ISO/TS 4452
(Main)Specification and demonstration of system reliability of single-use drug delivery systems
Specification and demonstration of system reliability of single-use drug delivery systems
This document addresses the specification and demonstration of system reliability to successfully deliver a dose based on the potential consequence of failure (harm) of a function or action or the absence of an attribute, as part of design verification, utilizing empirical methods as well as in vitro/in silico modelling. This includes risk-based techniques to establish and support the required reliability for all single use (disposable) drug delivery systems, including those that provide a single or multiple dose(s), that are provided to be delivered with a specified brand or type of medicinal product. Drug delivery systems covered by this document include, but are not limited to: ― Needle-based injection systems (ISO 11608-1); ― Needle-free injection systems (ISO 21649); ― Aerosol drug delivery systems (ISO 20072). Drug delivery systems not covered in this document: ― With containers that can be refilled multiple times or be replaced; ― Intended for dental use; ― Finished needles; ― Empty syringes; ― Catheters; ― Multi patient use. Pumps (IEC 60601-2-24 (if electronic) or ISO 28620 (if non-electronic)) or stand-alone prefilled syringes defined by ISO 11040-8, are excluded. NOTE Drug delivery systems not in scope of this document may still benefit from elements in this document but provisions of this document might not completely fulfil the basic safety and effectiveness of such drug delivery systems.
Spécification et démonstration de la fiabilité des systèmes d’administration de médicaments non réutilisables
General Information
Standards Content (Sample)
FINAL DRAFT
Technical
Specification
ISO/DTS 4452
ISO/TC 84
Specification and demonstration of
Secretariat: DS
system reliability of single-use drug
Voting begins on:
delivery systems
2025-06-17
Spécification et démonstration de la fiabilité des systèmes
Voting terminates on:
d’administration de médicaments non réutilisables
2025-08-12
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
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO
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.
Reference number
ISO/DTS 4452:2025(en) © ISO 2025
FINAL DRAFT
ISO/DTS 4452:2025(en)
Technical
Specification
ISO/DTS 4452
ISO/TC 84
Specification and demonstration of
Secretariat: DS
system reliability of single-use drug
Voting begins on:
delivery systems
Spécification et démonstration de la fiabilité des systèmes
Voting terminates on:
d’administration de médicaments non réutilisables
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.
© ISO 2025
IN ADDITION TO THEIR EVALUATION AS
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO
LOGICAL, COMMERCIAL AND USER PURPOSES, DRAFT
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
INTERNATIONAL STANDARDS MAY ON OCCASION HAVE
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
TO BE CONSIDERED IN THE LIGHT OF THEIR POTENTIAL
or ISO’s member body in the country of the requester.
TO BECOME STAN DARDS TO WHICH REFERENCE MAY BE
MADE IN NATIONAL REGULATIONS.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland Reference number
ISO/DTS 4452:2025(en) © ISO 2025
ii
ISO/DTS 4452:2025(en)
Contents Page
Foreword .iv
Introduction .v
1 Scope .1
2 Normative references .1
3 Terms and definitions . 2
4 Specification of system reliability and capability .3
4.1 General .3
4.2 Reliability level .3
4.3 Reliability level matrix .3
5 Requirements for demonstration of system reliability . 5
5.1 General .5
5.2 Reliability levels 1, 2 and 3 .5
5.3 Reliability levels 4 and 5 .5
6 Design verification. 5
6.1 General .5
6.2 Establishing conditions .6
6.3 Environmental and physical conditions .6
6.4 Combining conditions for testing .6
6.4.1 General .6
6.4.2 Sequential preconditioning.6
6.4.3 Simultaneous conditioning .7
6.4.4 Sequential and simultaneous conditioning .7
7 Maintaining system reliability .7
Annex A (informative) Example of a fault tree for a fictional mechanism .9
Annex B (informative) Q&A to provide context to the development of this document .12
Bibliography .15
iii
ISO/DTS 4452:2025(en)
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).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent
rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
patent(s) which may be required to implement this document. However, implementers are cautioned that
this may not represent the latest information, which may be obtained from the patent database available at
www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
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 84, Devices for administration of medicinal
products and catheters.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
ISO/DTS 4452:2025(en)
Introduction
Current industry standards cover the quality of performance, e.g. dose accuracy or injection depth, of
different types of drug delivery systems (DDS). These standards require the use of statistical tolerance
intervals to quantify this quality of performance for each individual primary function.
The term “reliability” is commonly used to refer to such quantification, i.e. a tolerance interval based on a
probability content and confidence level.
For at least two decades this approach has proven to be appropriate for many types of DDSs and continues
to do so.
Today these DDSs are used across a broad range of therapeutic areas to deliver medicinal products treating
chronic diseases of low immediate risk as well as potentially life-threatening acute illnesses.
Such DDSs not only need to meet the individual quality of performance for each primary function. They also
need to successfully execute a sequence of functions necessary for deliver the medicinal product.
In this document, the terms ‘capability ’ and ‘system reliability’ are introduced to differentiate between
the quality of performance of a primary function and the probability of each DDS to successfully deliver a
medicinal product respectively.
Based on the severity of potential harm of not delivering the medicinal product this document suggests five
reliability levels. Each of those is linked to minimum capability and system reliability values in line with
current industry practice.
Due to the more severe consequences of some DDSs failing to deliver the medicinal product, requirements for
demonstrating system reliability for the two highest reliability levels have also been added, as well as more
stringent requirements for challenging the DDSs based on the environmental conditions they are intended
to withstand and how these environmental conditions might need to be combined for testing purposes.
The document also emphasises that while both capability and system reliability must be demonstrated at
the conclusion of development (as demonstrated by design verification), they also need to be maintained
throughout manufacture of the DDS. In addition, the two highest reliability levels require additional effort to
ensure these expectations are met.
The establishment of a system reliability is not intended to change the testing for devices that are already
adequately addressed by the current standards (e.g. ISO 11608, ISO 20072 and ISO 21649). Specific detailed
considerations for these standards are addressed in Annex B.
Demonstration of system reliability is not limited to (verification) testing. The entire process of developing
the product and the application of control strategies ensures the DDS continuously meets the system
reliability requirements.
The concept of system reliability is a special case of reliability engineering that pertains to “out of box”
failures for all disposable single use DDSs for which there is a single opportunity to deliver a single dose of
a medicinal product. In contrast, reliability engineering is a collection of techniques to ensure performance
of durable or reusable DDSs over a long period of time and through multiple, successive actuations to ensure
consistent performance possibly over many years.
There can be examples of single-use devices which are built to have on-board a second (or “backup”) dose.
This document can be helpful in the development of such devices, but the reader should be aware that multi-
dose or reusable DDSs are outside the scope of this document (see Annex B for further details).
v
ISO/DTS 4452:2025(en)
Figure 1 — Structure of this document and its relation to risk management
vi
FINAL DRAFT Technical Specification ISO/DTS 4452:2025(en)
Specification and demonstration of system reliability of
single-use drug delivery systems
1 Scope
This document addresses the specification and demonstration of capability and system reliability to
successfully deliver a medicinal product as part of design verification and manufacture, utilizing empirical
methods as well as modelling. This includes risk-based techniques to establish and demonstrate the
required reliability level for all disposable single use drug delivery systems (DDSs) fo
...
ISO/CD TS DTS 4452:2025 (E)
ISO/TC 84/WG 17 N 132
Replaces N 131
Secretariat: DS
Date: 2025-06-02
Specification and demonstration of system reliability of single-use
drug delivery systems
CD stage
This draft contains the action items from the 11th meeting (January 2025) and the modifications made at
the WG 17 meeting (April 2025).
Action items incorporated: #052 (N124), #053 #054 #055.
A version with tracked changes is circulated as document N 131.
Project leader: Maximilian Michel (DE)
Next step: This version will be submitted for the DTS procedure, and the comments will be discussed at the
next F2F meeting in October 2025 (Cambridge, UK).
Warning for WDs and CDs
This document is not an ISO International Standard. It is distributed for review and comment. It is subject to change
without notice and may not be referred to as an International Standard.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which
they are aware and to provide supporting documentation.
ISO #####-#:####(X)
Spécification et démonstration de la fiabilité des systèmes d’administration de médicaments non réutilisables
© ISO #### – All rights reserved
ISO/CD TSDTS 4452:2025 (N 132:(en)
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
EmailE-mail: copyright@iso.org
Website: www.iso.orgwww.iso.org
Published in Switzerland
iii
ISO #####-#:####(X/DTS 4452:(en)
Contents
Foreword . v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Specification of system reliability and capability . 3
4.1 General . 3
4.2 Reliability level . 3
4.3 Reliability level matrix . 3
5 Requirements for demonstration of system reliability . 6
5.1 General . 6
5.2 Reliability levels 1, 2 and 3 . 6
5.3 Reliability levels 4 and 5 . 6
6 Design verification . 6
6.1 General . 6
6.2 Establishing conditions . 7
6.3 Environmental and physical conditions . 7
6.4 Combining conditions for testing . 7
7 Maintaining system reliability . 9
Annex A (informative) Example of a fault tree for a fictional mechanism . 11
Annex B (informative) Q&A to provide context to the development of this document . 17
Bibliography . 20
© ISO #### 2025 – All rights reserved
iv
ISO/CD TSDTS 4452:2025 (N 132:(en)
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).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent rights
in respect thereof. As of the date of publication of this document, ISO had not received notice of (a) patent(s)
which may be required to implement this document. However, implementers are cautioned that this may not
represent the latest information, which may be obtained from the patent database available at
www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
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'sISO’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 84, Devices for administration of medicinal
products and catheters.
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.
v
ISO #####-#:####(X/DTS 4452:(en)
Introduction
Current industry standards cover the quality of performance, e.g. dose accuracy or injection depth, of different
types of Drug Delivery Systemsdrug delivery systems (DDS). These standards require the use of statistical
tolerance intervals to quantify this quality of performance for each individual primary function.
The term “reliability” is commonly used to refer to such quantification, i.e. a tolerance interval based on a
probability content and confidence level.
For at least two decades this approach has proven to be appropriate for many types of DDSs and continues to
do so.
Today these DDSs are used across a broad range of therapeutic areas to deliver medicinal products treating
chronic diseases of low immediate risk as well as potentially life-threatening acute illnesses.
Such DDSs not only need to meet the individual quality of performance for each primary function. They also
need to successfully execute a sequence of functions necessary for deliver the medicinal product.
In this document, the terms ‘capability (3.1)-’ and ‘system reliability (3.6)reliability’ are introduced to
differentiate between the quality of performance of a primary function and the probability of each DDS to
successfully deliver a medicinal product respectively.
Based on the severity of potential harm of not delivering the medicinal product this document suggests five
reliability levels. Each of those is linked to minimum capability and system reliability values in line with
current industry practice.
Due to the more severe consequences of some DDSs failing to deliver the medicinal product, requirements for
demonstrating system reliability for the two highest reliability levels have also been added, as well as more
stringent requirements for challenging the DDSs based on the environmental conditions they are intended to
withstand and how these environmental conditions might need to be combined for testing purposes.
The document also emphasises that while both, capability and system reliability, must be demonstrated at the
conclusion of development (as demonstrated by design verification), they also need to be maintained
throughout manufacture of the DDS. In addition, the two highest reliability levels require additional effort to
ensure these expectations are met.
The establishment of a system reliability is not intended to change the testing for devices that are already
adequately addressed by the current standards (e.g. ISO 11608, ISO 20072 and ISO 21649). Specific detailed
considerations for these standards are addressed in Annex BAnnex B.
Demonstration of system reliability is not limited to (verification) testing. The entire process of developing
the product and the application of control strategies ensures the DDS continuously meets the system reliability
requirements.
The concept of system reliability is a special case of reliability engineering that pertains to “out of box” failures
for all disposable single use DDSs for which there is a single opportunity to deliver a single dose of a medicinal
product. In contrast, reliability engineering is a collection of techniques to ensure performance of durable or
reusable DDSs over a long period of time, and through multiple, successive actuations to ensure consistent
performance possibly over what may be many years.
There maycan be examples of single-use devices which are built to have on-board a second (or “backup”) dose.
This document maycan be helpful in the development of such devices, but the reader should be aware that
multi-dose or reusable DDSs are outside the scope of this document (see Annex BAnnex D for further details).
© ISO #### 2025 – All rights reserved
vi
ISO/CD TSDTS 4452:2025 (N 132:(en)
Figure 1 - — Structure of this document and its relation to risk management
vii
ISO/DTS 4452:(en)
Specification and demonstration of system reliability of single-use
drug delivery systems
1 Scope
This document addresses the specification and demonstration of capability and system reliability to
successfully deliver a medicinal product as part of design verification and manufacture, utilizing empirical
methods as well as modelling. This includes risk-based techniques to establish and demonstrate the required
reliability level for all disposable single use Drug Delivery Systemsdrug delivery systems (DDSs) for which
there is a single opportunity to deliver a single dose of a medicinal product.
DDSs covered by this document include, but are not limited to:
— Needleneedle-based injection systems (ISO 11608-1);
— Needleneedle-free injection systems (ISO 21649);
— Aerosolaerosol drug delivery systems (ISO 20072).
Not covered by thisThis document aredoes not cover:
— DDSs with containers that can be replaced;
— DDSs intended for dental use;
— finished needles;
— empty syringes;
— catheters;
— DDSs for multi-patient use;
— Pumps (pumps [IEC 60601-2-24 (if electronic) or ISO 28620 (if non-electronic)) )];
— stand-alone prefilled syringes defined by ISO 11040-8, are excluded. .
In this document system reliability is limited to assessing functional performance of the DDS and does not
address human factors/ or user interface considerations. These will be covered by a usability engineering
program in accordance with IEC 62366-1 as part of the overall development effort.
NOTE DDSs not in scope of this document can still benefit from elements in this document but provisions of this
document might not completely fulfil the basic safety and effectiveness of such DDSs.
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 11608-1:2022, Needle-based injection systems for medical use — Requirements and test methods — Part 1:
Needle-based injection systems
ISO/DTS 4452:(en)
ISO 20072:2009, Aerosol drug delivery device design verification — Requirements and test methods
ISO 21649:2023, Needle-free injection systems for medical use — Requirements and test methods for needle-free
injection systems
3 Terms and definitions
For the purposes of this doc
...
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