Sterilization of medical devices -- Guidance on the requirements for the validation and routine processing of ethylene oxide sterilization processes using parametric release

This document provides guidance on the requirements of ISO 11135 that apply when parametric release is used to release the product after exposure to the sterilization process. It provides a path for transition of existing cycles, as well as a path for the development and implementation of a parametric release specification for a new cycle. Additionally, it highlights the importance and interrelationship of other process factors, i.e. load configuration and equipment performance, which influence reproducibility of an ethylene oxide (EO) sterilization process. NOTE For ease of reference, the numbering of clauses in this document corresponds to that in the normative parts of ISO 11135. No additional guidance is offered for processes where the declaration of adequacy of the validated sterilization cycle includes a requirement for no growth in biological indicators (BIs) exposed to that process.

Stérilisation des dispositifs médicaux -- Lignes directrices concernant les exigences de validation et de traitement de routine des procédés de stérilisation à l’oxyde d’éthylène par libération paramétrique

Le présent document fournit des lignes directrices concernant les exigences de l'ISO 11135 qui s'appliquent lorsque la libération paramétrique est utilisée pour libérer le produit aprčs exposition au procédé de stérilisation. Il fournit une voie pour la transition des cycles existants, ainsi que pour la mise au point et la mise en œuvre d'une spécification de libération paramétrique pour un nouveau cycle. En outre, il souligne l'importance et les relations avec les autres facteurs du procédé, c'est-ŕ-dire la configuration de la charge et la performance de l'équipement, qui influencent la reproductibilité d'un procédé de stérilisation ŕ l'oxyde d'éthylčne (OE). NOTE Afin de faciliter la référence, la numérotation des articles du présent document correspond ŕ celle des parties normatives de l'ISO 11135. Aucune directive supplémentaire n'est fournie pour les procédés dans lesquels la déclaration d'adéquation du cycle de stérilisation validé inclut une exigence d'absence de croissance dans les indicateurs biologiques (IB) exposés ŕ ce procédé.

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Publication Date
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TECHNICAL ISO/TS
SPECIFICATION 21387
First edition
2020-09
Sterilization of medical devices —
Guidance on the requirements for the
validation and routine processing of
ethylene oxide sterilization processes
using parametric release
Stérilisation des dispositifs médicaux — Lignes directrices concernant
les exigences de validation et de traitement de routine des procédés de
stérilisation à l’oxyde d’éthylène par libération paramétrique
Reference number
ISO/TS 21387:2020(E)
ISO 2020
---------------------- Page: 1 ----------------------
ISO/TS 21387:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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
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Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/TS 21387:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Quality management systems ................................................................................................................................................................. 2

5 Sterilization agent characterization ................................................................................................................................................ 2

6 Process and equipment characterization ................................................................................................................................... 2

6.1 General ........................................................................................................................................................................................................... 2

6.2 Process characterization ................................................................................................................................................................ 2

6.3 Equipment characterization ........................................................................................................................................................ 2

7 Product definition ............................................................................................................................................................................................... 4

7.1 General ........................................................................................................................................................................................................... 4

7.2 Product safety, quality and performance ......................................................................................................................... 4

7.3 Microbiological quality .................................................................................................................................................................... 4

8 Process definition ................................................................................................................................................................................................ 5

9 Validation ..................................................................................................................................................................................................................... 5

9.1 General ........................................................................................................................................................................................................... 5

9.2 Installation qualification ................................................................................................................................................................ 6

9.2.1 Equipment ............................................................................................................................................................................. 6

9.2.2 Installation qualification ........................................................................................................................................... 7

9.3 Operational qualification ............................................................................................................................................................... 7

9.4 Performance qualification ............................................................................................................................................................. 8

9.4.1 General...................................................................................................................................................................................... 8

9.4.2 Performance qualification — Microbiological ....................................................................................... 9

9.4.3 Performance qualification — Physical .......................................................................................................... 9

9.5 R eview and approval of validation ........................................................................................................................................ 9

10 Routine monitoring and control .......................................................................................................................................................10

11 Product release from sterilization ..................................................................................................................................................11

12 Maintaining process effectiveness ..................................................................................................................................................12

12.1 General ........................................................................................................................................................................................................12

12.2 Maintenance of equipment ........................................................................................................................................................12

12.3 Requalification .....................................................................................................................................................................................12

12.4 Assessment of change ....................................................................................................................................................................12

12.5 Assessment of equi valence ........................................................................................................................................................13

13 ISO 11135:2014, Annex A .........................................................................................................................................................................13

14 ISO 11135:2014, Annex B .........................................................................................................................................................................13

Annex A (informative) Establishing specifications for parametric release based on routine

processing data ...................................................................................................................................................................................................14

Bibliography .............................................................................................................................................................................................................................17

© ISO 2020 – All rights reserved iii
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ISO/TS 21387:2020(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 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see 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 of the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/

iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
iv © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)
Introduction

ISO 11135 includes requirements for development, validation and routine control of ethylene oxide (EO)

sterilization processes. This document is intended to be used in conjunction with ISO 11135.

ISO 11135:2014:11.1 refers to criteria for designating conformity of the sterilization process used for a

particular sterilization load as including:

a) confirmation that the data recorded during routine processing meet the sterilization process

specification;

b) confirmation of no growth of the test organism for any biological indicator (BI) (if used).

Parametric release is the declaration of adequacy of routine processing for a validated sterilization

process based solely on measurement and documentation of physical process parameters rather than

results of BIs, therefore b) does not apply.

The term BI release is used when the declaration of adequacy of the validated sterilization cycle includes

a requirement for no growth in BIs exposed to that cycle.

The guidance in this document is informative and is not intended as a checklist for auditors. The

guidance in this document provides examples of methods considered to be suitable as a means for

conforming with the requirements of ISO 11135.

NOTE Sterilization in health care facilities differs from industrial sterilization, for example, the design of

processing areas, control of product bioburden, access to relevant expertise in EO sterilization and sterilization

equipment that might not be equipped to enable consideration of parametric release.

This guidance is intended for people who have knowledge of the principles of EO sterilization. Methods

other than those given in the guidance can be used if they are effective in achieving conformity with the

requirements of ISO 11135.
© ISO 2020 – All rights reserved v
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TECHNICAL SPECIFICATION ISO/TS 21387:2020(E)
Sterilization of medical devices — Guidance on the
requirements for the validation and routine processing
of ethylene oxide sterilization processes using
parametric release
1 Scope

This document provides guidance on the requirements of ISO 11135 that apply when parametric release

is used to release the product after exposure to the sterilization process. It provides a path for transition

of existing cycles, as well as a path for the development and implementation of a parametric release

specification for a new cycle. Additionally, it highlights the importance and interrelationship of other

process factors, i.e. load configuration and equipment performance, which influence reproducibility of

an ethylene oxide (EO) sterilization process.

NOTE For ease of reference, the numbering of clauses in this document corresponds to that in the normative

parts of ISO 11135.

No additional guidance is offered for processes where the declaration of adequacy of the validated

sterilization cycle includes a requirement for no growth in biological indicators (BIs) exposed to that

process.
2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 11135:2014, Sterilization of health-care products — Ethylene oxide — Requirements for the

development, validation and routine control of a sterilization process for medical devices

3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 11135:2014 and the

following apply.

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

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
absolute humidity
measure of water vapour in the air, regardless of temperature

Note 1 to entry: It is expressed as grams of moisture per cubic metre of air (g/m ).

[SOURCE: ISO 11139:2018, 3.136.1]
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ISO/TS 21387:2020(E)
3.2
gas concentration
weight of a specific gas in a given volume
Note 1 to entry: Concentration can be expressed as mg/l or g/m .
[SOURCE: ISO 11139:2018, 3.125]
3.3
humidity
measure of water vapour present in a gas

Note 1 to entry: Humidity is usually expressed as absolute humidity (3.1) (i.e. vapour pressure density), relative

humidity (3.4) or dew point.
[SOURCE: ISO 11139:2018, 3.136]
3.4
relative humidity
humidity relative to the maximum for a given temperature
Note 1 to entry: It is expressed in per cent.
[SOURCE: ISO 11139:2018, 3.136.2, definition modified.]
4 Quality management systems
No additional guidance specified or given.
5 Sterilization agent characterization
No additional guidance specified or given.
6 Process and equipment characterization
6.1 General
No additional guidance specified or given.
6.2 Process characterization
No additional guidance specified or given.
6.3 Equipment characterization
6.3.1 No additional guidance specified or given.
6.3.2 Additional guidance specified or given.
a) No additional guidance specified or given.
b) No additional guidance specified or given.
c) No additional guidance specified or given.

d) The equipment used for the measurement of temperature, EO and humidity should be specified.

2 © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)
NOTE 1 See also ISO 10012.

In addition to the requirements specified in ISO 11135:2014, Clause 10, equipment should monitor

and record the following parameters for parametric release:
— chamber humidity by direct measurement, during conditioning;

— chamber EO concentration by direct measurement, at intervals throughout EO exposure;

— data from a minimum of two independent temperature sensors placed in different locations.

The monitoring and recording systems should be defined, characterized and documented for each

parameter.

The location(s) of temperature, humidity and EO sensors or measuring devices should represent

the conditions in the chamber.
1) Humidity

Humidity can be measured as either RH or AH. RH sensors typically use capacitive thin film

technology and measure vapour pressure density at a given temperature. AH is a measure of the

water concentration in a given volume of air and can be measured using spectroscopic technology. It

can be measured with either a fixed sensor, via a sampling port in the chamber or with a data logger.

NOTE 2 RH can be determined by direct measurement or calculated from AH data.

Electronic sensors (e.g. capacitive thin film sensors) for measuring and recording (RH) can be

calibrated using saturated salt solutions or qualified RH generation systems.

NOTE 3 It is common to report humidity as RH which can be determined by direct measurement or

calculation when AH is directly measured.

RH sensors can be readily verified as being within their calibrated tolerances by comparing with a

reference sensor that is traceable to a national standard.

Exposure to EO can impact the accuracy of some humidity sensors, resulting in them falling outside

their calibrated tolerance. This may require more frequent calibration or verification of these

sensors. Alternatively, they may be treated between uses or isolated during EO exposure to avoid

potential adverse effects on the sensor.
2) EO concentration

For EO concentration measurement systems, the accuracy and precision should be known and

documented.

There are two commonly used technologies employed for measurement of EO concentration:

spectroscopic and gas chromatography (GC).

Spectroscopic technology measures the EO concentration by infrared (IR) light absorption of the

EO molecule. Gas chromatographic technology measures the EO concentration against a standard

curve after separation by an appropriate chromatographic column.

Measurement can be carried out either internally or externally. However, where the measurement

of the EO concentration is being carried out external to the chamber the following additional

aspects should be considered:
— length of pipework to the measurement sensor;

— compatibility of pipework to EO, for example appropriate grade of stainless steel;

— potential for leakage at connection points;

— heat tracing of pipework to minimize risk of condensation of EO or water vapour;

© ISO 2020 – All rights reserved 3
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ISO/TS 21387:2020(E)
— mechanism for extracting the EO from the chamber, for example pump or blower.
3) Temperature

The type of equipment used for temperature monitoring is the same for both parametric or BI

release, but two separate monitoring locations are required for parametric release. If the data

from the sensors are averaged, then these sensors should be of the same type (e.g. thermocouple,

thermistor, RTD probe) and have the same precision and accuracy.
e) No additional guidance specified or given.
f) No additional guidance specified or given.
g) No additional guidance specified or given.
6.3.3 No additional guidance specified or given.
6.3.4 No additional guidance specified or given.
6.3.5 No additional guidance specified or given.
7 Product definition
7.1 General
7.1.1 No additional guidance specified or given.
7.1.2 No additional guidance specified or given.
7.1.3 No additional guidance specified or given.
7.1.4 No additional guidance specified or given.
7.1.5 Load configuration should be specified and controlled.

Product, packaging materials, load density and configuration can impact EO concentration, humidity

and temperature of the sterilization load.
7.1.6 No additional guidance specified or given.
7.2 Product safety, quality and performance
No additional guidance specified or given.
7.3 Microbiological quality
No additional guidance specified or given.
4 © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)
8 Process definition

8.1 Specifications for humidity and EO concentration can be established based on the analysis of the

data gathered during process development or performance qualification (PQ).

The minimum specifications for humidity and EO concentration can be established based on data

gathered during the microbiological performance qualification (MPQ) and physical performance

qualification (PPQ) studies.

The maximum EO concentration specification should be established to ensure that product safety,

quality and performance is not compromised (see ISO 11135:2014, 7.2 and ISO 10993-7).

Additional PQ may be needed to establish the appropriateness of the process parameters and their

tolerances for parametric release. After PQ, the process specification includes the process parameters

and their tolerance for each parameter.

NOTE The specification for other parameters including, but not limited to, temperature, pressure and time,

can be established in the same manner for both parametric and BI release processes.

8.2 No additional guidance specified or given.
8.3 No additional guidance specified or given.
8.4 No additional guidance specified or given.
8.5 No additional guidance specified or given.
8.6 No additional guidance specified or given.
8.7 No additional guidance specified or given.
8.8 No additional guidance specified or given.
8.9 No additional guidance specified or given.
9 Validation
9.1 General
9.1.1 No additional guidance specified or given.
9.1.2 No additional guidance specified or given.
9.1.3 No additional guidance specified or given.

9.1.4 Additional PQ cycles can be performed to demonstrate the physical and microbiological

performance reproducibility. This might involve designing cycles to deliver the process parameters for

humidity, temperature and EO concentration at the established lower specification limit to confirm

achievement of the required SAL and at the established upper specification to assess product or

packaging functionality and EO residues.
© ISO 2020 – All rights reserved 5
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ISO/TS 21387:2020(E)
9.2 Installation qualification
9.2.1 Equipment
9.2.1.1 Additional guidance specified or given.
a) Temperature measurement

The requirement to measure temperature within the sterilizer from a minimum of two locations is

established to ensure that an undetected fault in a temperature sensor does not lead to the inadvertent

release of an improperly processed load. If there is a difference in the two temperature data points, the

acceptable temperature difference should be defined within the processing specification.

b) Humidity measurement

Direct analysis of the head space for RH can be performed using electronic sensors, GC, IR or other

spectroscopic methods currently available to indicate water vapour concentration. The benefit of these

methods is the real-time indication throughout the conditioning phase.

Electronic sensors require periodic calibration to offset the effect of exposure to the EO gas and can

require replacement, heat treatment of the electronic sensors or more frequent calibration after

repeated exposures to EO due to irreversible deterioration of materials currently utilized as sensing

elements.
c) EO concentration measurement

The frequency of analysis required to demonstrate that the EO concentration process parameters

and their tolerances are maintained throughout exposure time should be established during the PQ

studies. Monitoring throughout the exposure time period should also be done as part of the validation,

to determine how the EO concentration changes over time. The results of this analysis are specific to

the product and load configuration being analysed. The analysis performed during the PQ study will

result in documented specifications for how often direct analysis should be performed during routine

processing.

As required in ISO 11135:2014, 9.5.5, the number of defined intervals for EO concentration sampling

should be sufficient so that there is verification that the EO concentration will be within specification

throughout EO exposure. This could be as few as two samples, with one taken after the end of gas

injection or defined equilibration period and a second prior to sterilant removal. Typically, the number

of samples is greater, for example when gas make-ups are used. Where an inert gas addition is included

after EO injection, the ability to capture EO concentration data at the end of injection should be

considered.

To ensure that the readings are representative of conditions within the chamber, it is important to

consider a number of factors, including but not limited to:

— Location: it is important to ensure that the sensor(s) or the sampling location(s) for EO concentration,

humidity and temperature measurement are representative of the environment in the chamber. If

the sensors or sampling points are located within the recirculation system (if used), they should be

placed in a location avoiding excessive turbulence.

— Water condensation: sensors or sampling point should be oriented in a manner to avoid any risk of

build up or water condensation on the reading head of the sensor.

— Pressure influence: the measurement instrument should compensate for the impact of changing

pressures (if applicable).

— Temperature uniformity: sensors, sampling points or sample piping for EO concentration and

humidity might need to be either at or above the specified process temperature to give accurate

readings. To achieve this, the sensor, piping or both might require heating. Measuring equipment

should be located such that the maximum values of temperature and humidity specified for them

6 © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)

are not exceeded. The instructions provided by the measurement equipment manufacturer should

be followed.
9.2.1.2 No additional guidance specified or given.
9.2.1.3 No additional guidance specified or given.
9.2.2 Installation qualification
9.2.2.1 No additional guidance specified or given.
9.2.2.2 No additional guidance specified or given.
9.2.2.3 No additional guidance specified or given.
9.2.2.4 No additional guidance specified or given.
9.2.2.5 No additional guidance specified or given.
9.2.2.6 No additional guidance specified or given.
9.3 Operational qualification

9.3.1 RH in the sterilizer chamber can be verified using a calibrated electronic sensor located at

the analytical instrument sampling point of the sterilizer chamber. Analytical instruments such as gas

chromatographs (GC), IR or other spectroscopic methods are less common and are more complex than

the electronic sensor. Such analytical instruments can be calibrated by instrument manufacturers and

the calibration should be verified after installation prior to operational qualification (OQ).

Confirmation of EO sensor calibration can be conducted in one of several ways. Some analytical

instrument suppliers can provide an instruction that can be placed in the system to confirm

maintenance of calibration. An alternative method is to calibrate or verify the EO sensor against known

EO concentrations in a fixed volume of chamber or sample cell. There are three methods of determining

EO concentration:

Method 1: use of the ideal gas law, which is based upon pressure change and temperature of EO.

Method 2: use of the fixed volume of chamber (inclusive of relevant piping and recirculation system) or

sample cell and the weight of EO injected to them.
NOTE Method 1 or 2 can be used.

Method 3: comparison of measured concentration with a commercially available standard

concentration of EO.
Method 1 or 2 can be used to verify calibrations if the following are confirmed:
a) correct analysis of the EO in the storage container;
b) uniform EO mixture in the chamber;
c) accurate measurement of chamber pressure;

d) accurate measurement of chamber temperature at the sampling location, weight of EO added and

the volume of the chamber occupied by the EO.
© ISO 2020 – All rights reserved 7
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ISO/TS 21387:2020(E)
Confirmation of EO conc
...

SPÉCIFICATION ISO/TS
TECHNIQUE 21387
Première édition
2020-09
Stérilisation des dispositifs
médicaux — Lignes directrices
concernant les exigences de
validation et de traitement de
routine des procédés de stérilisation
à l’oxyde d’éthylène par libération
paramétrique
Sterilization of medical devices — Guidance on the requirements for
the validation and routine processing of ethylene oxide sterilization
processes using parametric release
Numéro de référence
ISO/TS 21387:2020(F)
ISO 2020
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ISO/TS 21387:2020(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2020

Tous droits réservés. Sauf prescription différente ou nécessité dans le contexte de sa mise en œuvre, 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, ou la diffusion sur l’internet ou sur un intranet, sans autorisation écrite préalable. Une autorisation peut

être demandée 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 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Genève
Tél.: +41 22 749 01 11
E-mail: copyright@iso.org
Web: www.iso.org
Publié en Suisse
ii © ISO 2020 – Tous droits réservés
---------------------- Page: 2 ----------------------
ISO/TS 21387:2020(F)
Sommaire Page

Avant-propos ..............................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Domaine d’application ................................................................................................................................................................................... 1

2 Références normatives ................................................................................................................................................................................... 1

3 Termes et définitions ....................................................................................................................................................................................... 1

4 Systèmes de management de la qualité ........................................................................................................................................ 2

5 Caractérisation de l’agent de stérilisation ................................................................................................................................. 2

6 Caractérisation du procédé et de l’équipement ................................................................................................................... 2

6.1 Généralités .................................................................................................................................................................................................. 2

6.2 Caractérisation du procédé .......................................................................................................................................................... 2

6.3 Caractérisation de l’équipement .............................................................................................................................................. 2

7 Définition du produit ....................................................................................................................................................................................... 4

7.1 Généralités .................................................................................................................................................................................................. 4

7.2 Sécurité, qualité et performance du produit ................................................................................................................. 4

7.3 Qualité microbiologique ................................................................................................................................................................. 5

8 Définition du procédé ..................................................................................................................................................................................... 5

9 Validation ..................................................................................................................................................................................................................... 5

9.1 Généralités .................................................................................................................................................................................................. 5

9.2 Qualification de l’installation ...................................................................................................................................................... 6

9.2.1 Équipement .......................................................................................................................................................................... 6

9.2.2 Qualification de l’installation ................................................................................................................................ 7

9.3 Qualification opérationnelle ........................................................................................................................................................ 7

9.4 Qualification de performance..................................................................................................................................................... 8

9.4.1 Généralités ............................................................................................................................................................................ 8

9.4.2 Qualification de performance — Microbiologique ............................................................................. 9

9.4.3 Qualification de performance — Physique ............................................................................................10

9.5 Revue et approbation de la validation .............................................................................................................................10

10 Surveillance et contrôle de routine ................................................................................................................................................11

11 Libération du produit après stérilisation ................................................................................................................................11

12 Maintien de l’efficacité du procédé ................................................................................................................................................12

12.1 Généralités ...............................................................................................................................................................................................12

12.2 Maintenance de l’équipement .................................................................................................................................................13

12.3 Requalification .....................................................................................................................................................................................13

12.4 Évaluation des modifications ..................................................................................................................................................13

12.5 Évaluation de l’équivalence .......................................................................................................................................................13

13 ISO 11135:2014, Annexe A .....................................................................................................................................................................14

14 ISO 11135:2014, Annexe B .....................................................................................................................................................................14

Annexe A (informative) Établissement des spécifications pour la libération paramétrique

basées sur les données de traitement de routine ...........................................................................................................15

Bibliographie ...........................................................................................................................................................................................................................18

© ISO 2020 – Tous droits réservés iii
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ISO/TS 21387:2020(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 procédures utilisées pour élaborer le présent document et celles destinées à sa mise à jour sont

décrites dans les Directives ISO/IEC, Partie 1. Il convient, en particulier, de prendre note des différents

critères d'approbation requis pour les différents types de documents ISO. Le présent document a été

rédigé conformément aux règles de rédaction données dans les Directives ISO/IEC, Partie 2 (voir www

.iso .org/ directives).

L'attention est attirée sur le fait que certains des éléments du présent document peuvent faire l'objet de

droits de propriété intellectuelle ou de droits analogues. L'ISO ne saurait être tenue pour responsable

de ne pas avoir identifié de tels droits de propriété et averti de leur existence. Les détails concernant

les références aux droits de propriété intellectuelle ou autres droits analogues identifiés lors de

l'élaboration du document sont indiqués dans l'Introduction et/ou dans la liste des déclarations de

brevets reçues par l'ISO (voir www .iso .org/ brevets).

Les appellations commerciales éventuellement mentionnées dans le présent document sont données

pour information, par souci de commodité, à l’intention des utilisateurs et ne sauraient constituer un

engagement.

Pour une explication de la nature volontaire des normes, la signification des termes et expressions

spécifiques de l'ISO liés à l'évaluation de la conformité, ou pour toute information au sujet de l'adhésion

de l'ISO aux principes de l’Organisation mondiale du commerce (OMC) concernant les obstacles

techniques au commerce (OTC), voir www .iso .org/ avant -propos.

Le présent document a été élaboré par le comité technique ISO/TC 198, Stérilisation des produits de santé.

Il convient que l’utilisateur adresse tout retour d’information ou toute question concernant le présent

document à l’organisme national de normalisation de son pays. Une liste exhaustive desdits organismes

se trouve à l’adresse www .iso .org/ fr/ members .html.
iv © ISO 2020 – Tous droits réservés
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ISO/TS 21387:2020(F)
Introduction

La norme ISO 11135 présente des exigences pour la mise au point, la validation et le contrôle de routine

des procédés de stérilisation à l’oxyde d’éthylène (OE). Le présent document est destiné à être utilisé

conjointement avec l’ISO 11135.

L’ISO 11135:2014:11.1 fait référence aux critères employés pour déclarer la conformité du procédé de

stérilisation pour une charge donnée comme comprenant:

a) la confirmation que les données enregistrées durant la stérilisation de routine sont conformes à la

spécification du procédé de stérilisation;

b) la confirmation de l’absence de croissance de l’organisme d’essai contenu dans tout indicateur

biologique (IB) (le cas échéant).

La libération paramétrique est la déclaration de l’adéquation du traitement de routine pour un

procédé de stérilisation validé, basée uniquement sur le mesurage et la documentation des paramètres

physiques du procédé plutôt que sur les résultats des IB, par conséquent b) ne s’applique pas.

Le terme libération par IB est utilisé lorsque la déclaration d’adéquation du cycle de stérilisation validé

inclut une exigence d’absence de croissance dans les IB exposés à ce cycle.

La directive présentée dans le présent document est à visée informative uniquement et n’est pas

destinée à servir de liste de contrôle pour des auditeurs. La directive présentée dans le présent

document fournit des exemples de méthodes considérées comme adaptées en tant que moyens de se

conformer aux exigences de l’ISO 11135.

NOTE La stérilisation dans les établissements de santé diffère de la stérilisation industrielle, par exemple,

par la conception des zones de traitement, le contrôle de la charge biologique, l’accès à une expertise pertinente en

matière de stérilisation à l’OE et à un équipement de stérilisation qui pourrait ne pas être équipé pour envisager

la libération paramétrique.

La présente directive est destinée aux personnes connaissant les principes de la stérilisation à l’OE.

Des méthodes autres que celles fournies dans la directive peuvent être utilisées si elles permettent

d’assurer la conformité aux exigences de l’ISO 11135.
© ISO 2020 – Tous droits réservés v
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SPÉCIFICATION TECHNIQUE ISO/TS 21387:2020(F)
Stérilisation des dispositifs médicaux — Lignes directrices
concernant les exigences de validation et de traitement de
routine des procédés de stérilisation à l’oxyde d’éthylène
par libération paramétrique
1 Domaine d’application

Le présent document fournit des lignes directrices concernant les exigences de l’ISO 11135 qui

s’appliquent lorsque la libération paramétrique est utilisée pour libérer le produit après exposition

au procédé de stérilisation. Il fournit une voie pour la transition des cycles existants, ainsi que pour

la mise au point et la mise en œuvre d’une spécification de libération paramétrique pour un nouveau

cycle. En outre, il souligne l’importance et les relations avec les autres facteurs du procédé, c’est-à-dire

la configuration de la charge et la performance de l’équipement, qui influencent la reproductibilité d’un

procédé de stérilisation à l’oxyde d’éthylène (OE).

NOTE Afin de faciliter la référence, la numérotation des articles du présent document correspond à celle des

parties normatives de l’ISO 11135.

Aucune directive supplémentaire n’est fournie pour les procédés dans lesquels la déclaration

d’adéquation du cycle de stérilisation validé inclut une exigence d’absence de croissance dans les

indicateurs biologiques (IB) exposés à ce procédé.
2 Références normatives

Les documents suivants sont cités dans le texte de sorte qu’ils constituent, pour tout ou partie de leur

contenu, des exigences 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 11135:2014, 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

3 Termes et définitions

Pour les besoins du présent document, les termes et définitions de l’ISO 11135:2014 ainsi que les

suivants, s’appliquent.

L’ISO et l’IEC tiennent à jour des bases de données terminologiques destinées à être utilisées en

normalisation, consultables aux adresses suivantes:

— ISO Online browsing platform: disponible à l’adresse https:// www .iso .org/ obp

— IEC Electropedia: disponible à l’adresse http:// www .electropedia .org/
3.1
humidité absolue

expression quantifiée de la vapeur d’eau contenue dans l’air, quelle que soit la température

Note 1 à l'article: Elle est exprimée en grammes d’humidité par mètre cube d’air (g/m ).

[SOURCE: ISO 11139:2018, 3.136.1]
© ISO 2020 – Tous droits réservés 1
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ISO/TS 21387:2020(F)
3.2
concentration de gaz
poids d’un gaz spécifique dans un volume donné
Note 1 à l'article: La concentration peut être exprimée en mg/l ou en g/m .
[SOURCE: ISO 11139:2018, 3.125]
3.3
humidité
expression quantifiée de la vapeur d’eau présente dans un gaz

Note 1 à l'article: L’humidité est généralement exprimée en termes d’humidité absolue (3.1) (c’est-à-dire la densité

de pression de vapeur), d’humidité relative (3.4) ou de point de rosée.
[SOURCE: ISO 11139:2018, 3.136]
3.4
humidité relative
humidité par rapport à la valeur maximale obtenue pour une température donnée
Note 1 à l'article: Elle est exprimée en pourcent.
[SOURCE: ISO 11139:2018, 3.136.2, définition modifiée.]
4 Systèmes de management de la qualité
Aucune directive supplémentaire n’est spécifiée ou fournie.
5 Caractérisation de l’agent de stérilisation
Aucune directive supplémentaire n’est spécifiée ou fournie.
6 Caractérisation du procédé et de l’équipement
6.1 Généralités
Aucune directive supplémentaire n’est spécifiée ou fournie.
6.2 Caractérisation du procédé
Aucune directive supplémentaire n’est spécifiée ou fournie.
6.3 Caractérisation de l’équipement
6.3.1 Aucune directive supplémentaire n’est spécifiée ou fournie.
6.3.2 Directives supplémentaires spécifiées ou fournies.
a) Aucune directive supplémentaire n’est spécifiée ou fournie.
b) Aucune directive supplémentaire n’est spécifiée ou fournie.
c) Aucune directive supplémentaire n’est spécifiée ou fournie.

d) Il convient de spécifier l’équipement utilisé pour le mesurage de la température, de l’OE et de

l’humidité.
2 © ISO 2020 – Tous droits réservés
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ISO/TS 21387:2020(F)
NOTE 1 Voir aussi l’ISO 10012.

Outre les exigences spécifiées dans l’ISO 11135:2014, Article 10, il convient de surveiller et

d’enregistrer les paramètres suivants de l’équipement pour la libération paramétrique:

— humidité de la chambre par mesurage direct pendant le conditionnement;

— concentration d’OE de la chambre par mesurage direct, périodiquement, tout au long de

l’exposition à l’OE;

— données fournies par un minimum de deux capteurs de température indépendants placés à des

endroits différents.

Il convient de définir, de caractériser et de documenter les systèmes de surveillance et

d’enregistrement pour chaque paramètre.

Il convient que l’emplacement ou les emplacements des capteurs ou des dispositifs de mesurage de

la température, de l’humidité et de l’OE représentent les conditions de la chambre.

1) Humidité

L’humidité peut être mesurée sous la forme de l’HR ou de l’HA. Les capteurs d’HR utilisent

généralement la technologie capacitive à couche mince et mesurent la densité de pression de

vapeur à une température donnée. L’HA est une mesure de la concentration d’eau dans un volume

donné d’air et elle peut être mesurée par une technologie spectroscopique. Elle peut être mesurée

au moyen d’un capteur fixe, via un port d’échantillonnage dans la chambre, ou au moyen d’un

enregistreur de données.

NOTE 2 L’HR peut être déterminée par mesurage direct ou calculée à partir des données d’HA.

Les capteurs électroniques (par exemple, capteurs capacitifs à couche mince) de mesurage et

d’enregistrement (HR) peuvent être étalonnés en utilisant des solutions de sels saturés ou des

générateurs d’HR de référence.

NOTE 3 Il est fréquent de rapporter l’humidité sous la forme de l’HR, qui peut être déterminée par

mesurage direct ou par calcul lorsque l’HA est mesurée directement.

Il est facile de vérifier que les capteurs d’HR sont conformes à leurs tolérances d’étalonnage par

comparaison avec un capteur de référence traçable jusqu’à un étalon national.

L’exposition à l’OE peut avoir une incidence sur l’exactitude de certains capteurs d’humidité,

conduisant à des valeurs situées en dehors de leur tolérance d’étalonnage. Cela peut nécessiter des

étalonnages ou des vérifications plus fréquents de ces capteurs. Ces capteurs peuvent également

être traités entre les utilisations ou isolés pendant l’exposition à l’OE afin d’éviter les effets

indésirables potentiels sur le capteur.
2) Concentration d’OE

Il convient de connaître et de documenter l’exactitude et la précision des systèmes de mesurage de

la concentration d’OE.

Deux technologies fréquemment employées sont utilisées pour le mesurage de la concentration

d’OE: la spectroscopie et la chromatographie en phase gazeuse (CPG).

La technologie spectroscopique mesure la concentration d’OE par absorption de la lumière

infrarouge (IR) par la molécule d’OE. La technologie de chromatographie en phase gazeuse mesure

la concentration d’OE par comparaison avec une courbe standard après séparation sur une colonne

de chromatographie appropriée.

Le mesurage peut être effectué en interne ou en externe. Toutefois, lorsque le mesurage de la

concentration d’OE est réalisé à l’extérieur de la chambre, il convient de tenir compte des aspects

supplémentaires suivants:
© ISO 2020 – Tous droits réservés 3
---------------------- Page: 8 ----------------------
ISO/TS 21387:2020(F)
— longueur de tuyauterie jusqu’au capteur de mesurage;

— compatibilité de la tuyauterie avec l’OE, par exemple nuance appropriée d’acier inoxydable;

— potentiel de fuite aux points de connexion;

— traçage thermique de la tuyauterie afin de réduire le plus possible le risque de condensation

d’OE ou de vapeur d’eau;

— mécanisme d’extraction de l’OE de la chambre, par exemple pompe ou ventilateur.

3) Température

Le type d’équipement utilisé pour la surveillance de la température est le même en libération

paramétrique qu’en libération basée sur les IB, mais deux emplacements de surveillance distincts

sont requis pour la libération paramétrique. Si la moyenne des données fournies par les capteurs est

utilisée, il convient que ces capteurs soient du même type (par exemple, thermocouple, thermistor,

sonde RTD) et possèdent la même précision et la même exactitude.
e) Aucune directive supplémentaire n’est spécifiée ou fournie.
f) Aucune directive supplémentaire n’est spécifiée ou fournie.
g) Aucune directive supplémentaire n’est spécifiée ou fournie.
6.3.3 Aucune directive supplémentaire n’est spécifiée ou fournie.
6.3.4 Aucune directive supplémentaire n’est spécifiée ou fournie.
6.3.5 Aucune directive supplémentaire n’est spécifiée ou fournie.
7 Définition du produit
7.1 Généralités
7.1.1 Aucune directive supplémentaire n’est spécifiée ou fournie.
7.1.2 Aucune directive supplémentaire n’est spécifiée ou fournie.
7.1.3 Aucune directive supplémentaire n’est spécifiée ou fournie.
7.1.4 Aucune directive supplémentaire n’est spécifiée ou fournie.
7.1.5 Il convient que la configuration de la charge soit spécifiée et contrôlée.

Le produit, les matériaux d’emballage, la densité de la charge et la configuration peuvent avoir une

incidence sur la concentration d’OE, l’humidité et la température de la charge de stérilisation.

7.1.6 Aucune directive supplémentaire n’est spécifiée ou fournie.
7.2 Sécurité, qualité et performance du produit
Aucune directive supplémentaire n’est spécifiée ou fournie.
4 © ISO 2020 – Tous droits réservés
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ISO/TS 21387:2020(F)
7.3 Qualité microbiologique
Aucune directive supplémentaire n’est spécifiée ou fournie.
8 Définition du procédé

8.1 Les spécifications relatives à l’humidité et à la concentration d’OE peuvent être établies sur la

base de l’analyse des données rassemblées pendant la mise au point du procédé ou la qualification de

performance (QP).

Les spécifications minimales concernant l’humidité et la concentration d’OE peuvent être établies à

partir des données rassemblées pendant les études de qualification de performance microbiologique

(QPM) et de qualification de performance physique (QPP).

Il convient que la spécification concernant la concentration maximale d’OE soit établie de manière

à garantir que la sécurité, la qualité et la performance du produit ne sont pas compromises

(voir l’ISO 11135:2014, 7.2 et l’ISO 10993-7).

Une QP supplémentaire peut être nécessaire pour établir le caractère approprié des paramètres du

procédé et leurs tolérances pour la libération paramétrique. Après la QP, la spécification du procédé

inclut les paramètres du procédé et les tolérances pour chaque paramètre.

NOTE Les spécifications concernant les autres paramètres, y compris, mais sans s’y limiter, la température,

la pression et le temps, peuvent être établies de la même manière pour les procédés de libération paramétrique et

basée sur les IB.
8.2 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.3 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.4 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.5 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.6 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.7 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.8 Aucune directive supplémentaire n’est spécifiée ou fournie.
8.9 Aucune directive supplémentaire n’est spécifiée ou fournie.
9 Validation
9.1 Généralités
9.1.1 Aucune directive supplémentaire n’est spécifiée ou fournie.
9.1.2 Aucune directive supplémentaire n’est spécifiée ou fournie.
9.1.3 Aucune directive supplémentaire n’est spécifiée ou fournie.

9.1.4 Des cycles supplémentaires de QP peuvent être réalisés pour démontrer la reproductibilité des

performances physiques et microbiologiques. Cela peut impliquer la conception de cycles délivrant

© ISO 2020 – Tous droits réservés 5
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ISO/TS 21387:2020(F)

les paramètres du procédé concernant l’humidité, la température et la concentration d’OE à la limite

inférieure de spécification établie pour confirmer l’obtention du niveau d’assurance de stérilité requis, et

à la spécification supérieure établie pour évaluer les fonctionnalités du produit ou de l’emballage et les

résidus d’OE.
9.2 Qualification de l’installation
9.2.1 Équipement
9.2.1.1 Directives supplémentaires spécifiées ou fournies.
a) Mesurage de la température

Il est nécessaire de mesurer la température dans le stérilisateur en au moins deux emplacements pour

éviter qu’un défaut non détecté dans un capteur de température n’entraîne par mégarde la libération

d’une charge traitée de manière inappropriée. En cas de différence dans les deux points de données

de température, il convient de définir la différence de température acceptable dans la spécification de

traitement.
b) Mesurage de l’humidité

L’HR dans l’espace libre peut être analysée directement à l’aide de capteurs électroniques, de CPG, d’IR

ou d’autres méthodes spectroscopiques existantes pouvant indiquer la concentration en vapeur d’eau.

L’avantage de ces méthodes est l’indication en temps réel tout au long de la phase de conditionnement.

Les capteurs électroniques nécessitent un étalonnage régulier pour compenser l’effet de l’exposition

à l’OE gazeux et peuvent nécessiter un remplacement, un traitement thermique ou un étalonnage plus

fréquent après des expositions répétées à l’OE, en raison de la détérioration irréversible des matériaux

actuellement utilisés dans les éléments sensibles.
c) Mesurage de la concentration d’OE

Il convient d’établir au cours des études de QP la fréquence d’analyse nécessaire à démontrer que la

concentration d’OE et les tolérances correspondantes sont maintenues pendant l’exposition. Il convient

que la surveillance pendant la durée de l’exposition fasse également partie de la validation, afin de

déterminer l’évolution de la concentration d’OE avec le temps. Les résultats de cette analyse sont

spécifiques au produit et à la configuration de charge analysés. L’analyse réalisée au cours de l’étude de

QP fournit des spécifications documentées décrivant la fréquence à laquelle il convient de mener une

analyse directe durant le traitement de routine.

Comme exigé par l’ISO 11135:2014, 9.5.5, il convient que le nombre d’intervalles définis pour

l’échantillonnage destiné à détermination de la concentration d’OE soit suffisant pour vérifier que la

concentration d’OE est conforme à la spécification tout au long de l’exposition à l’OE. Deux échantillons

peuvent suffire, l’un obtenu après la fin de l’injection de gaz ou de la période d’équilibrage définie, et le

second avant l’élimination du produit stérilisant. Généralement, le nombre d’échantillons est supérieur,

par exemple lorsque des apports de gaz sont utilisés. Lorsque l’ajout de gaz inerte est inclus après

l’injection d’OE, il convient de tenir compte de la capacité à capturer les données de concentration d’OE

à la fin de l’injection.

Pour garantir que les lectures sont représentatives des conditions à l’intérieur de la chambre, il est

important de tenir compte d’un certain nombre de facteurs incluant, sans s’y limiter:

— emplacement: il est important de s’assurer que le ou les capteurs ou l’emplacement ou les

emplacements de l’échantillonnage pour le mesurage de la concentration d’OE, de l’humidité et de la

température sont représentatifs de l’environnement dans la chambre. Si les capteurs ou les points

d’échantillonnage sont sit
...

TECHNICAL ISO/TS
SPECIFICATION 21387
First edition
Sterilization of medical devices —
Guidance on the requirements for the
validation and routine processing of
ethylene oxide sterilization processes
using parametric release
Stérilisation des dispositifs médicaux — Lignes directrices concernant
les exigences de validation et de traitement de routine des processus
de stérilisation à l’oxyde d’éthylène par libération paramétrique
PROOF/ÉPREUVE
Reference number
ISO/TS 21387:2020(E)
ISO 2020
---------------------- Page: 1 ----------------------
ISO/TS 21387:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii PROOF/ÉPREUVE © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Quality management systems ................................................................................................................................................................. 2

5 Sterilization agent characterization ................................................................................................................................................ 2

6 Process and equipment characterization ................................................................................................................................... 2

6.1 General ........................................................................................................................................................................................................... 2

6.2 Process characterization ................................................................................................................................................................ 2

6.3 Equipment characterization ........................................................................................................................................................ 2

7 Product definition ............................................................................................................................................................................................... 4

7.1 General ........................................................................................................................................................................................................... 4

7.2 Product safety, quality and performance ......................................................................................................................... 4

7.3 Microbiological quality .................................................................................................................................................................... 4

8 Process definition ................................................................................................................................................................................................ 4

9 Validation ..................................................................................................................................................................................................................... 5

9.1 General ........................................................................................................................................................................................................... 5

9.2 Installation qualification ................................................................................................................................................................ 5

9.2.1 Equipment ............................................................................................................................................................................. 5

9.2.2 Installation qualification ........................................................................................................................................... 6

9.3 Operational qualification ............................................................................................................................................................... 7

9.4 Performance qualification ............................................................................................................................................................. 8

9.4.1 General...................................................................................................................................................................................... 8

9.4.2 Performance qualification — Microbiological ....................................................................................... 9

9.4.3 Performance qualification — Physical .......................................................................................................... 9

9.5 R eview and approval of validation ........................................................................................................................................ 9

10 Routine monitoring and control .......................................................................................................................................................10

11 Product release from sterilization ..................................................................................................................................................10

12 Maintaining process effectiveness ..................................................................................................................................................11

12.1 General ........................................................................................................................................................................................................11

12.2 Maintenance of equipment ........................................................................................................................................................12

12.3 Requalification .....................................................................................................................................................................................12

12.4 Assessment of change ....................................................................................................................................................................12

12.5 Assessment of equi valence ........................................................................................................................................................13

13 ISO 11135:2014, Annex A .........................................................................................................................................................................13

14 ISO 11135:2014, Annex B .........................................................................................................................................................................13

Annex A (informative) Establishing specifications for parametric release based on routine

processing data ...................................................................................................................................................................................................14

Bibliography .............................................................................................................................................................................................................................17

© ISO 2020 – All rights reserved PROOF/ÉPREUVE iii
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ISO/TS 21387:2020(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 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see 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 of the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/

iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
iv PROOF/ÉPREUVE © ISO 2020 – All rights reserved
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ISO/TS 21387:2020(E)
Introduction

ISO 11135 includes requirements for development, validation and routine control of ethylene oxide (EO)

sterilization processes. This document is intended to be used in conjunction with ISO 11135.

ISO 11135:2014:11.1 refers to criteria for designating conformity of the sterilization process used for a

particular sterilization load as including:

a) confirmation that the data recorded during routine processing meet the sterilization process

specification;

b) confirmation of no growth of the test organism for any biological indicator (BI) (if used).

Parametric release is the declaration of adequacy of routine processing for a validated sterilization

process based solely on measurement and documentation of physical process parameters rather than

results of BIs, therefore b) does not apply.

The term BI release is used when the declaration of adequacy of the validated sterilization cycle includes

a requirement for no growth in BIs exposed to that cycle.

The guidance in this document is informative and is not intended as a checklist for auditors. The

guidance in this document provides examples of methods considered to be suitable as a means for

conforming with the requirements of ISO 11135.

NOTE Sterilization in health care facilities differs from industrial sterilization, for example, the design of

processing areas, control of product bioburden, access to relevant expertise in EO sterilization and sterilization

equipment that might not be equipped to enable consideration of parametric release.

This guidance is intended for people who have knowledge of the principles of EO sterilization. Methods

other than those given in the guidance can be used if they are effective in achieving conformity with the

requirements of ISO 11135.
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TECHNICAL SPECIFICATION ISO/TS 21387:2020(E)
Sterilization of medical devices — Guidance on the
requirements for the validation and routine processing
of ethylene oxide sterilization processes using
parametric release
1 Scope

This document provides guidance on the requirements of ISO 11135 that apply when parametric release

is used to release the product after exposure to the sterilization process. It provides a path for transition

of existing cycles, as well as a path for the development and implementation of a parametric release

specification for a new cycle. Additionally, it highlights the importance and interrelationship of other

process factors, i.e. load configuration and equipment performance, which influence reproducibility of

an ethylene oxide (EO) sterilization process.

NOTE For ease of reference, the numbering of clauses in this document corresponds to that in the normative

parts of ISO 11135.

No additional guidance is offered for processes where the declaration of adequacy of the validated

sterilization cycle includes a requirement for no growth in biological indicators (BIs) exposed to that

process.
2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 11135:2014, Sterilization of health-care products — Ethylene oxide — Requirements for the

development, validation and routine control of a sterilization process for medical devices

3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 11135:2014 and the

following apply.

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

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
absolute humidity
measure of water vapour in the air, regardless of temperature

Note 1 to entry: It is expressed as grams of moisture per cubic metre of air (g/m ).

[SOURCE: ISO 11139:2018, 3.136.1]
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ISO/TS 21387:2020(E)
3.2
gas concentration
weight of a specific gas in a given volume
Note 1 to entry: Concentration can be expressed as mg/l or g/m .
[SOURCE: ISO 11139:2018, 3.125]
3.3
humidity
measure of water vapour present in a gas

Note 1 to entry: Humidity is usually expressed as absolute humidity (3.1) (i.e. vapour pressure density), relative

humidity (3.4) or dew point.
[SOURCE: ISO 11139:2018, 3.136]
3.4
relative humidity
humidity relative to the maximum for a given temperature
Note 1 to entry: It is expressed in per cent.
[SOURCE: ISO 11139:2018, 3.136.2, definition modified.]
4 Quality management systems
No additional guidance specified or given.
5 Sterilization agent characterization
No additional guidance specified or given.
6 Process and equipment characterization
6.1 General
No additional guidance specified or given.
6.2 Process characterization
No additional guidance specified or given.
6.3 Equipment characterization
6.3.1 No additional guidance specified or given.
6.3.2
a) No additional guidance specified or given.
b) No additional guidance specified or given.
c) No additional guidance specified or given.

d) The equipment used for the measurement of temperature, EO and humidity should be specified.

NOTE See also ISO 10012.
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ISO/TS 21387:2020(E)

In addition to the requirements specified in ISO 11135:2014, Clause 10, equipment should monitor

and record the following parameters for parametric release:
— chamber humidity by direct measurement, during conditioning;

— chamber EO concentration by direct measurement, at intervals throughout EO exposure;

— data from a minimum of two independent temperature sensors placed in different locations.

The monitoring and recording systems should be defined, characterized and documented for each

parameter.

The location(s) of temperature, humidity and EO sensors or measuring devices should represent

the conditions in the chamber.
1) Humidity

Humidity can be measured as either RH or AH. RH sensors typically use capacitive thin film

technology and measure vapour pressure density at a given temperature. AH is a measure of the

water concentration in a given volume of air and can be measured using spectroscopic technology. It

can be measured with either a fixed sensor, via a sampling port in the chamber or with a data logger.

NOTE RH can be determined by direct measurement or calculated from AH data.

Electronic sensors (e.g. capacitive thin film sensors) for measuring and recording (RH) can be

calibrated using saturated salt solutions or qualified RH generation systems.

NOTE It is common to report humidity as RH which can be determined by direct measurement or

calculation when AH is directly measured.

RH sensors can be readily verified as being within their calibrated tolerances by comparing with a

reference sensor that is traceable to a national standard.

Exposure to EO can impact the accuracy of some humidity sensors, resulting in them falling outside

their calibrated tolerance. This may require more frequent calibration or verification of these

sensors. Alternatively, they may be treated between uses or isolated during EO exposure to avoid

potential adverse effects on the sensor.
2) EO concentration

For EO concentration measurement systems, the accuracy and precision should be known and

documented.

There are two commonly used technologies employed for measurement of EO concentration:

spectroscopic and gas chromatography (GC).

Spectroscopic technology measures the EO concentration by infrared (IR) light absorption of the

EO molecule. Gas chromatographic technology measures the EO concentration against a standard

curve after separation by an appropriate chromatographic column.

Measurement can be carried out either internally or externally. However, where the measurement

of the EO concentration is being carried out external to the chamber the following additional

aspects should be considered:
— length of pipework to the measurement sensor;

— compatibility of pipework to EO, for example appropriate grade of stainless steel;

— potential for leakage at connection points;

— heat tracing of pipework to minimize risk of condensation of EO or water vapour;

— mechanism for extracting the EO from the chamber, for example pump or blower.
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ISO/TS 21387:2020(E)
3) Temperature

The type of equipment used for temperature monitoring is the same for both parametric or BI

release, but two separate monitoring locations are required for parametric release. If the data

from the sensors are averaged, then these sensors should be of the same type (e.g. thermocouple,

thermistor, RTD probe) and have the same precision and accuracy.
e) No additional guidance specified or given.
f) No additional guidance specified or given.
g) No additional guidance specified or given.
6.3.3 No additional guidance specified or given.
6.3.4 No additional guidance specified or given.
6.3.4 No additional guidance specified or given.
7 Product definition
7.1 General
7.1.1 No additional guidance specified or given.
7.1.2 No additional guidance specified or given.
7.1.3 No additional guidance specified or given.
7.1.4 No additional guidance specified or given.
7.1.5 Load configuration should be specified and controlled.

Product, packaging materials, load density and configuration can impact EO concentration, humidity

and temperature of the sterilization load.
7.1.6 No additional guidance specified or given.
7.2 Product safety, quality and performance
No additional guidance specified or given.
7.3 Microbiological quality
No additional guidance specified or given.
8 Process definition

8.1 Specifications for humidity and EO concentration can be established based on the analysis of the

data gathered during process development or performance qualification (PQ).

The minimum specifications for humidity and EO concentration can be established based on data

gathered during the microbiological performance qualification (MPQ) and physical performance

qualification (PPQ) studies.
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ISO/TS 21387:2020(E)

The maximum EO concentration specification should be established to ensure that product safety,

quality and performance is not compromised (see ISO 11135:2014, 7.2 and ISO 10993-7).

Additional PQ may be needed to establish the appropriateness of the process parameters and their

tolerances for parametric release. After PQ, the process specification includes the process parameters

and their tolerance for each parameter.

NOTE The specification for other parameters including, but not limited to, temperature, pressure and time,

can be established in the same manner for both parametric and BI release processes.

8.2 No additional guidance specified or given.
8.3 No additional guidance specified or given.
8.4 No additional guidance specified or given.
8.5 No additional guidance specified or given.
8.6 No additional guidance specified or given.
8.7 No additional guidance specified or given.
8.8 No additional guidance specified or given.
8.9 No additional guidance specified or given.
9 Validation
9.1 General
9.1.1 No additional guidance specified or given.
9.1.2 No additional guidance specified or given.
9.1.3 No additional guidance specified or given.

9.1.4 Additional PQ cycles can be performed to demonstrate the physical and microbiological

performance reproducibility. This might involve designing cycles to deliver the process parameters for

humidity, temperature and EO concentration at the established lower specification limit to confirm

achievement of the required SAL and at the established upper specification to assess product or

packaging functionality and EO residues.
9.2 Installation qualification
9.2.1 Equipment
a) Temperature measurement

The requirement to measure temperature within the sterilizer from a minimum of two locations is

established to ensure that an undetected fault in a temperature sensor does not lead to the inadvertent

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ISO/TS 21387:2020(E)

release of an improperly processed load. If there is a difference in the two temperature data points, the

acceptable temperature difference should be defined within the processing specification.

b) Humidity measurement

Direct analysis of the head space for RH can be performed using electronic sensors, GC, IR or other

spectroscopic methods currently available to indicate water vapour concentration. The benefit of these

methods is the real-time indication throughout the conditioning phase.

Electronic sensors require periodic calibration to offset the effect of exposure to the EO gas and can

require replacement, heat treatment of the electronic sensors or more frequent calibration after

repeated exposures to EO due to irreversible deterioration of materials currently utilized as sensing

elements.
c) EO concentration measurement

The frequency of analysis required to demonstrate that the EO concentration process parameters

and their tolerances are maintained throughout exposure time should be established during the PQ

studies. Monitoring throughout the exposure time period should also be done as part of the validation,

to determine how the EO concentration changes over time. The results of this analysis are specific to

the product and load configuration being analysed. The analysis performed during the PQ study will

result in documented specifications for how often direct analysis should be performed during routine

processing.

As required in ISO 11135:2014, 9.5.5, the number of defined intervals for EO concentration sampling

should be sufficient so that there is verification that the EO concentration will be within specification

throughout EO exposure. This could be as few as two samples, with one taken after the end of gas

injection or defined equilibration period and a second prior to sterilant removal. Typically, the number

of samples is greater, for example when gas make-ups are used. Where an inert gas addition is included

after EO injection, the ability to capture EO concentration data at the end of injection should be

considered.

To ensure that the readings are representative of conditions within the chamber, it is important to

consider a number of factors, including but not limited to:

— Location: it is important to ensure that the sensor(s) or the sampling location(s) for EO concentration,

humidity and temperature measurement are representative of the environment in the chamber. If

the sensors or sampling points are located within the recirculation system (if used), they should be

placed in a location avoiding excessive turbulence.

— Water condensation: sensors or sampling point should be oriented in a manner to avoid any risk of

build up or water condensation on the reading head of the sensor.

— Pressure influence: the measurement instrument should compensate for the impact of changing

pressures (if applicable).

— Temperature uniformity: sensors, sampling points or sample piping for EO concentration and

humidity might need to be either at or above the specified process temperature to give accurate

readings. To achieve this, the sensor, piping or both might require heating. Measuring equipment

should be located such that the maximum values of temperature and humidity specified for them

are not exceeded. The instructions provided by the measurement equipment manufacturer should

be followed.
9.2.1.2 No additional guidance specified or given.
9.2.1.3 No additional guidance specified or given.
9.2.2 Installation qualification
9.2.2.1 No additional guidance specified or given.
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ISO/TS 21387:2020(E)
9.2.2.2 No additional guidance specified or given.
9.2.2.3 No additional guidance specified or given.
9.2.2.4 No additional guidance specified or given.
9.2.2.5 No additional guidance specified or given.
9.2.2.6 No additional guidance specified or given.
9.3 Operational qualification

9.3.1 RH in the sterilizer chamber can be verified using a calibrated electronic sensor located at

the analytical instrument sampling point of the sterilizer chamber. Analytical instruments such as gas

chromatographs (GC), IR or other spectroscopic methods are less common and are more complex than

the electronic sensor. Such analytical instruments can be calibrated by instrument manufacturers and

the calibration should be verified after installation prior to operational qualification (OQ).

Confirmation of EO sensor calibration can be conducted in one of several ways. Some analytical

instrument suppliers can provide an instruction that can be placed in the system to confirm

maintenance of calibration. An alternative method is to calibrate or verify the EO sensor against known

EO concentrations in a fixed volume of chamber or sample cell. There are three methods of determining

EO concentration:

Method 1: use of the ideal gas law, which is based upon pressure change and temperature of EO.

Method 2: use of the fixed volume of chamber (inclusive of relevant piping and recirculation system) or

sample cell and the weight of EO injected to them.
NOTE Method 1 or 2 can be used.

Method 3: comparison of measured concentration with a commercially available standard

concentration of EO.
Method 1 or 2 can be used to verify calibrations if the following are confirmed:
a) correct analysis of the EO in the storage container;
b) uniform EO mixture in the chamber;
c) accurate measurement of chamber pressure;

d) accurate measurement of chamber temperature at the sampling location, weight of EO added and

the volume of the chamber occupied by the EO.

Confirmation of EO concentration using either the ideal gas law and weight/volume calculations i

...

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