ISO/TS 4452:2025
(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 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) 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: — needle-based injection systems (ISO 11608-1); — needle-free injection systems (ISO 21649); — aerosol drug delivery systems (ISO 20072). This document does 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 [IEC 60601-2-24 (if electronic) or ISO 28620 (if non-electronic)]; — stand-alone prefilled syringes defined by ISO 11040-8. 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. 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.
Spécification et démonstration de la fiabilité des systèmes d’administration de médicaments non réutilisables
General Information
Standards Content (Sample)
Technical
Specification
ISO/TS 4452
First edition
Specification and demonstration of
2025-11
system reliability of single-use drug
delivery systems
Spécification et démonstration de la fiabilité des systèmes
d’administration de médicaments non réutilisables
Reference number
© ISO 2025
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ii
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
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
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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)
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rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
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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
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 delivery of 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).
Figure 1 illustrates the document structure and its relation to risk management.
v
Figure 1 — Structure of this document and its relation to risk management
vi
Technical Specification ISO/TS 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) 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:
— needle-based injection systems (ISO 11608-1);
— needle-free injection systems (ISO 21649);
— aerosol drug delivery systems (ISO 20072).
This document does 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 [IEC 60601-2-24 (if electronic) or ISO 28620 (if non-electronic)];
— stand-alone prefilled syringes defined by ISO 11040-8.
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.
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 doc
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