ISO 11135:2014
(Main)Sterilization of health-care products — Ethylene oxide — Requirements for the development, validation and routine control of a sterilization process for medical devices
Sterilization of health-care products — Ethylene oxide — Requirements for the development, validation and routine control of a sterilization process for medical devices
ISO 11135:2014 specifies requirements for the development, validation and routine control of an ethylene oxide sterilization process for medical devices in both the industrial and health care facility settings, and it acknowledges the similarities and differences between the two applications.
Stérilisation des produits de santé — Oxyde d'éthylène — Exigences de développement, de validation et de contrôle de routine d'un processus de stérilisation pour des dispositifs médicaux
L'ISO 11135:2014 spécifie les exigences relatives à la mise au point, à la validation et au contrôle de routine du procédé de stérilisation des dispositifs médicaux à l'oxyde d'éthylène dans l'industrie et dans les établissements de santé, et reconnaît les similitudes et différences entre les deux applications.
General Information
Relations
Buy Standard
Standards Content (Sample)
INTERNATIONAL ISO
STANDARD 11135
Second edition
2014-07-15
Sterilization of health-care
products — Ethylene oxide —
Requirements for the development,
validation and routine control of
a sterilization process for medical
devices
Stérilisation des produits de santé — Oxyde d’éthylène — Exigences
de développement, de validation et de contrôle de routine d’un
processus de stérilisation pour des dispositifs médicaux
Reference number
ISO 11135:2014(E)
©
ISO 2014
---------------------- Page: 1 ----------------------
ISO 11135:2014(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2014
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Published in Switzerland
ii © ISO 2014 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 11135:2014(E)
Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Normative references . 2
3 Terms and definitions . 3
4 Quality management systems .11
4.1 Documentation .11
4.2 Management responsibility .11
4.3 Product realization .11
4.4 Measurement, analysis and improvement — Control of nonconforming product .11
5 Sterilizing agent characterization .11
5.1 General .11
5.2 Sterilizing agent .12
5.3 Microbicidal effectiveness .12
5.4 Material effects.12
5.5 Safety and the environment .12
6 Process and equipment characterization .12
6.1 General .12
6.2 Process characterization .12
6.3 Equipment characterization .13
7 Product definition .14
7.1 General .14
7.2 Product safety, quality and performance .15
7.3 Microbiological quality .15
7.4 Documentation .15
8 Process definition .15
9 Validation .16
9.1 General .16
9.2 Installation qualification, IQ .17
9.3 Operational qualification, OQ .17
9.4 Performance qualification, PQ .18
9.5 Review and approval of validation .20
10 Routine monitoring and control .22
11 Product release from sterilization .23
12 Maintaining process effectiveness
.23
12.1 General .23
12.2 Maintenance of equipment .24
12.3 Requalification .24
12.4 Assessment of change .24
12.5 Assessment of equivalence .25
Annex A (normative) Determination of lethal rate of the sterilization process — Biological
indicator/bioburden approach .26
Annex B (normative) Conservative determination of lethal rate of the sterilization process —
Overkill approach .27
Annex C (informative) Temperature sensors, RH sensors and biological indicator numbers .29
© ISO 2014 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO 11135:2014(E)
Annex D (informative) Guidance on the application of the normative requirements .32
Annex E (normative) Single Lot Release .74
Bibliography .76
iv © ISO 2014 – All rights reserved
---------------------- Page: 4 ----------------------
ISO 11135:2014(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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2. www.iso.org/directives
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any
patent rights identified during the development of the document will be in the Introduction and/or on
the ISO list of patent declarations received. www.iso.org/patents
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO’s adherence to the WTO principles in the Technical Barriers
to Trade (TBT), see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 198, Sterilization of health care products.
ISO 11135:2014 cancels and replaces ISO 11135-1:2007 and ISO/TS 11135-2:2008, both of which have
been technically revised and condensed into a single standard.
© ISO 2014 – All rights reserved v
---------------------- Page: 5 ----------------------
ISO 11135:2014(E)
Introduction
A sterile medical device is one that is free of viable microorganisms. Medical devices produced under
standard manufacturing conditions in accordance with the requirements for quality management
systems (see for example ISO 13485) might, prior to sterilization, have microorganisms on them, albeit
in low numbers. Such medical devices are non-sterile. The purpose of sterilization is to inactivate the
microbiological contaminants and thereby transform the non-sterile medical devices into sterile ones.
The kinetics of inactivation of a pure culture of microorganisms by physical and/or chemical agents
used to sterilize medical devices can generally best be described by an exponential relationship
between the numbers of microorganisms surviving and the extent of treatment with the ethylene
oxide (EO); inevitably this means that there is always a finite probability that a microorganism might
survive regardless of the extent of treatment applied. For a given treatment, the probability of survival
is determined by the number and resistance of microorganisms and by the environment in which the
organisms exist during treatment. It follows that the sterility of any one medical device in a population
subjected to sterilization processing cannot be guaranteed and the sterility of a processed population is
defined in terms of the probability of there being a viable microorganism present on a medical device.
ISO 11135 describes requirements that, if met, will provide an ethylene oxide sterilization process
intended to sterilize medical devices, which has appropriate microbicidal activity. Furthermore,
compliance with the requirements ensures that validations conducted following this International
Standard will provide products that meet the defined requirements for sterile products with a high
degree of confidence. The specification for this probability is a matter for regulatory authorities and can
vary from country to country (see for example EN 556-1 and ANSI/AAMI ST67).
Generic requirements of the quality management systems for design and development, production,
installation and servicing are given in ISO 9001 and particular requirements for quality management
systems for medical device production are given in ISO 13485. The standards for quality management
systems recognize that, for certain processes used in manufacturing or reprocessing, the effectiveness
of the process cannot be fully verified by subsequent inspection and testing of the product. Sterilization
is an example of such a process. For this reason, sterilization processes are validated for use, the
performance of the sterilization process monitored routinely and the equipment maintained.
Exposure to a properly validated, accurately controlled sterilization process is not the only factor
associated with the provision of reliable assurance that the product is sterile and, in this regard, suitable
for its intended use. Attention is therefore given to a number of considerations including:
— the microbiological status of incoming raw materials and/or components;
— the validation and routine control of any cleaning and disinfection procedures used on the product;
— the control of the environment in which the product is manufactured or reprocessed, assembled
and packaged;
— the control of equipment and processes;
— the control of personnel and their hygiene;
— the manner and materials in which the product is packaged;
— the conditions under which product is stored.
The type of contamination on a product to be sterilized varies and this impacts upon the effectiveness
of a sterilization process. Products that have been used in a health care setting and are being presented
for resterilization in accordance with the manufacturer’s instructions (see ISO 17664) are a special case.
There is the potential for such products to possess a wide range of contaminating microorganisms and
residual inorganic and/or organic contamination in spite of the application of a cleaning process. Hence,
it is important to pay particular attention to the validation and control of the cleaning and disinfection
processes used during reprocessing. Mixed product loads are common in health care facilities with
throughput volumes dictated by historical and predicted demand for sterile product.
vi © ISO 2014 – All rights reserved
---------------------- Page: 6 ----------------------
ISO 11135:2014(E)
The requirements are the normative parts of ISO 11135 with which compliance is claimed. The guidance
given in the informative annexes is not normative and is not provided as a checklist for auditors. The
guidance in Annex D provides explanations and methods that are regarded as being suitable means for
complying with the requirements for industry and health care facilities.
The guidance, in Annex D, is intended for people who have a basic knowledge of the principles of EO
sterilization. Methods other than those given in the guidance can be used if they are effective in achieving
compliance with the requirements of ISO 11135.
The development, validation and routine control of a sterilization process comprises a number of
discrete but interrelated activities; e.g. calibration, maintenance, product definition, process definition,
installation qualification, operational qualification and performance qualification. While the activities
required by ISO 11135 have been grouped together and are presented in a particular order, ISO 11135
does not require that the activities be performed in the order in which they are presented. The activities
required are not necessarily sequential, as the programme of development and validation may be iterative.
It is possible that performing these different activities will involve a number of separate individuals
and/or organizations, each of whom undertakes one or more of these activities. This International
Standard does not specify the particular individuals or organizations to carry out the activities.
It is important that patient safety be addressed by minimizing exposure to EO and its by-products during
normal product use. ISO 10993-7 specifies limits for EO and ethylene chlorohydrin (ECH); however, no
exposure limits are set for ethylene glycol (EG) because risk assessment indicates that when EO residues
are controlled, it is unlikely that biologically significant residues of EG would be present.
© ISO 2014 – All rights reserved vii
---------------------- Page: 7 ----------------------
INTERNATIONAL STANDARD ISO 11135:2014(E)
Sterilization of health-care products — Ethylene oxide —
Requirements for the development, validation and routine
control of a sterilization process for medical devices
1 Scope
1.1 Inclusions
This International Standard specifies requirements for the development, validation and routine control
of an ethylene oxide sterilization process for medical devices in both the industrial and health care
facility settings, and it acknowledges the similarities and differences between the two applications.
NOTE 1 Among the similarities are the common need for quality systems, staff training, and proper safety
measures. The major differences relate to the unique physical and organizational conditions in health care
facilities, and to the initial condition of reusable medical devices being presented for sterilization.
NOTE 2 Health care facilities differ from medical device manufacturers in the physical design of processing
areas, in the equipment used, and in the availability of personnel with adequate levels of training and experience.
The primary function of the health care facility is to provide patient care; medical device reprocessing is just one
of a myriad of activities that are performed to support that function.
NOTE 3 In terms of the initial condition of medical devices, medical device manufacturers generally sterilize
large numbers of similar medical devices that have been produced from virgin material. Health care facilities,
on the other hand, must handle and process both new medical devices and reusable medical devices of different
descriptions and with varying levels of bioburden. They are therefore faced with the additional challenges of
cleaning, evaluating, preparing and packaging a medical device prior to sterilization. In this International
Standard, alternative approaches and guidance specific to health care facilities are identified as such.
NOTE 4 EO gas and its mixtures are effective sterilants that are primarily used for heat- and/or moisture-
sensitive medical devices that cannot be moist heat sterilized.
NOTE 5 Although the scope of this International Standard is limited to medical devices, it specifies requirements
and provides guidance that can be applicable to other health care products.
1.2 Exclusions
1.2.1 This International Standard does not specify requirements for the development, validation and
routine control of a process for inactivating the causative agents of spongiform encephalopathies such
as scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Specific recommendations
have been produced in particular countries for the processing of materials potentially contaminated with
these agents.
NOTE See ISO 22442-1, ISO 22442-2 and ISO 22442-3.
1.2.2 This International Standard does not detail a specified requirement for designating a medical
device as sterile.
NOTE Attention is drawn to national or regional requirements for designating medical devices as “sterile”.
See for example EN 556–1 or ANSI/AAMI ST67.
1.2.3 This International Standard does not specify a quality management system for the control of all
stages of production of medical devices.
© ISO 2014 – All rights reserved 1
---------------------- Page: 8 ----------------------
ISO 11135:2014(E)
NOTE The effective implementation of defined and documented procedures is necessary for the development,
validation and routine control of a sterilization process for medical devices. Such procedures are commonly
considered to be elements of a quality management system. It is not a requirement of this International Standard
to have a full quality management system during manufacture or reprocessing. The necessary elements are
normatively referenced at appropriate places in the text (see, in particular, Clause 4). Attention is drawn to the
standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing
of medical devices. National and/or regional regulations for the provision of medical devices might require the
implementation of a full quality management system and the assessment of that system by a third party.
1.2.4 This International Standard does not specify requirements for occupational safety associated
with the design and operation of EO sterilization facilities.
NOTE 1 For further information on safety, see examples in the Bibliography. National or regional regulations
may also exist.
NOTE 2 EO is toxic, flammable and explosive. Attention is drawn to the possible existence in some countries of
regulations giving safety requirements for handling EO and for premises in which it is used.
1.2.5 This International Standard does not cover sterilization by injecting EO or mixtures containing
EO directly into packages or a flexible chamber.
NOTE See ISO 14937 for these types of EO processes.
1.2.6 This International Standard does not cover analytical methods for determining levels of residual
EO and/or its reaction products.
NOTE 1 For further information see ISO 10993-7.
NOTE 2 Attention is drawn to the possible existence of national or regional regulations specifying limits for
the level of EO residues present on or in medical devices.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10012, Measurement management systems — Requirements for measurement processes and measuring
equipment
ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
ISO 11138-1:2006, Sterilization of health care products — Biological indicators — Part 1: General
requirements
ISO 11138-2:2009, Sterilization of health care products — Biological indicators — Part 2: Biological
indicators for ethylene oxide sterilization processes
ISO 11140-1, Sterilization of health care products — Chemical indicators — Part 1: General requirements
ISO 11737-1, Sterilization of medical devices — Microbiological methods — Part 1: Determination of a
population of microorganisms on products
ISO 11737-2, Sterilization of medical devices — Microbiological methods — Part 2: Tests of sterility
performed in the definition, validation and maintenance of a sterilization process
ISO 13485:2003/Cor 1:2009, Medical devices — Quality management systems — Requirements for
regulatory purposes — Technical Corrigendum 1
2 © ISO 2014 – All rights reserved
---------------------- Page: 9 ----------------------
ISO 11135:2014(E)
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
aeration
part of the sterilization process during which ethylene oxide and/or its reaction products desorb from
the medical device until predetermined levels are reached
Note 1 to entry: This can be performed within the sterilizer and/or in a separate chamber or room.
3.2
aeration area
either a chamber or a room in which aeration occurs
3.3
bioburden
population of viable microorganisms on or in product and/or sterile barrier system
[SOURCE: ISO/TS 11139:2006, definition 2.2]
3.4
biological indicator
test system containing viable microorganisms providing a defined resistance to a specified sterilization
process
[SOURCE: ISO/TS 11139:2006, definition 2.3]
3.5
calibration
set of operations that establish, under specified conditions, the relationship between values of a quantity
indicated by a measuring instrument or measuring system, or values represented by a material measure
or a reference material, and the corresponding values realized by standards
[SOURCE: ISO/TS 11139:2006, definition 2.4]
3.6
chemical indicator
test system that reveals a change in one or more pre-defined process variables based on a chemical or
physical change resulting from exposure to a process
[SOURCE: ISO/TS 11139:2006, definition 2.6]
3.7
conditioning
treatment of product within the sterilization cycle, but prior to ethylene oxide admission, to attain a
predetermined temperature and relative humidity
Note 1 to entry: This part of the sterilization cycle can be carried out either at atmospheric pressure or under
vacuum.
Note 2 to entry: See 3.27, preconditioning.
© ISO 2014 – All rights reserved 3
---------------------- Page: 10 ----------------------
ISO 11135:2014(E)
3.8
D value
D value
10
time or dose required to achieve inactivation of 90 % of a population of the test microorganism under
stated conditions
[SOURCE: ISO/TS 11139:2006, definition 2.11]
Note 1 to entry: For the purposes of this International Standard, the D value is the exposure time required to
achieve 90 % inactivation of the population of the test organism.
3.9
development
act of elaborating a specification
[SOURCE: ISO/TS 11139:2006, definition 2.13]
3.10
dew point
The temperature at which the saturation water vapour pressure is equal to the partial pressure of the
water vapour in the atmosphere
Note 1 to entry: Any cooling of the atmosphere below the dew point would produce water condensation.
3.11
establish
determine by theoretical evaluation and confirm by experimentation
[SOURCE: ISO/TS 11139:2006, definition 2.17]
3.12
ethylene oxide (EO) injection time
duration of the stage beginning with the first introduction of the EO (mixture) into the chamber to the
completion of that injection
3.13
exposure time
period for which the process parameters are maintained within their specified tolerances
[SOURCE: ISO/TS 11139:2006, definition 2.18]
Note 1 to entry: For the purpose of calculation of cycle lethality, it is the period of sterilization between the end of
EO injection and the beginning of EO removal.
3.14
fault
one or more of the process parameters lying outside of its/their specified tolerance(s)
[SOURCE: ISO/TS 11139:2006, definition 2.19]
3.15
flushing
procedure by which the ethylene oxide is removed from the load and chamber by either multiple alternate
admissions of filtered air, inert gas or steam and evacuations of the chamber or continuous passage of
filtered air, inert gas or
...
DRAFT INTERNATIONAL STANDARD ISO/DIS 11135.2
ISO/TC 198 Secretariat: ANSI
Voting begins on Voting terminates on
2012-09-20 2012-11-20
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ ORGANISATION INTERNATIONALE DE NORMALISATION
Sterilization of health-care products — Ethylene oxide —
Requirements for the development, validation and routine
control of a sterilization process for medical devices
Stérilisation des produits de santé — Oxyde d'éthylène — Exigences de développement, de validation et de
contrôle de routine d'un processus de stérilisation pour des dispositifs médicaux
[Revision of first edition (ISO 11135-1:2007) and ISO/TS 11135-2:2008]
ICS 11.080.01
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for Standardization (ISO), and
processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member bodies for a parallel
five-month enquiry.
Should this draft be accepted, a final draft, established on the basis of comments received, will be
submitted to a parallel two-month approval vote in ISO and formal vote in CEN.
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.
RECIPIENTS OF THIS DRAFT ARE INVITED TO SUBMIT, WITH THEIR COMMENTS, NOTIFICATION OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPORTING DOCUMENTATION.
© International Organization for Standardization, 2012
---------------------- Page: 1 ----------------------
ISO/DIS 11135.2
Copyright notice
This ISO document is a Draft International Standard and is copyright-protected by ISO. Except as permitted
under the applicable laws of the user’s country, neither this ISO draft nor any extract from it may be
reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic,
photocopying, recording or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
ii © ISO 2012 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/DIS 11135
Contents Page
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Normative references . 2
3 Terms and definitions . 3
4 Quality management systems . 10
4.1 Documentation . 10
4.2 Management responsibility . 10
4.3 Product realization . 11
4.4 Measurement, analysis and improvement — Control of nonconforming product . 11
5 Sterilizing agent characterization . 11
5.1 General . 11
5.2 Sterilizing agent . 11
5.3 Microbicidal effectiveness . 11
5.4 Material effects . 11
5.5 Safety and the environment . 12
6 Process and equipment characterization . 12
6.1 General . 12
6.2 Process characterization . 12
6.3 Equipment characterization . 13
7 Product definition . 14
7.1 General . 14
7.2 Product safety, quality and performance . 14
7.3 Microbiological quality . 14
7.4 Documentation . 15
8 Process definition . 15
9 Validation . 16
9.1 General . 16
9.2 Installation qualification . 16
9.2.1 Equipment . 16
9.2.2 Installation . 16
9.3 Operational qualification . 17
9.4 Performance qualification . 17
9.4.1 General . 17
9.4.2 Performance qualification — Microbiological . 18
9.4.3 Performance qualification — Physical . 18
9.5 Review and approval of validation . 19
10 Routine monitoring and control . 21
11 Product release from sterilization . 22
12 Maintaining process effectiveness . 23
12.1 General . 23
12.2 Maintenance of equipment . 23
12.3 Requalification . 23
12.4 Assessment of change . 24
12.5 Assessment of equivalence . 24
© ISO 2011 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/DIS 11135
Annex A (normative) Determination of lethal rate of the sterilization process — Biological
indicator/bioburden approach . 25
A.1 General . 25
A.2 Procedure . 25
Annex B (normative) Conservative determination of lethal rate of the sterilization process —
Overkill approach . 26
B.1 General . 26
B.2 Procedure . 26
Annex C (informative) Temperature sensors, RH sensors and biological indicator numbers . 28
C.1 Temperature sensors . 28
C.2 Humidity sensors . 29
C.3 Biological Indicators . 29
Annex D (informative) Guidance on the application of the normative requirements . 31
D.1 Scope . 31
D.2 Normative references . 31
D.3 Terms and definitions . 31
D.4 Quality management systems . 31
D.4.1 Documentation . 31
D.4.2 Management responsibility . 31
D.4.3 Product realization . 32
D.4.4 Measurement, analysis and improvement — Control of non-conforming product . 32
D.5 Sterilizing agent characterization . 32
D.5.1 General . 32
D.5.2 Sterilizing agent . 33
D.5.3 Microbicidal effectiveness . 33
D.5.4 Material effects . 33
D.5.5 Safety and the environment . 33
D.6 Process and equipment characterization. 34
D.6.1 General . 34
D.6.2 Process characterization . 34
D.6.3 Equipment characterization . 36
D.7 Product definition . 38
D.7.1 General . 38
D.7.2 Product safety, quality and performance . 41
D.7.3 Microbiological quality . 43
D.7.4 Documentation . 43
D.8 Process definition . 43
D.9 Validation . 46
D.9.1 General . 46
D.9.2 Installation qualification . 47
D.9.3 Operational qualification . 49
D.9.4 Performance qualification . 51
D.9.5 Review and approval of validation . 54
D.10 Routine monitoring and control . 55
D.11 Product Release from sterilization . 58
D.12 Maintaining process effectiveness . 58
D.12.1 General . 58
D.12.2 Maintenance of equipment . 59
D.12.3 Requalification Add IE Flowchart . 60
D.12.4 Assessment of change . 62
D.12.5 Assessment of equivalence . 63
D.13 Guidance on Annex A — Determination of lethal rate of the sterilization process —
Biological indicator/bioburden approach. 68
D.13.1 [A.1] General . 68
D.13.2 [A.2] Procedure . 70
D.14 Guidance on Annex B — Conservative determination of lethal rate of the sterilization
process — Overkill approach . 71
D.14.1 [B.1] General . 71
iv © ISO 2011 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/DIS 11135
D.14.2 [B.2] Procedure . 72
Annex E (normative) Single Lot Release . 74
© ISO 2011 – All rights reserved v
---------------------- Page: 5 ----------------------
ISO/DIS 11135
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.
ISO 11135 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
ISO 11135:20xx cancels and replaces ISO 11135-1:2007 Sterilization of health care products – Ethylene
oxide – Part 1: Requirements for the development, validation and routine control of a sterilization process for
medical devices and ISO/TS 11135-2:2008 Sterilization of health care products – Ethylene oxide – Part 2:
Guidance on the application of ISO 11135-1, both of which have been technically revised and condensed into
a single standard.
vi © ISO 2011 – All rights reserved
---------------------- Page: 6 ----------------------
ISO/DIS 11135
Introduction
A sterile medical device is one that is free of viable microorganisms. Medical devices produced under
standard manufacturing conditions in accordance with the requirements for quality management systems (see
for example ISO 13485) might, prior to sterilization, have microorganisms on them, albeit in low numbers.
Such medical devices are non-sterile. The purpose of sterilization is to inactivate the microbiological
contaminants and thereby transform the non-sterile medical devices into sterile ones.
The kinetics of inactivation of a pure culture of microorganisms by physical and/or chemical agents used to
sterilize medical devices can generally best be described by an exponential relationship between the numbers
of microorganisms surviving and the extent of treatment with the ethylene oxide (EO); inevitably this means
that there is always a finite probability that a microorganism may survive regardless of the extent of treatment
applied. For a given treatment, the probability of survival is determined by the number and resistance of
microorganisms and by the environment in which the organisms exist during treatment. It follows that the
sterility of any one medical device in a population subjected to sterilization processing cannot be guaranteed
and the sterility of a processed population is defined in terms of the probability of there being a viable
microorganism present on a medical device.
ISO 11135 describes requirements that, if met, will provide an ethylene oxide sterilization process intended to
sterilize medical devices, which has appropriate microbicidal activity. Furthermore, compliance with the
requirements ensures that validations conducted following this international standard will provide products that
meet the defined requirements for sterile products with a high degree of confidence. The specification for this
probability is a matter for regulatory authorities and can vary from country to country (see for example EN 556-
1 and ANSI/AAMI ST67).
Generic requirements of the quality management systems for design and development, production, installation
and servicing are given in ISO 9001 and particular requirements for quality management systems for medical
device production are given in ISO 13485. The standards for quality management systems recognise that, for
certain processes used in manufacturing or reprocessing, the effectiveness of the process cannot be fully
verified by subsequent inspection and testing of the product. Sterilization is an example of such a process. For
this reason, sterilization processes are validated for use, the performance of the sterilization process
monitored routinely and the equipment maintained.
Exposure to a properly validated, accurately controlled sterilization process is not the only factor associated
with the provision of reliable assurance that the product is sterile and, in this regard, suitable for its intended
use. Attention is therefore given to a number of considerations including:
—the microbiological status of incoming raw materials and/or components;
—the validation and routine control of any cleaning and disinfection procedures used on the product;
—the control of the environment in which the product is manufactured or reprocessed, assembled and
packaged;
—the control of equipment and processes;
—the control of personnel and their hygiene;
—the manner and materials in which the product is packaged;
—the conditions under which product is stored.
The type of contamination on a product to be sterilized varies and this impacts upon the effectiveness of a
sterilization process. Products that have been used in a health care setting and are being presented for
resterilization in accordance with the manufacturer's instructions (see ISO 17664) are a special case. There is
© ISO 2011 – All rights reserved vii
---------------------- Page: 7 ----------------------
ISO/DIS 11135
the potential for such products to possess a wide range of contaminating microorganisms and residual
inorganic and/or organic contamination in spite of the application of a cleaning process. Hence, it is important
to pay particular attention to the validation and control of the cleaning and disinfection processes used during
reprocessing. Mixed product loads are common in health care facilities with throughput volumes dictated by
historical and predicted demand for sterile product.
The requirements are the normative parts of ISO 11135 with which compliance is claimed. The guidance
given in the informative annexes is not normative and is not provided as a checklist for auditors. The guidance
in Annex D provides explanations and methods that are regarded as being suitable means for complying with
the requirements for industry and health care facilities.
The guidance, in Annex D, is intended for people who have a basic knowledge of the principles of EO
sterilization. Methods other than those given in the guidance can be used if they are effective in achieving
compliance with the requirements of ISO 11135.
The development, validation and routine control of a sterilization process comprises a number of discrete but
interrelated activities; e.g. calibration, maintenance, product definition, process definition, installation
qualification, operational qualification and performance qualification. While the activities required by
ISO 11135 have been grouped together and are presented in a particular order, ISO 11135 does not require
that the activities be performed in the order in which they are presented. The activities required are not
necessarily sequential, as the programme of development and validation may be iterative. It is possible that
performing these different activities will involve a number of separate individuals and/or organizations, each of
whom undertakes one or more of these activities. This International Standard does not specify the particular
individuals or organizations to carry out the activities.
It is important that patient safety be addressed by minimizing exposure to EO and its by-products during
normal product use. ISO 10993-7 specifies limits for EO and ethylene chlorohydrin (ECH); however, no
exposure limits are set for ethylene glycol (EG) because risk assessment indicates that when EO residues are
controlled, it is unlikely that biologically significant residues of EG would be present.
viii © ISO 2011 – All rights reserved
---------------------- Page: 8 ----------------------
DRAFT INTERNATIONAL STANDARD ISO/DIS 11135
Sterilization of health care products — Ethylene oxide —
Requirements for the development, validation and routine
control of a sterilization process for medical devices
1 Scope
1.1 Inclusions
This International Standard specifies requirements for the development, validation and routine control of an
ethylene oxide sterilization process for medical devices in both the industrial and health care facility settings,
and it acknowledges the similarities and differences between the two applications.
NOTE 1 Among the similarities are the common need for quality systems, staff training, and proper safety measures.
The major differences relate to the unique physical and organizational conditions in health care facilities, and to the initial
condition of reusable medical devices being presented for sterilization.
NOTE 2 Health care facilities differ from medical device manufacturers in the physical design of processing areas, in
the equipment used, and in the availability of personnel with adequate levels of training and experience. The primary
function of the health care facility is to provide patient care; medical device reprocessing is just one of a myriad of activities
that are performed to support that function.
NOTE 3 In terms of the initial condition of medical devices, medical device manufacturers generally sterilize large
numbers of similar medical devices that have been produced from virgin material. Health care facilities, on the other hand,
must handle and process both new medical devices and reusable medical devices of different descriptions and with
varying levels of bioburden. They are therefore faced with the additional challenges of cleaning, evaluating, preparing and
packaging a medical device prior to sterilization. In this International Standard, alternative approaches and guidance
specific to health care facilities are identified as such.
NOTE 4 EO gas and its mixtures are effective sterilants that are primarily used for heat- and/or moisture-sensitive
medical devices that cannot be moist heat sterilized.
NOTE 5 Although the scope of this International Standard is limited to medical devices, it specifies requirements and
provides guidance that may be applicable to other health care products.
1.2 Exclusions
1.2.1 This International Standard does not specify requirements for the development, validation and
routine control of a process for inactivating the causative agents of spongiform encephalopathies such as
scrapie, bovine spo
...
DRAFT INTERNATIONAL STANDARD ISO/DIS 11135
ISO/TC 198 Secretariat: ANSI
Voting begins on Voting terminates on
2000-09-15 2012-02-15
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ ORGANISATION INTERNATIONALE DE NORMALISATION
Sterilization of health-care products — Ethylene oxide —
Requirements for the development, validation and routine
control of a sterilization process for medical devices
Stérilisation des produits de santé — Oxyde d'éthylène — Exigences pour le développement, la validation et
la vérification de routine d'un processus de stérilisation pour les appareils médicaux
[Revision of first edition (ISO 11135-1:2007) and ISO/TS 11135-2:2008]
ICS 11.080.01
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for Standardization (ISO), and
processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member bodies for a parallel
five-month enquiry.
Should this draft be accepted, a final draft, established on the basis of comments received, will be
submitted to a parallel two-month approval 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.
RECIPIENTS OF THIS DRAFT ARE INVITED TO SUBMIT, WITH THEIR COMMENTS, NOTIFICATION OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPORTING DOCUMENTATION.
© International Organization for Standardization, 2011
---------------------- Page: 1 ----------------------
ISO/DIS 11135
Copyright notice
This ISO document is a Draft International Standard and is copyright-protected by ISO. Except as permitted
under the applicable laws of the user’s country, neither this ISO draft nor any extract from it may be
reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic,
photocopying, recording or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
ii © ISO 2011 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/DIS 11135
Contents Page
Foreword . vi
Introduction . vii
1 Scope . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Normative references . 2
3 Terms and definitions . 3
4 Quality management systems . 10
4.1 Documentation . 10
4.2 Management responsibility . 10
4.3 Product realization . 10
4.4 Measurement, analysis and improvement — Control of nonconforming product . 10
5 Sterilizing agent characterization . 11
5.1 General . 11
5.2 Sterilizing agent . 11
5.3 Microbicidal effectiveness . 11
5.4 Material effects . 11
5.5 Safety and the environment . 11
6 Process and equipment characterization . 11
6.1 General . 11
6.2 Process characterization . 11
6.3 Equipment characterization . 12
7 Product definition . 13
7.1 General . 13
7.2 Product safety, quality and performance . 14
7.3 Microbiological quality . 14
7.4 Documentation . 14
8 Process definition . 14
9 Validation . 15
9.1 General . 15
9.2 Installation qualification . 15
9.2.1 Equipment . 15
9.2.2 Installation . 16
9.3 Operational qualification . 16
9.4 Performance qualification . 16
9.4.1 General . 16
9.4.2 Performance qualification — Microbiological . 17
9.4.3 Performance qualification — Physical . 17
9.5 Review and approval of validation . 18
10 Routine monitoring and control . 20
11 Product Release from sterilization . 21
12 Maintaining process effectiveness . 22
12.1 General . 22
12.2 Maintenance of equipment . 22
12.3 Requalification . 22
12.4 Assessment of change . 22
© ISO 2011 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/DIS 11135
Annex A (normative) Determination of lethal rate of the sterilization process — Biological
indicator/bioburden approach . 24
A.1 General . 24
A.2 Procedure . 24
Annex B (normative) Conservative determination of lethal rate of the sterilization process —
Overkill approach . 25
B.1 General . 25
B.2 Procedure . 25
Annex C (informative) Temperature sensors, RH sensors and biological indicator numbers . 27
C.1 Temperature sensors . 27
C.2 Humidity sensors . 28
C.3 Biological Indicators . 28
Annex D (informative) Guidance on the application of the normative requirements . 30
D.1 Scope . 30
D.2 Normative requirements . 30
D.3 Terms and definitions . 30
D.4 Quality management systems . 30
D.4.1 Documentation . 30
D.4.2 Management responsibility . 30
D.4.3 Product realization . 31
D.4.4 Measurement, analysis and improvement — Control of non-conforming product . 31
D.5 Sterilizing agent characterization . 31
D.5.1 General . 31
D.5.2 Sterilizing agent . 32
D.5.3 Microbicidal effectiveness . 32
D.5.4 Material effects . 32
D.5.5 Safety and the environment . 32
D.6 Process and equipment characterization. 32
D.6.1 General . 33
D.6.2 Process characterization . 33
D.6.3 Equipment characterization . 34
D.7 Product definition . 37
D.7.1 General . 37
D.7.2 Product safety, quality and performance . 40
D.7.3 Microbiological quality . 41
D.7.4 Documentation . 41
D.8 Process definition . 41
D.9 Validation . 45
D.9.1 General . 45
D.9.2 Installation qualification . 45
D.9.3 Operational qualification . 47
D.9.4 Performance qualification . 49
D.9.5 Review and approval of validation . 52
D.10 Routine monitoring and control . 53
D.11 Product Release from sterilization . 55
D.12 Maintaining process effectiveness . 56
D.12.1 General . 56
D.12.2 Maintenance of equipment . 56
D.12.3 Requalification . 57
D.12.4 Assessment of change . 59
D.12.5 Assessment of equivalence . 60
D.13 Guidance on Annex A — Determination of lethal rate of the sterilization process —
Biological indicator/bioburden approach. 65
D.13.1 [A.1] General . 65
D.13.2 [A.2] Procedure . 67
D.14 Guidance on Annex B — Conservative determination of lethal rate of the sterilization
process — Overkill approach . 68
D.14.1 [B.1] General . 68
iv © ISO 2011 – All rights reserved
---------------------- Page: 4 ----------------------
ISO/DIS 11135
D.14.2 [B.2] Procedure . 68
Annex E . 70
Bibliography . 72
© ISO 2011 – All rights reserved v
---------------------- Page: 5 ----------------------
ISO/DIS 11135
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.
ISO 11135 was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
ISO 11135:20xx cancels and replaces ISO 11135-1:2007 Sterilization of health care products – Ethylene
oxide – Part 1: Requirements for the development, validation and routine control of a sterilization process for
medical devices and ISO/TS 11135-2:2008 Sterilization of health care products – Ethylene oxide – Part 2:
Guidance on the application of ISO 11135-1, both of which have been technically revised and condensed into
a single standard.
vi © ISO 2011 – All rights reserved
---------------------- Page: 6 ----------------------
ISO/DIS 11135
Introduction
A sterile medical device is one that is free of viable microorganisms. Medical devices produced under
standard manufacturing conditions in accordance with the requirements for quality management systems (see
for example ISO 13485) may, prior to sterilization, have microorganisms on them, albeit in low numbers. Such
medical devices are non-sterile. The purpose of sterilization is to inactivate the microbiological contaminants
and thereby transform the non-sterile medical devices into sterile ones.
The kinetics of inactivation of a pure culture of microorganisms by physical and/or chemical agents used to
sterilize medical devices can generally best be described by an exponential relationship between the numbers
of microorganisms surviving and the extent of treatment with the ethylene oxide (EO); inevitably this means
that there is always a finite probability that a microorganism may survive regardless of the extent of treatment
applied. For a given treatment, the probability of survival is determined by the number and resistance of
microorganisms and by the environment in which the organisms exist during treatment. It follows that the
sterility of any one medical device in a population subjected to sterilization processing cannot be guaranteed
and the sterility of a processed population is defined in terms of the probability of there being a viable
microorganism present on a medical device.
ISO 11135 describes requirements that, if met, will provide an ethylene oxide sterilization process intended to
sterilize medical devices, which has appropriate microbicidal activity. Furthermore, compliance with the
requirements ensures that validations conducted following this standard will provide products that meet the
defined requirements for sterile products with a high degree of confidence. The specification for this probability
is a matter for regulatory authorities and may vary from country to country (see for example EN 556-1 and
ANSI/AAMI ST67).
Generic requirements of the quality management systems for design and development, production, installation
and servicing are given in ISO 9001 and particular requirements for quality management systems for medical
device production are given in ISO 13485. The standards for quality management systems recognise that, for
certain processes used in manufacturing or reprocessing, the effectiveness of the process cannot be fully
verified by subsequent inspection and testing of the product. Sterilization is an example of such a process. For
this reason, sterilization processes are validated for use, the performance of the sterilization process
monitored routinely and the equipment maintained.
Exposure to a properly validated, accurately controlled sterilization process is not the only factor associated
with the provision of reliable assurance that the product is sterile and, in this regard, suitable for its intended
use. Attention is therefore given to a number of considerations including:
—the microbiological status of incoming raw materials and/or components;
—the validation and routine control of any cleaning and disinfection procedures used on the product;
—the control of the environment in which the product is manufactured or reprocessed, assembled and
packaged;
—the control of equipment and processes;
—the control of personnel and their hygiene;
—the manner and materials in which the product is packaged;
—the conditions under which product is stored.
The type of contamination on a product to be sterilized varies and this impacts upon the effectiveness of a
sterilization process. Products that have been used in a health care setting and are being presented for
resterilization in accordance with the manufacturer's instructions (see ISO 17664) should be regarded as a
© ISO 2011 – All rights reserved vii
---------------------- Page: 7 ----------------------
ISO/DIS 11135
special case. There is the potential for such products to possess a wide range of contaminating
microorganisms and residual inorganic and/or organic contamination in spite of the application of a cleaning
process. Hence, it is important to pay particular attention to the validation and control of the cleaning and
disinfection processes used during reprocessing. . Mixed product loads are common in healthcare facilities
with throughput volumes dictated by historical and predicted demand for sterile product.
The requirements are the normative parts of ISO 11135 with which compliance is claimed. The guidance
given in the informative annexes is not normative and is not provided as a checklist for auditors. The guidance
in Annex D provides explanations and methods that are regarded as being suitable means for complying with
the requirements for industry and health care facilities.
The guidance, in Annex D, is intended for people who have a basic knowledge of the principles of EO
sterilization. Methods other than those given in the guidance may be used if they are effective in achieving
compliance with the requirements of ISO 11135.
The development, validation and routine control of a sterilization process comprises a number of discrete but
interrelated activities; e.g. calibration, maintenance, product definition, process definition, installation
qualification, operational qualification and performance qualification. While the activities required by
ISO 11135 have been grouped together and are presented in a particular order, ISO 11135 does not require
that the activities be performed in the order in which they are presented. The activities required are not
necessarily sequential, as the programme of development and validation may be iterative. It is possible that
performing these different activities will involve a number of separate individuals and/or organizations, each of
whom undertakes one or more of these activities. This International Standard does not specify the particular
individuals or organizations to carry out the activities.
It is important that patient safety be addressed by minimizing exposure to EO and its by-products during
normal product use. ISO 10993-7 specifies limits for EO and ethylene chlorohydrin (ECH); however, no
exposure limits are set for ethylene glycol (EG) because risk assessment indicates that when EO residues are
controlled, it is unlikely that biologically significant residues of (EG would be present.
viii © ISO 2011 – All rights reserved
---------------------- Page: 8 ----------------------
DRAFT INTERNATIONAL STANDARD ISO/DIS 11135
Sterilization of health care products — Ethylene oxide —
Requirements for the development, validation and routine
control of a sterilization process for medical devices
1 Scope
1.1 Inclusions
1.1.1 This International Standard specifies requirements for the development, validation and routine control
of an ethylene oxide sterilization process for medical devices in both the industrial and health care facility
settings, and it acknowledges the similarities and differences between the two applications.
NOTE 1 Among the similarities are the common need for quality systems, staff training, and proper safety measures.
The major differences relate to the unique physical and organizational conditions in health care facilities, and to the initial
condition of re-usable medical devices being presented for sterilization.
NOTE 2 Health care facilities differ from medical device manufacturers in the physical design of processing areas, in
the equipment used, and in the availability of personnel with adequate levels of training and experience. The primary
function of the health care facility is to provide patient care; medical device reprocessing is just one of a myriad of activities
that are performed to support that function.
NOTE 3 In terms of the initial condition of medical devices, medical device manufacturers generally sterilize large
numbers of similar medical devices that have been produced from virgin material. Health care facilities, on the other hand,
must handle and process both new medical devices and re-usable medical devices of different descriptions and with
varying levels of bioburden. They are therefore faced with the additional challenges of cleaning, evaluating, preparing and
packaging a medical device prior to sterilization. In this International Standard, alternative approaches and guidance
specific to heal
...
NORME ISO
INTERNATIONALE 11135
Deuxième édition
2014-07-15
Stérilisation des produits de santé —
Oxyde d’éthylène — Exigences de
développement, de validation et de
contrôle de routine d’un processus
de stérilisation pour des dispositifs
médicaux
Sterilization of health-care products — Ethylene oxide —
Requirements for the development, validation and routine control of a
sterilization process for medical devices
Numéro de référence
ISO 11135:2014(F)
©
ISO 2014
---------------------- Page: 1 ----------------------
ISO 11135:2014(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2014
Droits de reproduction réservés. Sauf indication contraire, aucune partie de cette publication ne peut être reproduite ni utilisée
sous quelque forme que ce soit et par aucun procédé, électronique ou mécanique, y compris la photocopie, l’affichage sur
l’internet ou sur un Intranet, sans autorisation écrite préalable. Les demandes d’autorisation peuvent être adressées à l’ISO à
l’adresse ci-après ou au comité membre de l’ISO dans le pays du demandeur.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Publié en Suisse
ii © ISO 2014 – Tous droits réservés
---------------------- Page: 2 ----------------------
ISO 11135:2014(F)
Sommaire Page
Avant-propos .v
Introduction .vi
1 Domaine d’application . 1
1.1 Inclusions . 1
1.2 Exclusions . 1
2 Références normatives . 2
3 Termes et définitions . 3
4 Systèmes de management de la qualité .11
4.1 Documentation .11
4.2 Responsabilité de la direction .11
4.3 Réalisation du produit .11
4.4 Mesurages, analyse et amélioration — Maîtrise du produit non conforme .11
5 Caractérisation de l’agent stérilisant .11
5.1 Généralités .11
5.2 Agent stérilisant .12
5.3 Efficacité microbicide .12
5.4 Effets sur les matériaux .12
5.5 Sécurité et environnement .12
6 Caractérisation du procédé et de l’équipement .12
6.1 Généralités .12
6.2 Caractérisation du procédé .13
6.3 Caractérisation de l’équipement .14
7 Définition du produit .14
7.1 Généralités .14
7.2 Sécurité, qualité et performance du produit .15
7.3 Qualité microbiologique .15
7.4 Documentation .16
8 Définition du procédé .16
9 Validation .17
9.1 Généralités .17
9.2 Qualification de l’installation, QI .17
9.3 Qualification opérationnelle, QO .18
9.4 Qualification de performance, QP .18
9.5 Revue et approbation de la validation .20
10 Surveillance et contrôle de routine .22
11 Libération du produit après stérilisation .24
12 Maintien de l’efficacité du procédé
.24
12.1 Généralités .24
12.2 Maintenance de l’équipement .24
12.3 Requalification .25
12.4 Évaluation des modifications .25
12.5 Évaluation de l’équivalence .26
Annexe A (normative) Détermination du taux de létalité du procédé de stérilisation — Approche
indicateur biologique/charge biologique .27
Annexe B (normative) Détermination conservatrice du taux de létalité du procédé de
stérilisation — Approche de surdestruction .28
Annexe C (informative) Capteurs de température, capteurs HR et nombre
d’indicateurs biologiques .30
© ISO 2014 – Tous droits réservés iii
---------------------- Page: 3 ----------------------
ISO 11135:2014(F)
Annexe D (informative) Directives relatives à l’application des exigences normatives.33
Annexe E (normative) Libération d’un seul produit .80
Bibliographie .82
iv © ISO 2014 – Tous droits réservés
---------------------- Page: 4 ----------------------
ISO 11135:2014(F)
Avant-propos
L’ISO (Organisation internationale de normalisation) est une fédération mondiale d’organismes
nationaux de normalisation (comités membres de l’ISO). L’élaboration des Normes internationales est
en général confiée aux comités techniques de l’ISO. Chaque comité membre intéressé par une étude
a le droit de faire partie du comité technique créé à cet effet. Les organisations internationales,
gouvernementales et non gouvernementales, en liaison avec l’ISO participent également aux travaux.
L’ISO collabore étroitement avec la Commission électrotechnique internationale (IEC) en ce qui concerne
la normalisation électrotechnique.
Les modes opératoires utilisés pour élaborer ce documents et ceux destinés à sa maintenance ultérieure
sont décrits dans les Directives ISO/IEC, Partie 1. Il convient en particulier de noter les différents
critères d’approbation nécessaires pour les différents types de documents ISO. Ce document a été rédigé
conformément aux règles données dans les Directives ISO/IEC, Partie 2 (voir www.iso.org/directives).
L’attention est appelée sur le fait que certains des éléments du présent document peuvent faire l’objet
de droits de propriété intellectuelle. L’ISO ne saurait être tenue pour responsable de ne pas avoir
identifié de tels droits de propriété. Les détails de tout droit de propriété identifié pendant l’élaboration
du document figureront dans l’Introduction et/ou sur la liste ISO des déclarations de brevets reçues
(voir www.iso.org/patents).
Tout nom commercial utilisé dans le présent document est uniquement donné à titre informatif à
l’attention des utilisateurs et ne constitue pas une recommandation.
Pour obtenir une explication sur la signification de termes et expressions spécifiques à l’ISO se rapportant
à l’évaluation de la conformité, ainsi que des informations sur l’adhérence de l’ISO aux principes de
l’OMC relatifs aux obstacles techniques au commerce (OTC), se reporter à l’URL suivant: Avant-propos -
Informations complémentaires
Le comité responsable de ce document est l’ISO/TC 198, Stérilisation des produits de santé.
L’ISO 11135:2014 annule et remplace l’ISO 11135-1:2007 et l’ISO/TS 11135-2:2008, les deux ayant fait
l’objet d’une révision technique et d’un regroupement dans une seule norme.
© ISO 2014 – Tous droits réservés v
---------------------- Page: 5 ----------------------
ISO 11135:2014(F)
Introduction
Un dispositif médical est considéré comme stérile lorsqu’il est exempt de micro-organismes viables.
Des dispositifs médicaux produits dans des conditions de fabrication normalisées conformément aux
exigences des systèmes de management de la qualité (voir par exemple l’ISO 13485) peuvent, avant la
stérilisation, comporter des micro-organismes, bien qu’en nombre très réduit. Ces dispositifs médicaux
ne sont pas stériles. Le but de la stérilisation consiste à inactiver les contaminants microbiologiques, et
ce faisant, à transformer des dispositifs médicaux non stériles en produits stériles.
L’une des meilleures représentations de l’inactivation d’une culture pure de micro-organismes par
des agents physiques et/ou chimiques utilisés pour stériliser les dispositifs médicaux est d’établir une
relation exponentielle entre le nombre de micro-organismes survivants et l’ampleur du traitement
par l’oxyde d’éthylène; cela signifie inévitablement qu’il existe toujours une probabilité infime qu’un
micro-organisme survive, quelle que soit l’étendue du traitement appliqué. Pour un traitement donné,
la probabilité de survie est déterminée par le nombre et la résistance des micro-organismes et par
l’environnement dans lequel les organismes se trouvent au cours du traitement. Il s’ensuit que la stérilité
d’un dispositif médical donné appartenant à une population de dispositifs médicaux soumis à l’opération
de stérilisation ne peut être garantie et que la stérilité de la population de dispositifs médicaux traités
doit être définie en termes de probabilité qu’un micro-organisme viable soit présent sur un dispositif
médical.
L’ISO 11135 spécifie les exigences qui permettront de démontrer que le procédé de stérilisation à l’oxyde
d’éthylène destiné à stériliser les dispositifs médicaux présente une activité microbicide suffisante.
De plus, la conformité aux exigences garantit que les validations menées conformément à la présente
Norme internationale fourniront des produits qui répondent aux exigences définies pour les produits
stériles avec un haut niveau de fiabilité. La spécification de cette probabilité incombe aux autorités
réglementaires et peut varier d’un pays à l’autre (voir par exemple l’EN 556-1 et l’ANSI/AAMI ST67).
Les exigences génériques des systèmes de management de la qualité pour la conception et la mise au point,
la production, l’installation et l’entretien sont données dans l’ISO 9001 et les exigences particulières pour
les systèmes de management de la qualité pour la production de dispositifs médicaux sont données dans
l’ISO 13485. Les normes relatives aux systèmes de management de la qualité reconnaissent que, pour
certains procédés de stérilisation utilisés dans la fabrication ou le retraitement, l’efficacité du procédé
de stérilisation ne peut être complètement vérifiée par une inspection et des essais ultérieurs du produit.
La stérilisation est un exemple d’un tel processus. Pour cette raison, les procédés de stérilisation sont
validés avant leur mise en application, leur fonctionnement est périodiquement surveillé et l’entretien
du matériel est scrupuleusement effectué.
L’exposition à un procédé de stérilisation contrôlé avec exactitude, validé de manière appropriée n’est pas
le seul facteur associé à la garantie que le produit est stérile, et, à cet égard, adapté pour son usage prévu.
Une attention particulière doit par conséquent être apportée à un certain nombre de considérations
comprenant:
— le statut microbiologique des matières premières arrivantes et/ou des composants;
— la validation et le contrôle de routine de toute procédure de nettoyage et de désinfection utilisé sur
le produit;
— le contrôle de l’environnement dans lequel le produit est fabriqué ou retraité, assemblé et emballé;
— le contrôle de l’équipement et des procédés;
— le contrôle du personnel et de son hygiène;
— la manière et les matériaux utilisés pour l’emballage du produit;
— les conditions dans lesquelles le produit est stocké.
Le type de contamination sur un produit à stériliser varie et ceci a un impact sur l’efficacité d’un
processus de stérilisation. Les produits qui ont été utilisés dans des établissements de santé et qui sont
vi © ISO 2014 – Tous droits réservés
---------------------- Page: 6 ----------------------
ISO 11135:2014(F)
destinés à être stérilisés de nouveau conformément aux instructions du fabricant (voir l’ISO 17664)
sont considérés comme un cas spécial. Ces produits sont susceptibles de présenter un large éventail de
micro-organismes contaminants et une contamination inorganique et/ou organique résiduelle malgré
l’application d’un procédé de nettoyage. Ainsi, il est important d’apporter une attention particulière à
la validation et au contrôle des procédés de nettoyage et de désinfection utilisés durant l’opération de
retraitement. Les charges de produits mixtes sont courantes dans les établissements de santé avec des
volumes de rendement dictés par la demande historique et prévue de produits stériles.
Les exigences sont constituées par les parties normatives de l’ISO 11135 par rapport à laquelle la
conformité est déclarée. Le guide donné dans les annexes informatives n’est pas normatif et n’est pas
destiné à servir de liste de contrôle pour des auditeurs. Les directives figurant en Annexe D donnent des
explications et présentent des méthodes reconnues comme adaptées pour garantir la conformité aux
exigences de l’industrie et des établissements de santé.
Les directives, en Annexe D, s’adressent aux personnes possédant des connaissances de base des
principes de la stérilisation à l’oxyde d’éthylène. Des méthodes autres que celles données dans les
directives peuvent être utilisées à condition qu’elles soient efficaces pour assurer la conformité aux
exigences de l’ISO 11135.
La mise au point, la validation et le contrôle de routine d’un procédé de stérilisation comprennent un
certain nombre d’activités isolées, mais corrélées; par exemple l’étalonnage, la maintenance, la définition
du produit, la définition du procédé, la qualification de l’installation, la qualification opérationnelle et la
qualification de performance. Bien que les activités exigées par l’ISO 11135 ont été regroupées et sont
présentées selon un ordre particulier, l’ISO 11135 n’exige pas qu’elles se déroulent dans l’ordre présenté.
Les activités exigées ne sont pas nécessairement séquentielles, étant donné que les programmes de
mise au point et de validation peuvent être itératifs. Il est possible que le fait d’effectuer ces différentes
activités implique un certain nombre d’individus et/ou organismes, chacun d’entre eux entreprenant une
ou plusieurs de ces activités. La présente Norme internationale ne spécifie pas les individus particuliers
et les organismes qui effectuent les activités.
Il est important de prendre en compte la sécurité du patient en réduisant le plus possible l’exposition à
l’oxyde d’éthylène et ses produits dérivés lors de l’utilisation normale. L’ISO 10993-7 spécifie les limites
relatives à l’oxyde d’éthylène et au chlorhydrate d’éthylène (ECH); mais, aucune limite d’exposition n’est
définie pour l’éthylène glycol (EG), car l’évaluation des risques indique que lorsque les résidus d’oxyde
d’éthylène sont maîtrisés, la présence de résidus biologiquement significatifs d’éthylène glycol est peu
probable.
© ISO 2014 – Tous droits réservés vii
---------------------- Page: 7 ----------------------
NORME INTERNATIONALE ISO 11135:2014(F)
Stérilisation des produits de santé — Oxyde d’éthylène —
Exigences de développement, de validation et de contrôle
de routine d’un processus de stérilisation pour des
dispositifs médicaux
1 Domaine d’application
1.1 Inclusions
La présente Norme internationale spécifie les exigences relatives à la mise au point, à la validation et
au contrôle de routine du procédé de stérilisation des dispositifs médicaux à l’oxyde d’éthylène dans
l’industrie et dans les établissements de santé, et reconnaît les similitudes et différences entre les deux
applications.
NOTE 1 Parmi les points communs figure le même besoin de systèmes de qualité, de formation du personnel
et de mesures de sécurité appropriées. Les principales différences concernent les conditions matérielles et
organisationnelles propres à chaque établissement de santé, et l’état initial des dispositifs médicaux réutilisables
présentés pour la stérilisation.
NOTE 2 Les établissements de santé se distinguent des fabricants de dispositifs médicaux par la structure des
zones de traitement, le matériel utilisé et la disponibilité du personnel disposant du niveau requis en matière de
formation et d’expérience. La fonction première d’un établissement de santé est de fournir des soins aux patients;
le retraitement des dispositifs médicaux ne représente qu’une des innombrables activités mises en œuvre pour
assurer cette fonction.
NOTE 3 En ce qui concerne l’état initial des dispositifs médicaux, les fabricants stérilisent généralement
un grand nombre de dispositifs médicaux identiques produits à partir de matériau vierge. En revanche, les
établissements de santé doivent manipuler et traiter aussi bien des dispositifs médicaux neufs que des dispositifs
réutilisables, dont les caractéristiques et les niveaux de charge biologique varient. Ils doivent faire face à des
exigences supplémentaires de nettoyage, d’évaluation, de préparation et d’emballage des dispositifs médicaux
préalablement à leur stérilisation. La présente Norme internationale établit diverses approches et directives
spécifiquement adaptées aux établissements de santé.
NOTE 4 Cependant, l’oxyde d’éthylène gazeux et ses mélanges constituent des produits stérilisants efficaces
utilisés en premier lieu pour les dispositifs médicaux sensibles à la chaleur et/ou à l’humidité qui ne peuvent pas
être stérilisés par chaleur humide.
NOTE 5 Bien que le domaine d’application de la présente Norme internationale se limite aux dispositifs
médicaux, les exigences qu’il spécifie et le guide qu’il donne peuvent s’appliquer à d’autres produits de santé.
1.2 Exclusions
1.2.1 La présente Norme internationale ne spécifie pas d’exigences relatives à l’élaboration, à la validation
et au contrôle de routine d’un procédé d’inactivation des agents de prolifération des encéphalopathies
spongiformes telles que la tremblante du mouton, l’encéphalopathie spongiforme bovine et la maladie
de Creutzfeldt-Jakob. Des recommandations spécifiques ont été formulées dans certains pays pour le
traitement des matériaux potentiellement contaminés par ces agents.
NOTE Voir l’ISO 22442-1, ISO 22442-2 et l’ISO 22442-3.
1.2.2 La présente Norme internationale ne détaille pas d’exigence spécifiée pour caractériser un
dispositif médical comme étant stérile.
© ISO 2014 – Tous droits réservés 1
---------------------- Page: 8 ----------------------
ISO 11135:2014(F)
NOTE L’attention est attirée sur les exigences nationales ou régionales destinées à concevoir des dispositifs
médicaux «stériles». Voir par exemple l’EN 556–1 ou l’ANSI/AAMI ST67.
1.2.3 La présente Norme internationale ne spécifie pas de système de management de la qualité pour
le contrôle de toutes les étapes de production des dispositifs médicaux.
NOTE La mise en place efficace de procédures définies et documentées est nécessaire pour la mise au point,
la validation et le contrôle de routine d’un procédé de stérilisation pour les dispositifs médicaux. Ces procédures
sont généralement considérées comme les éléments d’un système de management de la qualité. La présente Norme
internationale n’exige pas d’avoir un système de management de la qualité complet pendant la fabrication ou le
retraitement. Les éléments nécessaires sont référencés de manière normative aux endroits appropriés dans le
texte (voir, en particulier, l’Article 4). L’attention est attirée sur les normes relatives aux systèmes de management
de la qualité (voir l’ISO 13485) qui contrôlent toutes les étapes de production ou de retraitement des dispositifs
médicaux. Les réglementations nationales et/ou régionales pour la fourniture de dispositifs médicaux peuvent
exiger la mise en place d’un système de management de la qualité complet et l’évaluation de ce système par une
tierce partie.
1.2.4 La présente Norme internationale ne spécifie aucune exigence en matière de sécurité du travail
associée à la conception et au fonctionnement des installations de stérilisation à l’oxyde d’éthylène.
NOTE 1 Pour plus de renseignements sur la sécurité, voir les exemples donnés dans la Bibliographie. Des
réglementations nationales ou régionales peuvent également exister.
NOTE 2 L’oxyde d’éthylène est toxique, inflammable et explosif. L’attention est attirée sur l’existence possible
dans certains pays de réglementations spécifiant des exigences de sécurité concernant sa manipulation et les
locaux où il est utilisé.
1.2.5 La présente Norme internationale ne traite pas de la stérilisation par injection directe d’oxyde
d’éthylène ou de ses mélanges dans les emballages ou une chambre flexible.
NOTE Voir l’ISO 14937 pour ces types de procédés à l’oxyde d’éthylène.
1.2.6 La présente Norme internationale ne traite pas des méthodes analytiques de détermination des
niveaux de résidus d’oxyde d’éthylène et/ou des produits de sa réaction.
NOTE 1 Pour plus de renseignements, voir l’ISO 10993-7.
NOTE 2 L’attention est attirée sur l’existence possible d’une réglementation nationale ou régionale fixant des
limites relatives au niveau de résidus d’oxyde d’éthylène présents sur ou dans les dispositifs médicaux.
2 Références normatives
Les documents ci-après, dans leur intégralité ou non, sont des références normatives indispensables à
l’application du présent document. Pour les références datées, seule l’édition citée s’applique. Pour les
références non datées, la dernière édition du document de référence s’applique (y compris les éventuels
amendements).
ISO 10012, Systèmes de management de la mesure — Exigences pour les processus et les équipements de
mesure.
ISO 10993-7, Évaluation biologique des dispositifs médicaux — Partie 7: résidus de stérilisation à l’oxyde
d’éthylène.
ISO 11138-1:2006, Stérilisation des produits sanitaires — Indicateurs biologiques — Partie 1: Exigences
générales.
ISO 11138-2:2009, Stérilisation des produits sanitaires — Indicateurs biologiques — Partie 2: indicateurs
biologiques pour la stérilisation à l’oxyde d’éthylène.
ISO 11140-1, Stérilisation des produits sanitaires — Indicateurs chimiques — Partie 1: Exigences générales
2 © ISO 2014 – Tous droits réservés
---------------------- Page: 9 ----------------------
ISO 11135:2014(F)
ISO 11737-1, Stérilisation des dispositifs médicaux — Méthodes microbiologiques — Partie 1: détermination
d’une population de micro-organismes sur des produits.
ISO 11737-2, Stérilisation des dispositifs médicaux — Méthodes microbiologiques — Partie 2: contrôles
de stérilité pratiqués au moment de la définition, de la validation et de la maintenance d’un procédé de
stérilisation.
ISO 13485:2003/Cor 1:2009, Dispositifs médicaux — Systèmes de management de la qualité — Exigences à
des fins réglementaires — Rectificatif technique 1.
3 Termes et définitions
Pour les besoins du présent document, les termes et définitions suivants s’appliquent.
3.1
aération
partie du procédé de stérilisation durant laquelle la désorption de l’oxyde d’éthylène et/ou des produits
de sa réaction du dispositif médical s’effectue jusqu’à l’obtention de niveaux prédéterminés
Note 1 à l’article: Ceci peut s’effectuer à l’intérieur du stérilisateur et/ou d’une chambre ou une pièce séparée.
3.2
zone d’aération
chambre ou pièce dans laquelle l’aération s’effectue
3.3
charge biologique
population de micro-organismes viables sur ou dans un produit et/ou un système de barrière stérile
[SOURCE: ISO/TS 11139:2006, définition 2.2]
3.4
indicateur biologique
système d’essai contenant des micro-organismes viables, garantissant une résistance définie à un
procédé de stérilisation spécifié
[SOURCE: ISO/TS 11139:2006, définition 2.3]
3.5
étalonnage
ensemble des opérations établissant, dans des conditions spécifiées, la relation entre les valeurs de la
grandeur indiquées par un appareil de mesure ou un système de mesure, ou les valeurs représentées par
une mesure matérialisée ou par un matériau de référence, et les valeurs correspondantes de la grandeur
réalisée par des étalons
[SOURCE: ISO/TS 11139:2006, définition 2.4]
3.6
indicateu
...
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.