Sterilization of health care products — Radiation — Part 4: Guidance on process control

This document provides additional guidance to that given in ISO 11137-3 on meeting the requirements specified in ISO 11137-1, ISO 11137-2 and ISO/TS 13004 for the establishment and control of a radiation sterilization process using gamma, electron beam, and X-irradiation.

Stérilisation des produits de santé — Irradiation — Partie 4: Recommandations sur le contrôle de processus

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TECHNICAL ISO/TS
SPECIFICATION 11137-4
First edition
2020-06
Sterilization of health care products —
Radiation —
Part 4:
Guidance on process control
Stérilisation des produits de santé — Irradiation —
Partie 4: Recommandations sur le contrôle de processus
Reference number
ISO/TS 11137-4:2020(E)
©
ISO 2020

---------------------- Page: 1 ----------------------
ISO/TS 11137-4:2020(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2020
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved

---------------------- Page: 2 ----------------------
ISO/TS 11137-4:2020(E)

Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms, definitions and symbols . 1
3.1 General . 1
3.2 Symbols . 3
4 Principles applied in validating and controlling an irradiation process .4
4.1 General . 4
4.2 Use of the dose measurement at the monitoring location . 4
4.2.1 General. 4
4.2.2 D as an indirect measurement of dose to product . 4
mon
4.2.3 D as a process monitor . 4
mon
4.2.4 D or D as a direct measurement of dose to product . 5
min max
4.3 Monitoring of critical process parameters . 5
5 Establishing process target doses . 6
5.1 Inputs and steps in establishing a process target dose . 6
5.1.1 General. 6
5.1.2 Process validation inputs (installation, operational and performance
qualification) . 7
5.1.3 Additional inputs . 7
5.1.4 Determine σ . 7
process
5.1.5 Product dose specifications . 8
5.1.6 Select coverage factor k . 8
5.1.7 Setting process target doses . 8
5.1.8 Analyse process output . 8
5.1.9 Review . . 8
5.2 Performance qualification outputs . 8
5.2.1 General. 8
5.2.2 Experimental design for PQ. 9
5.2.3 Processing categories . 9
5.3 Components of σ .10
process
5.3.1 General.10
5.3.2 Components related to measurement uncertainty .11
5.3.3 Components related to process variability .12
5.3.4 Combining components of uncertainty .13
5.3.5 Reducing σ .13
process
5.4 Establishing process target doses .16
5.4.1 Coverage factors .16
5.4.2 Process factors .17
5.4.3 Choice of target processing parameters .17
5.4.4 Assessing process capability .18
6 Routine monitoring and control .18
6.1 General .18
6.2 Product handling .19
6.2.1 Receipt of product .19
6.2.2 Loading .19
6.2.3 Unloading .19
6.2.4 Storage .20
6.2.5 Shipment .20
6.3 Processing of product .20
6.3.1 General.20
© ISO 2020 – All rights reserved iii

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ISO/TS 11137-4:2020(E)

6.3.2 Processing parameters .20
6.3.3 Location of dosimeters .21
6.3.4 Partially filled containers .21
6.3.5 Process interruptions .21
6.3.6 Transitions between densities .22
6.4 Special processing conditions .22
6.4.1 Off-carrier processing .22
6.4.2 Irradiation of product under modified environmental conditions .22
6.5 Process output interpretation .24
6.5.1 General.24
ster max,acc
6.5.2 Using an acceptance range based on D and D .24
mon mon
6.5.3 Using an acceptance range with alert and action levels .24
6.5.4 Using an acceptance range based on process monitoring .25
6.5.5 Investigation of a dose measurement outside of expectation .26
6.6 Collection and analysis of data .27
6.6.1 General.27
6.6.2 Dosimeter data trending .27
6.6.3 Parametric data trending .28
6.6.4 Statistical process control .29
7 Release of product from the irradiation process .30
8 Maintaining process effectiveness .31
8.1 General .31
8.2 Assessment of changes made to the product .31
8.3 Assessment of changes made to the equipment .31
Annex A (informative) Examples of setting process target dose ranges and interpretation of
process output .32
Bibliography .55
iv © ISO 2020 – All rights reserved

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ISO/TS 11137-4:2020(E)

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/ patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/
iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.
A list of all parts in the ISO 11137 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
© ISO 2020 – All rights reserved v

---------------------- Page: 5 ----------------------
ISO/TS 11137-4:2020(E)

Introduction
ISO 11137-1 describes the requirements for the development, validation and routine control of a
radiation sterilization process, and ISO 11137-3 gives guidance on dosimetric requirements in all stages
of this development, validation and control. The purpose of ISO/TS 11137-4 is to provide additional
guidance on the establishment and control of the irradiation process, including setting process target
doses and verifying that the process is in a state of control.
This document addresses the establishment of methods to set process target doses and verify the
process is in a state of control. Dosimetry is used during the validation of a radiation sterilization process
to measure doses, and the interpretation of dosimetry results from operational and performance
qualification studies is critical in establishing a process that will meet the requirements specified for
minimum and maximum dose as outlined in ISO 11137-1, ISO 11137-2 and ISO/TS 13004.
Routine dosimetry is used to monitor that the process is in a state of control and dose specifications
have been met. One purpose of this technical specification is to provide guidance on the application of
a dose measurement as a tool used for monitoring an irradiation process using statistical techniques.
The guidance given is not normative and is not provided as a checklist for auditors. The guidance
provides explanations and methods that are regarded as being suitable means for achieving conformity
with the minimum and maximum dose specifications. Methods other than those given in the guidance
may be used, if they are effective in achieving conformity with the requirements of ISO 11137-1,
ISO 11137-2 and ISO/TS 13004.
vi © ISO 2020 – All rights reserved

---------------------- Page: 6 ----------------------
TECHNICAL SPECIFICATION ISO/TS 11137-4:2020(E)
Sterilization of health care products — Radiation —
Part 4:
Guidance on process control
1 Scope
This document provides additional guidance to that given in ISO 11137-3 on meeting the requirements
specified in ISO 11137-1, ISO 11137-2 and ISO/TS 13004 for the establishment and control of a radiation
sterilization process using gamma, electron beam, and X-irradiation.
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 11137-1:2006, Sterilization of health care products — Radiation — Part 1: Requirements for
development, validation and routine control of a sterilization process for medical devices
ISO 11137-3:2017, Sterilization of health care products — Radiation — Part 3: Guidance on dosimetric
aspects of development, validation and routine control
3 Terms, definitions and symbols
For the purposes of this document, the terms and definitions given in ISO 11137-1, ISO 11137-3 and the
following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at http:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1 General
3.1.1
acceptance range
range within which the statistic under consideration lies with a specified probability when the process
is in a state of control
3.1.2
action level
value from monitoring that necessitates immediate intervention
[SOURCE: ISO 11139:2018, 3.5]
3.1.3
alert level
value from monitoring providing early warning of deviation from specified conditions
Note 1 to entry: An alert level value provides early warning of a potential deviation for a process under control.
Although further action is not required, increased supervision of the process is recommended.
© ISO 2020 – All rights reserved 1

---------------------- Page: 7 ----------------------
ISO/TS 11137-4:2020(E)

[SOURCE: ISO 11139:2018, 3.11, modified — Note 1 to entry has been added.]
3.1.4
cycle time
period of time an irradiation container spends in each dwell position in a gamma process, used as a
control parameter for dose
Note 1 to entry: Cycle time can also apply to x-ray and could also include the time required to move between
dwell positions.
[SOURCE: ISO 11139:2018, 3.73, modified — Note 1 to entry has been added.]
3.1.5
influence quantity
quantity that, in a direct measurement, does not affect the quantity that is actually measured, but
affects the relation between the indication and the measurement result
Note 1 to entry: In radiation processing dosimetry, this term includes temperature, relative humidity, time
intervals, light, radiation energy, absorbed-dose rate, and other factors that might affect dosimeter response, as
well as quantities associated with the measurement instrument.
[SOURCE: VIM 2012, 2.52, modified — Note 1 to entry added from ISO/ASTM 52701:2013.]
3.1.6
measurement uncertainty
parameter, associated with the result of a measurement, that characterizes the dispersion of the values
that could reasonably be attributed to the measurand
3.1.7
process control
specific activities to ensure process requirements are achieved
[SOURCE: ISO 11139:2018, 3.209]
3.1.8
process load
volume of material with a specified product loading configuration irradiated as a single entity
Note 1 to entry: The process load consists of one or more irradiation containers.
[SOURCE: ISO/ASTM 52303:2015, 3.1.10]
3.1.9
process target dose
D
target
dose, at a specified monitoring location, which the irradiation process parameters are set to deliver
3.1.10
process variability
measure of factors that result in a random distribution of data around the average that provides
information on how well the process can perform when all special cause variation is removed
3.1.11
Statistical Process Control
SPC
set of techniques for improving the quality of process output by reducing variability through the use of
one or more control charts and a corrective action strategy used to bring the process back into a state
of statistical control
[SOURCE: ASTM E2587-16]
2 © ISO 2020 – All rights reserved

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ISO/TS 11137-4:2020(E)

3.1.12
targeting buffer
standard factor or factors used to determine process target doses which has been demonstrated to be
more conservative calculated values of UF and UF during historical routine processing
lower upper
3.2 Symbols
Symbol Meaning
D direct measurement of minimum dose in a given irradiation container
min
D direct measurement of maximum dose in a given irradiation container
max
D direct measurement of dose at the routine monitoring position
mon
D Sterilization dose determined in accordance with
ster
ISO 11137-1:2006, 8.2
D maximum acceptable dose determined in accordance with
max,acc
ISO 11137-1:2006, 8.1
limit
D = D * UF calculated dose at the minimum dose position used for establishing
min ster lower
process parameters that ensures at a specified level of confidence that
D is met or exceeded during routine processing
ster
limit
D = D * UF calculated dose at the maximum dose position used for establishing
max max,acc upper
process parameters that ensures at a specified level of confidence that
D is not exceeded during routine processing
max,acc
min lower limit
UF = 1/(1 ‒ k * σ /100) process factor used to calculate D and D
lower process target min
min
(where σ is expressed as a percentage)
process
max upper limit
UF = 1/(1 + k * σ /100) process factor used to calculate D and D
upper process target max
max
(where σ is expressed as a percentage)
process
R = D / D ratio of minimum to monitor dose determined by dose mapping
min/mon min mon
R = D / D ratio of maximum to monitor dose determined by dose mapping
max/mon max mon
ster
D = D /R dose at the monitoring position that correlates to the sterilization dose
mon ster min/mon
specification
max,acc
D = D /R dose at the monitoring position that correlates to maximum acceptable
mon max,acc max/mon
dose specification
lower limit
D = D / R calculated dose at the routine monitoring position used for establishing
target min min/mon
process parameters that ensures at a specified level of confidence that
D is met or exceeded during routine processing
ster
upper limit
D = D / R calculated dose at the routine monitoring position used for establishing
target max max/mon
process parameters that ensures at a specified level of confidence that
D is not exceeded during routine processing
max,acc
σ component of uncertainty related to the calibration of the dosimetry
cal
system including the uncertainty reported by the calibration laborato-
ry, uncertainty in the mathematical fit of the calibration function, and
uncertainties due to influence quantities, but excluding components due
to the reproducibility of the dosimeter measurement (see σ )
rep
σ component of variability related to the radiation source and convey-
mach
or system
σ component of variability measured during a dose mapping exercise
map
σ standard deviation associated with the irradiation process used for
process
setting process target doses
max
   σ — The standard deviation associated with the process
process
                 maximum dose
min
   σ — The standard deviation associated with the process
process
                 minimum dose
σ component of variability associated with the reproducibility of the
rep
dosimeter measurement
© ISO 2020 – All rights reserved 3

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ISO/TS 11137-4:2020(E)

4 Principles applied in validating and controlling an irradiation process
4.1 General
Many dose measurements are made in the validation of an irradiation process as described in
ISO 11137-1 and ISO 11137-3. These measurements are used to establish a relationship between
processing parameters, monitoring dose, and the range of doses to a product, and to characterize the
variability associated with the process itself. These measurements are made with calibrated dosimetry
systems traceable to internationally recognized standards with a known level of uncertainty.
It is a requirement to monitor that the validated radiation sterilization process is in a state of control.
ISO 11137-1:2006, 10.6 requires the use of dosimeters in routine monitoring and control and provides
guidance on the additional review of monitoring of process parameters when determining that product
has been processed according to specification.
The combination of dose measurements, monitoring of the associated processing parameters used to
achieve those doses, and procedural controls are critical in establishing a process and determining
whether or not it is in a state of control.
4.2 Use of the dose measurement at the monitoring location
4.2.1 General
Analysis of measurements from routine monitoring dosimeters is used to determine whether or not
process specifications have been met. There are two methods of analysis that can be considered:
1) interpretation of dose measurements as a direct or indirect measure of dose delivered to
product; and
2) interpretation of dose measurements to monitor that a process is in a state of control.
In all cases, a validated process provides an expectation of the monitored dose based on derived process
target doses and associated processing parameters. The interpretation of the monitoring dose should
be documented in the process specification.
The ability to detect changes in the process is limited by the intrinsic variability of dose at the routine
monitoring location i.e. the variability measured when the process is in control. If σ of the monitoring
rep
dosimetry system is large or dosimeter placement imprecise, this variability might be significantly
higher than the true variability of the process. In such circumstances, significant changes in the process
could go undetected, because they are masked by the high intrinsic variability at the monitoring
location. Steps should be taken to minimise variability arising from the monitoring dosimetry system
and dosimeter placement. See 6.5.4 and Annex A, Example 3.
4.2.2 D as an indirect measurement of dose to product
mon
In an indirect measurement, the maximu
...

TECHNICAL ISO/TS
SPECIFICATION 11137-4
First edition
Sterilization of health care products —
Radiation —
Part 4:
Guidance on process control
Stérilisation des produits de santé — Irradiation —
Partie 4: Recommandations sur le contrôle de processus
PROOF/ÉPREUVE
Reference number
ISO/TS 11137-4:2020(E)
©
ISO 2020

---------------------- Page: 1 ----------------------
ISO/TS 11137-4:2020(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2020
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii PROOF/ÉPREUVE © ISO 2020 – All rights reserved

---------------------- Page: 2 ----------------------
ISO/TS 11137-4:2020(E)

Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms, definitions and symbols . 1
3.1 General . 1
3.2 Symbols . 3
4 Principles applied in validating and controlling an irradiation process .4
4.1 General . 4
4.2 Use of the dose measurement at the monitoring location . 4
4.2.1 General. 4
4.2.2 D as an indirect measurement of dose to product . 4
mon
4.2.3 D as a process monitor . 4
mon
4.2.4 D or D as a direct measurement of dose to product . 5
min max
4.3 Monitoring of critical process parameters . 5
5 Establishing process target doses . 6
5.1 Inputs and steps in establishing a process target dose . 6
5.1.1 General. 6
5.1.2 Process validation inputs (installation, operational and performance
qualification) . 7
5.1.3 Additional inputs . 7
5.1.4 Determine σ . 7
process
5.1.5 Product dose specifications . 8
5.1.6 Select coverage factor k . 8
5.1.7 Setting process target doses . 8
5.1.8 Analyse process output . 8
5.1.9 Review . . 8
5.2 Performance qualification outputs . 8
5.2.1 General. 8
5.2.2 Experimental design for PQ. 9
5.2.3 Processing categories . 9
5.3 Components of σ .10
process
5.3.1 General.10
5.3.2 Components related to measurement uncertainty .11
5.3.3 Components related to process variability .12
5.3.4 Combining components of uncertainty .13
5.3.5 Reducing σ .13
process
5.4 Establishing process target doses .16
5.4.1 Coverage factors .16
5.4.2 Process factors .17
5.4.3 Choice of target processing parameters .17
5.4.4 Assessing process capability .18
6 Routine monitoring and control .18
6.1 General .18
6.2 Product handling .19
6.2.1 Receipt of product .19
6.2.2 Loading .19
6.2.3 Unloading .19
6.2.4 Storage .20
6.2.5 Shipment .20
6.3 Processing of product .20
6.3.1 General.20
© ISO 2020 – All rights reserved PROOF/ÉPREUVE iii

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ISO/TS 11137-4:2020(E)

6.3.2 Processing parameters .20
6.3.3 Location of dosimeters .21
6.3.4 Partially filled containers .21
6.3.5 Process interruptions .21
6.3.6 Transitions between densities .22
6.4 Special processing conditions .22
6.4.1 Off-carrier processing .22
6.4.2 Irradiation of product under modified environmental conditions .22
6.5 Process output interpretation .24
6.5.1 General.24
ster max,acc
6.5.2 Using an acceptance range based on D and D .24
mon mon
6.5.3 Using an acceptance range with alert and action levels .24
6.5.4 Using an acceptance range based on process monitoring .25
6.5.5 Investigation of a dose measurement outside of expectation .26
6.6 Collection and analysis of data .27
6.6.1 General.27
6.6.2 Dosimeter data trending .27
6.6.3 Parametric data trending .28
6.6.4 Statistical process control .29
7 Release of product from the irradiation process .30
8 Maintaining process effectiveness .31
8.1 General .31
8.2 Assessment of changes made to the product .31
8.3 Assessment of changes made to the equipment .31
Annex A (informative) Examples of setting process target dose ranges and interpretation of
process output .32
Bibliography .55
iv PROOF/ÉPREUVE © ISO 2020 – All rights reserved

---------------------- Page: 4 ----------------------
ISO/TS 11137-4:2020(E)

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/ patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation 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.
A list of all parts in the ISO 11137 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
© ISO 2020 – All rights reserved PROOF/ÉPREUVE v

---------------------- Page: 5 ----------------------
ISO/TS 11137-4:2020(E)

Introduction
ISO 11137-1 describes the requirements for the development, validation and routine control of a
radiation sterilization process, and ISO 11137-3 gives guidance on dosimetric requirements in all stages
of this development, validation and control. The purpose of ISO/TS 11137-4 is to provide additional
guidance on the establishment and control of the irradiation process, including setting process target
doses and verifying that the process is in a state of control.
This document addresses the establishment of methods to set process target doses and verify the
process is in a state of control. Dosimetry is used during the validation of a radiation sterilization process
to measure doses, and the interpretation of dosimetry results from operational and performance
qualification studies is critical in establishing a process that will meet the requirements specified for
minimum and maximum dose as outlined in ISO 11137-1, ISO 11137-2 and ISO/TS 13004.
Routine dosimetry is used to monitor that the process is in a state of control and dose specifications
have been met. One purpose of this technical specification is to provide guidance on the application of
a dose measurement as a tool used for monitoring an irradiation process using statistical techniques.
The guidance given is not normative and is not provided as a checklist for auditors. The guidance
provides explanations and methods that are regarded as being suitable means for achieving conformity
with the minimum and maximum dose specifications. Methods other than those given in the guidance
may be used, if they are effective in achieving conformity with the requirements of ISO 11137-1,
ISO 11137-2 and ISO/TS 13004.
vi PROOF/ÉPREUVE © ISO 2020 – All rights reserved

---------------------- Page: 6 ----------------------
TECHNICAL SPECIFICATION ISO/TS 11137-4:2020(E)
Sterilization of health care products — Radiation —
Part 4:
Guidance on process control
1 Scope
This document provides additional guidance to that given in ISO 11137-3 on meeting the requirements
specified in ISO 11137-1, ISO 11137-2 and ISO/TS 13004 for the establishment and control of a radiation
sterilization process using gamma, electron beam, and X-irradiation.
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 11137-1:2006, Sterilization of health care products — Radiation — Part 1: Requirements for
development, validation and routine control of a sterilization process for medical devices
ISO 11137-3:2017, Sterilization of health care products — Radiation — Part 3: Guidance on dosimetric
aspects of development, validation and routine control
3 Terms, definitions and symbols
For the purposes of this document, the terms and definitions given in ISO 11137-1, ISO 11137-3 and the
following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at http:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1 General
3.1.1
acceptance range
range within which the statistic under consideration lies with a specified probability when the process
is in a state of control
3.1.2
action level
value from monitoring that necessitates immediate intervention
[SOURCE: ISO 11139:2018, 3.5]
3.1.3
alert level
value from monitoring providing early warning of deviation from specified conditions
Note 1 to entry: An alert level value provides early warning of a potential deviation for a process under control.
Although further action is not required, increased supervision of the process is recommended.
© ISO 2020 – All rights reserved PROOF/ÉPREUVE 1

---------------------- Page: 7 ----------------------
ISO/TS 11137-4:2020(E)

[SOURCE: ISO 11139:2018, 3.11, modified — Note 1 to entry has been added.]
3.1.4
cycle time
period of time an irradiation container spends in each dwell position in a gamma process, used as a
control parameter for dose
Note 1 to entry: Cycle time can also apply to x-ray and could also include the time required to move between
dwell positions.
[SOURCE: ISO 11139:2018, 3.73, modified — Note 1 to entry has been added.]
3.1.5
influence quantity
quantity that, in a direct measurement, does not affect the quantity that is actually measured, but
affects the relation between the indication and the measurement result
Note 1 to entry: In radiation processing dosimetry, this term includes temperature, relative humidity, time
intervals, light, radiation energy, absorbed-dose rate, and other factors that might affect dosimeter response, as
well as quantities associated with the measurement instrument.
[SOURCE: VIM 2012, 2.52, modified — Note 1 to entry added from ISO/ASTM 52701:2013.]
3.1.6
measurement uncertainty
parameter, associated with the result of a measurement, that characterizes the dispersion of the values
that could reasonably be attributed to the measurand
3.1.7
process control
specific activities to ensure process requirements are achieved
[SOURCE: ISO 11139:2018, 3.209]
3.1.8
process load
volume of material with a specified product loading configuration irradiated as a single entity
Note 1 to entry: The process load consists of one or more irradiation containers.
[SOURCE: ISO/ASTM 52303:2015, 3.1.10]
3.1.9
process target dose
D
target
dose, at a specified monitoring location, which the irradiation process parameters are set to deliver
3.1.10
process variability
measure of factors that result in a random distribution of data around the average that provides
information on how well the process can perform when all special cause variation is removed
3.1.11
Statistical Process Control
SPC
set of techniques for improving the quality of process output by reducing variability through the use of
one or more control charts and a corrective action strategy used to bring the process back into a state
of statistical control
[SOURCE: ASTM E2587-16]
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ISO/TS 11137-4:2020(E)

3.1.12
targeting buffer
standard factor or factors used to determine process target doses which has been demonstrated to be
more conservative calculated values of UF and UF during historical routine processing
lower upper
3.2 Symbols
Symbol Meaning
D direct measurement of minimum dose in a given irradiation container
min
D direct measurement of maximum dose in a given irradiation container
max
D direct measurement of dose at the routine monitoring position
mon
D Sterilization dose determined in accordance with
ster
ISO 11137-1:2006, 8.2
D maximum acceptable dose determined in accordance with
max,acc
ISO 11137-1:2006, 8.1
limit
D = D * UF calculated dose at the minimum dose position used for establishing
min ster lower
process parameters that ensures at a specified level of confidence that
D is met or exceeded during routine processing
ster
limit
D = D * UF calculated dose at the maximum dose position used for establishing
max max,acc upper
process parameters that ensures at a specified level of confidence that
D is not exceeded during routine processing
max,acc
min lower limit
UF = 1/(1 ‒ k * σ /100) process factor used to calculate D and D
lower process target min
min
(where σ is expressed as a percentage)
process
max upper limit
UF = 1/(1 + k * σ /100) process factor used to calculate D and D
upper process target max
max
(where σ is expressed as a percentage)
process
R = D / D ratio of minimum to monitor dose determined by dose mapping
min/mon min mon
R = D / D ratio of maximum to monitor dose determined by dose mapping
max/mon max mon
ster
D = D /R dose at the monitoring position that correlates to the sterilization dose
mon ster min/mon
specification
max,acc
D = D /R dose at the monitoring position that correlates to maximum acceptable
mon max,acc max/mon
dose specification
lower limit
D = D / R calculated dose at the routine monitoring position used for establishing
target min min/mon
process parameters that ensures at a specified level of confidence that
D is met or exceeded during routine processing
ster
upper limit
D = D / R calculated dose at the routine monitoring position used for establishing
target max max/mon
process parameters that ensures at a specified level of confidence that
D is not exceeded during routine processing
max,acc
σ component of uncertainty related to the calibration of the dosimetry
cal
system including the uncertainty reported by the calibration laborato-
ry, uncertainty in the mathematical fit of the calibration function, and
uncertainties due to influence quantities, but excluding components due
to the reproducibility of the dosimeter measurement (see σ )
rep
σ component of variability related to the radiation source and convey-
mach
or system
σ component of variability measured during a dose mapping exercise
map
σ standard deviation associated with the irradiation process used for
process
setting process target doses
max
   σ — The standard deviation associated with the process
process
                 maximum dose
min
   σ — The standard deviation associated with the process
process
                 minimum dose
σ component of variability associated with the reproducibility of the
rep
dosimeter measurement
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ISO/TS 11137-4:2020(E)

4 Principles applied in validating and controlling an irradiation process
4.1 General
Many dose measurements are made in the validation of an irradiation process as described in
ISO 11137-1 and ISO 11137-3. These measurements are used to establish a relationship between
processing parameters, monitoring dose, and the range of doses to a product, and to characterize the
variability associated with the process itself. These measurements are made with calibrated dosimetry
systems traceable to internationally recognized standards with a known level of uncertainty.
It is a requirement to monitor that the validated radiation sterilization process is in a state of control.
ISO 11137-1:2006, 10.6 requires the use of dosimeters in routine monitoring and control and provides
guidance on the additional review of monitoring of process parameters when determining that product
has been processed according to specification.
The combination of dose measurements, monitoring of the associated processing parameters used to
achieve those doses, and procedural controls are critical in establishing a process and determining
whether or not it is in a state of control.
4.2 Use of the dose measurement at the monitoring location
4.2.1 General
Analysis of measurements from routine monitoring dosimeters is used to determine whether or not
process specifications have been met. There are two methods of analysis that can be considered:
1) interpretation of dose measurements as a direct or indirect measure of dose delivered to
product; and
2) interpretation of dose measurements to monitor that a process is in a state of control.
In all cases, a validated process provides an expectation of the monitored dose based on derived process
target doses and associated processing parameters. The interpretation of the monitoring dose should
be documented in the process specification.
The ability to detect changes in the process is limited by the intrinsic variability of dose at the routine
monitoring location i.e. the variability measured when the process is in control. If σ of the monitoring
rep
dosimetry system is large or dosimeter placement imprecise, this variability might be significantly
higher than the true variability of the process. In such circumstances, significant changes in the process
could go undetected, because they are masked by the high intrinsic variability at the monitoring
location. Steps should be taken to minimise variability arising from the monitoring dosimetry system
and dosi
...

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