EN ISO 10993-7:2008

SLOVENSKI STANDARD
01-januar-2009
1DGRPHãþD
SIST EN ISO 10993-7:2000
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO2VWDQNLSRVWHULOL]DFLML]
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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
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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.

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

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.
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.

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.

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
ISO 10993-7:2008(E)
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ii © ISO 2008 – All rights reserved

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 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

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 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

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 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

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 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 per square centimetre for EO and
milligrams per square centimetre for ECH. The unit of square centimetre represents the surface area of the
patient-device interface.
NOTE The intent of this subclause is to prevent localized irritation due to EO or ECH released from the device.
4.3.5.2 Tolerable contact limit for EO
Either the EO TCL for surface contacting devices and implants shall not exceed 10 µg/cm or it shall exhibit
negligible irritation as specified in ISO 10993-10.
4.3.5.3 Tolerable contact limit for ECH for surface contacting devices
Either the ECH TCL for surface contacting devices and implants shall not exceed 5 mg/cm or it shall exhibit
negligible irritation as specified in ISO 10993-10.
4.3.6 Special situations
For multi-device systems the limits shall apply to each individual patient-contact device.
Residue of EO in intraocular lenses shall not exceed 0,5 µg EO per lens per day, or 1,25 µg per lens. Prorate
limits for other intraocular devices are set on the basis of the mass of the device, with the mass of an
intraocular lens taken as 20 mg. The acceptability of ECH levels in intraocular devices made from viscoelastic
materials that contain chlorine may need to be evaluated, as the level of ECH that results in ocular toxicity is
about four times greater than the corresponding EO level.
For blood cell separators used in patient and donor blood collection, the maximum allowable dose of EO is
10 mg and the maximum allowable dose of ECH shall not exceed 22 mg.
For blood oxygenators and blood separators, the maximum allowable dose of EO to patient is 60 mg and the
maximum allowable dose of ECH shall not exceed 45 mg.
For devices used in cardiopulmonary bypass procedures, the maximum allowable limits shall be 20 mg for EO
and 9 mg for ECH.
For extracorporeal blood purification devices, the EO and ECH limits specified shall be 4,6 mg/device, but the
allowable EO dose for a lifetime may be exceeded.
For drapes that are intended to contact only intact skin, the maximum allowable limits shall be the TCL of
2 2
10 µg/cm for EO and 5 mg/cm for ECH, or the drapes shall exhibit negligible irritation as specified in
ISO 10993-10.
NOTE The rationale for specifying EO limits for certain devices that are at variance with the general requirements
appears in Annex F.
A flowchart providing guidance for the application of this part of ISO 10993 to the determination of EO
residuals in medical devices is presented in Annex C.
4 © ISO 2008 – All rights reserved

ISO 10993-7:2008(E)
4.4 Determination of EO and ECH residuals
4.4.1 General
4.4.1.1 Procedure
The procedure for determining compliance with 4.3 consists of extracting the residue from samples,
determining the amount of residue, determining the contact surface of the device, and analysing and
interpreting the data.
DANGER — Analysts and others who obtain samples should perform all work involving the use of the
chemicals and solvents required for these methods in a fume cupboard whilst wearing appropriate
protective clothing, and should review the Material Safety Data information for each chemical prior to
such use. Healthcare workers using EO-sterilized medical devices shall take appropriate precautions
to protect against exposure to residues, which may be required by local occupational health and
safety regulations.
4.4.1.2 Ethylene oxide
This is a flammable gas that is irritating to body surfaces and highly reactive. It is mutagenic under many
conditions, has fetotoxic and teratogenic properties, can adversely effect testicular function and can produce
injury to many organ systems in the body. In cancer studies in animals, inhalation exposure produced several
types of neoplastic changes including leukaemia, brain tumours and mammary tumours while ingestion or
subcutaneous administration produced tumours only at the site of contact. One investigator has reported
higher cancer and mortality rates in some subpopulations of exposed workers. However, the results of several
studies in workers have shown even weaker associations. See References [177], [178] and [181]. In 1994 the
International Agency for Research on Cancer (IARC) reclassified EO as a human carcinogen (class 1) based
mainly on its mechanism of action. See Reference [75].
4.4.1.3 Ethylene chlorohydrin
This is a flammable liquid that is irritating to body surfaces, acutely toxic and readily absorbed through the skin
in toxic amounts. It has weak mutagenic potential, has some potential to produce fetotoxic and teratogenic
changes and can produce injury to several organ systems in the body including lungs, kidneys, central
nervous system and cardiovascular system. It was negative in cancer bioassays in animals.
4.4.2 Determination of residue
A valid method of extraction and measurement shall be used to determine the amount of EO and, where
necessary, ECH delivered to the patient.
If ECH is not detected based on the results of analyses performed using the methods given in either K.4.2 or
K.4.7, no further monitoring for ECH is required.
NOTE Many gas chromatography (GC) methods that use a capillary column instead of a packed column will produce
EO, ECH and EG results during a single sample run.
The guiding principle in selecting appropriate extraction methods (4.4.6) for the quantitative determination of
EO and, where necessary, ECH is the evaluation of the dose to the patient in order to show compliance with
the requirements set out in 4.3.
Where residues are shown to be within the requirements for products tested by exhaustive extraction, there is
no need to further challenge the device by simulated-use extraction, provided all applicable limits in 4.3 are
met. When exhaustive extraction is used, particular attention shall be paid to the limits expressed for the first
24 h and for the first 30 days in 4.3.
Many analytical methods for these EO-sterilization residuals have been described and are reviewed in the
Bibliography. However, the enormous diversity of materials and methods of construction of sterile medical
ISO 10993-7:2008(E)
devices may, in certain cases, still present problems in determining residual EO and ECH levels using the
methods given in the Bibliography. Therefore, any method that has been shown to be analytically sound (i.e.
demonstrated accuracy, precision, linearity, sensitivity, and selectivity) may be used, provided that it has been
validated. Annex A contains general validation requirements for gas chromatographic methods.
4.4.3 Product sampling and sample “blank”
4.4.3.1 Product sampling
Samples to be used for residual analysis shall be selected in such a manner as to be truly representative of
the product. When selecting samples, attention shall be given to the many factors described in Annex D.
Since many of these factors influence not only the initial levels of residuals in device components but also the
rate of residue dissipation, they shall also be considered when test samples are drawn from a processed load
and sent to the laboratory for analysis. Removal of the product samples from the processed load soon after a
sterilization cycle is completed and shipment to a laboratory far from the sterilization site or storage in the
laboratory for later analysis can jeopardize correlations of residual levels on the samples with those on the
rest of the load. Moreover, if samples cannot be drawn from the load and handled so that the effect on
aeration conditions for the sample will be negligible, an experiment to establish the relationship between the
sample aeration and load aeration at various seasons of the year shall be carried out.
Precautions shall be taken to minimize or control the effects of laboratory conditions on the rate of aeration for
test samples that have been removed from a product load (see D.1.5). In addition, operator and analyst safety
shall be ensured. Samples should remain with the product load until the day of analysis or until test samples
are retrieved and immediately frozen. The time between removal of samples from a controlled aeration area
and the beginning of extraction should be held to a minimum. Samples shall be sealed, shipped and stored
frozen when analysis is delayed. Samples shall be shipped on dry ice on overnight delivery. Dry ice shall
remain in the shipping container throughout the shipment and be present when the package is opened in the
laboratory. Test samples may also be taken directly from the product load at the desired aeration interval and
immediately placed into a headspace vial, which is sealed and then shipped to the laboratory for analysis. As
an alternative, samples may be extracted and the extraction fluid shipped to the analytical laboratory for
analysis. If the extraction fluid is water, then shipment shall be done such that the fluid is kept at ice-cold
temperatures (< 10 °C) until arrival. Testing should be carried out to measure hydrolysis of EO to EG.
Samples to be analysed shall be placed in a fume cupboard and removed from the packaging. Samples shall
be prepared according to any applicable pre-use instructions in the product labelling. Extractions shall be
started as soon as possible after the device has been removed from the packaging or pre-use preparations
have been completed.
4.4.3.2 Sample “blank”
To ensure that no other sample matrix components with the same retention time as any of the residues being
determined are present, a “blank” sample shall be evaluated for the possible presence of such interferences
by the extraction of a non-sterilized sample using the identical procedure being applied to the EO-sterilized
samples. In the event of materials being extracted from such a “blank” with conflicting or overlapping retention
times in the GC analysis, chromatographic conditions shall be modified to separate the interfering peak from
the analyte peak, or an alternative analytical procedure shall be used.
4.4.4 Sample/fluid ratios
The volume of fluid used to extract residues from devices, or representative sections of them, shall be
sufficient to maximize extraction efficiency while maintaining detection sensitivity. The nature and size of the
device sample therefore determines what constitutes the optimal fluid volume for extraction. Therefore, to
maximize analytical sensitivity, a minimum amount of extraction fluid should be used depending on the
extraction method required and size of the sample. Devices composed of highly absorbent materials or those
from which residues are extracted by filling may require sample/extraction fluid ratios reflecting increased fluid
volume. In any case, sample/extraction fluid ratios shall not undermine detection sensitivity.
6 © ISO 2008 – All rights reserved

ISO 10993-7:2008(E)
4.4.5 Extraction time and conditions
The aim of product extraction is to indicate the worst-case amount that could be delivered to the patient in
actual use of the device: on a daily basis for limited exposure items; on a daily and up to monthly basis for
prolonged exposure items; on a daily, monthly, and up to a lifetime basis for permanent contact items. As
indicated in Annexes E and F, exhaustive extraction as described below can be a useful alternative for
permanent contact devices, provided that shorter-term constraints are ensured.
4.4.6 Product extraction
4.4.6.1 Overview
There are two basic extraction methods used for the determination of EO-sterilization residuals in medical
devices: simulated-use extraction, which is the reference method; exhaustive extraction, which represents an
acceptable alternative in certain situations. The choice of extraction method shall be based on the intended
use of the device. Examples of suggested extraction methods are shown in Annex K.
The extraction method chosen shall represent the intended use of the product with the greatest challenge to
the patient and not solely expeditious analysis or to minimize the apparent concentration of residuals.
Extraction temperatures and times shall be determined based on the nature of the patient's exposure and the
patient's duration of contact with the device as described in 4.2 and 4.3. See ISO 10993-12 for extraction
temperatures.
The analyst is cautioned that for certain devices, simulated-use extraction may result in relatively large elution
volumes. Should this occur it might significantly increase the limit of detection for the residual material to the
point where a determination of compliance with this part of ISO 10993 is compromised.
Small devices shall be extracted in a suitable container. When a device is too large to be extracted in its
entirety, it may be necessary to extract several representative portions of the device components in order to
ensure confidence in the data derived.
These representative portions may be selected in one of two ways. If several varied materials are used, the
proportion of each component, as compared with the total sample mass, should parallel the ratio of that
component to the total mass of the device being tested. An alternative method would be to select one of the
components for testing, subsequent to an evaluation demonstrating that it represented the worst case with
regard to residual content. The method chosen shall be validated.
4.4.6.2 Simulated-use extraction (reference method)
Simulated-use aqueous extraction is the reference method in that it is the only method that produces results
directly comparable to the limits specified in 4.3. These limits are expressed in terms of delivered dose of EO
and ECH to patients.
Since it is necessary to evaluate the residue levels available to the patient, or other end user, from devices in
routine use, extraction methods that simulate use are required. Simulated-use extraction shall be carried out
under conditions that provide the greatest challenge to the intended use.
For example, many blood-contacting and parenteral devices can be extracted with water by filling or flushing
the blood or fluid path (whichever is appropriate). Samples shall be extracted for a time equivalent to or
exceeding the maximum time for single use, and at temperatures that provide the greatest realistic simulated
challenge.
To determine the dose of EO and, where necessary, ECH delivered to the patient or user over the course of
normal product use, simulated-use aqueous extraction procedures are used.
NOTE The amounts of EO (or ECH) extracted by simulating normal product use are not necessarily similar to the
total product residual content.
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