SIST EN ISO 10993-17:2003

Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002)

Migrated from Progress Sheet (TC Comment) (2000-07-10): New Tc forecast BP BLI 99-10-20 ++ Contact Mr Vyze ext 850 when processing this project through each stage

Biologische Beurteilung von Medizinprodukten - Teil 17: Nachweis zulässiger Grenzwerte für herauslösbare Bestandteile (ISO 10993-17:2002)

Dieser Teil der ISO 10993 legt das Verfahren zur Bestimmung zulässiger Grenzwerte für herauslösbare Bestandteile aus Medizinprodukten fest. Er ist für die Anwendung bei der Erstellung von Normen vorgesehen sowie für die Abschätzung geeigneter Grenzwerte in den Fällen, in denen keine Normen vorliegen. Er beschreibt einen systematischen Prozess, mit dem festgestellte Risiken durch toxikologisch gefährliche Substanzen, die in Medizinprodukten enthalten sind, quantitativ bestimmt werden können.
Dieser Teil der ISO 10993 ist nicht anwendbar für Produkte, die nicht mit dem Patienten in Kontakt kommen (z. B. Geräte für die in vitro-Diagnostik).
Die Exposition einer besonderen chemischen Substanz kann aus anderen Ursachen hervorgehen, z. B. Lebensmittel, Wasser und Luft. Dieser Teil der ISO 10993 behandelt nicht die mögliche Exposition durch diese Quellen.

Evaluation biologique des dispositifs médicaux - Partie 17: Etablissement des limites admissibles des substances relargables (ISO 10993-17:2002)

Biološko ovrednotenje medicinskih pripomočkov - 17. del: Postavitev dopustnih mej za izlužene snovi (ISO 10993-17:2002)

General Information

• Status: Withdrawn
• Publication Date: 28-Feb-2003
• Withdrawal Date: 17-May-2009
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 9900 - Withdrawal (Adopted Project)
• Start Date: 18-May-2009
• Due Date: 10-Jun-2009
• Completion Date: 18-May-2009
• Directive: 90/385/EEC - Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/BC/CEN/89/9 - Joint Standardization request to CEN/CENELEC concerning harmonized standards relating to horizontal aspects in the field of medical devices
• Ref Project: EN ISO 10993-17:2002 - Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002)

Relations

• Replaced By: SIST EN ISO 10993-17:2009 - Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002)
• Effective Date: 01-Jul-2009
• Replaced By: SIST EN ISO 10993-17:2009 - Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002)
• Effective Date: 08-Jun-2022

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-17:2003
01-marec-2003
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO3RVWDYLWHYGRSXVWQLK
PHM]DL]OXåHQHVQRYL,62
Biological evaluation of medical devices - Part 17: Establishment of allowable limits for
leachable substances (ISO 10993-17:2002)
Biologische Beurteilung von Medizinprodukten - Teil 17: Nachweis zulässiger
Grenzwerte für herauslösbare Bestandteile (ISO 10993-17:2002)
Evaluation biologique des dispositifs médicaux - Partie 17: Etablissement des limites
admissibles des substances relargables (ISO 10993-17:2002)
Ta slovenski standard je istoveten z: EN ISO 10993-17:2002
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-17:2003 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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EUROPEAN STANDARD
EN ISO 10993-17
NORME EUROPÉENNE
EUROPÄISCHE NORM
December 2002
ICS 11.100
English version
Biological evaluation of medical devices - Part 17: Establishment
of allowable limits for leachable substances (ISO 10993-
17:2002)
Evaluation biologique des dispositifs médicaux - Partie 17: Biologische Beurteilung von Medizinprodukten - Teil 17:
Etablissement des limites admissibles des substances Nachweis zulässiger Grenzwerte für herauslösbare
relargables (ISO 10993-17:2002) Bestandteile (ISO 10993-17:2002)
This European Standard was approved by CEN on 9 October 2002.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the Management Centre or to any CEN member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the Management Centre has the same status as the official
versions.
CEN members are the national standards bodies of Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece,
Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36  B-1050 Brussels
© 2002 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-17:2002 E
worldwide for CEN national Members.

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EN ISO 10993-17:2002 (E)
CORRECTED  2003-03-26
Foreword
This document (EN ISO 10993-17:2002) has been prepared by Technical Committee ISO/TC
194 "Biological evaluation of medical devices" in collaboration with Technical Committee
CEN/TC 206 "Biocompatibility of medical and dental materials and devices", the secretariat of
which is held by NEN.
This European Standard shall be given the status of a national standard, either by publication of
an identical text or by endorsement, at the latest by June 2003, and conflicting national
standards shall be withdrawn at the latest by June 2003.
This document has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association, and supports essential requirements of EU
Directive(s).
For relationship with EU Directive(s), see informative Annex ZB, which is an integral part of this
document.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of
the following countries are bound to implement this European Standard: Austria, Belgium, Czech
Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg,
Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 10993-17:2002 has been approved by CEN as EN ISO 10993-17:2002 without
any modifications.
NOTE Normative references to International Standards are listed in annex ZA (normative).
2

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EN ISO 10993-17:2002 (E)
Annex ZA
(normative)
Normative references to international publications
with their relevant European publications
This European Standard incorporates by dated or undated reference, provisions from other
publications. These normative references are cited at the appropriate places in the text and the
publications are listed hereafter. For dated references, subsequent amendments to or revisions of
any of these publications apply to this European Standard only when incorporated in it by
amendment or revision. For undated references the latest edition of the publication referred to
applies (including amendments).
NOTE Where an International Publication has been modified by common modifications, indicated
by (mod.), the relevant EN/HD applies.
Publication Year Title EN Year
ISO 10993-1 1997 Biological evaluation of medical EN ISO 10993-1 1997
devices - Part 1: Evaluation and
testing
3

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EN ISO 10993-17:2002 (E)
Annex ZB
(informative)
Clauses of this European Standard addressing essential requirements or
other provisions of EU Directives
This European Standard has been prepared under a mandate given to CEN by the European
Commission and the European Free Trade Association and supports essential requirements of
EU Directive 93/42/EEC.
WARNING Other requirements and other EU Directives may be applicable to the
product(s) falling within the scope of this standard.
The following clauses of this standard are likely to support requirements of Directive 93/42/EEC.
Compliance with these clauses of this standard provides one means of conforming with the
specific essential requirements of the Directive concerned and associated EFTA regulations.
Table ZA.1— Correspondence between this European Standard and EU Directives
Clause/subclause of this Corresponding Essential Comments
European Standard Requirement of Directive
93/42/EEC
4, 5, 6, 7, 8, 9 93/42/EWG:
Annex I: 1, 2, 6, 7.1, 7.2, 7.3, 7.5
4, 5, 6, 7, 8, 9 90/385/EWG:
Annex I: 1, 3, 5, 8, 9
4

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INTERNATIONAL ISO
STANDARD 10993-17
First edition
2002-12-01


Biological evaluation of medical devices —
Part 17:
Establishment of allowable limits for
leachable substances
Évaluation biologique des dispositifs médicaux —
Partie 17: Établissement des limites admissibles des substances
relargables




Reference number
ISO 10993-17:2002(E)
©
 ISO 2002

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ISO 10993-17:2002(E)
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ii © ISO 2002 – All rights reserved

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ISO 10993-17:2002(E)
Contents Page
Foreword . iv
Introduction. vi
1 Scope. 1
2 Normative reference. 1
3 Terms and definitions. 1
4 General principles for establishing allowable limits . 4
5 Establishment of tolerable intake (TI) for specific leachable substances . 5
5.1 General. 5
5.2 Exposure considerations for TI calculation . 7
5.3 Collection and evaluation of data. 7
5.4 Set TI for noncancer endpoints . 8
5.5 Set TI for cancer endpoints. 10
5.6 Establishment of tolerable contact levels (TCLs). 11
5.7 Risk assessment of mixtures. 13
6 Calculation of tolerable exposure (TE) . 13
6.1 General. 13
6.2 Exposure population. 14
6.3 Calculation of utilization factor from intended use pattern. 14
6.4 Tolerable exposure. 15
7 Feasibility evaluation. 16
8 Benefit evaluation. 16
9 Allowable limits. 17
10 Reporting requirements. 17
Annex A (informative) Some typical assumptions for biological parameters. 18
Annex B (informative) Risk assessment for mixtures of leachable substances. 20
Annex C (informative) Conversion of allowable limits for systemic exposure and for body surface
contact to maximum dose to patient from a medical device. 21
Annex D (informative) Risk analysis report . 23
Bibliography. 24

© ISO 2002 – All rights reserved iii

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ISO 10993-17:2002(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 3.
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 part of ISO 10993 may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-17 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
 Part 1: Evaluation and testing
 Part 2: Animal welfare requirements
 Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
 Part 4: Selection of tests for interactions with blood
 Part 5: Tests for in vitro cytotoxicity
 Part 6: Tests for local effects after implantation
 Part 7: Ethylene oxide sterilization residuals
 Part 8: Selection and qualification of reference materials for biological tests
 Part 9: Framework for identification and quantification of potential degradation products
 Part 10: Tests for irritation and delayed-type hypersensitivity
 Part 11: Tests for systemic toxicity
 Part 12: Sample preparation and reference materials
 Part 13: Identification and quantification of degradation products from polymeric medical devices
 Part 14: Identification and quantification of degradation products from ceramics
 Part 15: Identification and quantification of degradation products from metals and alloys
 Part 16: Toxicokinetic study design for degradation products and leachables
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ISO 10993-17:2002(E)
 Part 17: Establishment of allowable limits for leachable substances
 Part 18: Chemical characterization of materials
Future parts will deal with other relevant aspects of biological testing.
For the purposes of this part of ISO 10993, the CEN annex regarding fulfilment of European Council Directives has
been removed.
© ISO 2002 – All rights reserved v

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ISO 10993-17:2002(E)
Introduction
The determination of the suitability of a medical device for a particular use involves balancing any identified risks
with the clinical benefit to the patient associated with its use. Among the risks to be considered are those arising
from exposure to leachable substances arising from medical devices.
Risks associated with exposure to hazardous leachable substances are managed by identifying the leachable
substances, quantifying the associated risks and limiting exposure within tolerable levels. This part of ISO 10993
provides a method by which maximum tolerable levels can be calculated from available data on health risks.
Allowable limits may be based upon health risks that can be systemic or local, immediate or delayed, and range in
severity from minor localized adverse effects to life-threatening risks. These allowable limits are intended to be
derived, using this part of ISO 10993, by toxicologists or other knowledgeable and experienced individuals, capable
of making informed decisions based upon scientific data and a knowledge of medical devices.
The allowable limits derived may be used by anyone. In addition to use by ISO, other standards-developing
organizations, government agencies, regulatory bodies, and other users for setting allowable limits as standards or
regulations, manufacturers and processors may use the allowable limits derived to optimize processes and aid in
the choice of materials in order to protect patient health. Where risks associated with exposure to particular
leachable substances are unacceptable, this part of ISO 10993 can be used to qualify alternative materials or
processes.

vi © ISO 2002 – All rights reserved

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INTERNATIONAL STANDARD ISO 10993-17:2002(E)

Biological evaluation of medical devices —
Part 17:
Establishment of allowable limits for leachable substances
1 Scope
This part of ISO 10993 specifies a method for the determination of allowable limits for substances leachable from
medical devices. It is intended for use in deriving standards and estimating appropriate limits where standards do
not exist. It describes a systematic process through which identified risks arising from toxicologically hazardous
substances present in medical devices can be quantified.
This part of ISO 10993 is not applicable to devices that have no patient contact (e.g. in vitro diagnostic devices).
Exposure to a particular chemical substance may arise from sources other than the device, such as food, water or
air. This part of ISO 10993 does not address the potential for exposure from such sources.
2 Normative reference
The following normative document contains provisions which, through reference in this text, constitute provisions of
this part of ISO 10993. For dated references, subsequent amendments to, or revisions of, any of these publications
do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the
possibility of applying the most recent edition of the normative document indicated below. For undated references,
the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of
currently valid International Standards.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing
3 Terms and definitions
For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply.
3.1
allowable limit
AL
largest amount of a leachable substance that is deemed acceptable on a daily basis, when taken into the body
through exposure to a medical device
NOTE Allowable limits are expressed in dose to the patient for each applicable exposure period. The units used are mass
per unit time, e.g. milligrams per day. These doses represent tolerable risks for medical devices under the circumstances of
intended use.
3.2
benefit factor
BF
numerical factor that takes into account the health benefit from use of the medical device(s) containing the
leachable substance in question
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ISO 10993-17:2002(E)
3.3
concomitant exposure factor
CEF
numerical factor that accounts for patient exposure to many medical devices containing the same leachable
substance
NOTE This factor is used to adjust the product of TI and body mass downward.
3.4
default
value to be used, in the absence of data, for an uncertainty or other factor used in the calculation of the allowable
limit
3.5
harm to health
physical injury and/or damage to health
3.6
health benefit
likelihood of maintaining or improving health
3.7
health hazard
potential source of harm to health
3.8
health risk
combination of the likelihood of occurrence of harm to health and the severity of that harm
3.9
health risk analysis
use of available information to identify health hazards and to estimate health risk
3.10
leachable substance
chemical removed from a medical device by the action of water or other liquids related to the use of the device
EXAMPLE Additives, sterilant residues, process residues, degradation products, solvents, plasticizers, lubricants,
catalysts, stabilizers, anti-oxidants, colouring agents, fillers and monomers, among others.
3.11
lowest observed adverse effect level
LOAEL
lowest concentration or amount of a substance found by experiment or observation which causes detectable
adverse alteration of morphology, functional capacity, growth, development or life span of the target organism
under defined conditions of exposure
NOTE Alterations in morphology, functional capacity, growth, development or life span of the target organism may be
detected which are judged not to be adverse.
3.12
minimally irritating level
MIL
amount of a leachable substance that is minimally irritating to the patient
NOTE It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must
be multiplied by the volume (millilitres) used to get the mass (milligrams).
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ISO 10993-17:2002(E)
3.13
modifying factor
MF
mathematical product of uncertainty factors UF , UF and UF
1 2 3
3.14
multiple exposure
more than one exposure of the same patient to devices containing the same leachable substance, simultaneously
or at different times
3.15
non-irritating level
NIL
largest amount of a leachable substance that is not irritating to the patient
NOTE It is normally expressed in milligrams, although sometimes as milligrams per millilitre, in which case the value must
be multiplied by the volume (millilitres) used to get the mass (milligrams).
3.16
no observed adverse effect level
NOAEL
greatest concentration or amount of a substance found by experiment or observation which causes no detectable
adverse alteration of morphology, functional capacity, growth, development or life span of the target organism
under defined conditions of exposure
NOTE Alterations of morphology, functional capacity, growth, development or life span of the target organism may be
detected which are judged not to be adverse.
3.17
physiologically based pharmacokinetic modelling
PBPK modelling
system of modelling biological effects taking into account metabolic and pharmacokinetic differences among
species of animal
NOTE Such data should be utilized whenever they are available.
3.18
proportional exposure factor
PEF
numerical factor for patient exposure to a leachable substance that accounts for the fact that a medical device is
not typically utilized every day during the entire exposure category of interest
NOTE This factor is used to adjust the product of TI and body mass upwards.
3.19
repeated use
use of the same device by the same patient more than once without reprocessing
3.20
safety
freedom from unacceptable health risk
3.21
simultaneous use
use of more than one device by the same patient at the same time
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ISO 10993-17:2002(E)
3.22
tolerable contact level
TCL
tolerable contact exposure to a leachable substance resulting from contact with a medical device

NOTE It is normally expressed in milligrams per square centimetre of body surface.
3.23
TCL modifying factor
MF
TCL
mathematical product of uncertainty factors UF , UF and UF
4 5 6
3.24
tolerable exposure
TE
product of the tolerable intake, the body mass and the utilization factor
NOTE It is normally expressed in milligrams per day to the patient.
3.25
tolerable intake
TI
estimate of the average daily intake of a substance over a specified time period, on the basis of body mass, that is
considered to be without appreciable harm to health
NOTE It is normally expressed in milligrams per kilogram of body mass per day. It is derived as a part of the overall
establishment of allowable limits for a leachable substance in a medical device.
3.26
tolerable risk
risk which is accepted in a given context based upon the current values of society
3.27
uncertainty factor
UF
factor intended to account for the uncertainties inherent in estimating potential effects of a chemical on humans
from results obtained in human populations or surrogate species
3.28
utilization factor
UTF
numerical factor used to take into account the utilization of the device in terms of frequency of use and utilization in
conjunction with other medical devices that can be reasonably anticipated to contain the same leachable substance
4 General principles for establishing allowable limits
4.1 The process of establishing allowable limits (see Figure 1) for an identified substance leachable from medical
devices consists of
a) evaluating the biological risk associated with the leachable substance (see clause 5) by
 collecting data and identifying critical health endpoints,
 determining tolerable intakes (TI) that are specific for the route of entry and duration of exposure, and
 determining tolerable contact levels (TCL) if irritation is an appropriate endpoint;
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ISO 10993-17:2002(E)
b) determining the tolerable exposure (TE) of the patient to the leachable substance (see clause 6) by
 determining appropriate patient body mass (m ), and
B
 modifying the product of tolerable intake and body mass based upon a device utilization factor (UTF);
c) determining feasibility and applying benefit when appropriate. If the feasibility evaluation determines that the
TE is both technically and economically feasible, the TE becomes the allowable limit. In the event that the TE
is not technically or economically feasible (see clause 7), further modification of the TE based upon benefit
evaluation shall be performed on a case-by-case basis to establish the allowable limit (see clause 8).
4.2 Knowledgeable and experienced individuals, capable of making informed decisions based on the scientific
data available, shall implement the requirements of this part of ISO 10993 through the application of professional
judgement. This requires experience in the interpretation of toxicological data and toxicological risk assessment of
medical devices, together with knowledge of the use and benefit of medical devices and the feasibility of achieving
allowable limits determined.
4.3 The safety of medical devices requires an absence of unacceptable health risk. An analysis of the health
risks posed by specific leachable substances allows exposure limits to be established that permit an appropriate
degree of protection from harm to health in the event that the hazardous leachable substance would be released
into the body during the clinical use of the device. The degree of protection deemed appropriate in any situation is
dependent upon a number of factors, such as the nature of the hazard identified, the practicality of risk reduction
and the magnitude of the benefit derived from the use of the medical device. Assessment of the acceptability of a
health risk thus requires several complex factors to be investigated and balanced. Confidence in the risk
assessment is a function of the quality and quantity of data evaluated.
4.4 In the broadest sense, substances leachable from medical devices can be introduced into the body by
differing routes, ranging from skin absorption to ingestion, to inhalation, to direct systemic administration. In
addition, devices can be placed into one of three categories according to their durations of use. In turn, each usage
category may have multiple limits based upon multiple routes of exposure, as specified in ISO 10993-1. Thus, the
overall allowable limit for a particular leachable substance can have up to three components, a short-term limit, a
prolonged limit and a lifetime limit. In turn, each of these limits may need to be protective from multiple routes of
exposure. To achieve this, tolerable intake values (TI) are calculated individually for each route of exposure within
each applicable use category. That is, there may be multiple TIs, each route-specific, for a given usage category. In
many cases the toxicological data may have sufficient consistencies to permit the use of the lowest TI value for
either a usage category or a route of entry to best represent the toxicological effects of the leachable substance.
4.5 The first stage in the establishment of an allowable limit is the identification of a substance that may pose a
health hazard. Once a hazardous substance is selected, the process of establishing an allowable limit begins with
the establishment of tolerable intakes.
NOTE International Standards s
...