ISO/FDIS 13408-6

Aseptic processing of health care products

Traitement aseptique des produits de santé

Standards Content (sample)

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: [phone]
Fax: [phone]
Email: [e-mail]
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
---------------------- Page: 3 ----------------------
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
---------------------- Page: 4 ----------------------
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
---------------------- Page: 5 ----------------------
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
---------------------- Page: 6 ----------------------
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
---------------------- Page: 7 ----------------------
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.
2 © ISO 2020 – All rights reserved
---------------------- Page: 8 ----------------------
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
...