SIST EN ISO 10993-7:2009
Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals (ISO 10993-7:2008)
Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals (ISO 10993-7:2008)
This part of ISO 10993 specifies allowable limits for residual ethylene oxide (EO) and ethylene chlorohydrin (ECH) in individual EO-sterilized medical devices; procedures for the measurement of EO and ECH; and methods for determining compliance so that devices may be released. Additional background and guidance and a flowchart showing how the standard is applied are also included in informative annexes. EO-sterilized devices that have no patient contact (e.g., in vitro diagnostic devices) are not covered by this standard.
Biologische Beurteilung von Medizinprodukten - Teil 7: Ethylenoxid- Sterilisationsrückstände (ISO 10993-7:2008)
Dieser Teil von ISO 10993 legt die zulässigen Grenzwerte für Restethylenoxid (Rest EO) und Rest-Ethylenchlorhydrin (Rest-ECH) in einzelnen mit EO sterilisierten Medizinprodukten, die Verfahren für die Messung von EO und ECH sowie die Verfahren für die Bestimmung der Konformität fest, damit die Produkte freigegeben werden dürfen. Weitere Hintergrundinformationen, eine Anleitung und ein Flussdiagramm, auf dem dargestellt ist, wie die Norm angewendet wird, sind ebenfalls in den informativen Anhängen enthalten.
EO sterilisierte Produkte, die nicht mit Patienten in Berührung kommen (z. B. In vitro-Diagnostika), fallen nicht in den Anwendungsbereich dieser Norm.
Evaluation biologique des dispositifs médicaux - Partie 7: Résidus de stérilisation a l'oxyde d'éthylene (ISO 10993-7:2008)
L'ISO 10993-7:2007 spécifie les limites admissibles des résidus d'oxyde d'éthylène (OE) et de chlorhydrate d'éthylène (ECH) pour des dispositifs médicaux individuels stérilisés à l'oxyde d'éthylène, les modes opératoires pour le mesurage de l'oxyde d'éthylène et du chlorhydrate d'éthylène et les méthodes de mesure en vue de déterminer leur conformité et de procéder à leur libération. Une documentation supplémentaire, y compris des directives et un diagramme de flux sont également inclus dans les annexes informatives.
Biološko ovrednotenje medicinskih pripomočkov - 7. del: Ostanki po sterilizaciji z etilenoksidom (ISO 10993-7:2008)
Ta del ISO 10993 določa dopustne meje za ostanke etilenoksida (EO) in etilen klorohidrina (ECH) na posameznem medicinskem pripomočku, steriliziranem z etilenoksidom; postopke za merjenje EO in ECH; in metode za ugotavljanje skladnosti, da se pripomočki lahko sprostijo. Dodatne informacije in vodilo ter prikaz delovnih postopkov, ki razlagajo uporabo standarda, so vključeni v informativne dodatke. Ta standard ne zajema pripomočkov, steriliziranih z etilenoksidom, ki niso v stiku z bolnikom (npr. diagnostičnih preskusnih sistemov in vitro).
General Information
Relations
Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-7:2009
01-januar-2009
1DGRPHãþD
SIST EN ISO 10993-7:2000
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 2VWDQNLSRVWHULOL]DFLML]
HWLOHQRNVLGRP ,62
Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals
(ISO 10993-7:2008)
Biologische Beurteilung von Medizinprodukten - Teil 7: Ethylenoxid-
Sterilisationsrückstände (ISO 10993-7:2008)
Evaluation biologique des dispositifs médicaux - Partie 7: Résidus de stérilisation a
l'oxyde d'éthylene (ISO 10993-7:2008)
Ta slovenski standard je istoveten z: EN ISO 10993-7:2008
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-7:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-7:2009
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SIST EN ISO 10993-7:2009
EUROPEAN STANDARD
EN ISO 10993-7
NORME EUROPÉENNE
EUROPÄISCHE NORM
October 2008
ICS 11.100.20 Supersedes EN ISO 10993-7:1995
English Version
Biological evaluation of medical devices - Part 7: Ethylene oxide
sterilization residuals (ISO 10993-7:2008)
Évaluation biologique des dispositifs médicaux - Partie 7: Biologische Beurteilung von Medizinprodukten - Teil 7:
Résidus de stérilisation à l'oxyde d'éthylène (ISO 10993- Ethylenoxid- Sterilisationsrückstände (ISO 10993-7:2008)
7:2008)
This European Standard was approved by CEN on 23 September 2008.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the CEN Management Centre or to any CEN member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has the same status as the
official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36 B-1050 Brussels
© 2008 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-7:2008: E
worldwide for CEN national Members.
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SIST EN ISO 10993-7:2009
EN ISO 10993-7:2008 (E)
Contents Page
Foreword.3
Annex ZA (informative) Relationship between this International Standard and the Essential
Requirements of EU Directive 93/42/EEC Medical devices .4
Annex ZB (informative) Relationship between this International Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices .5
2
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SIST EN ISO 10993-7:2009
EN ISO 10993-7:2008 (E)
Foreword
This document (EN ISO 10993-7:2008) has been prepared by Technical Committee ISO/TC 194 "Biological
evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206 “Biological evaluation
of medical devices” the secretariat of which is held by NEN.
This European Standard shall be given the status of a national standard, either by publication of an identical
text or by endorsement, at the latest by April 2009, and conflicting national standards shall be withdrawn at the
latest by October 2011.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-7:1995.
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 EC Directives.
For relationship with EC Directives, see informative Annexes ZA and ZB, which are an integral part of this
document.
NOTE : The Essential Requirements of the Medical Devices Directives require that risks be reduced or
eliminated as far as possible and, specifically, that risks posed by residues be minimized and risks
posed by substances leaking from a device be reduced to a minimum. It is inherent in these Essential
Requirements that, within the maximum limits specified by this standard, exposure to a genotoxic
carcinogen should be reduced to levels as low as reasonably practicable, taking account of the
generally acknowledged state of the art, the technological level existing at the time of design and
technical and economic considerations compatible with a high level of health and safety.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following
countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 10993-7:2008 has been approved by CEN as a EN ISO 10993-7:2008 without any
modification.
3
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SIST EN ISO 10993-7:2009
EN ISO 10993-7:2008 (E)
Annex ZA
(informative)
Relationship between this International Standard and the Essential
Requirements of EU Directive 93/42/EEC Medical devices
This International Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 93/42/EEC on medical devices.
Once this standard is cited in the Official Journal of the European Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZA confers, within the limits of the scope of this standard, a presumption of conformity
with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZA — Correspondence between this International Standard and Directive 93/42/EEC on medical
devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Note
International Standard Directive 93/42/EEC
4, 5 Annex I, 7.2 and 7.5 For presumption of conformity, the
standard needs to be interpreted as
explained in the European Foreword.
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this International standard.
4
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SIST EN ISO 10993-7:2009
EN ISO 10993-7:2008 (E)
Annex ZB
(informative)
Relationship between this International Standard and the Essential
Requirements of EU Directive 90/385/EEC
on Active Implantable Medical Devices
This International Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 90/385/EEC on active implantable medical devices.
Once this standard is cited in the Official Journal of the European Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZB confers, within the limits of the scope of this standard, a presumption of conformity
with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZB — Correspondence between this International Standard and Directive 90/385/EEC on active
implantable medical devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Note
International Standard Directive 90/385/EEC
4, 5 Annex I, 9 For presumption of conformity, the
standard needs to be interpreted as
explained in the European Foreword.
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this International standard.
5
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SIST EN ISO 10993-7:2009
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SIST EN ISO 10993-7:2009
INTERNATIONAL ISO
STANDARD 10993-7
Second edition
2008-10-15
Biological evaluation of medical
devices —
Part 7:
Ethylene oxide sterilization residuals
Évaluation biologique des dispositifs médicaux —
Partie 7: Résidus de stérilisation à l'oxyde d'éthylène
Reference number
ISO 10993-7:2008(E)
©
ISO 2008
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
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ii © ISO 2008 – All rights reserved
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope .1
2 Normative references .1
3 Terms and definitions .1
4 Requirements.2
4.1 General.2
4.2 Categorization of devices .2
4.3 Allowable limits.3
4.4 Determination of EO and ECH residuals .5
5 Product release.10
5.1 General.10
5.2 Release of products without dissipation curve data .10
5.3 Procedure for product release using residue dissipation curves .10
Annex A (normative) Evaluation of gas chromatograms.12
Annex B (informative) Gas chromatographic determination for EO and ECH.15
Annex C (informative) Flowchart and guidance for the application of this part of ISO 10993 series
of standards to the determination of EO and ECH residuals in medical devices.19
Annex D (informative) Factors influencing product residual.26
Annex E (informative) Extraction conditions for determination of residual EO .28
Annex F (informative) Rationale for the provisions of this part of ISO 10993 .29
Annex G (informative) Establishment of allowable limits for EO .33
Annex H (informative) Establishment of allowable limits for ECH.50
Annex I (informative) Establishment of allowable limits for EG.59
Annex J (informative) Preparation of EO and ECH standards.63
Annex K (informative) Ethylene oxide residue measuring methods .67
Bibliography .74
© ISO 2008 – All rights reserved iii
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(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 10993-7 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-7:1995) 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 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
iv © ISO 2008 – All rights reserved
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(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]
© ISO 2008 – All rights reserved v
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
Introduction
Requirements for the development, validation and routine control of an ethylene oxide sterilization process for
medical devices are given in International Standards developed by ISO/TC 198. Certain requirements relating
to medical devices for biological testing, selection of tests, and the allocation of devices to categories are dealt
with in a variety of International Standards developed by ISO/TC 194. The specific requirement for ethylene
oxide and other sterilization process residuals was referred to ISO/TC 194. Other International Standards
delineate particular requirements for biological testing for specific products.
As noted in the introduction to ISO 11135-1:2007, when determining the suitability of ethylene oxide (EO) for
sterilization of medical devices, it is important to ensure that the levels of residual EO, ethylene chlorohydrin
(ECH) and ethylene glycol (EG) pose a minimal risk to the patient in normal product use. Therefore, it is
important that the use of alternative materials and sterilization processes be considered during product design
and development. EO is known to exhibit a number of biological effects. In the development of this part of
ISO 10993, consideration was given to these effects, which include irritation, organ damage, mutagenicity and
carcinogenicity in humans and animals, and reproductive effects in animals. Similar consideration was given
to the harmful effects of ECH and EG. In practice, for most devices, exposure to EO and ECH is considerably
lower than the maximum values specified in this part of ISO 10993.
Moreover, when the choice for EO sterilization has been made, irrespective of the provisions of this part of
ISO 10993, exposure to EO residues should be minimized. Requirements herein are in addition to the
biological evaluation and testing requirements for each individually designed medical device as indicated in
ISO 10993-1. The biological evaluation and testing requirements, combined with the EO-sterilization process
residue limits, form the justification that an EO-sterilized device is acceptable for use. Maximum allowable
residues for ethylene chlorohydrin (ECH), when ECH has been found to be present in medical devices
sterilized with EO, are also specified. Local effects (e.g., irritation) have been considered and are incorporated
in the tolerable contact limit (TCL) as given in 4.3.5.2 and Annex G for EO, and in 4.3.5.3 and Annex H for
ECH.
vi © ISO 2008 – All rights reserved
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SIST EN ISO 10993-7:2009
INTERNATIONAL STANDARD ISO 10993-7:2008(E)
Biological evaluation of medical devices —
Part 7:
Ethylene oxide sterilization residuals
1 Scope
This part of ISO 10993 specifies allowable limits for residual ethylene oxide (EO) and ethylene chlorohydrin
(ECH) in individual EO-sterilized medical devices, procedures for the measurement of EO and ECH, and
methods for determining compliance so that devices may be released. Additional background, including
guidance and a flowchart showing how this document is applied, are also included in the informative annexes.
EO-sterilized devices that have no patient contact (e.g., in vitro diagnostic devices) are not covered by this
part of ISO 10993.
NOTE This part of ISO 10993 does not specify limits for ethylene glycol (EG).
2 Normative references
The following referenced 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.
1)
ISO 10993-1:— , Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and delayed-type
hypersensitivity
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-17:2002, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-17 and the
following apply.
3.1
simulated-use extraction
extraction to demonstrate compliance with the requirements of this part of ISO 10993, by evaluating residue
levels available to the patient or user from devices during the routine use of a device with water extraction to
simulate product use
1) To be published. (Revision of ISO 10993-1:2003)
© ISO 2008 – All rights reserved 1
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
3.2
exhaustive extraction
extraction until the amount of EO or ECH in a subsequent extraction is less than 10 % of that detected in the
first extraction, or until there is no analytically significant increase in the cumulative residue levels detected
NOTE As it is not possible to demonstrate the exhaustive nature of residual recovery, the definition of exhaustive
extraction adopted is as above.
4 Requirements
4.1 General
NOTE Information on the derivation of the limits in this part of ISO 10993 as well as other important background
information and guidance relevant to the use of this document is contained in the informative annexes.
This clause specifies maximum allowable residues for ethylene oxide (EO) for each individual medical device
sterilized with EO. As noted in the introduction to ISO 11135-1:2007, when determining the suitability of EO for
sterilization of medical devices, it is important to ensure that the levels of residual EO, ethylene chlorohydrin
(ECH) and ethylene glycol (EG) pose a minimal risk to the patient in normal product use. Moreover, when the
choice for EO sterilization has been made, irrespective of the provisions of this standard, exposure to EO
residues should be minimized. Maximum allowable residues for ECH, when ECH has been found to be
present in medical devices sterilized with EO, are also specified. Local effects (e.g., irritation) have been
considered and are incorporated in the tolerable contact limit (TCL) as discussed in 4.3.5.2 and Annex G for
EO, and 4.3.5.3 and Annex H for ECH. No device limits are specified for EG because a risk assessment
(Annex I) indicates that calculated allowable levels are higher than those likely to occur in a medical device.
However, the potential exists for acute haemodynamic and haemolytic effects to occur following rapid
intravenous administration of hyperosmolar compounds like EG. Ethylene oxide sterilization of medical
devices would not be expected to produce hyperosmolar solutions. Methods for the determination of EO and
ECH are given in 4.4.
The requirements in this part of ISO 10993 are in addition to the biological testing requirements set out in
ISO 10993-1. For devices sterilized using ethylene oxide, attention shall be paid in particular to ISO 10993-3
and ISO 10993-10. All applicable requirements of ISO 10993-1 shall take into account the EO residual level at
the time of release for each individually designed medical device.
Results of the biological assessment of the device may dictate more stringent limits than those specified
in 4.3, which are designed to protect against systemic effects.
4.2 Categorization of devices
In establishing the maximum daily doses of EO and ECH that a medical device is allowed to deliver to
patients, devices shall be categorized according to the duration of contact.
Devices shall be placed into one of three exposure categories in accordance with ISO 10993-1:—, 5.3:
a) limited exposure (A) – devices whose cumulative single, multiple or repeated use or contact is up to 24 h;
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 should apply. With multiple exposures, the decision into which category a device is
placed should take into account the potential cumulative effect, bearing in mind the period of time over which
these exposures occur.
NOTE As it is applied in this part of ISO 10993, “multiple use” is defined to mean repeated use of the same device
type, e.g. dialyser cartridges.
2 © ISO 2008 – All rights reserved
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
4.3 Allowable limits
4.3.1 General
For each medical device, the maximum allowable doses of EO and ECH delivered to patients shall not exceed
the values given below for the exposure category that the device has been placed into in accordance with 4.2.
The limits for permanent contact and prolonged exposure devices are expressed as maximum average daily
doses. These limits carry additional constraints for the first 24 h of the exposure period and, in the case of the
permanent contact devices, for the first 30 days. These constraints place limitations on the amount of EO and
ECH that can be delivered to the patient during these early time periods. If data are available, consideration
should be given for proportioning the limits downward if multiple devices with the residue of concern are used
at one time, or proportioning the limits upward when device use is only for a part of the exposure period of
concern. These concomitant exposure factors (CEF) and proportional exposure factors (PEF) are given in
ISO 10993-17. The procedure that was used to establish the allowable limits is described in Annex G for EO,
in Annex H for ECH, and the rationale for considering the establishment of allowable limits for EG is described
in Annex I.
4.3.2 Permanent contact devices
The average daily dose of EO to patient shall not exceed 0,1 mg/d. In addition, the maximum EO dose shall
not exceed:
⎯ 4 mg in the first 24 h;
⎯ 60 mg in the first 30 d;
⎯ 2,5 g in a lifetime.
The average daily dose of ECH to patient shall not exceed 0,4 mg/d. In addition, the maximum ECH dose
shall not exceed:
⎯ 9 mg in the first 24 h;
⎯ 60 mg in the first 30 d;
⎯ 10 g in a lifetime.
4.3.3 Prolonged exposure devices
The average daily dose of EO to patient shall not exceed 2 mg/d. In addition, the maximum EO dose shall not
exceed:
⎯ 4 mg in the first 24 h;
⎯ 60 mg in the first 30 d.
The average daily dose of ECH to patient shall not exceed 2 mg/d. In addition, the maximum ECH dose shall
not exceed:
⎯ 9 mg in the first 24 h;
⎯ 60 mg in the first 30 d.
4.3.4 Limited exposure devices
The average daily dose of EO to patient shall not exceed 4 mg.
The average daily dose of ECH to patient shall not exceed 9 mg.
© ISO 2008 – All rights reserved 3
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SIST EN ISO 10993-7:2009
ISO 10993-7:2008(E)
4.3.5 Tolerable contact limits for surface contacting devices and implants
4.3.5.1 Overview
The tolerable contact limit (TCL) is expressed in units of micrograms
...
SLOVENSKI oSIST prEN ISO 10993-7:2006
PREDSTANDARD
april 2006
Biološko ovrednotenje medicinskih pripomočkov - 7. del: Ostanki po
sterilizaciji z etilenoksidom (ISO/DIS 10993-7:2006)
Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization
residuals (ISO/DIS 10993-7:2006)
ICS 11.100.20 Referenčna številka
oSIST prEN ISO 10993-7:2006(en)
© Standard je založil in izdal Slovenski inštitut za standardizacijo. Razmnoževanje ali kopiranje celote ali delov tega dokumenta ni dovoljeno
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EUROPEAN STANDARD
DRAFT
prEN ISO 10993-7
NORME EUROPÉENNE
EUROPÄISCHE NORM
February 2006
ICS Will supersede EN ISO 10993-7:1995
English Version
Biological evaluation of medical devices - Part 7: Ethylene oxide
sterilization residuals (ISO/DIS 10993-7:2006)
Evaluation biologique des dispositifs médicaux - Partie 7:
Résidus de stérilisation à l'oxyde d'éthylène (ISO/DIS
10993-7:2006)
This draft European Standard is submitted to CEN members for parallel enquiry. It has been drawn up by the Technical Committee
CEN/TC 206.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN in three official versions (English, French, German). A version in any other language
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Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice and
shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
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© 2006 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN ISO 10993-7:2006: E
worldwide for CEN national Members.
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prEN ISO 10993-7:2006 (E)
Foreword
This document (prEN ISO 10993-7:2006) 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 document is currently submitted to the parallel Enquiry.
This document will supersede EN ISO 10993-7:1995.
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).
Endorsement notice
The text of ISO 10993-7:2006 has been approved by CEN as prEN ISO 10993-7:2006 without
any modifications.
2
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DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-7
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2006-02-09 2006-07-09
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION • МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ • ORGANISATION INTERNATIONALE DE NORMALISATION
Biological evaluation of medical devices —
Part 7:
Ethylene oxide sterilization residuals
Évaluation biologique des dispositifs médicaux —
Partie 7: Résidus de stérilisation à l'oxyde d'éthylène
[Revision of first edition (ISO 10993-7:1995)]
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
stage.
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
INTERNATIONAL STANDARDS MAY ON OCCASION HAVE TO BE CONSIDERED IN THE LIGHT OF THEIR POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN NATIONAL REGULATIONS.
© International Organization for Standardization, 2006
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ISO/DIS 10993-7
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ii ISO 2006 – All rights reserved
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ISO/DIS 10993-7
Contents Page
Foreword .vi
Introduction.viii
1 Scope.1
2 Normative references.1
3 Terms and definitions .1
4 Requirements.2
4.1 General .2
4.2 Categorization of devices.2
4.3 Allowable limits .3
4.3.1 Permanent contact devices.3
4.3.2 Prolonged exposure devices .3
4.3.3 Limited exposure devices .3
4.3.4 Tolerable contact limits for EO for surface contacting devices and implants.4
4.3.5 Special situations.4
4.4 Determination of EO and ECH residuals.4
4.4.1 General .4
4.4.2 Determination of residue .5
4.4.3 Product sampling and sample “blank” .5
4.4.4 Sample/fluid ratios .6
4.4.5 Extraction time and conditions.6
4.4.6 Product extraction.6
4.4.7 Data analysis and interpretation.8
5 Product release.9
5.1 Release of products without dissipation curve data.10
5.2 Procedure for product release using residue dissipation curves.10
Annex A (normative) Evaluation of gas chromatograms .12
A.1 General.12
A.2 Background.12
A.3 Symbols and abbreviated terms .12
A.4 Minimum requirements.12
A.5 Chromatographic baseline .13
A.6 Resources.14
Annex B (informative) Gas chromatographic determination for EO and ECH .15
B.1 Chromatographic procedures.15
B.1.1 Preparation of standards.15
B.1.2 General.15
B.2 Criteria for validating gas chromatographic methods .15
B.2.1 Accuracy .15
B.2.2 Precision.16
B.2.3 Linearity.17
B.2.4 Method detection limit (MDL) .17
B.2.5 Quantitation limit (QL).17
Annex C (informative) Flowchart and guidance for the application of this part of the ISO 10993-
series of standards to the determination of EO residuals in medical devices .19
C.1 Background.19
C.2 Guidance.20
C.3 Simulated-use extraction procedure.22
C.3.1 Extraction fluid .22
© ISO 2005 – All rights reserved iii
DRAFT 2006
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ISO/DIS 10993-7
C.3.2 Extraction temperature . 22
C.3.3 Extraction time. 22
C.3.4 Extraction of device. 22
C.3.5 Grouping of devices . 23
C.3.6 Device kits and trays . 23
Annex D (informative) Factors influencing product residual. 26
D.1 Sterilization process parameters . 26
D.1.1 Material composition. 26
D.1.2 Packaging. 26
D.1.3 Ethylene oxide sterilization cycle . 26
D.1.4 Aeration. 26
D.1.5 Sample retrieval . 27
D.2 Controlling variables . 27
Annex E (informative) Extraction conditions for determination of residual EO . 28
Annex F (informative) Rationale for the provisions of this International Standard . 29
F.1 General. 29
F.2 Rationale for special situations. 29
F.2.1 General. 29
F.2.2 Intraocular lens limits. 29
F.2.3 Blood cell separators used in donor or patient blood collection. 30
F.2.4 Blood oxygenators and blood separators . 30
F.2.5 Devices used in cardiopulmonary bypass procedures . 30
F.2.6 Extra corporeal blood purification devices. 31
F.3 Rationale for 4.4, Determination of EO and ECH residuals. 31
F.3.1 Product extraction . 31
F.3.2 Analytical methods. 32
F.3.3 Rationale for 4.4.1.7, Data analysis and interpretation.32
Annex G (informative) Establishment of allowable limits for EO . 33
G.1 General. 33
G.2 Introduction. 33
G.3 Methods . 33
G.3.1 Route-to-route extrapolation of dose . 34
G.3.2 Noncancer risk assessment approach. 34
G.3.3 Cancer risk assessment approach . 34
G.3.4 Effects not considered in deriving TI values for EO .35
G.4 Noncancer-based TI values for EO . 35
G.4.1 Selection of critical studies . 35
G.4.2 Selection of uncertainty factors for noncancer effects . 36
G.4.3 Derivation of noncancer TI values for EO . 42
G.5 Cancer-based TI values for EO. 42
G.5.1 Approach 1: Linear extrapolation from human data. 43
G.5.2 Approach 2: Linear extrapolation from animal data . 43
G.5.3 Approach 3: Uncertainty factor approach. 43
G.5.4 Approach 4: Linear dose-response modeling of human data . 44
G.5.5 Comparison of cancer-based TI value. 44
G.5.6 Comparison of cancer-based TI values for EO. 45
G.6 Calculation of Tolerable Exposure (TE) levels . 45
G.6.1 Limited exposure TE . 45
G.6.2 Prolonged exposure TE . 45
G.6.3 Permanent exposure TE. 46
G.6.4 Calculation of Tolerable Contact Level (TCL). 46
G.7 Calculation of allowable limits . 48
G.8 Calculation of device limits . 48
G.8.1 Limited contact devices . 48
G.8.2 Prolonged contact devices . 48
G.8.3 Permanent contact devices . 49
G.8.4 Limit based on TCL value . 49
iv © ISO 2005 – All rights reserved
DRAFT 2006
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ISO/DIS 10993-7
Annex H (informative) Establishment of allowable limits for ECH.50
H.1 General.50
H.2 Introduction.50
H.3 Methods.50
H.3.1 Route-to-route extrapolation of dose.50
H.3.2 Non-cancer risk assessment approach .50
H.3.3 Cancer risk assessment approach.51
H.3.4 Effects not considered in deriving TI values for ECH .51
H.4 Non-cancer based TI values for ECH .51
H.4.1 Selection of critical studies.51
H.4.2 Selection of uncertainty factors for noncancer effects.56
H.5 Calculation of Tolerable Contact Level (TCL) .56
Annex I (informative) Establishment of Allowable Limits for EG.59
I.1 Background.59
I.2 General considerations.59
I.2.1 Limited exposure.59
I.2.2 Prolonged exposure.60
I.2.3 Permanent exposure.61
I.2.4 Tolerable Contact Limit (TCL) .62
Annex J (informative) Preparation of EO and ECH standards .63
J.1 Preparation of EO standards.63
J.1.1 EO standard dilutions for headspace methods .64
J.1.2 EO standard dilutions for solvent methods .64
J.2 Preparation of ECH standards .65
Annex K (informative) Ethylene oxide residue measuring methods .66
K.1 Results of interlaboratory evaluation of methods .66
K.1.1 EO methods .66
K.1.2 ECH methods.66
K.2 Apparatus and reagents .67
K.2.1 Apparatus.67
K.2.2 Reagents.67
K.3 Standard preparation .68
K.3.1 Preparation of ethylene oxide standards.68
K.3.2 Preparation of ethylene chlorohydrin standards .68
K.3.3 Preparation of propylene oxide (PO) standards .68
K.4 Product extraction.68
K.4.1 General.68
K.4.2 Extraction to simulate product use .68
K.4.3 Exhaustive procedure using thermal extraction.69
K.4.4 Exhaustive extraction with ethanol followed by headspace gas analysis of the ethanol
extract.69
K.4.5 Exhaustive extraction with solvent .70
K.4.6 Exhaustive extraction with ethanol followed by preparation of the bromohydrin derivative
and chromatography using a gas chromatograph equipped with an ECD.71
K.4.7 Simulated use extraction for ethylene chlorohydrin using water .72
K.4.8 Exhaustive extraction for ethylene chlorohydrin using water .72
K.5 Gas chromatography .72
K.5.1 Genera
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