ISO 10993-1:2009
(Main)Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process
Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process
ISO 10993-1:2009 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.
Évaluation biologique des dispositifs médicaux — Partie 1: Évaluation et essais au sein d'un processus de gestion du risque
L'ISO 10993-1:2009 décrit les principes généraux sur lesquels repose l'évaluation biologique des dispositifs médicaux dans un processus de gestion des risques, la classification générale des dispositifs, fondée sur la nature et la durée de leur contact avec le corps humain, l'évaluation de toutes les données existantes, l'identification de manques 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 et l'évaluation de la sécurité biologique du dispositif médical.
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INTERNATIONAL ISO
STANDARD 10993-1
Fourth edition
2009-10-15
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 10993-1:2009(E)
©
ISO 2009
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ISO 10993-1:2009(E)
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ISO 10993-1:2009(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.3
5 Categorization of medical devices .6
5.1 General .6
5.2 Categorization by nature of body contact .6
5.3 Categorization by duration of contact.7
6 Biological evaluation process.8
6.1 Material characterization .8
6.2 Biological evaluation tests .8
7 Interpretation of biological evaluation data and overall biological safety assessment .14
Annex A (informative) Biological evaluation tests .15
Annex B (informative) Guidance on the risk management process.16
Annex C (informative) Suggested procedure for literature review .19
Bibliography.21
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ISO 10993-1:2009(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 fourth edition cancels and replaces the third edition (ISO 10993-1:2003), which has been technically
revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
⎯ Part 1: Evaluation and testing within a risk management process
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for identification and quantification of potential degradation products
⎯ Part 10: Tests for irritation and skin sensitization
⎯ 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
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ISO 10993-1:2009(E)
⎯ Part 16: Toxicokinetic study design for degradation products and leachables
⎯ Part 17: Establishment of allowable limits for leachable substances
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials (Technical
Specification)
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices (Technical
Specification)
Future parts will deal with other relevant aspects of biological evaluation.
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ISO 10993-1:2009(E)
Introduction
The primary aim of this part of ISO 10993 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 be a guidance document
for 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 may exist in more than one physical form, and at the other extreme, of a complex instrument
or piece of apparatus, consisting of numerous components made of more than one material.
ISO 10993 addresses the determination of the effects of medical devices on tissues, mostly in a general way,
rather than in a specific device-type situation. Thus, for a complete biological safety evaluation, it classifies
medical devices according to the nature and duration of their anticipated contact with human tissues when in
use and indicates, in matrices, the biological data sets that are thought to be relevant in the consideration of
each device category.
The range of biological hazards is wide and complex. The tissue interaction with 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 tissue interaction might result in a less functional device, tissue interaction
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.
Tissue interactions 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 adjudged only with caution, as it cannot be unequivocally concluded that the same tissue
reactions 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 part of ISO 10993 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 tissue responses, minimizes the
number and exposure of test animals by giving preference to chemical constituent 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 ISO 10993 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.
This part of ISO 10993 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 device, its intended use and the current knowledge of
the medical device provided by review of the scientific literature and previous clinical experience.
Annex A contains an informative table that is generally helpful in identifying biological data sets recommended
in the evaluation of medical devices, according to their category of body contact and duration of clinical
exposure. Annex B contains guidance for the application of the risk management process to medical devices
which encompasses biological evaluation.
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INTERNATIONAL STANDARD ISO 10993-1:2009(E)
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management process
1 Scope
This part of ISO 10993 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 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. Other
parts of ISO 10993 cover specific tests, as indicated in the Foreword.
2 Normative references
The following documents are indispensable for the application of this document. For dated references, only
the edition cited applies. For undated references, the latest edition of the referenced document (including any
amendments) applies.
ISO 10993-2, 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
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
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ISO 10993-1:2009(E)
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 10993-18:2005, 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 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.
3.1
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,
⎯ 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 This definition has been developed by the Global Harmonization Task Force (GHTF).
[ISO 13485:2003, definition 3.7]
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ISO 10993-1:2009(E)
NOTE 2 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 (see Note 4);
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.
NOTE 3 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 subject to ISO 10993.
NOTE 4 Medical devices are different from drugs/biologics, and their biological evaluation requires a different approach.
NOTE 5 Medical devices can include dental devices.
3.2
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
3.3
final product
medical device in its “as-used” state, as defined by the manufacturer's specification or labelling
3.4
chemical constituent
any synthetic or natural substance that is used in a process for manufacturing materials and/or medical
devices, such as additives (antioxidants, UV stabilizers, dyestuff, etc.), processing aids (solvents, lubricants,
antifoaming agents, etc.)
3.5
data set
information from a variety of sources necessary to characterize the biological response of a device
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 set out in Figure 1. Annex B provides guidance on this process. The biological evaluation shall
be planned, carried out, and documented by knowledgeable and experienced professionals. See Annex C for
how to perform a literature review of existing data.
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 safety evaluation.
The evaluation programme shall include documented, informed decisions that assess the
advantages/disadvantages and relevance of:
a) the physical and chemical characteristics of the various candidate materials;
NOTE Where this information is already documented within the risk management for the device it can be included by
reference.
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ISO 10993-1:2009(E)
b) any history of clinical use or human exposure data;
c) any existing toxicology and other biological safety data on product and component materials, breakdown
products and metabolites;
d) test procedures.
Evaluation may 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.
4.2 In the selection of materials to be used in device manufacture, the first consideration shall be fitness for
purpose with regard to characteristics and properties of the material, which include chemical, toxicological,
physical, electrical, morphological and mechanical properties.
4.3 The following shall be taken into account for their relevance to the overall biological evaluation of the
device:
a) the material(s) of manufacture;
b) intended additives, process contaminants and residues (see ISO 10993-7 for ethylene oxide residues);
c) leachable substances (see ISO 10993-17);
d) degradation products (see ISO 10993-9, for general principles and 10993-13, 10993-14 and 10993-15 for
degradation products from polymers, ceramics and metals, respectively);
e) other components and their interactions in the final product;
f) the performance and characteristics of the final product;
g) physical characteristics of the final product, including but not limited to, porosity, particle size, shape and
surface morphology.
Identification of material chemical constituents and consideration of chemical characterization
(see ISO 10993-18) shall precede any biological testing (see Figure 1).
Physical effects of the device shall be considered if they impact the biocompatibility (see ISO/TS 10993-19).
For implanted devices, in addition to systemic effects, local effects should also be considered for risk
evaluation.
4.4 The choice of tests and the data required in a biological evaluation, and their interpretation, shall take
into account the chemical composition of the materials, including the conditions of exposure as well as the
nature, degree, frequency and duration of exposure of the medical device or its constituents to the body,
enabling the categorization of devices to facilitate the selection of appropriate tests (see Clause 5). The rigour
necessary in the biological evaluation is principally determined by the nature, degree, duration and frequency
of the exposure and the hazards identified for the material.
4.5 All known possible biological hazards shall be taken into account for every material and final product,
but this does not imply that testing for all possible hazards will be necessary or practical (see Clauses 5 and 6).
Test results cannot guarantee freedom from potential biological hazards, thus biological investigations shall be
followed by careful observations for unexpected adverse reactions or events in humans during clinical use of
the device.
The range of possible biological hazards is wide and can include short-term effects such as acute toxicity,
irritation to the skin, eye and mucosal surfaces, haemolysis and thrombogenicity, as well as long-term or
specific toxic effects such as subchronic and chronic toxic effects, sensitization, allergy, genotoxicity,
carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity.
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ISO 10993-1:2009(E)
a
This process only applies to those medical devices that contact the patient's body directly or indirectly.
Figure 1 — Summary of the systematic approach to a biological evaluation of medical
devices as part of a risk management process
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ISO 10993-1:2009(E)
4.6 Selection of any in vitro or in vivo tests shall be based on end-use applications. All tests shall be
conducted according to recognised current/valid best laboratory/quality practices, for example Good
Laboratory Practice (GLP) or ISO/IEC 17025, where applicable, and the data shall be evaluated by competent,
informed professionals.
In vitro test methods, which are appropriately validated, reasonably and practically available, reliable and
reproducible shall be considered for use in preference to in vivo tests. Whenever possible, in vitro screening
shall 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.
4.7 The materials or final product shall be re-evaluated 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 manufacturer's instructions or expectations concerning storage, e.g. changes in shelf
life and/or transport;
d) any change in the intended use of the product;
e) any evidence that the product may produce adverse effects when used in humans.
4.8 The biological evaluation shall take into account the nature and mobility of the chemical constituents 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.
5 Categorization of medical devices
5.1 General
Medical devices shall be categorized according to the nature and duration of body contact as described in 5.2
and 5.3. The categorization of medical devices facilitates identification of appropriate data sets (see Annex A).
The evaluation of any device that does not fall into one of the categories described shall follow the general
principles contained in this part of ISO 10993. Certain devices might fall into more than one category, in which
case evaluation appropriate to each category shall be carried out.
5.2 Categorization by nature of body contact
5.2.1 Surface-contacting devices
These include medical devices in contact with the following.
a) Skin
⎯ devices that contact intact skin surfaces only.
EXAMPLES Electrodes, external prostheses, fixation tapes, compression bandages and monitors of various types.
b) Mucosal membranes
⎯ devices that contact intact mucosal membranes.
EXAMPLES Contact lenses, urinary catheters, intravaginal and intra-intestinal devices (stomach tubes, sigmoidoscopes,
colonoscopes, gastroscopes), endotracheal tubes, bronchoscopes, some dental prostheses and orthodontic devices.
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ISO 10993-1:2009(E)
c) Breached or compromised surfaces
⎯ devices that contact breached or otherwise compromised body surfaces.
EXAMPLES Dressings or healing devices and occlusive patches, for ulcers, burns and granulation tissue.
5.2.2 External communicating devices
External communicating devices shall be categorized according to their 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 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 Laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples.
c) Circulating blood
⎯ devices that contact circulating blood.
EXAMPLES Intravascular catheters, temporary pacemaker electrodes, oxygenators, extracorporal oxygenator tubing
and accessories, dialysers, dialysis tubing and accessories, haemoadsorbents and immunoadsorbents.
5.2.3 Implant devices
Implant devices shall be categorized according to their contact with the following application sites:
a) Tissue/bone
⎯ devices principally contacting bone.
EXAMPLES Orthopaedic pins, plates, replacement joints, bone prostheses, bone cements and intra-osseous devices.
⎯ devices principally contacting tissue and tissue fluid.
EXAMPLES Pacemakers, drug supply devices, neuromuscular sensors and simulators, replacement tendons, breast
implants, artificial larynxes, subperiosteal implants, ligation clips and intra-uterine devices.
b) Blood
⎯ devices principally contacting blood.
EXAMPLES Pacemaker electrodes, artificial arteriovenous fistulae, heart valves, vascular grafts, internal drug-delivery
catheters and ventricular assist devices.
5.3 Categorization by duration of contact
Medical devices shall be categorized according to the anticipated duration of contact as follows.
a) Limited exposure (A) – devices whose cumulative single, multiple or repeated use or contact is up to 24 h.
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ISO 10993-1:2009(E)
b) Prolonged exposure (B) – devices whose cumulative single, multiple or repeated long-term use or contact
is likely to exceed 24 h but not 30 d.
c) Permanent contact (C) – devices whose cumulative single, multiple or repeated long-term use or contact
exceeds 30 d.
If a material or device can be placed in more than one duration category, the more rigorous testing and/or
evaluation considerations shall apply. With multiple exposures to the device, the decision into which category
a device is placed
...
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-1
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2006-11-02 2007-04-02
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION • МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ • ORGANISATION INTERNATIONALE DE NORMALISATION
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management system
Évaluation biologique des dispositifs médicaux —
Partie 1: Évaluation et essais au sein d'un système de gestion du risque
[Revision of third edition (ISO 10993-1:2003)]
ICS 11.100.20
ISO/CEN PARALLEL ENQUIRY
The CEN Secretary-General has advised the ISO Secretary-General that this ISO/DIS covers a subject
of interest to European standardization. In accordance with the ISO-lead mode of collaboration as
defined in the Vienna Agreement, consultation on this ISO/DIS has the same effect for CEN
members as would a CEN enquiry on a draft European Standard. Should this draft be accepted, a
final draft, established on the basis of comments received, will be submitted to a parallel two-month FDIS
vote in ISO and formal vote in CEN.
In accordance with the provisions of Council Resolution 15/1993 this document is circulated in
the English language only.
Conformément aux dispositions de la Résolution du Conseil 15/1993, ce document est distribué
en version anglaise seulement.
To expedite distribution, this document is circulated as received from the committee secretariat.
ISO Central Secretariat work of editing and text composition will be undertaken at publication
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Pour accélérer la distribution, le présent document est distribué tel qu'il est parvenu du
secrétariat du comité. Le travail de rédaction et de composition de texte sera effectué au
Secrétariat central de l'ISO au stade de publication.
THIS DOCUMENT IS A DRAFT CIRCULATED 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 BEING ACCEPTABLE FOR INDUSTRIAL, TECHNOLOGICAL, COMMERCIAL AND USER PURPOSES, DRAFT
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© International Organization for Standardization, 2006
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ISO/DIS 10993-1
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ISO/DIS 10993-1
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.3
5 Categorization of medical devices .7
5.1 General .7
5.2 Categorization by nature of body contact .7
5.2.1 Surface-contacting devices.7
5.2.2 External communicating devices .7
5.2.3 Implant devices.8
5.3 Categorization by duration of contact.8
6 Biological evaluation process.8
6.1 Material characterization .8
6.2 Biological evaluation tests .9
6.2.1 General .9
6.2.2 Test descriptions.10
7 Interpretation of biological evaluation data and overall biological safety assessment .14
Annex A (informative) Biological evaluation tests .15
Annex B (informative) Guidance on the risk management process.17
B.1 General.17
B.2 Risk management process.17
B.2.1 Risk analysis.17
B.2.2 Overall residual risk/benefit evaluation .18
B.2.3 Biological evaluation report .18
B.2.4 Post-production information.18
B.3 Testing and test reports.19
B.4 Biological evaluation report .19
B.5 Conclusion.19
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive (Add the reference and title of the Directive).20
Bibliography.21
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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,
and by Technical Committee CEN/TC 206, Biological evaluation of medical devices in collaboration.
This third edition cancels and replaces the second edition (EN ISO 10993-1:2003), which has been technically
revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
⎯ Part 1: Evaluation and testing within a risk management system
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for the 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
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⎯ Part 16: Toxicokinetic study design for degradation products and leachables
⎯ Part 17: Method for the establishment of allowable limits for leachable substances
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices
Future parts will deal with other relevant aspects of biological testing.
Annexes A and B are for information only.
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ISO/DIS 10993-1
Introduction
The primary aim of this part of ISO 10993 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 be the guidance document
for 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 does, at one extreme, consist of a
single material, which may exist in more than one physical form, and at the other extreme, of a complex
instrument or piece of apparatus, consisting of numerous components made of more than one material.
This international standard addresses the determination of the effects of medical devices on tissues, mostly in
a general way, rather than in a specific device-type situation. Thus, for a complete biological safety evaluation,
it classifies medical devices according to the nature and duration of their anticipated contact with human
tissues when in use and indicates, in matrices, the biological data sets that are thought to be relevant in the
consideration of each device category.
The range of biological hazards is wide and complex. The tissue interaction with 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 tissue interaction might result in a less functional device, tissue interaction
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.
Tissue interactions that are regarded as adverse caused by a material in one application might not be
regarded so 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 adjudged only with caution, as it cannot be unequivocally concluded that the same tissue reactions 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 part of ISO 10993 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 tissue responses, minimizes the
number and exposure of test animals by giving preference to chemical constituent 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 international standard will 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.
This part of ISO 10993 is intended for use by professionals, appropriately qualified by training and experience,
who are able to interpret its requirements and judge the outcomes of the evaluation for each medical device,
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.
Annex A contains an informative table which is generally helpful in identifying biological data sets
recommended in the evaluation of medical devices, according to their category of body contact and duration
of clinical exposure. Annex B contains guidance for the application of the risk management process to medical
devices which encompasses biological evaluation.
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DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-1
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management system
1 Scope
This part of ISO 10993 describes:
⎯ the general principles governing the biological evaluation of medical devices within a risk management
framework;
⎯ 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 analyze the biological safety of the medical device;
⎯ the assessment of the biological safety of the medical device.
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. Other
parts of ISO 10993 cover specific tests as indicated in the foreword.
2 Normative references
The following documents are indispensable for the application of this document. For dated references, only
the edition cited applies. For undated references, the latest edition of the referenced document (including any
amendments) applies.
ISO 10993-2, 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
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and delayed–type
hypersensitivity
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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 device
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 14971, Medical Devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this part of ISO 10993, the following terms and definitions apply.
3.1
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,
⎯ 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.
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NOTE 1 This definition has been developed by the Global Harmonization Task Force (GHTF). See bibliographic
reference [5]. [ISO 13485:2003, definition 3.7]
NOTE 2 Products, which may 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 (see Note 4),
4) disinfection substances,
5) devices incorporating animal and human tissues which may meet the requirements of the above
definition but are subject to different controls.
NOTE 3 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 subject to this international standard.
NOTE 4 Medical devices are different from drugs/biologics, and their biological evaluation requires a different approach.
NOTE 5 Medical devices may include dental devices.
3.2
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
3.3
final product
medical device in its "as-used"' state, as defined by the manufacturer's specification or labelling
3.4
chemical constituent
any synthetic or natural substance that is used in a process for manufacturing materials and/or medical
devices, such as additives (antioxidants, UV stabilizers, dyestuff, etc.), processing aids (solvents, lubricants,
antifoaming agents, etc.)
3.5
data set
information from a variety of sources necessary to characterise the biological response of a device.
4 General principles applying to biological evaluation of medical devices
4.1 The selection and evaluation of any material or medical device intended for use in humans shall form part
of a structured biological evaluation programme, as set out in Figure 1, within a risk management process.
Annex B, which is based on ISO 14971, provides guidance on this process. The biological evaluation shall be
planned, carried out, and documented by knowledgeable and experienced individuals.
The risk management plan shall identify aspects of the biological evaluation requiring specific technical
competencies and shall identify the person(s) responsible for biological safety evaluation.
The evaluation programme shall include documented informed decisions that assess the
advantages/disadvantages and relevance of:
a) the physical and chemical characteristics of the various candidate materials;
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ISO/DIS 10993-1
b) any history of clinical use or human exposure data;
c) any existing toxicology and other biological safety data on product and component materials, breakdown
products and metabolites;
d) test procedures.
Evaluation may 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.
4.2 In the selection of materials to be used in device manufacture, the first consideration shall be fitness for
purpose with regard to characteristics and properties of the material, which include chemical, toxicological,
physical, electrical, morphological and mechanical properties.
4.3 The following shall be taken into account for their relevance to the overall biological evaluation of the
device:
a) the material(s) of manufacture;
b) intended additives, process contaminants and residues (see ISO 10993-7 for ethylene oxide residues);
c) leachable substances (see ISO 10993-17);
d) degradation products (see ISO10993-9, -13, -14 and -15 for degradation products from polymers,
ceramics, and metals, respectively);
e) other components and their interactions in the final product;
f) the performance and characteristics of the final product;
g) physical characteristics of the final product, including but not limited to, porosity, particle size, shape, and
surface morphology.
Identification and quantification of extractable chemical constituents shall precede any biological testing as
specified in ISO 10993-18.
4.4 The choice of tests and the data required in a biological evaluation, and their interpretation, shall take into
account the chemical composition of the materials, including the conditions of exposure as well as the nature,
degree, frequency and duration of exposure of the medical device or its constituents to the body, enabling the
categorization of devices to facilitate the selection of appropriate tests (see clause 5). The rigour necessary in
the biological evaluation is principally determined by the nature, degree, duration and frequency of the
exposure and the hazards identified for the material.
4.5 All known possible biological hazards shall be taken into account for every material and final product, but
this does not imply that testing for all possible hazards will be necessary or practical (see clauses 5 and 6).
Test results cannot guarantee 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.
The range of possible biological hazards is wide and can include short-term effects such as acute toxicity,
irritation to the skin, eye and mucosal surfaces, haemolysis and thrombogenicity, as well as long-term or
specific toxic effects such as sub chronic and chronic toxic effects, sensitization, genotoxicity, carcinogenicity
(tumorigenicity) and effects on reproduction including teratogenicity.
4.6 Selection of any in vitro or in vivo tests shall be based on end-use applications. All tests shall be
conducted according to recognized current/valid best laboratory/quality practices, for example GLP or ISO
17025, where applicable, and the data shall be evaluated by competent, informed persons.
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In vitro test methods, which are appropriately validated, reasonably and practically available, reliable and
reproducible shall be considered for use in preference to in-vivo tests. Whenever possible, in vitro screening
shall 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.
4.7 The materials or final product shall be re-evaluated 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; e.g. changes in shelf life and/or transport;
d) any change in the intended use of the product;
e) any evidence that the product may produce adverse effects when used in humans.
4.8 The biological evaluation shall take into account the nature and mobility of the chemical constituents 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.
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ISO/DIS 10993-1
Figure 1 — Summary of the systematic approach to a biological evaluation of medical devices as part
of a risk management process
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...
NORME ISO
INTERNATIONALE 10993-1
Quatrième édition
2009-10-15
Évaluation biologique des dispositifs
médicaux —
Partie 1:
Évaluation et essais au sein d'un
processus de gestion du risque
Biological evaluation of medical devices —
Part 1: Evaluation and testing within a risk management process
Numéro de référence
ISO 10993-1:2009(F)
©
ISO 2009
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ISO 10993-1:2009(F)
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ISO 10993-1:2009(F)
Sommaire Page
Avant-propos .iv
Introduction.vi
1 Domaine d'application .1
2 Références normatives.1
3 Termes et définitions .2
4 Principes généraux applicables à l'évaluation biologique des dispositifs médicaux .4
5 Classification des dispositifs médicaux .7
5.1 Généralités .7
5.2 Classification suivant la nature du contact avec le corps du patient.7
5.3 Classification suivant la durée du contact .9
6 Processus d'évaluation biologique .9
6.1 Caractérisation de matériau .9
6.2 Essais d'évaluation biologique .10
7 Interprétation des données d'évaluation biologique et estimation biologique globale de
sécurité.15
Annexe A (informative) Essais d'évaluation biologique .16
Annexe B (informative) Directives concernant le processus de gestion du risque.17
Annexe C (informative) Processus suggéré de revue de littérature scientifique.20
Bibliographie.22
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ISO 10993-1:2009(F)
Avant-propos
L'ISO (Organisation internationale de normalisation) est une fédération mondiale d'organismes nationaux de
normalisation (comités membres de l'ISO). L'élaboration des Normes internationales est en général confiée
aux comités techniques de l'ISO. Chaque comité membre intéressé par une étude a le droit de faire partie du
comité technique créé à cet effet. Les organisations internationales, gouvernementales et non
gouvernementales, en liaison avec l'ISO participent également aux travaux. L'ISO collabore étroitement avec
la Commission électrotechnique internationale (CEI) en ce qui concerne la normalisation électrotechnique.
Les Normes internationales sont rédigées conformément aux règles données dans les Directives ISO/CEI,
Partie 2.
La tâche principale des comités techniques est d'élaborer les Normes internationales. Les projets de Normes
internationales adoptés par les comités techniques sont soumis aux comités membres pour vote. Leur
publication comme Normes internationales requiert l'approbation de 75 % au moins des comités membres
votants.
L'attention est appelée sur le fait que certains des éléments du présent document peuvent faire l'objet de
droits de propriété intellectuelle ou de droits analogues. L'ISO ne saurait être tenue pour responsable de ne
pas avoir identifié de tels droits de propriété et averti de leur existence.
L'ISO 10993-1 a été élaborée par le comité technique ISO/TC 194, Évaluation biologique des dispositifs
médicaux.
Cette quatrième édition annule et remplace la troisième édition (ISO 10993-1:2003), qui a fait l'objet d'une
révision technique.
L'ISO 10993 comprend les parties suivantes, présentées sous le titre général Évaluation biologique des
dispositifs médicaux:
⎯ Partie 1: Évaluation et essais au sein d'un processus de gestion du risque
⎯ Partie 2: Exigences relatives à la protection des animaux
⎯ Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction
⎯ Partie 4: Choix des essais pour les interactions avec le sang
⎯ Partie 5: Essais concernant la cytotoxicité in vitro
⎯ Partie 6: Essais concernant les effets locaux après implantation
⎯ Partie 7: Résidus de stérilisation à l'oxyde d'éthylène
⎯ Partie 9: Cadre pour l'identification et la quantification des produits potentiels de dégradation
⎯ Partie 10: Essais d'irritation et de sensibilisation cutanée
⎯ Partie 11: Essais de toxicité systémique
⎯ Partie 12: Préparation des échantillons et matériaux de référence
⎯ Partie 13: Identification et quantification de produits de dégradation de dispositifs médicaux à base de
polymères
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ISO 10993-1:2009(F)
⎯ Partie 14: Identification et quantification des produits de dégradation des céramiques
⎯ Partie 15: Identification et quantification des produits de dégradation issus des métaux et alliages
⎯ Partie 16: Conception des études toxicocinétiques des produits de dégradation et des substances
relargables
⎯ Partie 17: Établissement des limites admissibles des substances relargables
⎯ Partie 18: Caractérisation chimique des matériaux
⎯ Partie 19: Caractérisations physicochimique, morphologique et topographique des matériaux
[Spécification technique]
⎯ Partie 20: Principes et méthodes relatifs aux essais d'immunotoxicologie des dispositifs médicaux
[Spécification technique]
Des parties ultérieures concerneront d'autres aspects pertinents des essais biologiques.
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ISO 10993-1:2009(F)
Introduction
L'objectif principal de la présente partie de l'ISO 10993 est la protection de l'Homme vis-à-vis des risques
biologiques potentiels provoqués par l'utilisation de dispositifs médicaux. Elle constitue une compilation de
plusieurs normes et directives nationales et internationales concernant l'évaluation biologique des dispositifs
médicaux. Elle est destinée à servir de document de référence pour l'évaluation biologique des dispositifs au
sein d'un processus de gestion des risques, dans le cadre de l'évaluation et de la mise au point de chaque
dispositif. Cette approche combine l'examen et l'évaluation de toutes les données existantes avec, si
nécessaire, la sélection et la mise en œuvre d'essais complémentaires, ce qui permet d'accomplir une
évaluation complète des réponses biologiques pour chaque dispositif médical, en rapport avec sa sécurité
d'emploi. Il faut avoir conscience que le terme «dispositif médical» est d'une acception large qui va du
matériau simple, lequel peut exister sous plus d'une forme physique, à l'instrument ou partie d'appareillage
complexe constitué de nombreux composants constitués de plus d'un matériau.
L'ISO 10993 traite de la détermination des effets des dispositifs médicaux sur les tissus, de façon générale
plutôt que sous l'angle spécifique dispositif-situation type. Ainsi, pour une évaluation de sécurité biologique
complète, elle classifie les dispositifs médicaux suivant la nature et la durée prévues de contact avec les
tissus humains lors de leur emploi et indique, sous forme de tableaux, les ensembles de données qui sont
estimés pertinents pour chaque catégorie de dispositif.
La gamme des risques biologiques est vaste et complexe. L'interaction d'un tissu avec un matériau constitutif
ne peut être considérée indépendamment de l'ensemble de la conception du dispositif. Ainsi, lors de la
conception d'un dispositif, le choix du meilleur matériau quant à l'interaction avec les tissus peut conduire à un
dispositif moins fonctionnel, l'interaction tissulaire n'étant qu'une des nombreuses caractéristiques à prendre
en compte lors de ce choix. Lorsque le matériau est destiné à interagir avec le tissu afin de permettre au
dispositif de remplir sa fonction, l'évaluation biologique doit en tenir compte.
Les interactions d'un matériau avec le tissu qui sont considérées comme néfastes dans une application
peuvent ne pas être considérées de même dans une situation différente. L'évaluation biologique est fondée,
entre autres, sur des méthodes d'essai in vitro et in vivo et sur des modèles animaux; de sorte que le
comportement prévu lors de l'utilisation d'un dispositif sur l'homme ne puisse être affirmé qu'avec prudence,
car il ne peut être catégoriquement conclu que les mêmes réactions tissulaires se produisent aussi chez cette
espèce. De plus, les différentes façons de répondre à un même matériau selon les individus suggèrent que
certains patients puissent connaître des effets indésirables, même avec des matériaux bien connus.
Le rôle de la présente partie de l'ISO 10993 est de servir de cadre à l'établissement d'une évaluation
biologique qui, à mesure que la connaissance scientifique fait progresser notre compréhension des
mécanismes de base des réponses tissulaires, réduit le nombre et l'exposition des animaux d'essai en
donnant la préférence aux essais par produits chimiques et modèles in vitro, dans les situations où ces
méthodes donnent des informations aussi pertinentes que les modèles in vivo.
L'ISO 10993 n'est pas destinée à fournir un ensemble rigide de méthodes d'essai avec critères d'acceptation
et de refus. Cela pourrait se traduire soit par des contraintes inutiles sur le développement et l'emploi de
nouveaux dispositifs médicaux, soit par une mauvaise compréhension de la sécurité dans l'utilisation générale
des dispositifs médicaux. Lorsqu'une application particulière le justifie, les experts du produit ou du champ
d'application concerné peuvent choisir d'établir des essais et des critères spécifiques dans une norme
verticale de produit.
La présente partie de l'ISO 10993 est destinée à être utilisée par les professionnels, qualifiés par une
formation et une expérience appropriées, capable d'interpréter ses exigences et de juger des conclusions de
l'évaluation pour chaque dispositif médical, en tenant compte de tous les facteurs concernant le dispositif, son
emploi prévu et les connaissances en cours sur le dispositif médical apportées par la consultation de la
littérature scientifique et des expériences cliniques antérieures.
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ISO 10993-1:2009(F)
L'Annexe A contient un tableau informatif généralement utile pour l'identification des ensembles de données
biologiques recommandés dans l'évaluation des dispositifs médicaux, d'après leur catégorie de contact avec
le corps et de durée d'exposition clinique. L'Annexe B contient des directives pour l'application du processus
de gestion des risques aux dispositifs médicaux qui incluent l'évaluation biologique.
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NORME INTERNATIONALE ISO 10993-1:2009(F)
Évaluation biologique des dispositifs médicaux —
Partie 1:
Évaluation et essais au sein d'un processus de gestion du
risque
1 Domaine d'application
La présente partie de l'ISO 10993 décrit
⎯ les principes généraux sur lesquels repose l'évaluation biologique des dispositifs médicaux dans un
processus de gestion des risques,
⎯ la classification générale des dispositifs, fondée sur la nature et la durée de leur contact avec le corps
humain,
⎯ l'évaluation de toutes les données existantes,
⎯ l'identification de manques 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, et
⎯ l'évaluation de la sécurité biologique du dispositif médical.
La présente partie de l'ISO 10993 ne traite pas de l'essai des matériaux et des dispositifs qui n'entrent pas
directement ou indirectement en contact avec le corps du patient, pas plus qu'elle n'aborde les risques
biologiques dus aux défaillances mécaniques. Les autres parties de l'ISO 10993 traitent d'essais particuliers,
comme indiqué dans l'Avant-propos.
2 Références normatives
Les documents suivants sont indispensables pour l'application du présent document. Pour les références
datées, seule l'édition citée s'applique. Pour les références non datées, la dernière édition du document de
référence s'applique (y compris tous les amendements).
ISO 10993-2, Évaluation biologique des dispositifs médicaux — Partie 2: Exigences relatives à la protection
des animaux
ISO 10993-3, Évaluation biologique des dispositifs médicaux — Partie 3: Essais concernant la génotoxicité, la
cancérogénicité et la toxicité sur la reproduction
ISO 10993-4, Évaluation biologique des dispositifs médicaux — Partie 4: Choix des essais pour les
interactions avec le sang
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ISO 10993-1:2009(F)
ISO 10993-5, Évaluation biologique des dispositifs médicaux — Partie 5: Essais concernant la cytotoxicité in
vitro
ISO 10993-6, Évaluation biologique des dispositifs médicaux — Partie 6: Essais concernant les effets locaux
après implantation
ISO 10993-7, Évaluation biologique des dispositifs médicaux — Partie 7: Résidus de stérilisation à l'oxyde
d'éthylène
ISO 10993-9, Évaluation biologique des dispositifs médicaux — Partie 9: Cadre pour l'identification et la
quantification des produits potentiels de dégradation
ISO 10993-10, Évaluation biologique des dispositifs médicaux — Partie 10: Essais d'irritation et de
sensibilisation cutanée
ISO 10993-11, Évaluation biologique des dispositifs médicaux — Partie 11: Essais de toxicité systémique
ISO 10993-12, Évaluation biologique des dispositifs médicaux — Partie 12: Préparation des échantillons et
matériaux de référence
ISO 10993-13, Évaluation biologique des dispositifs médicaux. — Partie 13: Identification et quantification de
produits de dégradation de dispositifs médicaux à base de polymères
ISO 10993-14, Évaluation biologique des dispositifs médicaux — Partie 14: Identification et quantification des
produits de dégradation des céramiques
ISO 10993-15, Évaluation biologique des dispositifs médicaux — Partie 15: Identification et quantification des
produits de dégradation issus des métaux et alliages
ISO 10993-16, Évaluation biologique des dispositifs médicaux — Partie 16: Conception des études
toxicocinétiques des produits de dégradation et des substances relargables
ISO 10993-17, Évaluation biologique des dispositifs médicaux — Partie 17: Établissement des limites
admissibles des substances relargables
ISO 10993-18:2005, Évaluation biologique des dispositifs médicaux — Partie 18: Caractérisation chimique
des matériaux
ISO/TS 10993-19, Évaluation biologique des dispositifs médicaux — Partie 19: Caractérisations
physicochimique, morphologique et topographique des matériaux
ISO/TS 10993-20, Évaluation biologique des dispositifs médicaux — Partie 20: Principes et méthodes relatifs
aux essais d'immunotoxicologie des dispositifs médicaux
ISO 14971, Dispositifs médicaux — Application de la gestion des risques aux dispositifs médicaux
3 Termes et définitions
Pour les besoins du présent document, les termes et définitions suivants s'appliquent.
3.1
dispositif médical
instrument, appareil, équipement, machine, dispositif, implant, réactif in vitro ou calibreur, logiciel, matériel ou
tout autre article similaire ou associé, dont le fabricant prévoit qu'il soit utilisé, seul ou en association, chez
l'être humain pour une ou plusieurs des fins particulières suivantes:
⎯ diagnostic, prévention, surveillance, traitement ou atténuation d'une maladie;
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ISO 10993-1:2009(F)
⎯ diagnostic, surveillance, traitement, atténuation ou compensation d'une blessure;
⎯ étude, remplacement, modification ou soutien de l'anatomie ou d'un processus physiologique;
⎯ réanimation ou maintien en vie;
⎯ maîtrise de la conception;
⎯ désinfection des dispositifs médicaux,
apportant une information médicale au moyen d'examen in vitro d'échantillons issus du corps humain, et qui
n'accomplit pas son action prévue dans ou sur le corps humain par des voies pharmacologiques,
immunologiques ou métaboliques, mais qui peut être secondé dans ses fonctions par de tels moyens
NOTE 1 Cette définition a été élaborée par le groupe de travail sur l'harmonisation mondiale (GHTF).
[ISO 13485:2003, définition 3.7]
NOTE 2 Les produits pouvant être considérés comme des dispositifs médicaux dans certaines juridictions, mais pour
lesquels il n'existe pas encore d'approche harmonisée, sont
1) les aides pour les personnes handicapées,
2) les dispositifs de traitement/diagnostic des maladies et des blessures chez les animaux,
3) les accessoires des dispositifs médicaux (voir Note 4),
4) les substances de désinfection,
5) les dispositifs incorporant des tissus humains et des tissus animaux, pouvant répondre à la définition ci-dessus,
mais soumis à des contrôles différents.
NOTE 3 Il convient que les accessoires spécialement conçus par les fabricants pour être utilisés avec un dispositif
médical «parent» afin de lui permettre de remplir sa fonction soient soumis à la l'ISO 10993.
NOTE 4 Les dispositifs médicaux sont différents des agents biologiques/médicaments et exigent une approche
différente quant à leur évaluation biologique.
NOTE 5 Les dispositifs médicaux peuvent inclure les dispositifs dentaires.
3.2
matériau
polymère naturel ou synthétique, métal, alliage, céramique ou autre substance inerte, y compris les tissus
rendus non viables, utilisé comme dispositif ou partie de dispositif médical
3.3
produit fini
dispositif médical dans son état «prêt à l'emploi» tel que défini par la spécification ou l'identification du
fabricant
3.4
constituant chimique
substance synthétique ou naturelle utilisée dans un processus de fabrication de matériaux et/ou dispositifs
médicaux, telle que les additifs (antioxydants, stabilisants anti-UV, colorants, etc.), auxiliaires de fabrication
(solvants, lubrifiants, agents antimoussants, etc.)
3.5
ensemble de données
informations issues d'une variété de sources et nécessaires pour caractériser la réponse biologique d'un
dispositif
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ISO 10993-1:2009(F)
4 Principes généraux applicables à l'évaluation biologique des dispositifs
médicaux
4.1 L'évaluation biologique de tout matériau ou dispositif médical destiné à servir sur l'Homme doit faire
partie d'un programme structuré d'évaluation biologique au sein d'un processus de gestion des risques
conformément à l'ISO 14971, ainsi que le montre la Figure 1. L'Annexe B fournit des directives sur ce
processus. L'évaluation biologique doit être planifiée, effectuée et documentée par des personnes
expérimentées et compétentes. Voir l'Annexe C pour savoir comment accomplir une revue de la littérature
scientifique sur les données existantes.
Il convient que le plan de gestion des risques identifie les aspects de l'évaluation biologique qui réclament des
compétences techniques particulières ainsi que le(s) personne(s) responsable(s) de l'évaluation de la sécurité
biologique.
Le programme d'évaluation doit comporter des décisions fondées et justifiées qui évaluent les avantages/les
inconvénients et la pertinence
a) des caractéristiques chimiques et physiques des différents matériaux,
NOTE Si cette information est déjà documentée au sein du management du risque pour le dispositif, elle peut être
incluse comme référence.
b) de tout historique d'usage clinique ou toute donnée d'exposition humaine,
c) de toute donnée toxicologique et autre donnée de sécurité biologique sur le produit et les matériaux de
composition, les produits de dégradation et les métabolites, et
d) des modes opératoires d'essai.
L'évaluation peut inclure à la fois une étude d'expériences précliniques et cliniques probantes et des essais
réels. Une telle évaluation peut aboutir à la conclusion que les essais ne sont pas nécessaires si le matériau a
fait ses preuves dans un rôle et une forme physique particuliers équivalents à celui du dispositif en cours
d'étude.
4.2 Lors du choix des matériaux à utiliser pour la fabrication des dispositifs, la première considération doit
être l'adéquation à l'objectif, en tenant compte des caractéristiques et des propriétés du matériau, notamment
les propriétés chimiques, toxicologiques, physiques, électriques, morphologiques et mécaniques.
4.3 Les éléments suivants doivent être pris en compte pour leur pertinence dans l'évaluation globale du
dispositif:
a) le ou les matériaux utilisé(s) pour la fabrication;
b) les additifs, les contaminants et les résidus (voir l'ISO 10993-7 pour les résidus d'oxyde d'éthylène);
c) les substances relargables (voir l'ISO 10993-17);
d) les produits de dégradation (voir l'ISO 10993-9 pour les principes généraux et l'SO 10993-13,
l'SO 10993-14 et l'SO 10993-15, respectivement, pour les produits de dégradation des polymères, des
céramiques et des métaux);
e) les autres composants et leurs interactions dans le produit final;
f) les performances et les caractéristiques du produit fini;
g) les caractéristiques physiques du produit fini, y compris mais pas uniquement, la porosité, la taille des
particules, la forme et la morphologie de surface.
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ISO 10993-1:2009(F)
L'identification des composants chimiques des matériaux et la considération de la caractérisation chimique
(voir l'ISO 10993-18) doivent précéder tout essai biologique (voir Figure 1).
Les effets physiques du dispositif doivent être pris en compte s'ils influent sur la biocompatibilité (voir
l'ISO/TS 10993-19).
Pour les dispositifs implantés, dans une évaluation du risque, en plus des effets systémiques, il convient aussi
de tenir compte des effets locaux.
4.4 Le choix des essais et les données nécessaires dans une évaluation biologique et leur interprétation
doivent tenir compte de la composition chimique des matériaux, incluant les conditions d'exposition, ainsi que
de la nature, du degré, de la fréquence et de la durée d'exposition du corps humain au dispositif ou à ses
constituants, afin de permettre la classification des dispositifs pour faciliter la sélection des essais appropriés
(voir Article 5). La rigueur nécessaire dans l'évaluation biologique est principalement déterminée par la nature,
le degré, la durée et la fréquence de l'exposition et des dangers identifiés pour le matériau.
4.5 Tous les risques biologiques potentiels connus pour chaque matériau et pour le produit fini doivent être
pris en compte, mais cela n'implique pas que le contrôle de tous les dangers potentiels soit nécessaire ou
réalisable (voir Articles 5 et 6). Étant donné qu'aucun résultat d'essai ne peut constituer une assurance contre
le danger biologique potentiel, les investigations biologiques doivent être suivies par des observations
attentives des réactions négatives ou événements chez l'Homme lors des utilisations cliniques du dispositif.
La liste des dangers biologiques potentiels est large et peut comprendre des effets à court terme tels qu'une
toxicité aiguë, une irritation cutanée, oculaire et des surfaces des muqueuses, une hémolyse et une
thrombogénicité, ainsi que des effets à long terme ou toxiques spécifiques tels que des effets toxiques
subchroniques et chroniques, une sensibilisation, une allergie, une génotoxicité, une carcinogénicité
(tumorigénicité) et des effets sur la reproduction, incluant une tératogénicité.
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ISO 10993-1:2009(F)
a
Ce processus ne s'applique qu'aux dispositifs médicaux qui entrent directement ou indirectement en contact avec le corps du
patient.
Figure 1 — Résumé de l'approche systématique de l'évaluation biologique
de dispositifs médicaux dans le cadre d'un processus de gestion des risques
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ISO 10993-1:2009(F)
4.6 Le choix de tout essai in vitro ou in vivo doit être fondé sur les applications finales. Tous les essais
doivent être menés conformément aux meilleures pratiques de laboratoire/qualité en cours; par exemple les
bonnes pratiques de laboratoire (BPL) ou l'ISO 17025, le cas échéant, et les données doivent être évaluées
par des professionnels compétents et informés.
Les méthodes d'essai in vitro, validées, raisonnablement et pratiquement disponibles, fiables et reproductibles
doivent être préférées à l'emploi d'essais in vivo. Chaque fois que possible, un criblage doit être mené avant
les essais in vivo. Les résultats à retenir sont tous ceux qui permettent d'aboutir à une conclusion
indépendante.
4.7 Les matériaux ou le produit fini doivent être réévalués si l'un des phénomènes suivants se produit:
a) tout changement dans les matériaux utilisés lors de la fabrication du produit (source ou spécification);
b) tout changement de la composition, de la fabrication, de l'emballage primaire ou de la stérilisation du
produit;
c) tout changement dans les instructions du fabricant ou dans les attentes en ce qui concerne l'entreposage,
par exemple des modifications de durée de stockage et/ou de transport;
d) tout changement de l'utilisation prévue du produit;
e) tout signe d'effet défavorable possible lors de l'usage du produit sur l'homme.
4.8 L'évaluation biologique doit tenir compte de la nature et de la mobilité des constituants chimiques des
matériaux utilisés pour fabriquer le dispositif, ainsi que de toute autre information, essais non cliniques, études
cliniques et expérience post-commerciale qui permet d'avoir une évaluation globale.
5 Classification des dispositifs médicaux
5.1 Généralités
Les dispositifs médicaux doivent être classifiés selon la nature et la durée de leur contact avec le corps
humain, comme décrit en 5.2 et en 5.3. La classification des dispositifs médicaux facilite l'identification des
ensembles de données pertinents (voir Annexe A).
L'évaluation de tout dispositif n'entrant pas dans l'une des catégories décrites doit suivre les principes
généraux énoncés dans la présente partie de l'ISO 10993. Certains dispositifs peuvent appartenir à plus d'une
catégorie, auquel cas l'évaluation correspondant à chacune de ces catégories doit s'effectuer.
5.2 Classification suivant la nature du contact avec le corps du patient
5.2.1 Dispositifs au contact d'une surface
Ceux-ci comprennent les dispositifs médicaux au contact des surfaces suivantes.
a) Peau
⎯ dispositifs n'entrant en contact qu'avec de l
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