SIST EN ISO 10993-18:2009

SLOVENSKI STANDARD
kSIST prEN ISO 10993-18:2009
01-marec-2009
%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: prEN ISO 10993-18
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
kSIST prEN ISO 10993-18:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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kSIST prEN ISO 10993-18:2009

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kSIST prEN ISO 10993-18:2009
EUROPEAN STANDARD
FINAL DRAFT
prEN ISO 10993-18
NORME EUROPÉENNE
EUROPÄISCHE NORM
December 2008
ICS 11.100.20 Will supersede EN ISO 10993-18:2005
English Version
Biological evaluation of medical devices - Part 18: Chemical
characterization of materials (ISO 10993-18:2005)
Evaluation 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 draft European Standard is submitted to CEN members for unique acceptance procedure. It has been drawn up by the Technical
Committee CEN/TC 206.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN 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.
: This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice and
Warning
shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36  B-1050 Brussels
© 2008 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN ISO 10993-18:2008: E
worldwide for CEN national Members.

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kSIST prEN ISO 10993-18:2009
prEN ISO 10993-18:2008 (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

2

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kSIST prEN ISO 10993-18:2009
prEN ISO 10993-18:2008 (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
prEN ISO 10993-18:2008 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the
secretariat of which is held by NEN.
This document is currently submitted to the Unique Acceptance Procedure.
This document will supersede 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.
Endorsement notice
The text of ISO 10993-18:2005 has been approved by CEN as a prEN ISO 10993-18:2008 without any
modification.
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kSIST prEN ISO 10993-18:2009
prEN ISO 10993-18:2008 (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.












4

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kSIST prEN ISO 10993-18:2009
prEN ISO 10993-18:2008 (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 :
9

WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this standard.



5

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kSIST prEN ISO 10993-18:2009

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kSIST prEN 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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kSIST prEN ISO 10993-18:2009
ISO 10993-18:2005(E)
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ii © ISO 2005 – All rights reserved

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kSIST prEN 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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kSIST prEN 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
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kSIST prEN 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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kSIST prEN 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.

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kSIST prEN 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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kSIST prEN 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
g
polymer chain mobility and the diffusion rate in the phase. Usually the diffusion rate is considerably higher above the T
g
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.
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kSIST prEN 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
a
MS
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
a
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
of
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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kSIST prEN 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 methods cannot be identified, appropriate new methods
shall be developed. Prior to new method development, existing standards, monographs, scientific articles or
other relevant scientific documents should be consulted to check for existing appropriate test methods.
Methods from the literature may need to be adapted and validated before use.
The analytical methods used shall be validated, justified and reported (see Clause 8). The validation of an
analytical method is the process by which it is established that the performance characteristics of the method
meet the requirements for the intended analytical applications. Analytical methods shall
...