SIST EN ISO 10993-1:2021
(Main)Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2018, including corrected version 2018-11)
Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2018, including corrected version 2018-11)
This document specifies:
— the general principles governing the biological evaluation of medical devices within a risk
management process;
— the general categorization of medical devices based on the nature and duration of their contact with
the body;
— the evaluation of existing relevant data from all sources;
— the identification of gaps in the available data set on the basis of a risk analysis;
— the identification of additional data sets necessary to analyse the biological safety of the medical
device;
— the assessment of the biological safety of the medical device.
This document applies to evaluation of materials and medical devices that are expected to have direct
or indirect contact with:
— the patient's body during intended use;
— the user’s body, if the medical device is intended for protection (e.g., surgical gloves, masks and
others).
This document is applicable to biological evaluation of all types of medical devices including active,
non-active, implantable and non-implantable medical devices.
This document also gives guidelines for the assessment of biological hazards arising from:
— risks, such as changes to the medical device over time, as a part of the overall biological safety
assessment;
— breakage of a medical device or medical device component which exposes body tissue to new or
novel materials.
Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Devicespecific
or product standards address mechanical testing.
This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform
encephalopathy (TSE) agents and other pathogens.
Biologische Beurteilung von Medizinprodukten - Teil 1: Beurteilung und Prüfungen im Rahmen eines Risikomanagementsystems (ISO 10993-1:2018, einschließlich korrigierte Fassung 2018-11)
Dieses Dokument legt das Folgende fest:
- die allgemeinen Grundsätze, die für die biologische Beurteilung von Medizinprodukten innerhalb eines Risikomanagementverfahrens gelten;
- die allgemeine Einteilung von Medizinprodukten, basierend auf der Art und Dauer von deren Kontakt mit dem Körper;
- die Auswertung vorhandener relevanter Daten aus allen Quellen;
- die Ermittlung von Lücken in den verfügbaren Datensätzen auf der Grundlage einer Risikoanalyse;
- die Ermittlung zusätzlicher Datensätze, die für die Analyse der biologischen Sicherheit des Medizin¬produkts notwendig sind;
- die Beurteilung der biologischen Sicherheit des Medizinprodukts.
Dieses Dokument gilt für die Beurteilung von Materialien und Medizinprodukten, von denen erwartet wird, dass sie direkt oder indirekt in Kontakt kommen mit
- dem Körper des Patienten im Rahmen der bestimmungsgemäßen Verwendung, und/oder
- dem Körper des Anwenders, wenn das Medizinprodukt zum Schutz vorgesehen ist (z. B. OP-Hand-schuhe, Masken und andere Produkte).
Dieses Dokument ist anwendbar auf die biologische Beurteilung aller Arten an Medizinprodukten, einschließlich aktiver, nicht aktiver, implantierbarer und nicht implantierbarer Medizinprodukte.
Dieses Dokument bietet außerdem einen Leitfaden zur Beurteilung von biologischen Gefährdungen aufgrund von
- Risiken, wie etwa Veränderungen des Medizinprodukts im Laufe der Zeit, als Teil der biologischen Sicherheitsbewertung, und/oder
- Beschädigung eines Medizinprodukts oder eines Bestandteils des Medizinprodukts, was zur Folge hat, dass Körpergewebe neuen oder neu entstandenen Materialien ausgesetzt wird.
Andere Teile der ISO 10993 decken spezifische Aspekte der biologischen Beurteilungen und zugehörigen Prüfungen ab. Spezifische Normen für das Medizinprodukt oder Produktnormen behandeln die mechanische Prüfung.
Gefährdungen im Zusammenhang mit Bakterien, Schimmelpilzen, Hefen, Viren, den Erregern der Trans¬missiblen Spongiformen Enzephalopathie (TSE) und weiteren pathogenen Organismen werden in diesem Dokument nicht behandelt.
Évaluation biologique des dispositifs médicaux - Partie 1: Évaluation et essais au sein d'un processus de gestion du risque (ISO 10993-1:2018, y compris version corrigée 2018-11)
Le présent document spécifie:
— les principes généraux sur lesquels repose l'évaluation biologique des dispositifs médicaux dans un processus de gestion du risque;
— la classification générale des dispositifs médicaux, fondée sur la nature et la durée de leur contact avec le corps humain;
— l'évaluation de toutes les données pertinentes existantes;
— l'identification de lacunes dans les ensembles de données disponibles sur la base d'une analyse de risque;
— l'identification d'ensembles de données supplémentaires nécessaires à l'analyse de la sécurité biologique du dispositif médical;
— l'évaluation de la sécurité biologique du dispositif médical.
Le présent document s'applique à l'évaluation de matériaux et dispositifs médicaux qui sont destinés à entrer en contact direct ou indirect avec:
— le corps du patient pendant leur utilisation prévue;
— le corps de l'utilisateur si le dispositif médical est destiné à la protection (par exemple gants chirurgicaux, masques et autres).
Le présent document est applicable à l'évaluation biologique de tous types de dispositifs médicaux, y compris les dispositifs médicaux actifs, non actifs, implantables et non implantables.
Le présent document donne également des lignes directrices pour l'évaluation des dangers biologiques provenant de:
— risques tels que des modifications du dispositif médical au fil du temps, dans le cadre de l'évaluation de sécurité biologique générale;
— rupture d'un dispositif médical ou d'un composant de dispositif médical qui expose des tissus de l'organisme à des matériaux nouveaux.
Les autres parties de l'ISO 10993 couvrent des aspects spécifiques des évaluations biologiques et des essais associés. Des normes de produits ou spécifiques aux dispositifs traitent des essais mécaniques.
Le présent document exclut les dangers relatifs aux bactéries, moisissures, levures, virus, agents de l'encéphalopathie spongiforme transmissible (EST) et autres agents pathogènes.
Biološko ovrednotenje medicinskih pripomočkov - 1. del: Ocena in preskušanje znotraj procesa obvladovanja tveganja (ISO 10993-1:2018, vključno s popravkom verzije 2018-11)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-1:2021
01-februar-2021
Nadomešča:
SIST EN ISO 10993-1:2010
SIST EN ISO 10993-1:2010/AC:2010
Biološko ovrednotenje medicinskih pripomočkov - 1. del: Ocena in preskušanje
znotraj procesa obvladovanja tveganja (ISO 10993-1:2018, vključno s popravkom
verzije 2018-11)
Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk
management process (ISO 10993-1:2018, including corrected version 2018-11)
Biologische Beurteilung von Medizinprodukten - Teil 1: Beurteilung und Prüfungen im
Rahmen eines Risikomanagementsystems (ISO 10993-1:2018, einschließlich korrigierte
Fassung 2018-11)
Évaluation biologique des dispositifs médicaux - Partie 1: Évaluation et essais au sein
d'un processus de gestion du risque (ISO 10993-1:2018, y compris version corrigée
2018-11)
Ta slovenski standard je istoveten z: EN ISO 10993-1:2020
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
SIST EN ISO 10993-1:2021 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-1:2021
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SIST EN ISO 10993-1:2021
EN ISO 10993-1
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2020
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-1:2009
English Version
Biological evaluation of medical devices - Part 1:
Evaluation and testing within a risk management process
(ISO 10993-1:2018, including corrected version 2018-11)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil 1:
1: Évaluation et essais au sein d'un processus de Beurteilung und Prüfungen im Rahmen eines
gestion du risque (ISO 10993-1:2018, y compris Risikomanagementsystems (ISO 10993-1:2018,
version corrigée 2018-11) einschließlich korrigierte Fassung 2018-11)
This European Standard was approved by CEN on 10 December 2020.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2020 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-1:2020 E
worldwide for CEN national Members.
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SIST EN ISO 10993-1:2021
EN ISO 10993-1:2020 (E)
Contents Page
European foreword . 3
2
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SIST EN ISO 10993-1:2021
EN ISO 10993-1:2020 (E)
European foreword
This document (EN ISO 10993-1:2020) has been prepared by Technical Committee ISO/TC 194
"Biological and clinical evaluation of medical devices" in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by June 2021, and conflicting national standards shall be
withdrawn at the latest by June 2021.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-1:2009.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the
United Kingdom.
Endorsement notice
The text of ISO 10993-1:2018, including corrected version 2018-11 has been approved by CEN as
EN ISO 10993-1:2020 without any modification.
3
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SIST EN ISO 10993-1:2021
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SIST EN ISO 10993-1:2021
INTERNATIONAL ISO
STANDARD 10993-1
Fifth edition
2018-08
Corrected version
2018-10
Biological evaluation of medical
devices —
Part 1:
Evaluation and testing within a risk
management process
Évaluation biologique des dispositifs médicaux —
Partie 1: Évaluation et essais au sein d'un processus de gestion du
risque
Reference number
ISO 10993-1:2018(E)
©
ISO 2018
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2018 – All rights reserved
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General principles applying to biological evaluation of medical devices .5
5 Categorization of medical devices . 9
5.1 General . 9
5.2 Categorization by nature of body contact . 9
5.2.1 Non-contacting medical devices. 9
5.2.2 Surface-contacting medical devices .10
5.2.3 Externally communicating medical devices .10
5.2.4 Implant medical devices .11
5.3 Categorization by duration of contact .11
5.3.1 Contact duration categories .11
5.3.2 Transitory-contacting medical devices .11
5.3.3 Medical devices with multiple contact duration categories .11
6 Biological evaluation process .12
6.1 Physical and chemical information for biological risk analysis .12
6.2 Gap analysis and selection of biological endpoints for assessment .12
6.3 Biological testing .13
6.3.1 General.13
6.3.2 Testing for evaluation .14
7 Interpretation of biological evaluation data and overall biological risk assessment .18
Annex A (informative) Endpoints to be addressed in a biological risk assessment.20
Annex B (informative) Guidance on the conduct of biological evaluation within a risk
management process .25
Annex C (informative) Suggested procedure for literature review .38
Bibliography .40
© ISO 2018 – All rights reserved iii
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www .iso .org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
This fifth edition cancels and replaces the fourth edition (ISO 10993-1:2009), which has been technically
revised. It also incorporates the Technical Corrigendum ISO 10993-1:2009/Cor.1:2010.
The main changes compared to the previous edition are as follows:
a) revised Annex A “Endpoints to be addressed in a biological risk assessment” with new columns for
“physical and/or chemical information” and “material mediated pyrogenicity” as well as columns
for “chronic toxicity,” “carcinogenicity,” “reproductive/developmental toxicity,” and “degradation”
which now indicates “endpoints” to be considered with “E” (instead of “tests” to be conducted with
an “X”);
b) replaced Annex B “Guidance on the risk management process” with “Guidance on the conduct of
biological evaluation within a risk management process” (formerly ISO TR 15499);
c) additional definitions for terms used throughout the ISO 10993 series of standards;
d) additional information on the evaluation of “Non-contacting medical devices” and new information
on the evaluation of “Transitory-contacting medical devices”;
e) additional information on the evaluation of nanomaterials, and absorbable materials;
f) additional reference to ISO 18562 (all parts) for “Biocompatibility evaluation of breathing gas
pathways in healthcare applications”;
g) significant editing changes throughout the document;
A list of all parts in the ISO 10993 series can be found on the ISO website.
This corrected version of ISO 10993-1:2018 incorporates the following correction.
iv © ISO 2018 – All rights reserved
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
th
—In Table A.1, 6 column, “Sensitization” has been added as a table heading.
© ISO 2018 – All rights reserved v
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
Introduction
The primary aim of this document is the protection of humans from potential biological risks arising
from the use of medical devices. It is compiled from numerous International and national standards
and guidelines concerning the biological evaluation of medical devices. It is intended to describe the
biological evaluation of medical devices within a risk management process, as part of the overall
evaluation and development of each medical device. This approach combines the review and evaluation
of existing data from all sources with, where necessary, the selection and application of additional tests,
thus enabling a full evaluation to be made of the biological responses to each medical device, relevant
to its safety in use. The term “medical device” is wide-ranging and, at one extreme, consists of a single
material, which can exist in more than one physical form, and at the other extreme, of a medical device
consisting of numerous components made of more than one material.
This document addresses the determination of the biological response to medical devices, mostly in a
general way, rather than in a specific device-type situation. Thus, for a complete biological evaluation, it
classifies medical devices according to the nature and duration of their anticipated contact with human
tissues when in use and indicates, in a matrix, the biological endpoints that are thought to be relevant in
the consideration of each medical device category. See also 3.14, Note 1 to entry.
The range of biological hazards is wide and complex. The biological response to a constituent material
alone cannot be considered in isolation from the overall medical device design. Thus, in designing a
medical device, the choice of the best material with respect to its biocompatibility might result in a
less functional medical device, biocompatibility being only one of a number of characteristics to be
considered in making that choice. Where a material is intended to interact with tissue in order to
perform its function, the biological evaluation needs to address this.
Biological responses that are regarded as adverse, caused by a material in one application, might not be
regarded as such in a different situation. Biological testing is based upon, among other things, in vitro
and ex vivo test methods and upon animal models, so that the anticipated behaviour when a medical
device is used in humans can be judged only with caution, as it cannot be unequivocally concluded
that the same biological response will also occur in this species. In addition, differences in the manner
of response to the same material among individuals indicate that some patients can have adverse
reactions, even to well-established materials.
The primary role of this document is to serve as a framework in which to plan a biological evaluation. A
secondary role is to utilize scientific advances in our understanding of basic mechanisms, to minimize
the number and exposure of test animals by giving preference to in vitro models and to chemical,
physical, morphological, and topographical characterization testing, in situations where these methods
yield equally relevant information to that obtained from in vivo models.
It is not intended that this document provide a rigid set of test methods, including pass/fail criteria,
as this might result in either an unnecessary constraint on the development and use of novel medical
devices, or a false sense of security in the general use of medical devices. Where a particular application
warrants it, experts in the product or in the area of application concerned can choose to establish
specific tests and criteria, described in a product-specific vertical standard.
ISO 10993 series is intended for use by professionals, appropriately qualified by training and experience,
who are able to interpret its requirements and judge the outcome of the evaluation for each medical
device, taking into consideration all the factors relevant to the medical device, its intended use and the
current knowledge of the medical device provided by review of the scientific literature and previous
clinical experience.
Informative Annex A contains a table that is generally helpful in identifying endpoints recommended
in the biocompatibility evaluation of medical devices, according to their category of body contact and
duration of clinical exposure. Informative Annex B contains guidance for the application of the risk
management process to medical devices which encompasses biological evaluation.
vi © ISO 2018 – All rights reserved
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SIST EN ISO 10993-1:2021
INTERNATIONAL STANDARD ISO 10993-1:2018(E)
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management process
1 Scope
This document specifies:
— the general principles governing the biological evaluation of medical devices within a risk
management process;
— the general categorization of medical devices based on the nature and duration of their contact with
the body;
— the evaluation of existing relevant data from all sources;
— the identification of gaps in the available data set on the basis of a risk analysis;
— the identification of additional data sets necessary to analyse the biological safety of the medical
device;
— the assessment of the biological safety of the medical device.
This document applies to evaluation of materials and medical devices that are expected to have direct
or indirect contact with:
— the patient's body during intended use;
— the user’s body, if the medical device is intended for protection (e.g., surgical gloves, masks and
others).
This document is applicable to biological evaluation of all types of medical devices including active,
non-active, implantable and non-implantable medical devices.
This document also gives guidelines for the assessment of biological hazards arising from:
— risks, such as changes to the medical device over time, as a part of the overall biological safety
assessment;
— breakage of a medical device or medical device component which exposes body tissue to new or
novel materials.
Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Device-
specific or product standards address mechanical testing.
This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform
encephalopathy (TSE) agents and other pathogens.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-2:2006, Biological evaluation of medical devices — Part 2: Animal welfare requirements
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood
ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
ISO 10993-11:2017, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
degradation products from metals and alloys
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for
immunotoxicology testing of medical devices
ISO 14971:2007, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http: //www .electropedia .org/
— ISO Online browsing platform: available at https: //www .iso .org/obp
3.1
biocompatibility
ability of a medical device (3.14) or material (3.12) to perform with an appropriate host response in a
specific application
3.2
biological risk
combination of the probability of harm to health occurring as a result of adverse reactions associated
with medical device (3.14) or material (3.12) interactions, and the severity of that harm
2 © ISO 2018 – All rights reserved
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
3.3
biological safety
freedom from unacceptable biological risk (3.2) in the context of the intended use
3.4
chemical constituent
any synthetic or natural substance that is used in a process for manufacturing materials (3.12) and/
or medical devices (3.14), including the base material(s), additives (antioxidants, UV stabilizers, color
additives, dyes, etc.), and processing aids (solvents, lubricants, antifoaming agents, etc.)
3.5
data set
information, such as physical and/or chemical characterization, toxicity data, etc. from a variety of
sources necessary to characterize the biological response to a medical device
3.6
direct contact
medical device (3.14) or medical device component that comes into physical contact with body tissue
3.7
externally communicating medical device
medical device (3.14) or medical device component that is partially or wholly located outside the body
but has either direct or indirect contact with the internal body fluids and/or tissues
3.8
final product
medical device (3.14) or medical device component that has been subjected to all manufacturing
processes for the “to be marketed” medical device including packaging and if applicable, sterilization
3.9
geometry
device configuration
shape and relative arrangement of the parts of the medical device (3.14)
3.10
implant
medical device (3.14) which is intended to be totally introduced into the human body or to replace an
epithelial surface or the surface of the eye by means of clinical intervention and which is intended to
remain in place after the procedure
3.11
indirect contact
medical device (3.14) or medical device component through which a fluid or gas passes, prior to the fluid
or gas coming into physical contact with body tissue (in this case the medical device or medical device
component itself does not physically contact body tissue)
3.12
material
synthetic or natural polymer, metal or alloy, ceramic, or composite, including tissue rendered non-
viable, used as a medical device (3.14) or any part thereof
3.13
material characterization
broad and general process of collecting existing information about a material’s chemistry, structure
and other properties, and if appropriate, new data, to facilitate the evaluation of these properties
3.14
medical device
any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software,
material (3.12) or other similar or related article, intended by the manufacturer to be used, alone or in
combination, for human beings, for one or more of the specific medical purpose(s) of:
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SIST EN ISO 10993-1:2021
ISO 10993-1:2018(E)
— diagnosis, prevention, monitoring, treatment or alleviation of disease;
— diagnosis, monitoring, treatment, alleviation of or compensation for an injury;
— investigation, replacement, modification, or support of the anatomy or of a physiological process;
— supporting or sustaining life;
— control of conception;
— disinfection of medical devices;
— providing information by means of in vitro examination of specimens derived from the human body;
and does not achieve its primary intended action by pharmacological, immunological or metabolic
means, in or on the human body, but which may be assisted in its intended function by such means.
Medical devices include dental devices.
Note 1 to entry: Products which may be considered to be medical devices in some jurisdictions but not in others
include:
— disinfection substances;
— aids for persons with disabilities;
— devices incorporating animal and/or human tissues;
— devices for in vitro fertilization or assisted reproduction technologies;
[SOURCE: GHTF/SG1/N071: 2012, 5.1 modified to clarify that dental devices are included]
3.15
nanomaterial
material (3.12) with any external dimension in the nanoscale or having internal structure or surface
structure in the nanoscale
[SOURCE: ISO/TR 10993-22:2017, 3. 7, modified — Notes to entry have been deleted.]
3.16
non-contacting
indicates that the medical device (3.14) or medical device component has neither d
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-1:2017
01-maj-2017
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Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk
management process (ISO/DIS 10993-1:2017)
Biologische Beurteilung von Medizinprodukten - Teil 1: Beurteilung und Prüfungen im
Rahmen eines Risikomanagementsystems (ISO/DIS 10993-1:2017)
Évaluation biologique des dispositifs médicaux - Partie 1: Évaluation et essais au sein
d'un processus de gestion du risque (ISO/DIS 10993-1:2017)
Ta slovenski standard je istoveten z: prEN ISO 10993-1
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-1:2017 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-1:2017
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oSIST prEN ISO 10993-1:2017
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-1
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2017-02-20 2017-05-14
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management process
Évaluation biologique des dispositifs médicaux —
Partie 1: Évaluation et essais au sein d’un processus de gestion du risque
ICS: 11.100.20
THIS DOCUMENT IS A DRAFT CIRCULATED
This document is circulated as received from the committee secretariat.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
ISO/CEN PARALLEL PROCESSING
BEING ACCEPTABLE FOR INDUSTRIAL,
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USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-1:2017(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2017
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oSIST prEN ISO 10993-1:2017
ISO/DIS 10993-1:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
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ii © ISO 2017 – All rights reserved
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oSIST prEN ISO 10993-1:2017
ISO/DIS 10993-1:2017(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General principles applying to biological evaluation of medical devices .5
5 Categorization of medical devices . 9
5.1 General . 9
5.2 Categorization by nature of body contact . 9
5.2.1 Non-contacting devices . 9
5.2.2 Transient-contacting devices .10
5.2.3 Surface-contacting devices .10
5.2.4 External communicating devices .10
5.2.5 Implant devices .11
5.3 Categorization by duration of contact .11
6 Biocompatibility evaluation process .12
6.1 Biological risk assessment .12
6.1.1 Physical and chemical information .12
6.1.2 General: Gap analysis and selection of biological endpoints for assessment .12
6.1.3 Biological testing.14
7 Interpretation of biological evaluation data and overall biological safety assessment .18
Annex A (informative) Endpoints to be addressed in a biological risk assessment.20
Annex B (informative) Guidance on the conduct of biological evaluation within a risk
management process .25
Annex C (informative) Suggested procedure for literature review .38
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered .40
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered .42
Bibliography .44
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oSIST prEN ISO 10993-1:2017
ISO/DIS 10993-1:2017(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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/ patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity assessment,
as well as information about ISO’s adherence to the World Trade Organization (WTO) principles in the
Technical Barriers to Trade (TBT) see the following URL: www . i so .org/ iso/ foreword .html.
The committee responsible for this document is ISO/TC 194, Biological and clinical evaluation of medical
devices.
This fifth edition cancels and replaces the fourth edition (ISO 10993-1:2009), which has been technically
revised.
It also incorporates the Corrigendum ISO 10993-1:2009/Cor.1.
The following technical were changes:
a) revised Annex A “Endpoints to be addressed in a biological risk assessment”;
b) replaced Annex B “Guidance on the risk management process” with “Guidance on the conduct of
biological evaluation within a risk management process” (formally TR 15499);
c) editing changes in the genotoxicity section and other sections of the normative document;
d) additional definitions for terms used throughout the 10993 series of standards added;
e) additional “Non-contacting devices” and “Transient-contacting devices” categories.
A list of all parts in the ISO 10993- series can be found on the ISO website.
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oSIST prEN ISO 10993-1:2017
ISO/DIS 10993-1:2017(E)
Introduction
The primary aim of this document is the protection of humans from potential biological risks arising
from the use of medical devices. It is compiled from numerous International and national standards
and guidelines concerning the biological evaluation of medical devices. It is intended to describe the
biological evaluation of medical devices within a risk management process, as part of the overall
evaluation and development of each device. This approach combines the review and evaluation of
existing data from all sources with, where necessary, the selection and application of additional tests,
thus enabling a full evaluation to be made of the biological responses to each medical device, relevant
to its safety in use. It must be appreciated that the term “medical device” is wide-ranging and, at one
extreme, consists of a single material, which can exist in more than one physical form, and at the other
extreme, of a medical device consisting of numerous components made of more than one material.
This document addresses the determination of the biological response to medical devices, mostly in a
general way, rather than in a specific device-type situation. Thus, for a complete biological evaluation, it
classifies medical devices according to the nature and duration of their anticipated contact with human
tissues when in use and indicates, in a matrix the biological endpoints that are thought to be relevant in
the consideration of each device category.
NOTE Products which might be considered to be medical devices in some jurisdictions but for which there is
not yet a harmonized approach, are:
1) aids for disabled/handicapped people;
2) devices for the treatment/diagnosis of diseases and injuries in animals;
3) accessories for medical devices;
4) disinfection substances;
5) devices incorporating animal and human tissues, which might meet the requirements of the above definition
but are subject to different controls.
The range of biological hazards is wide and complex. The biological response to a constituent material
alone cannot be considered in isolation from the overall device design. Thus, in designing a device, the
choice of the best material with respect to its biocompatibility might result in a less functional device,
biocompatibility being only one of a number of characteristics to be considered in making that choice.
Where a material is intended to interact with tissue in order to perform its function, the biological
evaluation needs to address this.
Biological responses that are regarded as adverse, caused by a material in one application, might not be
regarded as such in a different situation. Biological testing is based upon, among other things, in vitro
and ex vivo test methods and upon animal models, so that the anticipated behaviour when a device is
used in humans can be judged only with caution, as it cannot be unequivocally concluded that the same
biological response will also occur in this species. In addition, differences in the manner of response to
the same material among individuals indicate that some patients can have adverse reactions, even to
well-established materials.
The role of this document is to serve as a framework in which to plan a biological evaluation which, as
scientific knowledge advances our understanding of the basic mechanisms of host responses, minimizes
the number and exposure of test animals by giving preference to chemical, physical, morphological,
and topographical characterization testing and in vitro models, in situations where these methods yield
equally relevant information to that obtained from in vivo models.
It is not intended that this document provide a rigid set of test methods, including pass/fail criteria,
as this might result in either an unnecessary constraint on the development and use of novel medical
devices, or a false sense of security in the general use of medical devices. Where a particular application
warrants it, experts in the product or in the area of application concerned can choose to establish
specific tests and criteria, described in a product-specific vertical standard.
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oSIST prEN ISO 10993-1:2017
ISO/DIS 10993-1:2017(E)
The ISO 10993- series of standards are intended for use by professionals, appropriately qualified
by training and experience, who are able to interpret its requirements and judge the outcome of the
evaluation for each, taking into consideration all the factors relevant to the device, its intended use
and the current knowledge of the medical device provided by review of the scientific literature and
previous clinical experience.
Informative Annex A contains a table that is generally helpful in identifying endpoints recommended
in the biocompatibility evaluation of medical devices, according to their category of body contact and
duration of clinical exposure. Informative Annex B contains guidance for the application of the risk
management process to medical devices which encompasses biological evaluation.
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oSIST prEN ISO 10993-1:2017
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-1:2017(E)
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management process
1 Scope
This part document describes:
— the general principles governing the biological evaluation of medical devices within a risk
management process;
— the general categorization of devices based on the nature and duration of their contact with the body;
— the evaluation of existing relevant data from all sources;
— the identification of gaps in the available data set on the basis of a risk analysis;
— the identification of additional data sets necessary to analyse the biological safety of the medical
device;
— the assessment of the biological safety of the medical device.
This part document applies to evaluation of materials and devices that are expected to have direct
or indirect contact with the patient’s body during intended use. In addition, this document applies to
medical devices that are expected to have direct or indirect contact with the clinician’s body, if the
device is intended to protect the clinician (e.g., surgical gloves, masks and others). This document
is applicable to biological evaluation of all types of medical devices including active, non-active,
implantable and non-implantable medical devices.
Biological hazards arising from other risks, such as mechanical failures or changes to the device over
time, should be considered as a part of the overall biological safety assessment, and can be addressed
by relevant biocompatibility, mechanical or other in vivo animal testing or other information. Other
parts of ISO 10993 cover specific aspects of biological assessments and related tests.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interaction with blood
ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
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ISO/DIS 10993-1:2017(E)
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
ISO 10993-11, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
degradation products from metals and alloys
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
ISO/TS 10993-19, Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and
topographical characterization of materials
ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for
immunotoxicology testing of medical devices
ISO/TR 10993-22, Biological evaluation of medical devices — Part 22: Guidance on nanomaterials
ISO 14971, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
biocompatibility
ability of a medical device or material to perform with an appropriate host response in a specific
application
Note 1 to entry: This can be demonstrated by biological testing, as well as assessment of effects of leachable
chemicals and/or morphological properties (e.g., bound chemicals, topological features) of the medical device
or materials, and device performance (e.g., maintenance of mechanical integrity) potentially impacting the
biological response.
3.2
biological risk
probability of harm to health occurring as a result of medical device or material interactions
3.3
biological safety
freedom from unacceptable risk in the context of the intended use
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3.4
chemical constituent
any synthetic or natural substance that is used in a process for manufacturing materials and/or medical
devices, including the base material(s), additives (antioxidants, UV stabilizers, color additives, dyes,
etc.), and processing aids (solvents, lubricants, antifoaming agents, etc.)
3.5
data set
information, such as physical and/or chemical characterization, toxicity data, etc. from a variety of
sources necessary to characterize the biological response of a device
3.6
direct contact
term used for a device or device component that comes into physical contact with body tissue
3.7
externally communicating
term used for a device or device component that is placed within the body during a medical procedure,
with a portion of the device residing within the body, and another portion of the device outside of the body
3.8
final product
medical device or device component that includes all manufacturing processes for the “to be marketed”
device including packaging and sterilization, if applicable
3.9
implant
term used for a device or device component that that is placed entirely within the body during a medical
procedure
3.10
indirect contact
term used for a device or device component through which a fluid or gas passes, prior to the fluid or gas
coming into physical contact with body tissue (in this case the device or device component itself does
not physically contact body tissue)
3.11
material
any synthetic or natural polymer, metal, alloy, ceramic or other non-viable substance, including tissue
rendered non-viable, used as a medical device or any part thereof
3.12
material characterization
the broad and general process by which a material’s chemistry, structure and properties are evaluated
and measured, to include assessment of compositional, structural, and mechanical properties, if
appropriate
3.13
medical device
any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator,
software, material or other similar or related article, intended by the manufacturer to be used, alone or
in combination, for human beings for one or more of the specific purpose(s) of:
— diagnosis, prevention, monitoring, treatment or alleviation of disease,
— diagnosis, monitoring, treatment, alleviation of or compensation for an injury,
— investigation, replacement, modification, or support of the anatomy or of a physiological process,
— supporting or sustaining life,
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ISO/DIS 10993-1:2017(E)
— control of conception,
— disinfection of medical devices,
— providing information for medical purposes by means of in vitro examination of specimens derived
from the human body,
and which does not achieve its primary 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 to entry: This definition has been developed by the Global Harmonization Task Force (GHTF).
Accessories intended specifically by manufacturers to be used together with a “parent” medical device
to enable that medical device to achieve its intended purpose, should be assessed according to the
ISO 10993- series of standards.
[SOURCE: ISO 14971:2007, definition 2.9, modified to refer to ISO 10993]
Medical devices are different from drugs/biologics, and their biological evaluation requires a different
approach.
Medical devices can include dental devices.
3.14
non-contact
term used to indicate that the device or device component has neither direct nor indirect contact with
body tissues
3.15
physical and chemical information
knowledge regarding formulation, manufacturing processes, geometric and physical properties and
type of body contact and clinical use that is used to determine whether any additional biological or
material characterization testing is needed
3.16
risk analysis
systematic use of available information to identify hazards and to estimate the risk
[SOURCE: ISO 14971:2007, definition 2.17]
3.17
risk assessment
overall process comprising a risk analysis and a risk evaluation
[SOURCE: ISO 14971:2007, definition 2.18]
3.18
risk evaluation
process of comparing the estimated risk against given risk criteria to determine the acceptability of
the risk
[SOURCE: ISO 14971:2007, definition 2.21]
3.19
risk management
systematic application of management policies, procedures and practices to the tasks of analysing,
evaluating, controlling and monitoring risk
[SOURCE: ISO 14971:2007, definition 2.22]
3.20
toxic
capable of causing an adverse biological response
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3.21
toxicological hazard
potential for a chemical substance or material to cause an adverse biological reaction, taking into
account the nature of the reaction and the dose required to elicit it
3.22
toxicological risk
probability of a specified degree of an adverse reaction occurring in response to a specified level of
exposure
3.23
toxicological threshold
a limit, such as a tolerable intake (TI), tolerable exposure (TE), allowable limit (AL) value, or Threshold
of Toxicological Concern (TTC) below which adverse effects are not expected for relevant biological
endpoints
3.24
transient contact
term used for a device or device component that has a very brief duration of contact with body tissue
(e.g., for less than one minute)
4 General principles applying to biological evaluation of medical devices
4.1 The biological evaluation of any material or medical device intended for use in humans shall
form part of a structured biological evaluation programme within a risk management process in
accordance with ISO 14971, as given in Figure 1. This risk management process involves identification of
biological hazards, estimation of the associated biological risks, and determination of their acceptability.
Annex B provides guidance on this process. The biological evaluation shall be planned, carried out, and
documented by knowledgeable and experienced professionals.
The risk management plan should identify aspects of the biological evaluation requiring specific
technical competencies and shall identify the person(s) responsible for the biological evaluation.
The evaluation programme shall include documented, informed consideration of
advantages/disadvantages and relevance of:
a) device configuration and a listing of a device’s materials of construction (qualitative) and where
necessary, the proportion and amount (mass) of each material in the device (quantitative);
b) the physical and chemical characteristics of the various candidate materials of construction and
their composition;
NOTE Where this information is already documented within the risk management for the device it can
be included by reference.
c) any history of clinical use or human exposure data;
NOTE Previous regulatory approval history can be relevant.
d) any existing toxicology and other biological safety data on product and component materials,
breakdown products and metabolites;
e) test procedures.
Evaluation can include both a study of relevant preclinical and clinical experience and actual testing.
Such an evaluation might result in the conclusion that no testing is needed if the material has a
demonstrable safe history of use in a specified role and physical form that is equivalent to that of the
device under design. The type of information that can be useful to demonstrate equivalence is included
in Annex B. Testing is usually not necessary when sufficient information is already available to perform
a risk assessment of the mate
...
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