended use of the device including surrounding fluids, tissues and

biomolecules
4 Principles for design of degradation studies
4.1 General

The approach to the assessment of degradation varies with the nature of the material under investigation,

the medical device and the anatomical location of the specific device. The in vitro degradation models

chosen for evaluation shall be representative of these factors. The studies to be conducted do not

require a biological environment, but one that simulates the conditions of the intended clinical use.

Experience has shown that in some degradation processes, in vitro models do not reflect all aspects of

the service environment, e.g. mechanical processes can influence degradation, and should be taken into

account when defining the model service environment.
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Experience has also shown that material property changes during degradation can result in different

biological responses. The user is urged to be aware of those property changes and apply the relevant

material specific standards (e.g. crystallization of polymers).

Materials-specific or product-specific degradation standards that address identification and

quantification of degradation products should be considered in the design of degradation studies.

ISO 10993-13 (for polymers), ISO 10993-14 (for ceramics) or ISO 10993-15 (for metals and alloys) shall

apply if no suitable material-specific standard exists. Devices composed of two or more material types

should consider all relevant degradation standards.

ISO 10993-13, ISO 10993-14 and ISO 10993-15 consider only those degradation products generated by a

chemical alteration of the finished device. They are not applicable to degradation of the device induced

during its intended use by mechanical stress, wear or electromagnetic radiation. For such degradation

other methods should be considered.
4.2 Preliminary considerations

Careful consideration of the potential for intended or unintended degradation of a material is essential

to the evaluation of the biological safety of a device. Part of this consideration is an assessment of the

chemical characteristics and known degradation mechanisms, followed by an assessment of the need

for, and design of, experimental degradation studies.

It is neither necessary nor practical to conduct degradation studies for all medical devices. Consideration

of the need for degradation studies is provided in Annex A. The assessment of the need for experimental

degradation studies shall include a review of the literature and/or documented clinical experience.

Guidance on proper reviewing of the literature can be found in ISO 10993-1. Such an assessment can

potentially result in the conclusion that no further testing is needed.

Guidance on the biological evaluation of leachables including degradation products is given in

ISO 10993-1, ISO 10993-16 and ISO 10993-17. See ISO 10993-12 for guidance on the extraction of

leachables from medical devices and ISO 10993-18 for guidance on the chemical characterization

of materials and their leachables used in medical devices. See ISO/TS 10993-19 for guidance on the

physico-chemical, morphological and topographical characterization of materials. Consideration of

these standards prior to conducting degradation studies can prove helpful in distinguishing degradation

products from other leachables.

NOTE Despite the difference between degradation products and other leachables, it might be possible to

combine a study on degradation products with a study on other leachable components. Distinguishing between

degradation products and other types of leachables need not be necessary for further biological evaluation

studies. However, when a reduction of the level of leachable components is deemed necessary as a risk control

measure, this information is important. Additionally, some degradation products can not leach from the device,

but still impact the properties of the device.
4.3 Study design

A degradation study plan complete with the purpose of the study shall be designed and documented

to address the issues identified in 4.1. The approved study plan shall define the analytical methods by

which the following characteristics of degradation products are to be investigated:

a) chemical properties;
b) physicochemical properties;
c) physical morphology (as applicable).

The approved study plan shall also describe the methods used to generate degradation products. The

methods should be optimized for detection of degradable substances and justified.

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The approved study plan for multi-component device
...