BS EN ISO 10993-9:2021

Biological evaluation of medical devices

Part 9: Framework for identification and quantification

of potential degradation products

bsi.
BS EN ISO 10993-9:2021 BRITISH STANDARD

National foreword

This British Standard is the UK implementation of

EN ISO 10993-9:2021. It is identical to ISO 10993-9:2019. It supersedes
BS EN ISO 10993-9:2009, which is withdrawn.

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. It is intended to support requirements
of the EU legislation detailed in the European Foreword. A European
Annex, usually Annex ZA or ZZ, describes how this publication relates to
that EU legislation.

For the Great Britain market ( England, Scotland and Wales), if UK

Government has designated this publication for conformity with UKCA
marking (or similar) legislation, it may contain an additional National
Annex. Where such a National Annex exists, it shows the correlation
between this publication and the relevant UK legislation. If there is no
National Annex of this kind, the relevant Annex ZA or ZZ in the body
of the European text will indicate the relationship to UK regulation
applicable in Great Britain. References to EU legislation may need to be
read in accordance with the UK designation and the applicable UK 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. Therefore
Annex ZA/ ZZ in the European text, and references to EU legislation, are
still valid for this market.

UK Government is responsible for legislation. For information on

legislation and policies relating to that legislation, consult the relevant
pages of www.gov.uk.

© The British Standards Institution 2022

Published by BSI Standards Limited 2022

ISBN 978 0 580 97078 8

BRITISH STANDARD BS EN ISO 10993-9:2021

ICS 11.100.20

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 31 May 2022.

Amendments/corrigenda issued since publication

Date Text affected
EUROPEAN STANDARD EN ISO 10993-9

NORME EUROPEENNE

EUROPAISCHE NORM September 2021

JCS 11.100.20 Supersedes EN ISO 10993-9:2009

English Version

Biological evaluation of medical devices - Part 9:

Framework for identification and quantification of
potential degradation products (ISO 10993-9:2019)

Evaluation biologique des dispositifs medicaux Biologische Beurteilung von Medizinprodukten - Tei!
- Partie 9: Cadre pour !'identification et 9: Rahmen zur Identifizierung und Quantifizierung
la quantification des produits potentiels von moglichenAbbauprodukten (ISO 10993-9:2019)
de degradation (ISO 10993-9:2019)

This European Standard was approved by CEN on 26 May 2021.

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, Cy prus, Czech Republic, Denmark,
Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden,
Switzerland, Turkey and United Kingdom.

EUROPEAN COMMITTEE FOR STANDARDIZATION

COMITE EURO PEEN DE NORMALISATION

EUROPAISCHES KOMITEE FUR NORMUNG

CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

© 2021 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-9:2021: E
worldwide for CEN national Members
BS EN ISO 10993-9:2021
EN ISO 10993-9:2021 (E)

European foreword

This document (EN ISO 10993-9:2021) 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 March 2022, and conflicting national standards shall
be withdrawn at the latest by March 2022.

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 supersedes EN ISO 10993-9:2009.

This document has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of EU
Directive(s) / Regulation(s).

For the relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.

Any feedback and questions on this document should be directed to the users' national standards
body/national committee. A complete listing of these bodies can be found on the CEN websites.

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 document '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

Normative references as listed Equivalent dated standard

in Clause 2 of the ISO standard EN ISO or IEC

ISO 10993-1 EN ISO 10993-1:2020b ISO 10993-1:2018

ISO 10993-2 EN ISO 10993-2:2020 ISO 10993-2: 2020a

ISO 10993-13 EN ISO 10993-13:2010 ISO 10993-13:2010

ISO 10993-14 EN ISO 10993-14:2009 ISO 10993-14:2001

ISO 10993-15 EN ISO 10993-15:2020b ISO 10993-15:2019

a Under preparation. Documents are at final stage and have to be submitted to ISO/CS for FDIS vote.
a Under preparation at European level.

NOTE This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2020.

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

ii
 BS EN ISO 10993-9:2021
EN ISO 10993-9:2021 (E)

of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the
United Kingdom.

Endorsement notice
The text of ISO 10993-9:2019 has been approved by CEN as EN ISO 10993-9:2021 without any
modification.

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BS EN ISO 10993-9:2021
EN ISO 10993-9:2021 (E)

AnnexZA
(informative)

Relationship between this European Standard and the general

health and safety requirements of Regulation (EU) 2017 /7 45 on
medical devices aimed to be covered

This European standard has been prepared under a Commission's standardisation request to provide
one voluntary means of conforming to the General Safety and Performance Requirements of Regulation
( EU ) 2017/745 of 5 April 2017 concerning medical devices [OJ L 117 ].

Once this standard is cited in the Official Journal of the European Union under that Regulation,
compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits
of the scope of this standard, a presumption of conformity with the corresponding General Safety and
Performance Requirements of that Regulation, and associated EFTA regulations.

NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Regulation (EU ) 2017/745. This means that risks have to
be 'reduced as far as possible', 'reduced to the lowest possible level', 'reduced as far as possible and appropriate',
'removed or reduced as far as possible', 'eliminated or reduced as far as possible', 'removed or minimized as far
as possible', or 'minimized', according to the wording of the corresponding General Safety and Performance
Requirement.

NOTE 2 The manufacturer's policy for determining acceptable risk must be in compliance with General Safety
and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.

NOTE 3 This Annex 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 a General Safety and Performance Requirement does not appear in Table ZA.1. it means that it is
not addressed by this European Standard.

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 BS EN ISO 10993-9:2021
EN ISO 10993-9:2021 (E)

Table ZA.1 - Correspondence between this European Standard and Annex I of Regulation
(EU) 2017/745
General health and safety Require- Clause(s)/sub-clause(s) of this EN Remarks/Notes
ments of Regulation ( EU) 2017/745
10.1 a), b), c) and h) 4 and Annex A 10.1 a), b), c) and h) only partly covered
by ISO 10993-9, since the standard
does not provide requirements on
design and manufacture.

However, this part of ISO 10993 pro-

vides considerations on how to plan a
degradation study in order to obtain
quantitative degradation data as a
basis for the safety evaluation of a
medical device.

Therefore, this standard provides a

means to evaluate degradation risks
associated with the materials which
are used.

More product group specific informa-

tion can be found in

ISO 10993-13 ( polymers),

ISO 10993-14 (ceramics) and

ISO 10993-15 (metals and alloys)

These tests are not intended to evaluate

or determine the performance of the
test sample in terms of mechanical or
functional loading.

For 10.1 a), flammability is not covered.

10.4.1 (first paragraph)
4 and Annex A 10.4.1 is only partly covered by this
d o cument. However, this part of
ISO 10993 specifies the general prin-
ciples that govern the design, conduct
and interpretation of studies to identify
and quantify degradation products
arising from materials intended for
use in medical devices in order to
obtain quantitative degradation data
as a basis for the safety evaluation of
a medical device.

Therefore, this standard provides a

means to investigate the risks posed
by degradation products that may
be released from the medical device.

This document does not apply to parti-

des, wear debris or processing residues

GENERAL NOTE Presumption of conformity depends on also complying with the relevant parts of the
ISO 10993- series.

WA RNING 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.

WA RNING 2 Other Union legislation may be applicable to the product(s) falling within the scope of
this standard.

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BS EN ISO 10993-9:2021
ISO 10993-9:2019

Contents Page

Foreword ...................................................................................................................................................................................................................................... vii

Introduction............................................................................................................................................................................................................................ viii
1 Scope ................................................................................................................................................................................................................................. 1
2 Normative references ...................................................................................................................................................................................... 1
3 Terms and definitions ..................................................................................................................................................................................... 1
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 ....... ............................................................. 6
Annex B (informative) Degradation study considerations ............................................................................................................ 8
Bibliography .............................................................................................................................................................................................................................10

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 BS EN ISO 10993-9:2021
ISO 10993-9:2019

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.
orgfiso/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.

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

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BS EN ISO 10993-9:2021
ISO 10993-9:2019

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 document, causes mostly particulate debris, whereas non­
mechanical degradation can lead to the release of 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 might 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.

viii ©ISO 2019 -All rights reserved

 BS EN ISO 10993-9:2021

INTE RNAT IONAL STANDA RD ISO 10993-9:2019

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 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.

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

3 Terms and definitions

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

©ISO 2019 All rights reserved

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BS EN ISO 10993-9:2021
ISO 10993-9:2019

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

ISO Online browsing platform: available at https://www.iso.org/obp

IEC Electropedia: available at http://www.electropedia.org/

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 document reserved for metallic materials.

3.5
substance
single chemical element or compound, or a complex structure of compounds

3.6
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 some in vitro models do not reflect all aspects of the service environment
(e.g. mechanical processes) that can influence the degradation process. All such factors should be taken
into account when modelling the service environment in vitro.

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
materials-specific standards (e.g. crystallization of polymers).

2 ©ISO 2019 -All rights reserved

 BS EN ISO 10993-9:2021
ISO 10993-9:2019

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. Refer to
Annex A to determine when degradation studies should be considered. 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 10993-18 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 can 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 might 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 cannot leach from the device
but can 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 for generating degradation products should be optimized and scientifically justified. The
degradation products should be identified and quantified using methods described in ISO 10993-18.

©ISO 2019 All rights reserved

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BS EN ISO 10993-9:2021
ISO 10993-9:2019

The approved study plan for multi-component devices shall take into account each individual
component/material and shall consider synergistic effects on the degradation of the different
components as well as the possibility of secondary reactions between/among the degradation products.

NOTE Degradation can in most cases be modelled by in vitro tests. During degradation pH needs to be
controlled to a clinically relevant range, especially if pH can affect degradation product composition. The user
needs to be aware that both the degradation rate and amount of generated by-products can be affected if pH is
different from that expected for the service environment.

4.4 Characterization of degradation products from medical devices

The degradation products produced in the study can be particulate or soluble compounds or ions.
Appropriate analytical methods to characterize these products shall be used and reported in the
study report. These methods shall be adequately qualified for their intended purpose. If particles
are generated, they shall be characterized with regard to size, shape, surface area and other relevant
characteristics.

Because the physical and chemical properties of particulate materials can change at the nanoscale
(approximately 1 nm to 100 nm), this can affect their toxicological properties. For those medical devices
composed of or containing nanoscale materials, the user is referred to ISO/TR 10993-22 for a thorough
consideration of the impact on the risk assessment of nanoscale products.

If biological evaluation of the degradation products is required, then care shall be taken in the design of
the degradation study in order to ensure that it does not interfere with the biological assay.

Considerations for the degradation study are provided in Annex B. The protocol shall include

a) identification and characterization of device and/or material and intended use,

b) identification and characterization of possible mechanism of degradation,

c) identification and characterization of known, probable and potential degradation products, and

d) test methodologies.

The extent and rate of release of degradation products depends on variables such as manufacturing
processes that alter surface composition and structures; migration to the surface from within the
material; solubility in, and chemical composition of, the physiological milieu; etc.

5 Study report
The study report shall include the following information, where relevant:

a) description of material(s) or device (see B.2) , including intended use and nature of body contact;

b) description of proposed degradation mechanism(s) (e.g., hydrolytic, enzymatic, oxidative, etc.), and
how the degradation study is appropriately designed to assess the proposed mechanism(s);

c) description of the degradation study procedures (e.g. test article, sample size, degradation media,
ratio of test article vs. degradation media, study conditions, experimental steps and parameters,
sampling strategy, monitoring and observation, etc.);

d) description of analytical methods, including quantification limits and controls;

e) statement of compliance to appropriate good laboratory practices and/or to quality management

systems for test laboratories (e.g. ISO/IEC 17025);

f) identification and quantification of degradation products (e.g. form and condition of degradation
products, their stability and controls used);

g) summary of results;

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 BS EN ISO 10993-9:2021
ISO 10993-9:2019

h) interpretation and discussion of results.

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BS EN ISO 10993-9:2021
ISO 10993-9:2019

Annex A
(normative)

Consideration of the need for degradation studies

Degradation studies shall be considered if:

a) the device is designed to be absorbed by the body or

b) the device is intended to be implanted for longer than thirty days or

c) an informed consideration of the material(s) system indicates that toxic degradation products
could be released during body contact.

However, degradation studies might not be needed if sufficient material formulation, and manufacturing
process information are available and degradation data relevant to degradation products in the
intended use already exist.

NOTE Relevant degradation data can include information on degradation mechanism, degradation rate,
identification and quantity of degradation products, and particle shape/size and distribution.

The need for in vivo studies shall be considered in light of results from in vitro studies.

Where appropriate, in vitro experiments shall be considered for investigating theoretically possible
degradation processes. In vivo studies shall take into consideration ISO 10993-2. In vivo and in vitro
studies shall also be considered for determining the probability of occurrence of degradation and the
identification of probable degradation products and the degradation rate.

The flowchart in Figure A.1 illustrates the logic applicable to these considerations. For polymers that
are intended to hydrolytically degrade, e.g. polylactide, the user is referred to ISO 13781.

6 ©ISO 2019 -All rights reserved

 BS EN ISO 10993-9:2021
ISO 10993-9:2019

Degradation
Apply
assessment
ISO 10993-9
complete

Degradation
Yes
assessment
complete

Complete degredation
Yes assessments by applying
ISO 10993 standards
corresponding to material type

Complete degradation
No assessments following
appropriate standards or provide
a scientific rationale for protocols

Figure A.1 - Flowchart illustrating consideration of the need for degradation studies

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ISO 10993-9:2019

AnnexB
(informative)

Degradation study considerations

B.1 General
This annex contains aspects that need to be considered in the evaluation of possible degradation.

Appropriate practical studies should be considered in the case where essential information is missing
on the degradation of devices or materials and the biological effects of potential degradation products.

B.2 Description of medical device and/or material

The following should be considered when describing the device or material under study:

a) name of medical device and/or material;

b) function of medical device;

c) intended use;

d) intended biological environment;

e) composition of the material;

f) conditioning of the material (e.g. processing, sterilization);

g) surface condition;

h) dimensions;

i) construction of device or material under study (e.g. single component, single component to be used
with others and the nature of their interaction, or multicomponent device - assessment carried
out for each component material);

j) contact duration;

k) shelf life;

NOTE For some products storage can impact degradation, and therefore degradation studies to support
labelled shelf life can be important.

l) other relevant characterizations.

B.3 Assessment of potential and known degradation products

B.3.1 General

Degradation of material can occur within the bulk, or majority, of the material. Degradation can also
occur at the surface of the material. Both bulk and surface degradation can occur at the same time and
can influence one another.

8 ©ISO 2019 -All rights reserved

 BS EN ISO 10993-9:2021
ISO 10993-9:2019

B.3.2 Bulk material changes

Intended or unintended changes in the bulk material can lead to particulate degradation products and
can influence the stability of the surface. For example, bulk material changes can occur as follows:

during fabrication;

during sterilization;

during storage and due to instability;

during implantation and while implanted;

during changes in the physical state (swelling, phase transitions, etc.);

by intended in vivo degradation.

B.3.3 Release of substances from the surface

Release of substances from the surface can be induced by processes such as the following:

chemical reactions (e.g. depolymerization);

leaching;

diffusion;

peeling, scaling off.

B.3.4 Multicomponent device or device used with other components

In addition to the considerations for single-component systems, items such as the following need to
be addressed:

breakdown of structures;

delamination;

migration of substances from one component to another;

possibility of reactions between/among degradation products.

©ISO 2019 All rights reserved

- 9
BS EN ISO 10993-9:2021
ISO 10993-9:2019

Bibliography

[1] ISO 10271, Dentistry- Corrosion test methods for metallic materials

[2] ISO 10993-16, Biological evaluation of medical devices - Part 16: Toxicokinetic study design for
degradation products and leachables

[3] ISO 10993-17, Biological evaluation of medical devices- Part 17: Establishment of allowable limits
for leachable substances

[4] ISO 10993-18:2005, Biological evaluation of medical devices - Part 18: Chemical characterization
of materials

[5] ISO/TS 10993-19, Biological evaluation of medical devices - Part 19: Physico-chemical,
morphological and topographical characterization of materials

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

[7 ] ISO 13781, Implants for surgery - Homopolymers, copolymers and blends on poly(lactide) - In
vitro degradation testing

[8] ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories

10 ©ISO 2019 -All rights reserved

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