FprEN ISO 10993-1

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

Biologische Beurteilung von Medizinprodukten - Teil 1: Beurteilung und Prüfungen im

Évaluation biologique des dispositifs médicaux - Partie 1: Évaluation et essais au sein

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

All rights reserved. Unless otherwise specified, 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

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

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

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

Any trade name used in this document is information given for the convenience of users and does not

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

This fifth edition cancels and replaces the fourth edition (ISO 10993-1:2009), which has been technically

b) replaced Annex B “Guidance on the risk management process” with “Guidance on the conduct of

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.

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

NOTE Products which might be considered to be medical devices in some jurisdictions but for which there is

5) devices incorporating animal and human tissues, which might meet the requirements of the above definition

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

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

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

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

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

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

— the general principles governing the biological evaluation of medical devices within a risk

— the general categorization of devices based on the nature and duration of their contact with the body;

— 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

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,

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.

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

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

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

ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of

ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of

ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of

ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for

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

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

ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for

ISO/TR 10993-22, Biological evaluation of medical devices — Part 22: Guidance on nanomaterials

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

ability of a medical device or material to perform with an appropriate host response in a specific

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

probability of harm to health occurring as a result of medical device or material interactions

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,

information, such as physical and/or chemical characterization, toxicity data, etc. from a variety of

term used for a device or device component that comes into physical contact with body tissue

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

medical device or device component that includes all manufacturing processes for the “to be marketed”

term used for a device or device component that that is placed entirely within the body during a medical

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

any synthetic or natural polymer, metal, alloy, ceramic or other non-viable substance, including tissue

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

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

— diagnosis, monitoring, treatment, alleviation of or compensation for an injury,

— investigation, replacement, modification, or support of the anatomy or of a physiological process,

— providing information for medical purposes by means of in vitro examination of specimens derived

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

Medical devices are different from drugs/biologics, and their biological evaluation requires a different

term used to indicate that the device or device component has neither direct nor indirect contact with

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

systematic use of available information to identify hazards and to estimate the risk

process of comparing the estimated risk against given risk criteria to determine the acceptability of

systematic application of management policies, procedures and practices to the tasks of analysing,

potential for a chemical substance or material to cause an adverse biological reaction, taking into

probability of a specified degree of an adverse reaction occurring in response to a specified level of

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

term used for a device or device component that has a very brief duration of contact with body tissue

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

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.

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

NOTE Where this information is already documented within the risk management for the device it can

d) any existing toxicology and other biological safety data on product and component materials,

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