EN ISO 10993-1:2009

Biological evaluation of medical devices - Part 1: Evaluation and testing (ISO 10993-1:2003)

This part of ISO 10993 describes a) the general principles governing the biological evaluation of medical devices; b) the categorization of devices based on the nature and duration of their contact with the body; c) the selection of appropriate tests.

Biologische Beurteilung von Medizinprodukten Teil 1: Beurteilung und Prüfung (ISO 10993-1:2003)

Dieser Teil von ISO 10993 beschreibt
a) die allgemeinen Grundsätze, die für die biologische Beurteilung von Medizinprodukten gelten,
b) die Einteilung von Medizinprodukten basierend auf Applikationsort und Kontaktdauer mit dem
menschlichen Körper,
c) die Auswahl geeigneter Prüfverfahren.
Dieser Teil von ISO 10993 gilt nicht für Prüfungen von Materialien und Produkten, die weder direkt oder
indirekt mit dem Körper des Patienten in Kontakt kommen. Diese Norm beschreibt auch nicht biologische
Gefährdungen, die durch mechanisches Versagen hervorgerufen werden.
ANMERKUNG Andere Teile der Reihe ISO 10993 [1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18] decken spezifische
Prüfungen ab (siehe auch die Begründung in A.2).

Évaluation biologique des dispositifs médicaux - Partie 1: Evaluation et essais (ISO 10993-1:2003)

Biološko ovrednotenje medicinskih pripomočkov - 1. del: Ocena in preskušanje (ISO 10993-1:2003)

General Information

• Status: Withdrawn
• Publication Date: 09-Jun-2009
• Withdrawal Date: 14-Oct-2009
• ICS: 11.100 - Laboratory medicine
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Drafting Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Current Stage: 9960 - Withdrawal effective - Withdrawal
• Due Date: 15-Oct-2009
• Completion Date: 15-Oct-2009
• Mandate: M/BC/CEN/89/9 - Joint Standardization request to CEN/CENELEC concerning harmonized standards relating to horizontal aspects in the field of medical devices
• Ref Project: SIST EN ISO 10993-1:2009 - Biological evaluation of medical devices - Part 1: Evaluation and testing (ISO 10993-1:2003)

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-1:2009
01-september-2009
1DGRPHãþD
SIST EN ISO 10993-1:2003
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO2FHQDLQSUHVNXãDQMH
,62
Biological evaluation of medical devices - Part 1: Evaluation and testing (ISO 10993-
1:2003)
Biologische Beurteilung von Medizinprodukten Teil 1: Beurteilung und Prüfungen (ISO
10993-1:2003)
Evaluation biologique des dispositifs médicaux - Partie 1: Evaluation et essais (ISO
10993-1:2003)
Ta slovenski standard je istoveten z: EN ISO 10993-1:2009
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-1:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

---------------------- Page: 1 ----------------------

SIST EN ISO 10993-1:2009

---------------------- Page: 2 ----------------------

SIST EN ISO 10993-1:2009
EUROPEAN STANDARD
EN ISO 10993-1
NORME EUROPÉENNE
EUROPÄISCHE NORM
June 2009
ICS 11.100.20 Supersedes EN ISO 10993-1:2003
English Version
Biological evaluation of medical devices - Part 1: Evaluation and
testing (ISO 10993-1:2003)
Évaluation biologique des dispositifs médicaux - Partie 1: Biologische Beurteilung von Medizinprodukten Teil 1:
Evaluation et essais (ISO 10993-1:2003) Beurteilung und Prüfung (ISO 10993-1:2003)
This European Standard was approved by CEN on 23 May 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 10993-1:2009: E
worldwide for CEN national Members.

---------------------- Page: 3 ----------------------

SIST EN ISO 10993-1:2009
EN ISO 10993-1:2009 (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

2

---------------------- Page: 4 ----------------------

SIST EN ISO 10993-1:2009
EN ISO 10993-1:2009 (E)
Foreword
The text of ISO 10993-1:2003 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 10993-1:2009 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 December 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 10993-1:2003.
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 EU Directives, see informative Annex 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 10993-1:2003 has been approved by CEN as a EN ISO 10993-1:2009 without any
modification.
3

---------------------- Page: 5 ----------------------

SIST EN ISO 10993-1:2009
EN ISO 10993-1:2009 (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
3, 4, 5, 6, 7 The presumption of conformity
Annex I:
depends on applying the other
7.1, 7.2, 7.5
parts of the EN ISO 10993

series that are relevant

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


4

---------------------- Page: 6 ----------------------

SIST EN ISO 10993-1:2009
EN ISO 10993-1:2009 (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
3, 4, 5, 6, 7 The presumption of conformity
Annex I :
depends on applying the other
9
parts of the EN ISO 10993
series that are relevant

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




5

---------------------- Page: 7 ----------------------

SIST EN ISO 10993-1:2009

---------------------- Page: 8 ----------------------

SIST EN ISO 10993-1:2009


INTERNATIONAL ISO
STANDARD 10993-1
Third edition
2003-08-01


Biological evaluation of medical
devices —
Part 1:
Evaluation and testing
Évaluation biologique des dispositifs médicaux —
Partie 1: Évaluation et essais




Reference number
ISO 10993-1:2003(E)
©
ISO 2003

---------------------- Page: 9 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
PDF disclaimer
This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but
shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In
downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat
accepts no liability in this area.
Adobe is a trademark of Adobe Systems Incorporated.
Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation
parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In
the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below.


©  ISO 2003
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or
ISO's member body in the country of the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail [e-mail]
Web www.iso.org
Published in Switzerland

ii © ISO 2003 — All rights reserved

---------------------- Page: 10 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope. 1
2 Terms and definitions. 1
3 General principles applying to biological evaluation of medical devices . 2
4 Categorization of medical devices . 3
5 Testing. 4
6 Selection of biological evaluation tests. 7
7 Assurance of test methods. 8
Annex A (informative) Rationale .11
Annex B (informative) Flow chart to aid in ensuring a systematic approach to biological
evaluation of medical devices . 13
Bibliography . 14

© ISO 2003 — All rights reserved iii

---------------------- Page: 11 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(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 10993-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This third edition cancels and replaces the second edition (ISO 10993-1:1997), of which it constitutes a minor
revision.
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 8: Selection and qualification of reference materials for biological tests
— 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
iv © ISO 2003 — All rights reserved

---------------------- Page: 12 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
— Part 17: Establishment of allowable limits for leachable substances
— Part 18: Chemical characterization of materials
Future parts will deal with other relevant aspects of biological testing.
© ISO 2003 — All rights reserved v

---------------------- Page: 13 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
Introduction
This part of ISO 10993 is a combination/harmonization of numerous international and national standards and
guidelines concerning the biological evaluation of medical devices. It is intended to be the overall guidance
document for the selection of tests enabling evaluation of biological responses relevant to the safety of
medical devices and materials.
The role of this part of ISO 10993 is to serve as a framework in which to plan such a biological evaluation
which minimizes the number and exposure of test animals.
The protection of humans is the primary goal of ISO 10993.
The appropriate selection and interpretation of biological evaluation tests requires an understanding of the
rationale behind such testing. An informative rationale for the use of this part of ISO 10993 is provided in
Annex A. Annex B contains a flow chart to aid in the systematic approach to the biological evaluation of
medical devices. A bibliography is given at the end of the text.

vi © ISO 2003 — All rights reserved

---------------------- Page: 14 ----------------------

SIST EN ISO 10993-1:2009
INTERNATIONAL STANDARD ISO 10993-1:2003(E)

Biological evaluation of medical devices —
Part 1:
Evaluation and testing
1 Scope
This part of ISO 10993 describes
a) the general principles governing the biological evaluation of medical devices;
b) the categorization of devices based on the nature and duration of their contact with the body;
c) the selection of appropriate tests.
This part of ISO 10993 does not cover testing of materials and devices that do not come into direct or indirect
contact with the patient's body, nor does it cover biological hazards arising from any mechanical failure.
NOTE Other parts of ISO 10993 cover specific tests (see also the rationale in A.2).
2 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
2.1
medical device
any instrument, apparatus, appliance, material or other article, including software, whether used alone or in
combination, intended by the manufacturer to be used for human beings solely or principally for the purpose
of:
 diagnosis, prevention, monitoring, treatment or alleviation of disease;
 diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
 investigation, replacement or modification of the anatomy or of a physiological process;
 control of conception;
and which does not achieve its principal intended action in or on the human body by pharmacological,
immunological or metabolic means, but which may be assisted in its function by such means
NOTE 1 Devices are different from drugs, and their biological evaluation requires a different approach.
NOTE 2 Use of the term “medical device” includes dental devices.
2.2
material
any synthetic or natural polymer, metal, alloy, ceramic or other nonviable substance, including tissue rendered
nonviable, used as a medical device or any part thereof
© ISO 2003 — All rights reserved 1

---------------------- Page: 15 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
2.3
final product
medical device in its “as-used” state
3 General principles applying to biological evaluation of medical devices
3.1 The selection and evaluation of any material or device intended for use in humans requires a structured
programme of assessment.
In the design process, an informed decision shall be made and documented that weighs the
advantages/disadvantages of the various choices of material and test procedure. To give assurance that the
final product will perform as intended and be safe for human use, the programme shall include a biological
evaluation.
The biological evaluation shall be planned, carried out and documented by knowledgeable and experienced
individuals capable of making informed decisions based on the advantages and disadvantages of the various
materials and test procedures available.
3.2 In the selection of materials to be used in device manufacture, the first consideration should be fitness
for purpose with regard to characteristics and properties of the material, which include chemical, toxicological,
physical, electrical, morphological and mechanical properties.
3.3 The following should be considered for their relevance to the overall biological evaluation of the device:
a) the material(s) of manufacture;
b) intended additives, process contaminants and residues;
c) leachable substances;
d) degradation products;
e) other components and their interactions in the final product;
f) the properties and characteristics of the final product.
NOTE If appropriate, identification and quantification of extractable chemical entities of the final product should
precede biological evaluation (see ISO 10993-9).
3.4 Tests to be used in biological evaluation, and the interpretation of the results of such tests, should take
into account the chemical composition of the materials, including the conditions of exposure and the nature,
degree, frequency and duration of exposure of the device or its constituents to the body. By following these
principles, devices can be categorized to facilitate the selection of appropriate tests (see Clause 4). This part
of ISO 10993 is concerned with the tests to be carried out on materials and/or the final product.
The range of potential biological hazards is wide and may include:
a) short-term effects (e.g. acute toxicity, irritation to the skin, eye and mucosal surfaces, sensitization,
haemolysis and thrombogenicity);
b) long-term or specific toxic effects [e.g. subchronic and chronic toxic effects, sensitization, genotoxicity,
carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity].
3.5 All potential biological hazards should be considered for every material and final product, but this does
not imply that testing for all potential hazards will be necessary or practical (see Clause 6).
3.6 Any in vitro or in vivo tests shall be based on end-use applications and appropriate good laboratory
practice followed by evaluation by competent informed persons. Whenever possible, in vitro screening should
2 © ISO 2003 — All rights reserved

---------------------- Page: 16 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
be carried out before in vivo tests are commenced. Test data, complete to the extent that an independent
analysis could be made, shall be retained (see A.2, “Subclause 3.6”).
3.7 The materials or final product shall be considered for biological re-evaluation if any of the following
occurs:
a) any change in the source or in the specification of the materials used in the manufacture of the product;
b) any change in the formulation, processing, primary packaging or sterilization of the product;
c) any change in the final product during storage;
d) any change in the intended use of the product;
e) any evidence that the product may produce adverse effects when used in humans.
3.8 The biological evaluation performed in accordance with this part of ISO 10993 should be considered in
conjunction with the nature and mobility of the ingredients in the materials used to manufacture the device and
other information, other non-clinical tests, clinical studies and post-market experience for an overall
assessment (see A.2, “Subclause 3.8”).
4 Categorization of medical devices
4.1 General
Following the general principles laid down in Clause 3, medical devices can be categorized to facilitate the
selection of appropriate tests.
The testing of any device that does not fall into one of the categories described should follow the general
principles contained in this part of ISO 10993. Certain devices may fall into more than one category, in which
case testing appropriate to each category should be considered.
Medical devices shall be categorized according to the nature and duration of body contact as described in 4.2
and 4.3.
4.2 Categorization by nature of body contact
4.2.1 Non-contact devices
Medical devices that do not contact the patient's body directly or indirectly are not included in the scope of
ISO 10993.
4.2.2 Surface-contacting devices
These include medical devices in contact with the following surfaces:
a) skin: devices that contact intact skin surfaces only; examples include electrodes, external prostheses,
fixation tapes, compression bandages and monitors of various types;
b) mucosal membranes: devices that contact intact mucosal membranes; examples include contact lenses,
urinary catheters, intravaginal and intraintestinal devices (stomach tubes, sigmoidoscopes, colonoscopes,
gastroscopes), endotracheal tubes, bronchoscopes, dental prostheses, orthodontic devices and
intrauterine devices;
c) breached or compromised surfaces: devices that contact breached or otherwise compromised body
surfaces; examples include dressings, healing devices and occlusive patches for ulcers, burns and
granulation tissue.
© ISO 2003 — All rights reserved 3

---------------------- Page: 17 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
4.2.3 External communicating devices
These include medical devices in contact with the following application sites:
a) blood path, indirect: devices that contact the blood path at one point and serve as a conduit for entry
into the vascular system; examples include solution administration sets, extension sets, transfer sets and
blood administration sets;
b) tissue/bone/dentin: devices that contact tissue, bone or pulp/dentin systems; examples include
laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples;
c) circulating blood: devices that contact circulating blood; examples include intravascular catheters,
temporary pacemaker electrodes, oxygenators, extracorporal oxygenator tubing and accessories,
dialysers, dialysis tubing and accessories, haemoadsorbents and immunoadsorbents.
4.2.4 Implant devices
These include medical devices in contact with the following application sites:
a) tissue/bone:
1) devices principally contacting bone; examples include orthopaedic pins, plates, replacement joints,
bone prostheses, bone cements and intraosseous devices;
2) devices principally contacting tissue and tissue fluid; examples include pacemakers, drug supply
devices, neuromuscular sensors and stimulators, replacement tendons, breast implants, artificial
larynxes, subperiostal implants and ligation clips;
b) blood: devices principally contacting blood; examples include pacemaker electrodes, artificial
arteriovenous fistulae, heart valves, vascular grafts, internal drug-delivery catheters and ventricular assist
devices.
4.3 Categorization by duration of contact
Medical devices shall be categorized according to the duration of contact as follows:
a) Limited exposure (A): devices whose single or multiple use or contact is likely to be up to 24 h;
b) Prolonged exposure (B): devices whose single, multiple or long-term use or contact is likely to exceed
24 h but not 30 days;
c) Permanent contact (C): devices whose single, multiple or long-term use or contact exceeds 30 days.
If a material or device may be placed in more than one duration category, the more rigorous testing
requirements shall apply. With multiple exposures to the device, the decision into which category a device is
placed should take into account the potential cumulative effect, bearing in mind the period of time over which
these exposures occur.
5 Testing
5.1 General
In addition to the general principles laid down in Clause 3, the following shall apply to biological testing of
medical devices.
a) Testing shall be performed on the final product, or on representative samples taken from the final product
or from materials processed in the same manner as the final product.
4 © ISO 2003 — All rights reserved

---------------------- Page: 18 ----------------------

SIST EN ISO 10993-1:2009
ISO 10993-1:2003(E)
b) The choice of test procedures shall take into account:
1) the nature, degree, duration, frequency and conditions of exposure to or contact of humans with the
device in the normal intended use;
2) the chemical and physical nature of the final product;
3) the toxicological activity of the chemical elements or compounds in the formulation of the final
product;
4) that certain tests (e.g. those designed to assess systemic effects) may not be applicable where the
presence of leachable materials has been excluded, or where leachables have a known and
acceptable toxicity profile;
5) the relationship of device surface area to recipient body size;
6) the existing information based on the literature, experience and non-clinical tests;
7) that the protection of humans is the primary goal of this document, a secondary goal being to ensure
animal welfare and to minimize the number and exposure of test animals.
c) If extracts of the devices are prepared, the solvents and conditions of extraction used shall be appropriate
to the nature and use of the final product.
d) Positive and negative controls shall be used where appropriate.
e) Test results cannot ensure freedom from potential biological hazard, thus biological investigations shall
be followed by careful observations for unexpected adverse reactions or events in humans during clinical
use of the device.
A bibliography of International Standards and guidelines on biological-response test methods is given at the
end of the text.
5.2 Initial evaluation tests
5.2.1 General
The tests that shall be considered for initial biological response are given in 5.2.2 to 5.2.10.
5.2.2 Cytotoxicity
With the use of cell culture techniques, these tests determine the lysis of cells (cell death), the inhibition of cell
growth, and other effects on cells caused by medical devices, materials and/or their extracts. Cytotoxicity tests
are described in ISO 10993-5.
5.2.3 Sensitization
These tests estimate, using an appropriate model, the potential of medical devices, materials and/or their
extracts for contact sensitization. These tests are appropriate because exposure or contact to even minute
amounts of potential leachables can
...

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.SUHVNXãDQMHBiologische Beurteilung von Medizinprodukten Teil 1: Beurteilung und Prüfungen (ISO 10993-1:2003)Evaluation biologique des dispositifs médicaux - Partie 1: Evaluation et essais (ISO 10993-1:2003)Biological evaluation of medical devices - Part 1: Evaluation and testing (ISO 10993-1:2003)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:FprEN ISO 10993-1kSIST FprEN ISO 10993-1:2009enkSIST FprEN ISO 10993-1:2009SLOVENSKI
STANDARD



kSIST FprEN ISO 10993-1:2009



EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTFprEN ISO 10993-1January 2009ICS 11.100.20Will supersede EN ISO 10993-1:2003
English VersionBiological evaluation of medical devices - Part 1: Evaluation andtesting (ISO 10993-1:2003)Evaluation biologique des dispositifs médicaux - Partie 1:Evaluation et essais (ISO 10993-1:2003)Biologische Beurteilung von Medizinprodukten Teil 1:Beurteilung und Prüfungen (ISO 10993-1:2003)This draft European Standard is submitted to CEN members for unique acceptance procedure. It has been drawn up by the TechnicalCommittee CEN/TC 206.If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations whichstipulate 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 languagemade by translation under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has thesame 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.Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice andshall not be referred to as a European Standard.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre:
Avenue Marnix 17,
B-1000 Brussels© 2009 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. FprEN ISO 10993-1:2009: EkSIST FprEN ISO 10993-1:2009



FprEN ISO 10993-1:2009 (E) 2 Contents Page Foreword .3Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 kSIST FprEN ISO 10993-1:2009



FprEN ISO 10993-1:2009 (E) 3 Foreword The text of ISO 10993-1:2003 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 FprEN ISO 10993-1:2009 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 10993-1:2003. 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 EU Directives, see informative Annex ZA and ZB, which is an integral part of this document. Endorsement notice The text of ISO 10993-1:2003 has been approved by CEN as a FprEN ISO 10993-1:2009 without any modification. kSIST FprEN ISO 10993-1:2009



FprEN ISO 10993-1:2009 (E) 4 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 EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 3, 4, 5, 6, 7
Annex I: 7.1, 7.2, 7.5 The presumption of conformity depends on applying the other parts of the EN ISO 10993 series that are relevant
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST FprEN ISO 10993-1:2009



FprEN ISO 10993-1:2009 (E) 5 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 EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 3, 4, 5, 6, 7 Annex I : 9 The presumption of conformity depends on applying the other parts of the EN ISO 10993 series that are relevant
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST FprEN ISO 10993-1:2009



kSIST FprEN ISO 10993-1:2009



Reference numberISO 10993-1:2003(E)© ISO 2003
INTERNATIONAL STANDARD ISO10993-1Third edition2003-08-01Biological evaluation of medical devices — Part 1: Evaluation and testing Évaluation biologique des dispositifs médicaux — Partie 1: Évaluation et essais
kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat accepts no liability in this area. Adobe is a trademark of Adobe Systems Incorporated. Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below.
©
ISO 2003 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel.
+ 41 22 749 01 11 Fax
+ 41 22 749 09 47 E-mail
[e-mail] Web
www.iso.org Published in Switzerland
ii © ISO 2003 — All rights reserved
kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) © ISO 2003 — All rights reserved iii Contents Page Foreword.iv Introduction.vi 1 Scope.1 2 Terms and definitions.1 3 General principles applying to biological evaluation of medical devices.2 4 Categorization of medical devices.3 5 Testing.4 6 Selection of biological evaluation tests.7 7 Assurance of test methods.8 Annex A (informative)
Rationale.11 Annex B (informative)
Flow chart to aid in ensuring a systematic approach to biological evaluation of medical devices.13 Bibliography.14
kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) iv © ISO 2003 — All rights reserved 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 10993-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This third edition cancels and replaces the second edition (ISO 10993-1:1997), of which it constitutes a minor revision. 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 8: Selection and qualification of reference materials for biological tests — 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 kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) © ISO 2003 — All rights reserved v — Part 17: Establishment of allowable limits for leachable substances — Part 18: Chemical characterization of materials Future parts will deal with other relevant aspects of biological testing. kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) vi © ISO 2003 — All rights reserved Introduction This part of ISO 10993 is a combination/harmonization of numerous international and national standards and guidelines concerning the biological evaluation of medical devices. It is intended to be the overall guidance document for the selection of tests enabling evaluation of biological responses relevant to the safety of medical devices and materials. The role of this part of ISO 10993 is to serve as a framework in which to plan such a biological evaluation which minimizes the number and exposure of test animals. The protection of humans is the primary goal of ISO 10993. The appropriate selection and interpretation of biological evaluation tests requires an understanding of the rationale behind such testing. An informative rationale for the use of this part of ISO 10993 is provided in Annex A. Annex B contains a flow chart to aid in the systematic approach to the biological evaluation of medical devices. A bibliography is given at the end of the text.
kSIST FprEN ISO 10993-1:2009



INTERNATIONAL STANDARD ISO 10993-1:2003(E) © ISO 2003 — All rights reserved 1 Biological evaluation of medical devices —
Part 1: Evaluation and testing 1 Scope This part of ISO 10993 describes a) the general principles governing the biological evaluation of medical devices; b) the categorization of devices based on the nature and duration of their contact with the body; c) the selection of appropriate tests. This part of ISO 10993 does not cover testing of materials and devices that do not come into direct or indirect contact with the patient's body, nor does it cover biological hazards arising from any mechanical failure. NOTE Other parts of ISO 10993 cover specific tests (see also the rationale in A.2). 2 Terms and definitions For the purposes of this document, the following terms and definitions apply. 2.1 medical device any instrument, apparatus, appliance, material or other article, including software, whether used alone or in combination, intended by the manufacturer to be used for human beings solely or principally for the purpose of:  diagnosis, prevention, monitoring, treatment or alleviation of disease;  diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;  investigation, replacement or modification of the anatomy or of a physiological process;  control of conception; and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means NOTE 1 Devices are different from drugs, and their biological evaluation requires a different approach. NOTE 2 Use of the term “medical device” includes dental devices. 2.2 material any synthetic or natural polymer, metal, alloy, ceramic or other nonviable substance, including tissue rendered nonviable, used as a medical device or any part thereof kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) 2 © ISO 2003 — All rights reserved 2.3 final product medical device in its “as-used” state 3 General principles applying to biological evaluation of medical devices 3.1 The selection and evaluation of any material or device intended for use in humans requires a structured programme of assessment. In the design process, an informed decision shall be made and documented that weighs the advantages/disadvantages of the various choices of material and test procedure. To give assurance that the final product will perform as intended and be safe for human use, the programme shall include a biological evaluation. The biological evaluation shall be planned, carried out and documented by knowledgeable and experienced individuals capable of making informed decisions based on the advantages and disadvantages of the various materials and test procedures available. 3.2 In the selection of materials to be used in device manufacture, the first consideration should be fitness for purpose with regard to characteristics and properties of the material, which include chemical, toxicological, physical, electrical, morphological and mechanical properties. 3.3 The following should be considered for their relevance to the overall biological evaluation of the device: a) the material(s) of manufacture; b) intended additives, process contaminants and residues; c) leachable substances; d) degradation products; e) other components and their interactions in the final product; f) the properties and characteristics of the final product. NOTE If appropriate, identification and quantification of extractable chemical entities of the final product should precede biological evaluation (see ISO 10993-9). 3.4 Tests to be used in biological evaluation, and the interpretation of the results of such tests, should take into account the chemical composition of the materials, including the conditions of exposure and the nature, degree, frequency and duration of exposure of the device or its constituents to the body. By following these principles, devices can be categorized to facilitate the selection of appropriate tests (see Clause 4). This part of ISO 10993 is concerned with the tests to be carried out on materials and/or the final product. The range of potential biological hazards is wide and may include: a) short-term effects (e.g. acute toxicity, irritation to the skin, eye and mucosal surfaces, sensitization, haemolysis and thrombogenicity); b) long-term or specific toxic effects [e.g. subchronic and chronic toxic effects, sensitization, genotoxicity, carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity]. 3.5 All potential biological hazards should be considered for every material and final product, but this does not imply that testing for all potential hazards will be necessary or practical (see Clause 6). 3.6 Any in vitro or in vivo tests shall be based on end-use applications and appropriate good laboratory practice followed by evaluation by competent informed persons. Whenever possible, in vitro screening should kSIST FprEN ISO 10993-1:2009



ISO 10993-1:2003(E) © ISO 2003 — All rights reserved 3 be carried out before in vivo tests are commenced. Test data, complete to the extent that an independent analysis could be made, shall be retained (see A.2, “Subclause 3.6”). 3.7 The materials or final product shall be considered for biological re-evaluation if any of the following occurs: a) any change in the source or in the specification of the materials used in the manufacture of the product; b) any change in the formulation, processing, primary packaging or sterilization of the product; c) any change in the final product during storage; d) any change in the intended use of the product; e) any evidence that the product may produce adverse effects when used in humans. 3.8 The biological evaluation performed in accordance with this part of ISO 10993 should be considered in conjunction with the nature and mobility of the ingredients in the materials used to manufacture the device and other information, other non-clinical tests, clinical studies and post-market experience for an overall assessment (see A.2, “Subclause 3.8”). 4 Categorization of medical devices 4.1 General Following the general principles laid down in Clause 3, medical devices can be categorized to facilitate the selection of appropriate tests. The testing of any device that does not fall into one of the categories described should follow the general principles contained in this part of ISO 10993. Certain devices may fall into more than one category, in which case testing appropriate to each category should be considered. Medical devices shall be categorized according to the nature and duration of body contact as described in 4.2 and 4.3. 4.2 Categorization by nature of body contact 4.2.1 Non-contact devices Medical devices that do not contact the patient's body directly or indirectly are not included in the scope of ISO 10993. 4.2.2 Surface-contacting devices These include medical devices in contact with the following surfaces: a) skin: devices that contact intact skin surfaces only; examples include electrodes, external prostheses, fixation tapes, compression bandages and monitors of various types; b) mucosal membranes: de
...