Biological evaluation of medical devices - Part 18: Chemical characterization of materials (ISO 10993-18:2005)

ISO 10993-18:2005 describes a framework for the identification of a material and the identification and quantification of its chemical constituents. The chemical characterization information generated can be used for a range of important applications, for example, as part of an assessment of the overall biological safety of a medical device (ISO 10993-1 and 14971), as a measurement of the level of a leachable substance in a medical device in order to allow the assessment of compliance with the allowable limit derived for that substance from health based risk assessment (ISO 10993-17), for judging equivalence of a proposed material to a clinically established material, for judging equivalence of a final device to a prototype device to check the relevance of data on the latter to be used to support the assessment of the former, or for screening of potential new materials for suitability in a medical device for a proposed clinical application.
ISO 10993-18:2005 does not address the identification or quantification of degradation products, which is covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15.
The ISO 10993 series of standards is applicable when the material or device comes into contact with the body directly or indirectly (see 4.2.1 of ISO 10993-1).
ISO 10993-18:2005 is intended for suppliers of materials and manufacturers of medical devices, when carrying out a biological safety assessment.

Biologische Beurteilung von Medizinprodukten - Teil 18: Chemische Charakterisierung von Werkstoffen (ISO 10993-18:2005)

Dieser Teil von ISO 10993 beschreibt einen Rahmen für die Identitätsbestimmung eines Werkstoffs und die
qualitative und quantitative Bestimmung seiner chemischen Bestandteile. Die so gewonnenen Angaben über
die chemische Charakterisierung können in einer Vielzahl wichtiger Anwendungen benutzt werden, zum
Beispiel:
⎯ als Teil der Beurteilung der allgemeinen biologischen Sicherheit eines Medizinprodukts (ISO 10993-1 und
ISO 14971);
⎯ bei der Bestimmung der Konzentration herauslösbarer Substanzen in einem Medizinprodukt, um die
Beurteilung der Einhaltung zulässiger Grenzwerte, die für die betreffende Substanz auf der Basis einer
gesundheitsbezogenen Risikobewertung ermittelt wurden (ISO 10993-17) zu ermöglichen;
⎯ bei der Beurteilung der Gleichwertigkeit eines vorgesehenen Werkstoffs mit einem klinisch eingeführten
Material;
⎯ bei der Beurteilung der Gleichwertigkeit eines Endprodukts mit dessen Prototyp, in dem die ermittelten
Daten des Endproduktes mit denen des Prototyps verglichen und überprüft werden;
⎯ bei der Screeninguntersuchung möglicher neuer Werkstoffe in Bezug auf deren Eignung für ein
Medizinprodukt hinsichtlich der vorgesehenen klinischen Anwendung.
Dieser Teil der ISO 10993 behandelt nicht den qualitativen oder quantitativen Nachweis von Abbauprodukten,
der durch ISO 10993-9, -13, -14 und -15 abgedeckt wird.
Die Normenreihe ISO 10993 ist anwendbar, wenn der Werkstoff oder das Produkt direkt oder indirekt mit dem
Körper in Kontakt kommt (siehe ISO 10993-1:2003, 4.2.1).
Die ISO 10993-18 ist für Werkstofflieferanten und Hersteller von Medizinprodukten vorgesehen, wenn diese
eine Beurteilung der biologischen Sicherheit vornehmen.

Évaluation biologique des dispositifs médicaux - Partie 18: Caractérisation chimique des matériaux (ISO 10993-18:2005)

L'ISO 10993-18:2005 décrit un cadre servant à l'identification d'un matériau et à la détermination et la quantification de ses composés chimiques. Les informations relatives à la caractérisation chimique obtenues peuvent servir à une large gamme d'applications importantes notamment, par exemple prendre part à l'évaluation de la sécurité biologique globale d'un dispositif médical (ISO 10993-1 et ISO 14971), mesurer le niveau de substances relargables dans un dispositif médical afin d'évaluer la conformité avec les limites admissibles pour cette substance dérivées d'une évaluation des risques relatifs à la santé (ISO 10993-17), juger de l'équivalence entre un matériau proposé et un matériau cliniquement établi, juger de l'équivalence d'un dispositif final à un prototype pour vérifier la pertinence des données relatives au prototype utilisées pour l'évaluation dudit dispositif; sélectionner les nouveaux matériaux potentiels afin de déterminer le caractère adéquat de ceux-ci au sein d'un dispositif médical pour une application clinique proposée.
L'ISO 10993-18:2005 ne traite pas de l'identification ou de la quantification des produits de dégradation qui sont abordés dans l'ISO 10993-9, l'ISO 10993-13, l'ISO 10993-14 et l'ISO 10993-15.
Les normes de la série ISO 10993 s'appliquent en cas de contact direct ou indirect entre le matériau ou le dispositif et le corps (voir l'ISO 10993-1, 4.2.1).
L'ISO 10993-18:2005 s'adresse aux fournisseurs de matériaux et aux fabricants de dispositifs médicaux pour la conduite d'une évaluation de la sécurité biologique.

Biološko ovrednotenje medicinskih pripomočkov - 18. del: Kemična opredelitev lastnosti materialov (ISO 10993-18:2005)

General Information

Status
Withdrawn
Publication Date
28-Apr-2009
Current Stage
9960 - Withdrawal effective - Withdrawal
Completion Date
27-May-2020

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SLOVENSKI STANDARD
SIST EN ISO 10993-18:2009
01-julij-2009
1DGRPHãþD
SIST EN ISO 10993-18:2005
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO.HPLþQDRSUHGHOLWHY
ODVWQRVWLPDWHULDORY ,62

Biological evaluation of medical devices - Part 18: Chemical characterization of materials

(ISO 10993-18:2005)

Biologische Beurteilung von Medizinprodukten - Teil 18: Chemische Charakterisierung

von Werkstoffen (ISO 10993-18:2005)

Evaluation biologique des dispositifs médicaux - Partie 18 : Caractérisation chimique des

matériaux (ISO 10993-18:2005)
Ta slovenski standard je istoveten z: EN ISO 10993-18:2009
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-18:2009 en

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

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SIST EN ISO 10993-18:2009
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SIST EN ISO 10993-18:2009
EUROPEAN STANDARD
EN ISO 10993-18
NORME EUROPÉENNE
EUROPÄISCHE NORM
April 2009
ICS 11.100.20 Supersedes EN ISO 10993-18:2005
English Version
Biological evaluation of medical devices - Part 18: Chemical
characterization of materials (ISO 10993-18:2005)

Évaluation biologique des dispositifs médicaux - Partie 18: Biologische Beurteilung von Medizinprodukten - Teil 18:

Caractérisation chimique des matériaux (ISO 10993- Chemische Charakterisierung von Werkstoffen (ISO 10993-

18:2005) 18:2005)
This European Standard was approved by CEN on 12 April 2009.

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 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 Management Centre has the same status as the

official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,

France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,

Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels

© 2009 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-18:2009: E

worldwide for CEN national Members.
---------------------- Page: 3 ----------------------
SIST EN ISO 10993-18:2009
EN ISO 10993-18:2009 (E)
Contents Page

Foreword ..............................................................................................................................................................3

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

Requirements of EU Directive 93/42/EEC on Medical Devices ........................................................4

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

Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices .....................5

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SIST EN ISO 10993-18:2009
EN ISO 10993-18:2009 (E)
Foreword

The text of ISO 10993-18:2005 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation

of medical devices” of the International Organization for Standardization (ISO) and has been taken over as EN

ISO 10993-18:2009 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the

secretariat of which is held by NEN.

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 October 2009, and conflicting national standards shall be withdrawn at

the latest by March 2010.

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 10993-18:2005.

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 93/42/EEC on

Medical Devices and 90/385/EEC on Active Implantable Medical Devices.

For relationship with the EU Directives, see informative Annexes ZA and ZB, which is an integral part 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, Cyprus, Czech

Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,

Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,

Sweden, Switzerland and the United Kingdom.
Endorsement notice

The text of ISO 10993-18:2005 has been approved by CEN as a EN ISO 10993-18:2009 without any

modification.
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SIST EN ISO 10993-18:2009
EN ISO 10993-18:2009 (E)
Annex ZA
(informative)
Relationship between this European Standard and the Essential Requirements of
EU Directive 93/42/EEC on Medical Devices

This European Standard has been prepared under a mandate given to CEN by the European Commission

and the European Free Trade Association to provide a means of conforming to Essential Requirements of the

New Approach Directive 93/42/EEC on medical devices.

Once this standard is cited in the Official Journal of the European Communities under that Directive and has

been implemented as a national standard in at least one Member State, compliance with the clauses of this

standard given in table ZA 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.

Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical

devices

Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes

EN Directive 93/42/EEC
5, 6, 7, 8 & Annex A
Annex I:
7.1, 7.2, 7.5

WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within

the scope of this standard.
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SIST EN ISO 10993-18:2009
EN ISO 10993-18:2009 (E)
Annex ZB
(informative)
Relationship between this European Standard and the Essential Requirements of
EU Directive 90/385/EEC on Active Implantable Medical Devices

This European Standard has been prepared under a mandate given to CEN by the European Commission

and the European Free Trade Association to provide a means of conforming to Essential Requirements of the

New Approach Directive 90/385/EEC on active implantable medical devices.

Once this standard is cited in the Official Journal of the European Communities under that Directive and has

been implemented as a national standard in at least one Member State, compliance with the clauses of this

standard given in table ZB 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.

Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active

implantable medical devices

Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes

EN Directive 90/385/EEC
5, 6, 7, 8, & Annex A
Annex I :

WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within

the scope of this standard.
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SIST EN ISO 10993-18:2009
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SIST EN ISO 10993-18:2009
INTERNATIONAL ISO
STANDARD 10993-18
First edition
2005-07-01
Biological evaluation of medical
devices —
Part 18:
Chemical characterization of materials
Évaluation biologique des dispositifs médicaux —
Partie 18: Caractérisation chimique des matériaux
Reference number
ISO 10993-18:2005(E)
ISO 2005
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
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ii © ISO 2005 – All rights reserved
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
Contents Page

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

Introduction ....................................................................................................................................................... vi

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

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

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

4 Symbols and abbreviated terms ......................................................................................................... 3

5 General principles................................................................................................................................. 3

6 Characterization procedure ................................................................................................................. 4

6.1 General................................................................................................................................................... 4

6.2 Step 1 — Qualitative information ........................................................................................................ 5

6.3 Step 2 — Material equivalence ............................................................................................................ 5

6.4 Step 3 — Quantitative information...................................................................................................... 5

6.5 Step 4 — Quantitative risk assessment.............................................................................................. 5

6.6 Step 5 — Estimated clinical exposure to chemicals present........................................................... 6

7 Chemical characterization parameters and methods ....................................................................... 6

7.1 General................................................................................................................................................... 6

7.2 Polymers................................................................................................................................................ 7

7.3 Metals and alloys .................................................................................................................................. 8

7.4 Ceramics................................................................................................................................................ 8

7.5 Natural macromolecules ...................................................................................................................... 9

8 Reporting of data obtained ................................................................................................................ 10

Annex A (normative) Flowchart summarizing the stepwise generation of chemical

characterization data for use in toxicological risk assessment .................................................... 11

Annex B (informative) Information sources for chemical characterization ............................................... 13

Annex C (informative) Principles for judging toxicological equivalency ................................................... 16

Bibliography ..................................................................................................................................................... 17

© ISO 2005 – All rights reserved iii
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(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.

International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.

The main task of technical committees is to prepare International Standards. Draft International Standards

adopted by the technical committees are circulated to the member bodies for voting. Publication as an

International Standard requires approval by at least 75 % of the member bodies casting a vote.

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.

ISO 10993-18 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.

ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:

 Part 1: Evaluation and testing
 Part 2: Animal welfare requirements
 Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
 Part 4: Selection of tests for interactions with blood
 Part 5: Tests for in vitro cytotoxicity
 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 delayed-type hypersensitivity
 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

 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
iv © ISO 2005 – All rights reserved
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
 Part 18: Chemical characterization of materials
The following parts are under preparation:
 Part 19: Physico-chemical, mechanical and morphological characterization

 Part 20: Principles and methods for immunotoxicology testing of medical devices

Future parts will deal with other relevant aspects of biological testing.

For the purposes of this part of ISO 10993, the CEN annex regarding fulfilment of European Council

Directives has been removed.
© ISO 2005 – All rights reserved v
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
Introduction

ISO 10993-1 provides a framework for a structured programme of assessment for the evaluation of biological

safety. Clause 3 of ISO 10993-1:2003 states that in the selection of materials to be used for device

manufacture the first consideration should be fitness for purpose. This should have regard to the

characteristics and properties of the material, which include chemical, toxicological, physical, electrical,

morphological and mechanical properties. This information is necessary prior to any biological evaluation.

Subclause 7.2 of ISO 10993-1:2003 notes that the continuing acceptability of a biological evaluation is an

aspect of a quality management system.

Also ISO 14971 points out that a toxicological risk analysis should take account of the chemical nature of the

materials.

The requirements specified in this document are intended to yield the following information, which will be of

value in predicting the biological response of the materials:

 The chemical composition of the materials used in the manufacturing process including processing

additives and residues e.g. trace chemicals, cleaning, disinfection and testing agents, acids and caustic

substances.

 The characterization of materials to be used in the production of medical devices, as well as in devices in

their final form.
 Identification of the materials of construction of the medical device.

 The potential of medical device materials to release substances or breakdown products due to the

manufacturing process.

 Changes in the materials of construction, which result from changes in the manufacturing process or

insufficient control of the manufacturing process.

The compositional characteristics of the materials of manufacture are mainly under the control of the suppliers

of these materials. However other characteristics are chiefly influenced by the requirements to be met by the

finished medical device as well as the processes used by the medical device manufacturer.

vi © ISO 2005 – All rights reserved
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SIST EN ISO 10993-18:2009
INTERNATIONAL STANDARD ISO 10993-18:2005(E)
Biological evaluation of medical devices —
Part 18:
Chemical characterization of materials
1 Scope

This part of ISO 10993 describes a framework for the identification of a material and the identification and

quantification of its chemical constituents. The chemical characterization information generated can be used

for a range of important applications, for example:

 As part of an assessment of the overall biological safety of a medical device (ISO 10993-1 and 14971).

 Measurement of the level of a leachable substance in a medical device in order to allow the assessment

of compliance with the allowable limit derived for that substance from health based risk assessment

(ISO 10993-17).

 Judging equivalence of a proposed material to a clinically established material.

 Judging equivalence of a final device to a prototype device to check the relevance of data on the latter to

be used to support the assessment of the former.

 Screening of potential new materials for suitability in a medical device for a proposed clinical application.

This part of ISO 10993 does not address the identification or quantification of degradation products, which is

covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15.

The ISO 10993 series of standards is applicable when the material or device comes into contact with the body

directly or indirectly (see 4.2.1 of ISO 10993-1:2003).

This part of ISO 10993 is intended for suppliers of materials and manufacturers of medical devices, when

carrying out a biological safety assessment.
2 Normative references

The following referenced documents are indispensable for the application 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 10993-1:2003, Biological evaluation of medical devices — Part 1: Evaluation and testing

ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for

leachable substances

ISO 14971:2000, Medical devices — Application of risk management to medical devices

© ISO 2005 – All rights reserved 1
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
3 Terms and definitions

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

3.1
supplier

person or company who manufactures and/or supplies the basic starting materials to be used in the

manufacture of a medical device
3.2
manufacturer

natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device

before it is placed on the market under his own name, regardless of whether these operations are carried out

by that person himself or on his behalf by a third party
3.3
component

item which is manufactured from a basic starting material but is not itself a medical device, since it forms only

one part of a medical device
3.4
convertor

person or company who converts or fabricates a basic raw material into a semi-finished product (e.g. lengths

of rod, tubing or lay-flat film)
3.5
chemical characterization

identification of a material and the identification and quantification of the chemicals present in materials or

finished medical devices
3.6
exhaustive extraction

extraction until the amount of residues in a subsequent extraction is less than 10 % of that detected in the first

extraction

NOTE Extraction is a complex process influenced by time, temperature, surface-area-to-volume-ratio, extraction

medium and the phase equilibrium of the material. The phase equilibrium of a material controls the relative amounts of

amorphous and crystalline phases present. For the amorphous phase, the glass transition temperature, T , dictates the

polymer chain mobility and the diffusion rate in the phase. Usually the diffusion rate is considerably higher above the T

compared with that below. The diffusion rate is lowest in the crystalline phase.

The extraction conditions should not alter the phase equilibrium of the material. Phase alteration may affect the amount

and type of extractables. The effects of higher temperatures or other conditions on extraction kinetics and the identity of

the extractant(s) should be considered carefully if exhaustive extraction is used. For example, there are a few concerns in

using elevated temperatures:

a) the energy of the increased temperature may cause increased cross-linking of a polymer and therefore decrease the

amount of free monomer that is available to migrate from the polymer;

b) the increased temperature could cause degradant materials to form that are not typically found in the finished device

under use conditions;

c) the increased temperature could cause the disappearance of a leachable material typically found in the finished

device.
3.7
simulated extraction

extraction for evaluating potential risk to the patient or user during routine use of a device, using an extraction

method with an appropriate medium that simulates product use
NOTE See NOTE to 3.6.
2 © ISO 2005 – All rights reserved
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)
4 Symbols and abbreviated terms
The following abbreviated terms are used in Clause 7.
Table 1 — Methodology abbreviations
Abbreviated term Analytical method
DMTA Dynamic mechanical thermal analysis
DSC Differential scanning calorimetry
EDX-SEM Electron dispersal X-ray analysis – scanning electron microscopy
FTIR Fourier transform infra red (spectroscopy)
GC Gas chromatography
Mass spectroscopy
GPC Gel permeation chromatography
HPLC High performance liquid chromatography
ICP Inductively coupled plasma
IR Infrared (spectroscopy)
NMR Nuclear magnetic resonance (spectroscopy)
UV Ultraviolet (spectroscopy)
XPS X-ray photoelectron spectroscopy
XRF X-ray fluorescence
2D PAGE Two-dimensional polyacrylamide gel electrophoresis

Mass spectroscopy is frequently combined with chromatographic techniques such as GC-MS, LC-MS and MS-MS.

5 General principles

Consideration of the chemical characterization of the materials from which a medical device is made is a

necessary first step in assessing the biological safety of the device. It is also important in judging equivalence

a) a proposed material to a clinically established material, and
b) a prototype device to a final device.

An overview of the chemical characterization procedure outlined in this document and its relationship to risk

assessment is given in Annex A.

Qualitative data shall be obtained to describe the chemical composition of a material. When relevant to

biological safety, quantitative data shall also be obtained. For some materials compositional information may

be readily available as part of the material specification. Materials such as polymers may possess more

complex formulations and compositional details should be obtained from the supplier of the material. In the

absence of such details appropriate analytical techniques should be applied to a material to yield

compositional data.

Identification of the constituents of a material intended for use in the manufacture of a medical device enables

the intrinsic toxicity of each constituent to be investigated. The data obtained are intended for use by the

medical device manufacturer as part of the overall biological safety evaluation of the medical device. It is

therefore important that controls should be introduced to prevent a material supplier from changing the

composition of a material supplied under a specific commercial trade name or supply agreement without prior

© ISO 2005 – All rights reserved 3
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SIST EN ISO 10993-18:2009
ISO 10993-18:2005(E)

notification to the medical device manufacturer. The manufacturer should assess the consequences of any

notified changes on the biological safety of the product.

Any of the constituents of a material or additives used in the process of manufacture of a medical device are

potentially bio-available. However it is necessary to obtain information demonstrating the extent to which the

constituents will be available under the actual conditions of use of the finished product to estimate the risk

arising from them. This can be estimated from extraction tests on the material. Appropriate extraction

conditions (simulated extraction) are used to ensure that any constituent which is likely to be released during

finished product use will be released into the extraction media. The extract obtained can be analysed

qualitatively and/or quantitatively to generate data that can then be used in the biological safety evaluation of

the medical device.

The extent of chemical characterization required should reflect the nature and duration of the clinical exposure

and shall be determined by the toxicological risk assessor based on the data necessary to evaluate the

biological safety of the device. It will also reflect the physical form of the materials used, e.g. liquids, gels,

polymers, metals, ceramics, composites or biologically sourced material.

The successful completion of the chemical characterization outlined in this document requires the close

collaboration of material scientists, analytical chemists and toxicological risk assessors. In this partnership, the

material scientist and analytical chemist provide the necessary qualitative and quantitative data that a risk

assessor may use to determine device safety.
6 Characterization procedure
6.1 General

The generation of chemical characterization data is a step-wise process linked to risk assessment and a

flowchart composed of 5 steps is given in Annex A. The chemical characterization requirements and guidance

at each step are specified in 6.2 to 6.6. The analytical methods shall be selected to give the required

information for the toxicological evaluation. If suitable met
...

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