ISO/TS 4452:2025

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
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii
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
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
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 document (including any amendments) applies.
ISO 11608-1, Needle-based injection systems for medical use — Requirements and test methods — Part 1:
Needle-based injection systems
ISO 20072, Aerosol drug delivery device design verification — Requirements and test methods
ISO 21649, Needle-free injection systems for medical use — Requirements and test methods

3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
capability
measure of a drug delivery system’s (3.3) ability to fulfil a primary function under specified conditions within
its labelled expiration date
Note 1 to entry: Capability is usually stated as a statistical tolerance interval (e.g. 97,5 % probability content with
95 % confidence) or with similar statistical characteristics.
Note 2 to entry: Capability, within this document, is primarily used in reference to an individual primary function
rather than a collective (i.e. all primary functions).
Note 3 to entry: The term primary function is used based upon the definition in ISO 11608-1. The entirety of primary
functions of a drug delivery system, in accordance with ISO 11608-1, is similar in principle to both “performance
profile” in ISO 21649 and “device functionality profile” in ISO 20072.
3.2
control strategy
predefined controls that are derived from current product and process understanding that ensures process
performance and product quality necessary to maintain the reliability level
3.3
drug delivery system
DDS
given combination of a medical device and a medicinal product, whether provided as separate products or
integrated as a single product, intended to deliver the medicinal product
3.4
in-use condition
specified environmental and physical condition(s) to which the drug delivery system (3.3) will be exposed
during preparation and delivery, which are those to which the drug delivery system will be exposed during
in-use testing
Note 1 to entry: The conditions are as determined by the manufacturer.
Note 2 to entry: The exposure/conditioning of drug delivery system to bring or acclimate them to conditions at which
they are to be tested (in-use conditions) are not considered precondition or pre-conditions.
3.5
precondition
specified environmental and physical condition(s) to which the drug delivery system (3.3) will be exposed
before preparation and delivery, which are those to which the drug delivery system will be exposed prior to
in-use testing
Note 1 to entry: The conditions are as determined by the manufacturer.
Note 2 to entry: Throughout this document the application of precondition(s) is referred to as preconditioning.

3.6
system reliability
ability of a drug delivery system (3.3) to execute a sequence of functions necessary for delivery of the
medicinal product as defined by the manufacturer under given conditions within the labelled expiration date
Note 1 to entry: The system reliability can be expressed as “less than 1 failure per 100 000 units”, or as a probability of
success such as 99,999 % at 95 % confidence.
Note 2 to entry: As the number of samples needed to objectively establish very high levels of system reliability through
objective testing can be prohibitive (almost 300 000 for a 99,999 % reliability), some products, particularly those that
require a very high level of system reliability, should use theoretical modelling or empirical testing, or both, during
product development.
4 Specification of system reliability and capability
4.1 General
Minimum system reliability is independent of the minimum capability of individual primary functions of a
DDS, but this document requires these primary functions to meet their minimum capability.
EXAMPLE A DDS of reliability level 4 (see 4.2) requires a minimum system reliability of 99,9 %. However, the
medicinal product might still achieve a clinically relevant treatment effect when delivered at 99,0 % dose accuracy
capability. Completion of the dose delivery function is subject to a more stringent requirement than accuracy of the
delivered dose in this example.
4.2 Reliability level
The reliability level matrix in Table 1 correlates five reliability levels to five severity of harm levels.
The manufacturer shall select the reliability level for each DDS from Table 1 based on the harm to the patient
associated with the overall failure to deliver the medicinal product.
Reliability levels 1, 2 and 3 are considered “low to moderate risk” levels and deemed as sufficiently addressed
by current industry standards (see 5.2).
For reliability levels 4 and 5 additional activities are necessary to ensure a DDS meets expectations (see 5.3).
Both cases are detailed in Clause 5.
4.3 Reliability level matrix
Based on the specified reliability level, Table 1 shall be used to specify:
a) the required minimum capability of individual primary functions that are necessary to deliver the
medicinal product;
b) the required minimum system reliability for the DDS;
c) appropriate control strategies for maintaining capability and system reliability.

Table 1 — Reliability level matrix
Reliability Severity of potential harm Minimum Minimum Control strategy
level (potential consequence) (verified) system
c
capability of reliability
an individual
primary
b,c
function
5 Death or permanent impairment 99,99 % 99,999 % Standard Quality Systems and Controls plus additional measures
during design (e.g. Fault-Tree Analysis) and testing (e.g. sequential or
simultaneous conditioning) and manufacture (e.g. statistical process
control of critical to function dimensions) to ensure system reliability
at the point of use.
4 Injury that would result in permanent 99,0 % 99,9 % Standard Quality Systems and Controls plus additional measures
impairment without medical interven- during design (e.g. Fault-Tree Analysis) and testing (e.g. sequential o
...