ISO 25424:2018 Sterilization of health care products — Low temperature steam and formaldehyde — Requirements for development, validation and routine control of a sterilization process for medical devices

INTERNATIONAL ISO
STANDARD 25424

Second edition
2018-10

Sterilization of health care products —
Low temperature steam and
formaldehyde — Requirements for
development, validation and routine
control of a sterilization process for
medical devices

Stérilisation des produits de santé — Formaldéhyde et vapeur à faible
température — Exigences pour le développement, la validation et
le contrôle de routine d'un procédé de stérilisation pour dispositifs
médicaux

Reference number
ISO 25424:2018(E)

© ISO 2018

ISO 25424:2018(E)


COPYRIGHT PROTECTED DOCUMENT

© ISO 2018

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:
Website: www.iso.org

Published in Switzerland

ii  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


Contents Page

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

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

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

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

3 Terms and definitions...................................................................................................................................................................................... 2

4 Quality management system elements.......................................................................................................................................... 8

4.1 General............................................................................................................................................................................................................ 8

4.2 Documentation........................................................................................................................................................................................ 8

4.3 Management responsibility.......................................................................................................................................................... 8

4.4 Product realization............................................................................................................................................................................... 9

4.5 Control of non-conforming product...................................................................................................................................... 9

5 Sterilizing agent characterization....................................................................................................................................................... 9

5.1 General............................................................................................................................................................................................................ 9

5.2 Sterilizing agent...................................................................................................................................................................................... 9

5.3 Microbicidal effectiveness.............................................................................................................................................................. 9

5.4 Material effects..................................................................................................................................................................................... 10

5.5 Environmental considerations................................................................................................................................................ 10

6 Process and equipment characterization.................................................................................................................................10

6.1 General......................................................................................................................................................................................................... 10

6.2 Process......................................................................................................................................................................................................... 10

6.3 Equipment................................................................................................................................................................................................. 11

7 Product definition.............................................................................................................................................................................................11

8 Process definition..............................................................................................................................................................................................12

9 Validation...................................................................................................................................................................................................................13

9.1 General......................................................................................................................................................................................................... 13

9.2 Installation qualification.............................................................................................................................................................. 14

9.2.1 General................................................................................................................................................................................... 14

9.2.2 Installation.......................................................................................................................................................................... 14

9.2.3 Equipment........................................................................................................................................................................... 14

9.3 Operational qualification............................................................................................................................................................. 15

9.4 Performance qualification........................................................................................................................................................... 15

9.4.1 General................................................................................................................................................................................... 15

9.4.2 Performance qualification — Physical........................................................................................................ 16

9.4.3 Performance qualification — Microbiological..................................................................................... 16

9.4.4 Performance qualification — Desorption and drying................................................................... 17

9.5 Review and approval of validation...................................................................................................................................... 17

10 Routine monitoring and control........................................................................................................................................................18

10.1 General......................................................................................................................................................................................................... 18
10.2 Biological indicators......................................................................................................................................................................... 18
10.3 Chemical indicators.......................................................................................................................................................................... 18
10.4 Records........................................................................................................................................................................................................ 18

11 Product release from sterilization...................................................................................................................................................19

12 Maintaining process effectiveness...................................................................................................................................................19

12.1 General......................................................................................................................................................................................................... 19
12.2 Maintenance of equipment......................................................................................................................................................... 19
12.3 Requalification...................................................................................................................................................................................... 19
12.4 Assessment of change..................................................................................................................................................................... 20

Annex A (normative) Process definition based on inactivation of reference microorganisms
and knowledge of bioburden on product items to be sterilized.......................................................................21

© ISO 2018 – All rights reserved  iii

ISO 25424:2018(E)


Annex B (normative) Process definition based on inactivation of reference microorganisms............22
Annex C (informative) Guidance on application of this document.....................................................................................25
Annex D (informative) Environmental aspects regarding development, validation and

routine control of low temperature steam and formaldehyde processes..............................................35
Bibliography..............................................................................................................................................................................................................................40

iv  © ISO 2018 – All rights reserved

ISO 25424:2018(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 on 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 the following
URL: 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 25424:2009), which has been technically
revised. The main changes compared to the previous edition are as follows:

— alignment with EN 14180:2014;

— alignment with ISO 14937:2009;

— alignment of definitions with ISO 11139:2018;

— addition of relevant literature.

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 2018 – All rights reserved  v

ISO 25424:2018(E)


Introduction

A sterile medical device is one that is free of viable microorganisms. International Standards that
specify requirements for validation and routine control of sterilization processes require, when it
is necessary to supply a sterile medical device, that adventitious microbiological contamination of a
medical device prior to sterilization be minimized. Even so, medical devices produced under standard
manufacturing conditions in accordance with the requirements for quality management systems
(see, for example, ISO 13485) could, prior to sterilization, have microorganisms on them, albeit in
low numbers. Such medical devices are non-sterile. The purpose of sterilization is to inactivate the
microbiological contaminants and thereby transform the nonsterile medical devices into sterile ones.

The kinetics of inactivation of a pure culture of microorganisms by physical and/or chemical agents used
to sterilize medical devices generally can best be described by an exponential relationship between the
number of microorganisms surviving and the extent of treatment with the sterilizing agent; inevitably
this means that there is always a finite probability that a microorganism survives regardless of the
extent of treatment applied. For a given treatment, the probability of survival is determined by the
number and resistance of microorganisms and by the environment in which the organisms exist during
treatment. It follows that the sterility of any one medical device in a population subjected to sterilization
processing cannot be guaranteed and the sterility of a processed population is defined in terms of the
probability of there being a viable microorganism present on a medical device.

This document describes requirements that, if met, will provide a sterilization process with appropriate
microbicidal activity intended to sterilize medical devices. Furthermore, conformity with the
requirements ensures that the sterilization process is both reliable and reproducible so that predictions
can be made, with reasonable confidence, that there is a low level of probability of there being a viable
microorganism present on a medical device after sterilization. Specification of this probability is a
matter for regulatory authorities and can vary from country to country (see, for example, EN 556-1 and
ANSI/AAMI ST67).

Generic requirements of the quality management system for design and development, production,
installation and servicing are given in ISO 9001 and particular requirements for quality management
systems for medical device production are given in ISO 13485. The standards for quality management

systems recognise that, for certain processes used in manufacturing, the effectiveness of the process
cannot be fully verified by subsequent inspection and testing of the product. Sterilization is an example
of such a process. For this reason, sterilization processes are validated for use, the performance of the
sterilization process is monitored routinely and the equipment is maintained.

Exposure to a properly validated, accurately controlled sterilization process is not the only factor
associated with the provision of reliable assurance that a processed medical device is sterile and, in
this regard, suitable for its intended use. Attention is also given to a number of factors including:

a) the microbiological status of incoming raw materials and/or components;

b) the validation and routine control of any cleaning and disinfection procedures used on the
medical device;

c) the control of the environment in which the medical device is manufactured, assembled and
packaged;

d) the control of equipment and processes;

e) the control of personnel and their hygiene;

f) the manner and materials in which the medical device is packaged;

g) the conditions under which the medical device is stored.

The type of contamination on a medical device to be sterilized varies, and this influences the
effectiveness of a sterilization process. Medical devices that have been used in a health care setting
and that are being presented for resterilization in accordance with the manufacturer's instructions

vi  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


(see ISO 17664) should be regarded as special cases. There is the potential for such medical devices
to possess a wide range of contaminating microorganisms and residual inorganic and/or organic
contamination in spite of the application of a cleaning process. Hence, particular attention has to be
given to the validation and control of the cleaning and disinfection processes used during reprocessing.

The requirements are the normative parts of this document with which conformity is claimed. The
guidance given in Annex C is not normative and is not provided as a checklist for auditors. The guidance
provides explanations and methods that are regarded as being a suitable means for conforming with
the requirements. Methods other than those given in the guidance can be used if they are effective in
achieving conformity with the requirements of this document.

The development, validation and routine control of a sterilization process comprise a number of discrete
but interrelated activities, for example, calibration, maintenance, product definition, process definition,
installation qualification, operational qualification and performance qualification. While the activities
required by this document have been grouped together and are presented in a particular order, this
document does not require that the activities be performed in the order that they are presented. The
activities required are not necessarily sequential, as the programme of development and validation
can be iterative. The responsibility for carrying out the activities required by this document will vary
from case to case. This document requires that the responsibilities of the various parties be defined
(see 4.3) but does not specify to whom the responsibilities are allocated. Annex C provides guidance on
allocation of responsibility.

Activities required by this document could also give rise to an environmental burden that can be
considered and minimized, e.g. by utilizing flexibility in planning. Environmental aspects are addressed
in Annex D of this document.

© ISO 2018 – All rights reserved  vii


INTERNATIONAL STANDARD ISO 25424:2018(E)

Sterilization of health care products — Low temperature
steam and formaldehyde — Requirements for
development, validation and routine control of a
sterilization process for medical devices

1 Scope

1.1 Inclusions

1.1.1 This document specifies requirements for the development, validation and routine control
of a low temperature steam and formaldehyde (LTSF) sterilization process for medical devices using
a mixture of low temperature steam and formaldehyde as sterilizing agent and which operates below
ambient pressure.

NOTE Although the scope of this document is limited to medical devices, it specifies requirements and
provides guidance that can be applicable to other products and equipment.

1.1.2 This document is intended to be applied by process developers, manufacturers of sterilization
equipment, manufacturers of medical devices to be sterilized and the organizations with responsibility
for sterilizing medical devices (see ISO 14937:2009, Table E.1).

1.2 Exclusions

1.2.1 This document does not specify requirements for the development, validation and routine control
of a process for inactivating the causative agents of spongiform encephalopathies such as scrapie, bovine

spongiform encephalopathy and Creutzfeldt-Jakob disease. Specific recommendations have been produced
in particular countries for the processing of materials potentially contaminated with these agents.

NOTE See ISO 22442-1, ISO 22442-2 and ISO 22442-3.

1.2.2 This document does not specify requirements for designating a medical device as “STERILE”.
Such requirements are given in EN 556-1.

1.2.3 This document does not specify a quality management system for the control of all stages of
production of medical devices.

NOTE It is not a requirement of this document to have a complete quality management system during
manufacture or reprocessing, but those elements of such a system that are required are normatively referenced
at appropriate places in the text. Attention is drawn to the standards for quality management systems (see
ISO 13485) that control all stages of production or reprocessing of medical devices including the sterilization
process. Further guidance is given in E.4 of ISO 14937:2009.

1.2.4 This document does not specify requirements for occupational safety associated with the design
and operation of LTSF sterilization facilities.

NOTE 1 Safety requirements for sterilizers are specified in IEC 61010-2-040.

NOTE 2 Attention is also drawn to the existence in some countries of regulations stipulating safety
requirements.

© ISO 2018 – All rights reserved  1

ISO 25424:2018(E)


1.2.5 This document does not cover analytical methods for determining levels or residues of
formaldehyde and/or its reaction products.

NOTE 1 Attention is drawn to EN 14180.

NOTE 2 Attention is drawn to the possible existence in some countries of statutory regulations specifying
limits for the level of formaldehyde residues on medical devices and products.

1.2.6 This document does not cover preparatory measures that might be necessary before sterilization
such as cleaning, disinfection and packing.

NOTE For reprocessable medical devices, the manufacturer(s) of these devices can supply information on
the preparatory measures (see ISO 17664).

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 11138-1, Sterilization of health care products — Biological indicators — Part 1: General requirements

ISO 11138-5:2017, Sterilization of health care products — Biological indicators — Part 5: Biological
indicators for low-temperature steam and formaldehyde sterilization processes

ISO 11140-1, Sterilization of health care products — Chemical indicators — Part 1: General requirements

ISO 11737-1, Sterilization of health care products — Microbiological methods — Part 1: Determination of a
population of microorganisms on products

ISO 11737-2, Sterilization of medical devices — Microbiological methods — Part 2: Tests of sterility
performed in the definition, validation and maintenance of a sterilization process

3 Terms and definitions

For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— IEC Electropedia: available at https:​//www​.electropedia​.org/

— ISO Online browsing platform: available at https:​//www​.iso​.org/obp

3.1
bioburden
population of viable microorganisms on or in product (3.25) and/or sterile barrier system

[SOURCE: ISO 11139:2018, 3.23]

3.2
biological indicator
BI
test system containing viable microorganisms providing a specified resistance to a specified
sterilization process (3.39)

[SOURCE: ISO 11139:2018, 3.29, modified — “BI” has been added.]

2  © ISO 2018 – All rights reserved

ISO 25424:2018(E)



3.3
calibration
operation that, under specified conditions, in a first step, establishes a relation between the quantity
values with measurement uncertainties provided by the measurement standards and corresponding
indications with associated measurement uncertainties and, in a second step, uses this information to
establish a relation for obtaining a measurement result from an indication

[SOURCE: ISO/IEC Guide 99:2007, 2.39, modified — The notes to entry have been deleted.]

3.4
change control
assessment and determination of the appropriateness of a proposed alteration to product (3.25),
process or equipment

[SOURCE: ISO 11139:2018, 3.39]

3.5
chemical indicator
test system that reveals change in one or more pre-defined process variables (3.24) based on a chemical
or physical change resulting from exposure to a process

Note 1 to entry: An indicator intended to be used only in combination with a specific test load is also termed an
indicator (both together becoming an indicator system).

[SOURCE: ISO 11139:2018, 3.43, modified — Note 1 to entry has been added.]

3.6
conditioning

treatment of product (3.25) prior to the exposure phase (3.10) to attain a specified temperature, relative
humidity, or other process variable (3.24) throughout the load (3.16)

[SOURCE: ISO 11139:2018, 3.58]

3.7
desorption
removal of the sterilizing agent (3.40) from the chamber and the load (3.16) at the end of the exposure
phase (3.10)

[SOURCE: ISO 11139:2018, 3.78]

3.8
D value
D10 value
time or dose required under stated conditions to achieve inactivation of 90 % of a population of the test
microorganisms

Note 1 to entry: For LTSF sterilization (3.37) the D value is given in minutes.

[SOURCE: ISO 11139:2018, 3.75, modified — Note 1 to entry has been added]

3.9
establish
determine by theoretical evaluation and confirm by experimentation

[SOURCE: ISO 11139:2018, 3.107]

3.10
exposure phase

cycle stage between the introduction of the sterilizing or disinfecting agent into the chamber and when
the agent is removed

[SOURCE: ISO 11139:2018, 3.111]

© ISO 2018 – All rights reserved  3

ISO 25424:2018(E)


3.11
fault
situation in which one or more of the process or cycle parameters is/are outside its/their specified
tolerance(s)

[SOURCE: ISO 11139:2018, 3.116]

3.12
FBIO value
expression of the resistance of a biological indicator (3.2) calculated as the product of the logarithm of
the initial population of microorganisms and the D value (3.8)

Note 1 to entry: The FBIO value can be used to express the “total resistance” of the biological indicator.

[SOURCE: ISO 11139:2018, 3.113.2, modified — Note 1 to entry has been added.]

3.13
holding time
period during which process parameters (3.23) are maintained, within their specified tolerances

[SOURCE: ISO 11139:2018, 3.133]

3.14
inoculated carrier
supporting material on or in which a specified number of viable test microorganisms has been deposited

[SOURCE: ISO 11139:2018, 3.144]

3.15
installation qualification
IQ
process of establishing (3.9) by objective evidence that all key aspects of the process equipment and
ancillary system installation comply with the approved specification

[SOURCE: ISO 11139:2018, 3.220.2]

3.16
load
product (3.25), equipment or materials to be processed together within an operating cycle

[SOURCE: ISO 11139:2018, 3.155]

3.17
LTSF-equilibration time
period which elapses between the attainment of the sterilization temperature at the reference
measurement point (3.27) and the attainment of the sterilization temperature at all points within the
load (3.16)

[SOURCE: EN 14180:2014, 3.18]

3.18
medical device
instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use or calibrator,
software, material or other similar related article, intended by the manufacturer to be used, alone or in
combination, for human beings for one or more of the specific medical purpose(s) of:

— diagnosis, prevention, monitoring, treatment or alleviation of disease;

— diagnosis, monitoring, treatment, alleviation of or compensation for an injury;

— investigation, replacement, modification or support of the anatomy or of a physiological process;

— supporting or sustaining life;

4  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


— control of conception;

— disinfection of medical devices;

— providing information by means of in vitro examination of specimens derived from the human body;

and does not achieve its primary intended action by pharmacological, immunological or metabolic
means, but which may be assisted in its intended function by such means

Note 1 to entry: Products which can be considered to be medical devices in some jurisdictions, but not in others
include:

— items specifically intended for cleaning or sterilization (3.37) of medical devices;

— pouches, reel goods, sterilization wrap, and reusable containers for packaging of medical devices for
sterilization;

— disinfection substances;

— aids for persons with disabilities;

— devices incorporating animal and/or human tissues;

— devices for in vitro fertilization or assisted reproduction technologies.

[SOURCE: ISO 13485:2016, 3.11, modified — The first two list items in Note 1 to entry have been added.]

3.19
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment operates within predetermined
limits when used in accordance with its operational procedures

[SOURCE: ISO 11139:2018, 3.220.3]

3.20
parametric release
declaration that product (3.25) is sterile (3.35) based on records demonstrating that the process
variables (3.24) were delivered within specified tolerances

[SOURCE: ISO 11139:2018, 3.193]

3.21
performance qualification
PQ
process of establishing (3.9) by objective evidence that the process, under anticipated conditions,
consistently produces a product (3.25) which meets all predetermined requirements

[SOURCE: ISO 11139:2018, 3.220.4]

3.22
process challenge device
PCD
item providing a defined resistance to a cleaning, disinfection, or sterilization process (3.39) and used to
assess performance of the process

Note 1 to entry: The device is so constituted that a biological or chemical indicator (3.5) can be put in the place
which is the most difficult to reach by sterilizing agent(s) (3.40) and does not interfere with the function of the
process challenge device.

[SOURCE: ISO 11139:2018, 3.205, modified — Note 1 to entry has been added.]

© ISO 2018 – All rights reserved  5

ISO 25424:2018(E)


3.23
process parameter
specified value for a process variable (3.24)

Note 1 to entry: The specification for a process includes the process parameters and their tolerances

[SOURCE: ISO 11139:2018, 3.211]

3.24
process variable
chemical or physical attribute within a cleaning, disinfection, packaging, or sterilization process (3.39),
changes in which can alter its effectiveness

EXAMPLE Time, temperature, pressure, concentration, humidity, wavelength.

[SOURCE: ISO 11139:2018, 3.213]

3.25
product
tangible result of a process

EXAMPLE Raw material(s), intermediate(s), sub-assembly(ies), health care product(s).

[SOURCE: ISO 11139:2018, 3.217]

3.26
recognized culture collection
depository authority under the Budapest Treaty on The International Recognition of the Deposit of
Microorganisms for the Purposes of Patent and Regulation

[SOURCE: ISO 11139:2018, 3.222]

3.27
reference measurement point

location of the sensor controlling the operating cycle

[SOURCE: ISO 11139:2018, 3.227]

3.28
reference microorganism
microbial strain obtained from a recognized culture collection (3.26)

[SOURCE: ISO 11139:2018, 3.228]

3.29
requalification
repetition of part or all of validation (3.42) for the purpose of confirming the continued acceptability of
a specified process

[SOURCE: ISO 11139:2018, 3.220.5]

3.30
residues challenge device
item used to assess the effectiveness of desorption (3.7)

[SOURCE: ISO 11139:2018, 3.232]

3.31
services
supplies from an external source needed for the function of equipment

[SOURCE: ISO 11139:2018, 3.252]

6  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


3.32
specify
stipulate in detail within an approved document

[SOURCE: ISO 11139:2018, 3.259]

3.33
sterilant
chemical or combination of chemicals used to generate a sterilizing agent (3.40)

Note 1 to entry: The sterilant usually contains stabilizers, e.g. alcohols.

[SOURCE: ISO 11139:2018, 3.268, modified — Note 1 to entry has been added.]

3.34
sterilant/sterilizing agent injection
introduction of sterilant/sterilizing agent into the evacuated chamber until the set operating pressure
has been attained or the specified quantity of sterilant/sterilizing agent has been delivered

[SOURCE: ISO 11139:2018, 3.269]

3.35
sterile
free from viable microorganisms

[SOURCE: ISO 11139:2018, 3.271]

3.36
sterility
state of being free from viable microorganisms

Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be proven.

[SOURCE: ISO 11139:2018, 3.274, modified — Note 1 to entry has been added.]

3.37
sterilization
process used to render product (3.25) free from viable microorganisms

Note 1 to entry: In a sterilization process (3.39), the nature of microbial inactivation is exponential and thus the
survival of a microorganism on an individual item can be expressed in terms of probability. While this probability
can be reduced to a very low number, it can never be reduced to zero.

[SOURCE: ISO 11139:2018, 3.277]

3.38
sterilization cycle
predetermined sequence of stages performed in a sterilizer to achieve product (3.25) free of viable
microorganisms

[SOURCE: ISO 11139:2018, 3.279]

3.39
sterilization process
series of actions or operations needed to achieve the specified requirements for sterility (3.36)

Note 1 to entry: This series of actions includes pre-treatment of product (3.25) (if necessary), exposure under
defined conditions to the sterilizing agent (3.40) and any necessary post treatment. The sterilization process
does not include any cleaning, disinfection or packaging operations that precede sterilization.

[SOURCE: ISO 11139:2018, 3.284]

© ISO 2018 – All rights reserved  7

ISO 25424:2018(E)


3.40
sterilizing agent
physical or chemical entity, or combination of entities, having sufficient microbicidal activity to achieve
sterility (3.36) under defined conditions

[SOURCE: ISO 11139:2018, 3.288]

3.41
inactivation curve
graphical representation of inactivation of a population of microorganisms with increasing exposure to
a microbicidal agent under stated conditions

[SOURCE: ISO 11139:2018, 3.137]

3.42
validation
confirmation process, through the provision of objective evidence that the requirements for a specific
intended use or application have been fulfilled

Note 1 to entry: The objective evidence needed for a validation is the result of a test or other form of determination
such as performing alternative calculations or reviewing documents.

Note 2 to entry: The word “validated” is used to designate the corresponding status.

Note 3 to entry: The use conditions for validation can be real or simulated.

[SOURCE: ISO 9000:2015, 3.8.13, modified — “process” has been added to the definition.]

4 Quality management system elements

4.1 General

To ensure the consistent quality of the processes described in this document, the implementation of a
quality management system, such as ISO 13485, is advised.

Although a management system needs to be considered as a whole, the following elements should be
regarded as indispensable: documentation, management responsibility, product realization, control of
non-conforming product.

4.2 Documentation

4.2.1 Procedures for each phase of the development, validation, routine control, and product release
from sterilization shall be specified.

4.2.2 Documents and records required by this document shall be reviewed and approved by designated
personnel (see 4.3.1). Documents and records shall be controlled in accordance with an established
quality management system, such as ISO 13485.

4.3 Management responsibility

4.3.1 The responsibility and authority for implementing and performing the procedures described in
this document shall be specified. Responsibility shall be assigned to competent personnel in accordance
with an established quality management system, such as ISO 13485.

4.3.2 If the requirements of this document are undertaken by different organizations with separate
quality management systems, the responsibilities and authority of each party shall be specified.

8  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


4.4 Product realization

4.4.1 Procedures for purchasing shall be specified. These procedures shall conform to an established
quality management system, such as ISO 13485.

4.4.2 Procedures for identification and traceability of product shall be specified. These procedures
shall conform to an established quality management system, such as ISO 13485.

NOTE ISO 13485 details requirements for design reviews.

4.4.3 Procedures conforming to established quality management system such as ISO 13485 shall be
specified for the calibration or adjustment of equipment, including instrumentation for test purposes
used in meeting the requirements of this document.

4.5 Control of non-conforming product

Procedures for control of product designated as non-conforming and for correction, corrective action

and preventive action shall be specified. These procedures shall conform to an established quality
management system, such as ISO 13485.

5 Sterilizing agent characterization

5.1 General

The purpose of this activity is to define the sterilizing agent, demonstrate its microbicidal effectiveness,
identify the factors which influence microbicidal effectiveness, assess the effects that exposure to the
sterilizing agent has on materials and identify requirements for safety of personnel and protection of
the environment.

NOTE 1 The characteristics of LTSF-processes are well known after decades of practical use and
development[22][23][24][25][26][31]. Development of new processes can however necessitate new studies.

NOTE 2 If characterization studies of a sterilizing agent with a non-traditional formaldehyde mixture is
necessary, these studies can be undertaken under formal design and development controls (see ISO 13485).

5.2 Sterilizing agent

A specification for the sterilant and for the process to generate the sterilizing agent shall be generated.
This shall include, if appropriate, conditions for storage to maintain the sterilant within its specification
for the duration of any stated shelf life.

NOTE 1 For further guidance see EN 14180:2014, 10.3.

NOTE 2 The LTSF-sterilization process is a modified steam sterilization process[26]. A formaldehyde solution
(sterilant) is evaporated into a gas mixture containing steam and formaldehyde. The microbicidal activity is
achieved by the condensate film on the surface of the medical devices to be sterilized.

5.3 Microbicidal effectiveness

Data shall be available to demonstrate the microbicidal effectiveness of the sterilizing agent in the
process. The microbicidal effectiveness of LTSF and its use in processes has been comprehensively
documented and is available in the literature[22][23][24][25][31][32].

NOTE Manufacturers of sterilizers can be requested to make these data available for their customers.

© ISO 2018 – All rights reserved  9

ISO 25424:2018(E)


5.4 Material effects

The effects of low temperature steam and formaldehyde on materials, both in the sterilizer and in
products, are generally well known after decades of practical use (see, for example, References [19],
[20], [21], [28], [29] and [30]). However, when new materials are introduced, the effects of sterilizing
agent exposure with respect to material compatibility and formaldehyde residue levels after processing
shall be assessed (repeated when applicable) and documented (see also 7.4, 7.5 and 7.8).

NOTE The manufacturer of the sterilizer or of the product can be requested to supply information about any
restriction or limitation of application of the process on specific product with respect to product integrity and
residue levels of sterilizing agent (see also ISO 17664).

5.5 Environmental considerations

The potential impact on the environment of the use of formaldehyde in the sterilization process shall
be assessed and measures to protect the environment shall be identified. This assessment, including
potential impact (if any) and measures for control (if identified), shall be documented.

NOTE 1 See also Annex D.

NOTE 2 Attention is also drawn to the existence in some countries of regulations stipulating environmental
requirements.

6 Process and equipment characterization

6.1 General

The purpose of this activity is to define the entire sterilization process and the sterilizer equipment
necessary to deliver the sterilization process safely and reproducibly.

6.2 Process

6.2.1 The load shall be exposed to the sterilizing agent under defined and controlled conditions.
The process parameters, together with their tolerances, shall be established and documented. These
tolerances shall be based upon knowledge of the combination of process parameters yielding the
minimum acceptable microbicidal effectiveness and yielding acceptable product.

NOTE Minimum requirements for LTSF-sterilizers can be found in EN 14180:2014, 6.1.

6.2.2 Means of monitoring and controlling the process variables shall be determined and specified.
NOTE See EN 14180:2014, Clause 5.

6.2.3 The quality of steam used throughout the sterilization cycle shall be specified. It shall be suitable
for its intended use with regard to equipment and product.

NOTE See EN 14180:2014, 10.4.

6.2.4 Any treatment of product that is required following exposure to the sterilizing agent to ensure
the safety and functionality of the product shall be defined as part of the sterilization process and
documented.

NOTE Minimum requirements for the performance of the desorption and drying phase of the cycle can be
found in EN 14180:2014, 6.2 and 6.3.

6.2.5 The sterilization cycle shall include:
a) air removal;

10  © ISO 2018 – All rights reserved

ISO 25424:2018(E)


b) conditioning;
NOTE Conditioning can be carried out fully using sterilizing agent.

c) sterilant injection;
d) LTSF-equilibration time and holding time;
e) desorption;
f) air admission to atmospheric pressure.
NOTE For further information, see EN 14180:2014, Figure 4.

6.3 Equipment

6.3.1 The equipment to be used for LTSF sterilization shall be specified.

6.3.2 The specification shall include but is not limited to:
— description of the sterilizer equipment;

— its installation, its accessories;
— its consumables;
— other related items specified as provided with the sterilizer.
NOTE EN 14180:2014, Clause 9, specifies information to be supplied by the manufacturer of the sterilizer.

6.3.3 The conditions for storage of formaldehyde solution prior to and during use shall conform to the
specification; see 5.2.

6.3.4 Software used to control and/or monitor the process shall be prepared in accordance with a
quality management system that provides documented evidence (see 4.2.2) that the software meets its
design intention.
NOTE Attention is drawn to ISO/IEC 90003.

6.3.5 Means shall be provided to ensure that a failure in a control function does not lead to a failure in
recording of process parameters such that an ineffective process appears effective.
NOTE 1 This can be achieved either by the use of independent systems for control and monitoring, or a
crosscheck between values for process variables derived from control and monitoring, which identifies any
discrepancies and indicates a fault.
NOTE 2 EN 14180 requires independent control and recording systems.

7 Product definition

7.1 The purpose of this activity is to define the product to be sterilized, including the microbiological
quality of the product prior to sterilization and the manner in which the product is packaged and
presented for sterilization.

© ISO 2018 – All rights reserved  11

ISO 25424:2018(E)


7.2 Product definition activities shall be performed before application of the sterilization process to a
new or altered product, package or loading pattern.

A demonstration of equivalence to previously validated product, package or loading pattern shall be
deemed to conform to this requirement. Any demonstration of equivalence shall be documented.

NOTE Conforming to this requirement could necessitate appropriate written information to be provided to
the organization undertaking the sterilization process by the manufacturer of the medical device (see ISO 17664)
and/or the manufacturer of the sterilization equipment and/or the manufacturer of packaging materials.

7.3 Product and packaging shall be designed to allow removal of air and facilitate penetration of
sterilizing agent. The location within the product at which sterilization is most difficult to achieve shall
be identified.

7.4 It shall be demonstrated by assessment or tests, as applicable, that the specified sterilization
process does not affect the materials used for and/or the correct functioning of the product and its
packaging.

NOTE After decades of practical use, substantial experience is available regarding material compatibility to
LTSF[28][29][30].

7.5 For resterilization of products, the effects of repeated processing on the product and its packaging
shall be evaluated (see also ISO 17664).

7.6 A system shall be specified and maintained to ensure that the condition of the product presented
for sterilization, including microbiological, organic and inorganic contamination levels, is controlled and
does not compromise the effectiveness of the sterilization process.

7.7 The effectiveness of the system defined in accordance with 7.6 shall be demonstrated. For medical

devices to be supplied for single use, this demonstration shall include estimation of bioburden in
accordance with ISO 11737-1. For reusable medical devices, this demonstration shall include assessment
of the effectiveness of preparatory measures such as cleaning and, if applicable, disinfecting. This can
also include an assessment of any organic and inorganic contamination.

NOTE The ISO 15883 series on equipment for cleaning and disinfecting medical devices prior to sterilization
includes methods to demonstrate the effectiveness of a cleaning and disinfecting process.

7.8 The medical device manufacturer shall evaluate the formaldehyde retention characteristics of
product compared to that of the desorption efficacy indicator.

NOTE 1 EN 14180:2014, C.5, specifies the desorption efficacy indicator as a paper disc.

The results evaluation shall consider the available toxicological data.

NOTE 2 EN 14180:2014, Annex E., specifies a limit.

8 Process definition

8.1 The purpose of this activity is to obtain a detailed specification for the sterilization process
to be applied to defined product (see Clause 7) to achieve the required microbicidal efficacy, without
compromising the safety, quality and performance of that product.

8.2 The sterilization process applicable for defined product shall be established by demonstrating the
attainment of process parameters by measurements, if practical, and

a) demonstrating an overkill by using the method described in Annex B, or

12  © ISO 2018 – All rights reserved