Aseptic processing of health care products — Part 6: Isolator systems

This document specifies the requirements for and provides guidance on the specification, selection, qualification, bio-decontamination, validation, operation and control of isolator systems related to aseptic processing of health care products and processing of cell-based health care products. This document does not specify requirements for restricted access barrier systems (RABS). This document does not supersede or replace national regulatory requirements such as Good Manufacturing Practices (GMPs) and/or compendia requirements that pertain in particular to national or regional jurisdictions. This document does not specify requirements for isolators used for sterility testing; however, some of the principles and information in this document could be applicable to this application. This document does not define biosafety containment requirements.

Traitement aseptique des produits de santé — Partie 6: Systèmes isolateurs

Le présent document spécifie les exigences et fournit les recommandations relatives à la spécification, la sélection, la qualification, la bio-décontamination, la validation, au fonctionnement et au contrôle des systèmes isolateurs utilisés pour le traitement aseptique des produits de santé et le traitement des produits de santé à base de cellules. Le présent document ne spécifie aucune exigence concernant les systèmes de barrière à accès restreint (RABS). Le présent document n’a pas pour vocation de remplacer ou d’annuler des exigences réglementaires nationales, telles que les bonnes pratiques de fabrication (BPF) et/ou les exigences officielles, qui relèvent des juridictions nationales ou régionales particulières. Le présent document ne spécifie aucune exigence pour les isolateurs utilisés dans le cadre d’essais de stérilité ; cependant, certains principes et informations contenus dans le présent document peuvent s’appliquer à cette application. Le présent document ne définit pas d’exigences de confinement de biosécurité.

General Information

Status
Published
Publication Date
12-Apr-2021
Current Stage
6060 - International Standard published
Start Date
13-Apr-2021
Completion Date
13-Apr-2021
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INTERNATIONAL ISO
STANDARD 13408-6
Second edition
2021-04
Aseptic processing of health care
products —
Part 6:
Isolator systems
Traitement aseptique des produits de santé —
Partie 6: Systèmes isolateurs
Reference number
ISO 13408-6:2021(E)
ISO 2021
---------------------- Page: 1 ----------------------
ISO 13408-6:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021

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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Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 13408-6:2021(E)
Contents Page

Foreword ..........................................................................................................................................................................................................................................v

Introduction ................................................................................................................................................................................................................................vi

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

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

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

4 Quality system elements .............................................................................................................................................................................. 3

5 Basic principle of isolator systems .................................................................................................................................................... 3

5.1 General ........................................................................................................................................................................................................... 3

5.2 Negative pressure isolators .......................................................................................................................................................... 4

6 Isolator system specification ................................................................................................................................................................... 4

6.1 General .......................................................................................................................................................................................................... 4

6.2 Risk management ................................................................................................................................................................................. 4

6.2.1 General...................................................................................................................................................................................... 4

6.2.2 Negative pressure isolator systems ................................................................................................................. 5

6.3 User requirement specification ................................................................................................................................................ 5

7 Design of isolator systems .......................................................................................................................................................................... 5

7.1 General ........................................................................................................................................................................................................... 5

7.2 Materials of construction ............................................................................................................................................................... 6

7.3 Air-handling system ........................................................................................................................................................................... 6

7.3.1 General...................................................................................................................................................................................... 6

7.3.2 Air change rate ...................................................................... ............................................................................................. 6

7.3.3 Airflow pattern .................................................................................................................................................................. 6

7.3.4 Temperature/humidity .............................................................................................................................................. 7

7.3.5 Particulate air specifications ................................................................................................................................. 7

7.3.6 Recirculation of air ......................................................................................................................................................... 7

7.3.7 Pressure differentials ................................................................................................................................................... 7

7.4 Operator interface ................................................................................................................................................................................ 7

7.4.1 Isolator gloves/sleeves ............................................................................................................................................... 7

7.4.2 Suits/half-suits .................................................................................................................................................................. 8

7.4.3 Access to the isolator/transfer systems....................................................................................................... 8

7.4.4 Devices acting as transfer ports .......................................................................................................................... 8

7.5 Ancillary isolator equipment ...................................................................................................................................................... 9

7.5.1 Portable and mobile equipment ......................................................................................................................... 9

7.6 Surrounding room classification ............................................................................................................................................. 9

7.7 Process utilities ...................................................................................................................................................................................... 9

8 Validation ..................................................................................................................................................................................................................... 9

8.1 General ........................................................................................................................................................................................................... 9

8.2 Design qualification .........................................................................................................................................................................10

8.2.1 General...................................................................................................................................................................................10

8.2.2 Product/process application ..............................................................................................................................10

8.2.3 Ergonomics ........................................................................................................................................................................10

8.2.4 Cleaning ................................................................................................................................................................................10

8.2.5 Bio-decontamination ................................................................................................................................................11

8.2.6 Selection of bio-decontamination agent ...................................................................................................11

8.2.7 Development and validation of bio-decontamination processes .......................................12

8.2.8 Bio-decontamination agent generation and testing .......................................................................12

8.2.9 Bio-decontamination parameters ..................................................................................................................13

8.2.10 Aeration and residue limits .................................................................................................................................13

8.2.11 Log reduction ...................................................................................................................................................................13

8.2.12 Surface bio-decontamination of items .......................................................................................................14

8.2.13 Development and validation of sterilization processes .............................................................14

© ISO 2021 – All rights reserved iii
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ISO 13408-6:2021(E)

8.3 Installation qualification .............................................................................................................................................................14

8.3.1 General...................................................................................................................................................................................14

8.3.2 Installation .........................................................................................................................................................................14

8.4 Operational qualification ............................................................................................................................................................15

8.5 Performance qualification ..........................................................................................................................................................16

8.5.1 General...................................................................................................................................................................................16

8.5.2 Cleaning ................................................................................................................................................................................16

8.5.3 Bio-decontamination ................................................................................................................................................16

8.5.4 Process simulation tests .........................................................................................................................................16

8.6 Review and approval of validation .....................................................................................................................................16

8.7 Requalification .....................................................................................................................................................................................17

9 Routine monitoring and control .......................................................................................................................................................17

9.1 Procedures ...............................................................................................................................................................................................17

9.2 System integrity ..................................................................................................................................................................................17

9.3 Bio-decontamination process monitoring ...................................................................................................................17

9.4 Environmental monitoring ........................................................................................................................................................18

9.5 Change control .....................................................................................................................................................................................18

9.6 Maintenance and calibration ...................................................................................................................................................18

10 Personnel training ...........................................................................................................................................................................................19

Annex A (informative) Devices acting as transfer ports for portable and mobile equipment ..............20

Annex B (informative) Isolator system — Explanation of terms used and flow of air and

material .......................................................................................................................................................................................................................23

Annex C (informative) Isolator system — Direct/indirect product contact surfaces .....................................24

Bibliography .............................................................................................................................................................................................................................25

iv © ISO 2021 – All rights reserved
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ISO 13408-6:2021(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.

This second edition cancels and replaces the first edition (ISO 13408-6:2005), which has been

technically revised. It also incorporates the Amendment ISO 13408-6:2005/Amd.1:2013. The main

changes compared to the previous edition are as follows:
— changes to the Introduction;
— changes to the Scope;
— addition of the new Clause 5 "Basic principle of Isolator system";

— addition of risk management approach in Clause 6 "Isolator system specification";

— addition of new informative Annex A "Devices acting as transfer ports for portable and mobile

equipment";

— addition of new informative Annex B "Isolator system – Explanation of terms used and flow of air

and material";

— addition of new informative Annex C "Isolator system – Direct/indirect product contact surfaces "

A list of all parts in the ISO 13408 series can be found on the ISO website.

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.
© ISO 2021 – All rights reserved v
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ISO 13408-6:2021(E)
Introduction

A health care product that is labelled “sterile” is manufactured using suitably designed, validated and

controlled processes. Wherever possible, it is terminally sterilized in its final, sealed container. When

this is not possible, the product is aseptically processed.

Aseptic processing is an exacting and demanding discipline designed to maintain sterility through all

stages of preparation, manufacturing, filling and sealing in final containers. It relies on a number of

independent factors for prevention of recontamination of previously sterilized components during the

assembly or filling of product into a final container.

An effective risk management system addressing aseptic processing design (including the use of

barrier separation technology), validation and control, and which identifies, assesses, eliminates

(where applicable) and controls contamination risks is a prerequisite to provide assurance of sterility

for aseptically processed product.

Various separation systems exist to protect the critical processing zone of an aseptic processing area

from non-viable particulate and microbiological contamination and to separate process operators from

the critical processing zone.

These systems range from controlled airflow devices based on aerodynamic protection through

to separation barriers that combine physical and aerodynamic protection to separate the external

cleanroom environment from the critical processing zone, minimizing exposure of this zone to process

operators and thereby reducing the opportunities for contamination during processing.

Isolator systems provide physical separation whilst facilitating operator intervention into the

controlled processing environment under barrier conditions typically via sealed glove-sleeve systems

that are physically connected with glove-ports to the isolator barrier screen(s). To establish a controlled

environment, reduction of viable and non-viable particulates within isolators is achieved by validated

and reproducible cleaning and bio-decontamination processes, principally achieved through the use of

automated methods.

In addition to control of bio-contamination and non-viable particulates, isolator systems can include

control features, which together with operating practices provide product containment to control cross

contamination between process contaminants and product batches, and to manage risk to operators.

vi © ISO 2021 – All rights reserved
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INTERNATIONAL STANDARD ISO 13408-6:2021(E)
Aseptic processing of health care products —
Part 6:
Isolator systems
1 Scope

This document specifies the requirements for and provides guidance on the specification, selection,

qualification, bio-decontamination, validation, operation and control of isolator systems related to

aseptic processing of health care products and processing of cell-based health care products.

This document does not specify requirements for restricted access barrier systems (RABS).

This document does not supersede or replace national regulatory requirements such as Good

Manufacturing Practices (GMPs) and/or compendia requirements that pertain in particular to national

or regional jurisdictions.

This document does not specify requirements for isolators used for sterility testing; however, some of

the principles and information in this document could be applicable to this application.

This document does not define biosafety containment requirements.
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 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements

ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies

ISO 13408-7, Aseptic processing of health care products — Part 7: Alternative processes for medical devices

and combination products

ISO 14644-1:2015, Cleanrooms and associated controlled environments — Part 1: Classification of air

cleanliness by particle concentration

ISO 14644-7, Cleanrooms and associated controlled environments — Part 7: Separative devices (clean air

hoods, gloveboxes, isolators and mini-environments)

ISO 18362, Manufacture of cell-based health care products — Control of microbial risks during processing

ISO/IEC 90003, Software engineering — Guidelines for the application of ISO 9001:2015 to computer

software

ISO 11139, Sterilization of health care products — Vocabulary of terms used in sterilization and related

equipment and process standards
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 11139 and the following apply.

© ISO 2021 – All rights reserved 1
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ISO 13408-6:2021(E)

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
ancillary isolator equipment

equipment that can be attached to or detached from the isolator whilst ensuring separation of the

internal and external environment
3.2
bio-decontamination
removal and/or reduction of biological contaminants to an acceptable level
[SOURCE: ISO 11139:2018, 3.27]
3.3
decontamination device
means used to deliver the agent for the decontamination process
3.4
isolator

enclosure capable of preventing ingress of contaminants by means of physical

separation of the interior from the exterior that is capable of being subject to reproducible interior bio-

decontamination and where operators always remain separated from the interior of the enclosure by

means of an absolute physical barrier

Note 1 to entry: If containment requirements apply (i.e. aseptic processing of hazardous materials) egress also

has to be prevented.
[SOURCE: ISO 11139:2018, 3.149]
3.5
isolator system
isolator (3.4) with transfer system(s), and ancillary isolator equipment (3.1)
[SOURCE: ISO 11139:2018, 3.150]
3.6
safety data sheet
SDS

document specifying the properties of a substance, its potential hazardous effects for humans and the

environment, and the precautions necessary to handle and dispose of the substance safely

[SOURCE: ISO 11139:2018, 3.239]
3.7
sterile barrier system
SBS

device acting as interface between the interiors of an isolator and ancillary isolator equipment (3.1)

minimum package that minimizes the risk of ingress of microorganisms and allows aseptic presentation

of the sterile contents at the point of use
[SOURCE: ISO 11139:2018, 3.272]
3.8
transfer port

interface between the interior of an isolator (3.4) and ancillary isolator equipment (3.1)

Note 1 to entry: See example figures in Annex A.
2 © ISO 2021 – All rights reserved
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ISO 13408-6:2021(E)
[SOURCE: ISO 11139:2018, 3.304]
3.9
transfer system

equipment and process that allows ingress and/or egress of material to an isolator (3.4) without

compromising its environmental quality
4 Quality system elements

Quality elements as defined in ISO 13408-1:2008, Clause 4 shall be implemented to assure control over

all activities affecting isolator systems.
5 Basic principle of isolator systems
5.1 General

An isolator system comprises a piece of equipment, or collection of equipment and control systems

that provides a controlled environment suitable for aseptic processing that shall be separated from the

operator and the surrounding environment using barrier technologies. An isolator system consists of

an isolator, its utilities and its surrounding environment, and can include transfer systems and ancillary

isolator equipment.

Movement of materials in and out of the isolator is a principal risk in maintaining the quality of the

controlled environment. Materials are generally loaded into the isolator before bio-decontamination.

After bio-decontamination of the isolator and during operation, ingress of materials to and egress from

the isolator shall occur via transfer systems that maintain the quality of the controlled environment.

All components, materials and equipment parts shall be sterile/bio-decontaminated before being

transferred into a bio-decontaminated isolator, unless bio-decontamination is conducted inside the

device acting as a transfer port.

Isolator systems shall be classified into open and closed systems according to the construction and

operation of their transfer systems.

Closed isolator systems shall exclusively incorporate transfer systems that separate the controlled

environment from the surrounding environment during operation through the use of a solid physical

barrier. A closed system shall restrict the movement of materials through the system to defined batches.

EXAMPLE 1 Autoclaves, pass-through chambers and rapid transfer port (RTP) containers.

Open isolator systems shall incorporate at least one transfer system that provides separation of the

controlled environment from the surrounding environment through use of a fluid barrier. Open systems

shall allow for the continuous movement of material through the isolator system.
EXAMPLE 2 Exit mouse holes, depyrogenation tunnels and electron beam systems.

NOTE 1 Portable and mobile equipment with aseptic transfer ports can allow for connection of an isolator to

another aseptic environment during operation.

Specification of a transfer system shall consider the quality of the surrounding environment, whether

the transfer system is for ingress and/or egress of items and the characteristics of the items to be

transferred.

Isolator system design shall include protective measures for maintaining the quality of the controlled

environment based on risk management.

Air supplied to the isolator and the transfer systems shall pass through a filter, usually a high

efficiency particulate air (HEPA) or better, which shall render the air at a cleanliness level equivalent

to the controlled environment. Surfaces of the isolator system shall be bio-decontaminated. Materials

© ISO 2021 – All rights reserved 3
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ISO 13408-6:2021(E)

entering the controlled environment shall possess a level of cleanliness equivalent to or better than the

controlled environment.

Direct product contact surfaces of items within the controlled environment shall be sterilized.

Operators shall access items located within the isolator system via a physical barrier (e.g. glove). Direct

product contact surfaces of items within the controlled environment shall be sterilized by a validated

process (see 8.2.1).
NOTE 2 Most isolators are operated under positive pressure conditions.
NOTE 3 See Annex B for an example layout of an isolator system.
5.2 Negative pressure isolators

A negative pressure isolator protects the operator and the surrounding environment by providing

containment during the processing of hazardous or potent product. It can be used to assist in the

management of product quality, containment, bio-contamination risk (where applicable) and safety

issues. To effect containment, the critical work zone within the isolator shall be maintained at a

negative pressure to the environment surrounding the isolator system. Risk management shall

...

NORME ISO
INTERNATIONALE 13408-6
Deuxième édition
2021-04
Traitement aseptique des produits
de santé —
Partie 6:
Systèmes isolateurs
Aseptic processing of health care products —
Part 6: Isolator systems
Numéro de référence
ISO 13408-6:2021(F)
ISO 2021
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ISO 13408-6:2021(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2021

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.

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Publié en Suisse
ii © ISO 2021 – Tous droits réservés
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ISO 13408-6:2021(F)
Sommaire Page

Avant-propos ................................................................................................................................................................................................................................v

Introduction ................................................................................................................................................................................................................................vi

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

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

3 Termes et définitions ....................................................................................................................................................................................... 2

4 Éléments du système qualité ................................................................................................................................................................... 3

5 Principe de base des systèmes isolateurs .................................................................................................................................. 3

5.1 Généralités .................................................................................................................................................................................................. 3

5.2 Isolateurs à pression négative ................................................................................................................................................... 4

6 Spécification des systèmes isolateurs ............................................................................................................................................ 4

6.1 Généralités ................................................................................................................................................................................................. 4

6.2 Gestion des risques ............................................................................................................................................................................. 4

6.2.1 Généralités ............................................................................................................................................................................ 4

6.2.2 Systèmes isolateurs à pression négative ..................................................................................................... 5

6.3 Spécification des exigences de l’utilisateur .................................................................................................................... 5

7 Conception des systèmes isolateurs ................................................................................................................................................. 6

7.1 Généralités .................................................................................................................................................................................................. 6

7.2 Matériaux de construction ............................................................................................................................................................ 6

7.3 Système de traitement de l’air ................................................................................................................................................... 6

7.3.1 Généralités ............................................................................................................................................................................ 6

7.3.2 Taux de renouvellement de l’air ......................................................................................................................... 7

7.3.3 Schéma d’écoulement de l’air ............................................................................................................................... 7

7.3.4 Température/humidité .............................................................................................................................................. 7

7.3.5 Spécifications atmosphériques particulaires .......................................................................................... 7

7.3.6 Recyclage de l’air ............................................................................................................................................................. 8

7.3.7 Pressions différentielles ............................................................................................................................................ 8

7.4 Interface de l’opérateur ................................................................................................................................................................... 8

7.4.1 Gants/manchons isolants......................................................................................................................................... 8

7.4.2 Combinaisons/demi-combinaisons ................................................................................................................ 8

7.4.3 Accès à l’isolateur/systèmes de transfert .................................................................................................. 9

7.4.4 Dispositifs agissant comme des ports de transfert ............................................................................ 9

7.5 Équipement d’isolateur auxiliaire .......................................................................................................................................... 9

7.5.1 Appareils portables et mobiles ............................................................................................................................ 9

7.6 Classification des salles environnantes ..........................................................................................................................10

7.7 Utilités du procédé ............................................................................................................................................................................10

8 Validation ..................................................................................................................................................................................................................10

8.1 Généralités ...............................................................................................................................................................................................10

8.2 Qualification de la conception ................................................................................................................................................10

8.2.1 Généralités .........................................................................................................................................................................10

8.2.2 Application du produit/procédé .....................................................................................................................11

8.2.3 Ergonomie ..........................................................................................................................................................................11

8.2.4 Nettoyage.............................................................................................................................................................................11

8.2.5 Bio-décontamination ................................................................................................................................................12

8.2.6 Sélection de l’agent de bio-décontamination .......................................................................................12

8.2.7 Mise au point et validation de procédés de bio-décontamination .....................................12

8.2.8 Production et essai de l’agent de bio-décontamination ..............................................................13

8.2.9 Paramètres de bio-décontamination ...........................................................................................................13

8.2.10 Aération et limites de résidus ............................................................................................................................14

8.2.11 Réduction logarithmique .......................................................................................................................................14

8.2.12 Bio-décontamination de surfaces d’objets .............................................................................................14

8.2.13 Mise au point et validation de procédés de stérilisation ..........................................................15

© ISO 2021 – Tous droits réservés iii
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ISO 13408-6:2021(F)

8.3 Qualification de l’installation ...................................................................................................................................................15

8.3.1 Généralités .........................................................................................................................................................................15

8.3.2 Installation .........................................................................................................................................................................15

8.4 Qualification opérationnelle .....................................................................................................................................................16

8.5 Qualification des performances ............................................................................................................................................16

8.5.1 Généralités .........................................................................................................................................................................16

8.5.2 Nettoyage.............................................................................................................................................................................17

8.5.3 Bio-décontamination ................................................................................................................................................17

8.5.4 Essais de simulation de procédé .....................................................................................................................17

8.6 Revue et approbation de la validation .............................................................................................................................17

8.7 Requalification .....................................................................................................................................................................................18

9 Surveillance et contrôle de routine ................................................................................................................................................18

9.1 Modes opératoires ............................................................................................................................................................................18

9.2 Intégrité du système ........................................................................................................................................................................18

9.3 Surveillance du procédé de bio-décontamination.................................................................................................19

9.4 Surveillance environnementale .............................................................................................................................................19

9.5 Contrôle des modifications ........................................................................................................................................................19

9.6 Maintenance et étalonnage .......................................................................................................................................................19

10 Formation du personnel ............................................................................................................................................................................20

Annexe A (informative) Dispositifs agissant comme des ports de transfert pour appareils

mobiles et portables ......................................................................................................................................................................................21

Annexe B (informative) Système isolateur — Explication des termes utilisés, de

l’écoulement de l’air et des flux de matériaux ....................................................................................................................24

Annexe C (informative) Système isolateur — Surfaces en contact direct/indirect avec le produit .25

Bibliographie ...........................................................................................................................................................................................................................27

iv © ISO 2021 – Tous droits réservés
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ISO 13408-6:2021(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’Organization mondiale du commerce (OMC) concernant les obstacles

techniques au commerce (OTC), voir le lien suivant : www .iso .org/ iso/ fr/ avant -propos.

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

Cette deuxième édition annule et remplace la première édition (ISO 13408-6:2005), qui a fait l’objet

d’une révision technique. Elle intègre également l’amendement ISO 13408-6:2005/Amd.1:2013. Les

principales modifications par rapport à l’édition précédente sont les suivantes :

— modifications apportées à l’Introduction ;
— modifications apportées au Domaine d’application ;
— ajout d’un nouvel Article 5 « Principe de base des systèmes isolateurs » ;

— ajout d’une approche de gestion des risques dans l’Article 6 « Spécification des systèmes isolateurs » ;

— ajout d’une nouvelle Annexe A informative « Dispositifs agissant comme des ports de transfert pour

appareils mobiles et portables » ;

— ajout d’une nouvelle Annexe B informative « Système isolateur — Explication des termes utilisés, de

l’écoulement de l’air et des flux de matériaux » ;

— ajout d’une nouvelle Annexe C informative « Système isolateur — Surfaces en contact direct/indirect

avec le produit ».

Une liste de toutes les parties de la série ISO 13408 se trouve sur le site web de l’ISO.

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.
© ISO 2021 – Tous droits réservés v
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ISO 13408-6:2021(F)
Introduction

Un produit de santé étiqueté « stérile » est fabriqué au moyen de procédés conçus, validés et contrôlés de

manière appropriée. Dans la mesure du possible, celui-ci est soumis à une stérilisation terminale dans

son conteneur final scellé. Lorsque cela est impossible, le produit est soumis à un traitement aseptique.

Le traitement aseptique est une discipline rigoureuse et exigeante destinée à maintenir la stérilité

dans toutes les étapes de préparation, fabrication, remplissage et scellage dans des conteneurs finaux.

Il repose sur divers facteurs indépendants pour la prévention de la recontamination de composants

précédemment stérilisés durant l’assemblage ou le remplissage d’un produit dans un conteneur final.

Un système efficace de gestion des risques qui couvre la conception (incluant l’utilisation de la

technologie de séparation par barrière), la validation et le contrôle du traitement aseptique et qui

identifie, évalue, élimine (le cas échéant) et maîtrise les risques de contamination est une condition

indispensable pour ensurer la stérilité d’un produit traité aseptiquement.

Il existe différents systèmes de séparation destinés à protéger la zone critique de traitement d’une zone

de traitement aseptique de la contamination particulaire et microbiologique non viable et à isoler les

opérateurs du procédé de la zone critique de traitement.

Ces systèmes vont des dispositifs à flux d’air contrôlé basés sur la protection aérodynamique

aux barrières de séparation combinant une protection physique et aérodynamique pour séparer

l’environnement de salle propre extérieur de la zone critique de traitement, réduisant ainsi l’exposition

de cette zone aux opérateurs du procédé et, de ce fait, les occasions de contamination au cours du

traitement.

Les systèmes isolateurs fournissent une séparation physique tout en facilitant l’intervention de

l’opérateur dans l’environnement de traitement maîtrisé dans des conditions de barrière, généralement

au moyen de systèmes gants/manchons hermétiques physiquement reliés avec des ronds de gant à

l’écran ou aux écrans barrière de l’isolateur. Pour établir un environnement maîtrisé, une réduction des

particules viables et non viables dans les isolateurs est obtenue par des procédés de nettoyage et de bio-

décontamination validés et reproductibles, principalement par le recours à des méthodes automatisées.

Outre la maîtrise de la bio-contamination et des particules non viables, les systèmes isolateurs peuvent

comprendre des dispositifs de contrôle qui, associés à des pratiques opérationnelles, ensurent le

confinement du produit afin de maîtriser la contamination croisée entre les contaminants du procédé

et les lots de produits, et gérer les risques auxquels sont exposés les opérateurs.

vi © ISO 2021 – Tous droits réservés
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NORME INTERNATIONALE ISO 13408-6:2021(F)
Traitement aseptique des produits de santé —
Partie 6:
Systèmes isolateurs
1 Domaine d’application

Le présent document spécifie les exigences et fournit les recommandations relatives à la spécification,

la sélection, la qualification, la bio-décontamination, la validation, au fonctionnement et au contrôle

des systèmes isolateurs utilisés pour le traitement aseptique des produits de santé et le traitement des

produits de santé à base de cellules.

Le présent document ne spécifie aucune exigence concernant les systèmes de barrière à accès

restreint (RABS).

Le présent document n’a pas pour vocation de remplacer ou d’annuler des exigences réglementaires

nationales, telles que les bonnes pratiques de fabrication (BPF) et/ou les exigences officielles, qui

relèvent des juridictions nationales ou régionales particulières.

Le présent document ne spécifie aucune exigence pour les isolateurs utilisés dans le cadre d’essais de

stérilité ; cependant, certains principes et informations contenus dans le présent document peuvent

s’appliquer à cette application.
Le présent document ne définit pas d’exigences de confinement de biosécurité.
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 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements

ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies

ISO 13408-7, Aseptic processing of health care products — Part 7: Alternative processes for medical devices

and combination products

ISO 14644-1:2015, Cleanrooms and associated controlled environments — Part 1: Classification of air

cleanliness by particle concentration

ISO 14644-7, Cleanrooms and associated controlled environments — Part 7: Separative devices (clean air

hoods, gloveboxes, isolators and mini-environments)

ISO 18362, Manufacture of cell-based health care products — Control of microbial risks during processing

ISO/IEC 90003, Ingénierie du logiciel — Lignes directrices pour l’application de l’ISO 9001:2015 aux

logiciels informatiques

ISO 11139, Sterilization of health care products — Vocabulary of terms used in sterilization and related

equipment and process standards
© ISO 2021 – Tous droits réservés 1
---------------------- Page: 7 ----------------------
ISO 13408-6:2021(F)
3 Termes et définitions

Pour les besoins du présent document, les termes et définitions de l’ISO 11139 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
équipement d’isolateur auxiliaire

équipement, pouvant être lié ou non à l’isolateur, qui garantit la séparation de l’environnement intérieur

et extérieur
3.2
bio-décontamination
élimination et/ou réduction des contaminants biologiques à un niveau acceptable
[SOURCE: ISO 11139:2018, 3.27]
3.3
dispositif de décontamination
moyen utilisé pour la délivrance de l’agent lors du procédé de décontamination
3.4
isolateur

espace clos capable d’éviter l’entrée de contaminants, à l’aide d’une séparation

intérieure/extérieure physique totale, pouvant également subir une bio-décontamination intérieure

reproductible et où les opérateurs du procédé restent toujours séparés de l’intérieur de l’espace clos au

moyen d’une barrière physique absolue

Note 1 à l'article: Si des exigences de confinement s’appliquent (à savoir, un traitement aseptique de matériaux

dangereux), la fuite doit également être évitée.
[SOURCE: ISO 11139:2018, 3.149]
3.5
système isolateur

isolateur (3.4) doté de systèmes de transfert et d’un équipement d’isolateur auxiliaire (3.1)

[SOURCE: ISO 11139:2018, 3.150]
3.6
fiche technique de sécurité
FTS

document spécifiant les propriétés d’une substance, ses effets dangereux potentiels pour l’homme

et l’environnement, et les précautions nécessaires pour manipuler et éliminer la substance en toute

sécurité
[SOURCE: ISO 11139:2018, 3.239]
3.7
système de barrière stérile
SBS

emballage minimal qui réduit le plus possible le risque de pénétration des microorganismes et permet

une présentation aseptique du contenu stérile au point d’utilisation
[SOURCE: ISO 11139:2018, 3.272]
2 © ISO 2021 – Tous droits réservés
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ISO 13408-6:2021(F)
3.8
port de transfert

interface entre les parties intérieures d’un isolateur (3.4) et un équipement d’isolateur auxiliaire (3.1)

Note 1 à l'article: Voir les figures d’exemple données dans l’Annexe A.
[SOURCE: ISO 11139:2018, 3.304]
3.9
système de transfert

équipement et procédé qui permettent l’infiltration et/ou la fuite de matériaux d’un isolateur (3.4) sans

compromettre sa qualité environnementale
4 Éléments du système qualité

Les éléments de qualité sont définis dans l’ISO 13408-1:2008 ; l’Article 4 doit être mis en œuvre afin

d’ensurer le contrôle sur l’ensemble des activités influant sur les systèmes isolateurs.

5 Principe de base des systèmes isolateurs
5.1 Généralités

Un système isolateur se compose d’une unité d’équipement ou d’un ensemble d’équipements et de

systèmes de contrôle assurant un environnement maîtrisé approprié pour le traitement aseptique qui

doivent être séparés de l’opérateur et du milieu ambiant à l’aide de technologies d’isolation par barrière.

Un système isolateur est constitué d’un isolateur, de ses utilités et de son milieu ambiant, et peut inclure

des systèmes de transfert et des équipements d’isolateur auxiliaires.

Les déplacements de matériaux dans et hors de l’isolateur constituent un risque majeur pour le

maintien de la qualité de l’environnement maîtrisé. Les matériaux sont généralement chargés dans

l’isolateur avant la bio-décontamination. Après la bio-décontamination de l’isolateur et pendant

son fonctionnement, l’infiltration et la fuite de matériaux de l’isolateur doivent se produire par

l’intermédiaire des systèmes de transfert, qui maintiennent la qualité de l’environnement maîtrisé.

Tous les composants, matériaux et parties d’équipement doivent être stériles/bio-décontaminés

avant leur transfert dans un isolateur ayant fait l’objet d’une bio-décontamination, à moins que la bio-

décontamination soit effectuée à l’intérieur du dispositif agissant comme un port de transfert.

Les systèmes isolateurs doivent être classés en systèmes ouverts et fermés selon la conception et le

fonctionnement de leurs systèmes de transfert.

Les systèmes isolateurs fermés doivent comporter exclusivement des systèmes de transfert qui séparent

l’environnement maîtrisé du milieu ambiant pendant le fonctionnement au moyen d’une barrière

physique solide. Un système fermé doit restreindre le déplacement des matériaux dans le système à des

lots définis.

EXEMPLE 1 Autoclaves, sas de transfert et récipients de ports de transfert rapides (RTP).

Les systèmes isolateurs ouverts doivent comprendre au moins un système de transfert qui ensure la

séparation de l’environnement maîtrisé et du milieu ambiant au moyen d’une barrière étanche aux

liquides. Les systèmes ouverts doivent permettre le déplacement continu de matériaux dans le système

isolateur.

EXEMPLE 2 Trous de souris d’évacuation, tunnels de dépyrogénation et systèmes à faisceau d’électrons.

NOTE 1 Les appareils mobiles et portables dotés de ports de transfert aseptiques peuvent permettre de relier

un isolateur à un autre environnement aseptique au cours du fonctionnement.
© ISO 2021 – Tous droits réservés 3
---------------------- Page: 9 ----------------------
ISO 13408-6:2021(F)

La spécification d’un système de transfert doit tenir compte de la qualité du milieu ambiant, de la

destination du système de transfert à l’entrée et/ou la sortie d’objets et des caractéristiques des objets

à transférer.

La conception du système isolateur doit inclure des mesures de protection pour le maintien de la qualit

...

FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 13408-6
ISO/TC 198
Aseptic processing of health care
Secretariat: ANSI
products —
Voting begins on:
2020-03-11
Part 6:
Voting terminates on:
Isolator systems
2020-05-06
Traitement aseptique des produits de santé —
Partie 6: Systèmes isolateurs
ISO/CEN PARALLEL PROCESSING
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 SUPPOR TING
DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO-
ISO/FDIS 13408-6:2020(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN-
DARDS TO WHICH REFERENCE MAY BE MADE IN
NATIONAL REGULATIONS. ISO 2020
---------------------- Page: 1 ----------------------
ISO/FDIS 13408-6:2020(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
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/FDIS 13408-6:2020(E)
Contents Page

Foreword ..........................................................................................................................................................................................................................................v

Introduction ................................................................................................................................................................................................................................vi

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

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

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

4 Quality system elements .............................................................................................................................................................................. 3

5 Basic principle of isolator systems .................................................................................................................................................... 3

5.1 General ........................................................................................................................................................................................................... 3

5.2 Negative pressure isolators .......................................................................................................................................................... 4

6 Isolator system specification ................................................................................................................................................................... 4

6.1 General .......................................................................................................................................................................................................... 4

6.2 Risk management ................................................................................................................................................................................. 4

6.2.1 General...................................................................................................................................................................................... 4

6.2.2 Negative pressure isolator systems ................................................................................................................. 5

6.3 User requirement specification ................................................................................................................................................ 5

7 Design of isolator systems .......................................................................................................................................................................... 5

7.1 General ........................................................................................................................................................................................................... 5

7.2 Materials of construction ............................................................................................................................................................... 6

7.3 Air-handling system ........................................................................................................................................................................... 6

7.3.1 General...................................................................................................................................................................................... 6

7.3.2 Air change rate ...................................................................... ............................................................................................. 6

7.3.3 Airflow pattern .................................................................................................................................................................. 6

7.3.4 Temperature/humidity .............................................................................................................................................. 7

7.3.5 Particulate air specifications ................................................................................................................................. 7

7.3.6 Recirculation of air ......................................................................................................................................................... 7

7.3.7 Pressure differentials ................................................................................................................................................... 7

7.4 Operator interface ................................................................................................................................................................................ 7

7.4.1 Isolator gloves/sleeves ............................................................................................................................................... 7

7.4.2 Suits/half-suits .................................................................................................................................................................. 8

7.4.3 Access to the isolator/transfer systems....................................................................................................... 8

7.4.4 Devices acting as transfer ports .......................................................................................................................... 8

7.5 Ancillary isolator equipment ...................................................................................................................................................... 9

7.5.1 Portable and mobile equipment ......................................................................................................................... 9

7.6 Surrounding room classification ............................................................................................................................................. 9

7.7 Process utilities ...................................................................................................................................................................................... 9

8 Validation ..................................................................................................................................................................................................................... 9

8.1 General ........................................................................................................................................................................................................... 9

8.2 Design qualification .........................................................................................................................................................................10

8.2.1 General...................................................................................................................................................................................10

8.2.2 Product/process application ..............................................................................................................................10

8.2.3 Ergonomics ........................................................................................................................................................................10

8.2.4 Cleaning ................................................................................................................................................................................10

8.2.5 Bio-decontamination ................................................................................................................................................11

8.2.6 Selection of bio-decontamination agent ...................................................................................................11

8.2.7 Development and validation of bio-decontamination processes .......................................12

8.2.8 Bio-decontamination agent generation and testing .......................................................................12

8.2.9 Bio-decontamination parameters ..................................................................................................................13

8.2.10 Aeration and residue limits .................................................................................................................................13

8.2.11 Log reduction ...................................................................................................................................................................13

8.2.12 Surface bio-decontamination of items .......................................................................................................14

8.2.13 Development and validation of sterilization processes .............................................................14

© ISO 2020 – All rights reserved iii
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ISO/FDIS 13408-6:2020(E)

8.3 Installation qualification .............................................................................................................................................................14

8.3.1 General...................................................................................................................................................................................14

8.3.2 Installation .........................................................................................................................................................................14

8.4 Operational qualification ............................................................................................................................................................15

8.5 Performance qualification ..........................................................................................................................................................16

8.5.1 General...................................................................................................................................................................................16

8.5.2 Cleaning ................................................................................................................................................................................16

8.5.3 Bio-decontamination ................................................................................................................................................16

8.5.4 Process simulation tests .........................................................................................................................................16

8.6 Review and approval of validation .....................................................................................................................................16

8.7 Requalification .....................................................................................................................................................................................17

9 Routine monitoring and control .......................................................................................................................................................17

9.1 Procedures ...............................................................................................................................................................................................17

9.2 System integrity ..................................................................................................................................................................................17

9.3 Bio-decontamination process monitoring ...................................................................................................................17

9.4 Environmental monitoring ........................................................................................................................................................18

9.5 Change control .....................................................................................................................................................................................18

9.6 Maintenance and calibration ...................................................................................................................................................18

10 Personnel training ...........................................................................................................................................................................................19

Annex A (informative) Devices acting as transfer ports for portable and mobile equipment ..............20

Annex B (informative) Isolator system — Explanation of terms used and flow of air and

material .......................................................................................................................................................................................................................23

Annex C (informative) Isolator system — Direct/indirect product contact surfaces .....................................24

Annex ZA (informative) Relationship between this European Standard and the essential

requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered ................................................25

Annex ZB (informative) Relationship between this European Standard and the essential

requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered ....................................................27

Annex ZC (informative) Relationship between this European Standard and the essential

requirements of Directive 98/79/EC [OJ L 331] aimed to be covered .......................................................29

Annex ZD (informative) Relationship between this European Standard and the General

Safety and Performance requirements of Regulation (EU) 2017/745 aimed to be

covered ......... ................................................................................................................................................................................................................31

Annex ZE (informative) Relationship between this European Standard and the General

Safety and Performance Requirements of Regulation (EU) 2017/746 aimed to be

covered ......... ................................................................................................................................................................................................................34

Bibliography .............................................................................................................................................................................................................................36

iv © ISO 2020 – All rights reserved
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ISO/FDIS 13408-6:2020(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.

This second edition cancels and replaces the first edition (ISO 13408-6:2005), which has been

technically revised. It also incorporates the Amendment ISO 13408-6:2005/Amd.1:2013.The main

changes compared to the previous edition are as follows:
— changes to the Introduction;
— changes to the Scope;
— addition of the new Clause 5 "Basic principle of Isolator system";

— addition of risk management approach in Clause 6 "Isolator system specification";

— addition of new informative Annex A "Devices acting as transfer ports for portable and mobile

equipment";

— addition of new informative Annex B "Isolator system – Explanation of terms used and flow of air

and material";

— addition of new informative Annex C "Isolator system – Direct/indirect product contact surfaces "

A list of all parts in the ISO 13408 series can be found on the ISO website.

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.
© ISO 2020 – All rights reserved v
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ISO/FDIS 13408-6:2020(E)
Introduction

A health care product that is labelled “sterile” is manufactured using suitably designed, validated and

controlled processes. Wherever possible, it is terminally sterilized in its final, sealed container. When

this is not possible, the product is aseptically processed.

Aseptic processing is an exacting and demanding discipline designed to maintain sterility through all

stages of preparation, manufacturing, filling and sealing in final containers. It relies on a number of

independent factors for prevention of recontamination of previously sterilized components during the

assembly or filling of product into a final container.

An effective risk management system addressing aseptic processing design (including the use of

barrier separation technology), validation and control, and which identifies, assesses, eliminates

(where applicable) and controls contamination risks is a prerequisite to provide assurance of sterility

for aseptically processed product.

Various separation systems exist to protect the critical processing zone of an aseptic processing area

from non-viable particulate and microbiological contamination and to separate process operators from

the critical processing zone.

These systems range from controlled airflow devices based on aerodynamic protection through

to separation barriers that combine physical and aerodynamic protection to separate the external

cleanroom environment from the critical processing zone, minimizing exposure of this zone to process

operators and thereby reducing the opportunities for contamination during processing.

Isolator systems provide physical separation whilst facilitating operator intervention into the

controlled processing environment under barrier conditions typically via sealed glove-sleeve systems

that are physically connected with glove-ports to the isolator barrier screen(s). To establish a controlled

environment, reduction of viable and non-viable particulates within isolators is achieved by validated

and reproducible cleaning and bio-decontamination processes, principally achieved through the use of

automated methods.

In addition to control of bio-contamination and non-viable particulates, isolator systems can include

control features, which together with operating practices provide product containment to control cross

contamination between process contaminants and product batches, and to manage risk to operators.

vi © ISO 2020 – All rights reserved
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FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 13408-6:2020(E)
Aseptic processing of health care products —
Part 6:
Isolator systems
1 Scope

This document specifies the requirements for and provides guidance on the specification, selection,

qualification, bio-decontamination, validation, operation and control of isolator systems related to

aseptic processing of health care products and processing of cell-based health care products.

This document does not specify requirements for restricted access barrier systems (RABS).

This document does not supersede or replace national regulatory requirements such as Good

Manufacturing Practices (GMPs) and/or compendia requirements that pertain in particular to national

or regional jurisdictions.

This document does not specify requirements for isolators used for sterility testing; however, some of

the principles and information in this document could be applicable to this application.

This document does not define biosafety containment requirements.
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 13408-1:2008, Aseptic processing of health care products — Part 1: General requirements

ISO 13408-4, Aseptic processing of health care products — Part 4: Clean-in-place technologies

ISO 13408-7, Aseptic processing of health care products — Part 7: Alternative processes for medical devices

and combination products

ISO 14644-1:2015, Cleanrooms and associated controlled environments — Part 1: Classification of air

cleanliness by particle concentration

ISO 14644-7, Cleanrooms and associated controlled environments — Part 7: Separative devices (clean air

hoods, gloveboxes, isolators and mini-environments)

ISO 18362, Manufacture of cell-based health care products — Control of microbial risks during processing

ISO/IEC 90003, Software engineering — Guidelines for the application of ISO 9001:2000 to computer

software

ISO 11139, Sterilization of health care products — Vocabulary of terms used in sterilization and related

equipment and process standards
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 11139 and the following apply.

© ISO 2020 – All rights reserved 1
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ISO/FDIS 13408-6:2020(E)

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
ancillary isolator equipment

equipment that can be attached to or detached from the isolator whilst ensuring separation of the

internal and external environment
3.2
bio-decontamination
removal and/or reduction of biological contaminants to an acceptable level
[SOURCE: ISO 11139:2018, 3.27]
3.3
decontamination device
means used to deliver the agent for the decontamination process
3.4
isolator

enclosure capable of preventing ingress of contaminants by means of physical

separation of the interior from the exterior that is capable of being subject to reproducible interior bio-

decontamination and where operators always remain separated from the interior of the enclosure by

means of an absolute physical barrier

Note 1 to entry: If containment requirements apply (i.e. aseptic processing of hazardous materials) egress also

has to be prevented.
[SOURCE: ISO 11139:2018, 3.149]
3.5
isolator system
isolator (3.4) with transfer system(s), and ancillary isolator equipment (3.1)
[SOURCE: ISO 11139:2018, 3.150]
3.6
safety data sheet
SDS

document specifying the properties of a substance, its potential hazardous effects for humans and the

environment, and the precautions necessary to handle and dispose of the substance safely

[SOURCE: ISO 11139:2018, 3.239]
3.7
sterile barrier system
SBS

device acting as interface between the interiors of an isolator and ancillary isolator equipment (3.1)

minimum package that minimizes the risk of ingress of microorganisms and allows aseptic presentation

of the sterile contents at the point of use
[SOURCE: ISO 11139:2018, 3.272]
3.8
transfer port

interface between the interior of an isolator (3.4) and ancillary isolator equipment (3.1)

Note 1 to entry: See example figures in Annex A.
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ISO/FDIS 13408-6:2020(E)
[SOURCE: ISO 11139:2018, 3.304]
3.9
transfer system

equipment and process that allows ingress and/or egress of material to an isolator (3.4) without

compromising its environmental quality
4 Quality system elements

Quality elements as defined in ISO 13408-1:2008, Clause 4 shall be implemented to assure control over

all activities affecting isolator systems.
5 Basic principle of isolator systems
5.1 General

An isolator system comprises a piece of equipment, or collection of equipment and control systems

that provides a controlled environment suitable for aseptic processing that shall be separated from the

operator and the surrounding environment using barrier technologies. An isolator system consists of

an isolator, its utilities and its surrounding environment, and can include transfer systems and ancillary

isolator equipment.

Movement of materials in and out of the isolator is a principal risk in maintaining the quality of the

controlled environment. Materials are generally loaded into the isolator before bio-decontamination.

After bio-decontamination of the isolator and during operation, ingress of materials to and egress from

the isolator shall occur via transfer systems that maintain the quality of the controlled environment.

All components, materials and equipment parts shall be sterile/bio-decontaminated before being

transferred into a bio-decontaminated isolator, unless bio-decontamination is conducted inside the

device acting as a transfer port.

Isolator systems shall be classified into open and closed systems according to the construction and

operation of their transfer systems.

Closed isolator systems shall exclusively incorporate transfer systems that separate the controlled

environment from the surrounding environment during operation through the use of a solid physical

barrier. A closed system shall restrict the movement of materials through the system to defined batches.

EXAMPLE 1 Autoclaves, pass-through chambers and rapid transfer port (RTP) containers.

Open isolator systems shall incorporate at least one transfer system that provides separation of the

controlled environment from the surrounding environment through use of a fluid barrier. Open systems

shall allow for the continuous movement of material through the isolator system.
EXAMPLE 2 Exit mouse holes, depyrogenation tunnels and el
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