Sterilization of health care products -- Radiation

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

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Publication Date
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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
---------------------- 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 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
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
---------------------- Page: 8 ----------------------
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
---------------------- Page: 9 ----------------------
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
---------------------- Page: 3 ----------------------
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.
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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.

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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
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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