ISO 24190:2023

Biotechnology — Analytical methods — Risk-based approach for method selection and validation for rapid microbial detection in bioprocesses

This document provides guidance, a framework and a risk-based approach for the selection and validation of methods for rapid microbial detection in cellular therapeutic product manufacturing. This document provides a flexible risk-based framework for the detection of microbial contamination in cellular therapeutic products and cellular intermediates. This document provides general requirements and risks associated with cellular therapeutic product manufacturing, with flexibility to address differences in specific manufacturing processes of each unique cellular therapeutic product. This document primarily addresses sterility testing in cellular therapeutic product manufacturing. This document is applicable to other cell-derived therapeutic product manufacturing. This document focuses on rapid microbial test methods (RMTMs) used for both in-process and final product testing. Viral testing in cellular therapeutic product manufacturing is not included in this document.

Biotechnologie — Méthodes d'analyse — Approche basée sur les risques pour la sélection et la validation de méthodes pour la détection microbienne rapide dans les bioprocédés

General Information

• Status: Published
• Publication Date: 30-May-2023
• ICS: 07.080 - Biology. Botany. Zoology
• Technical Committee: ISO/TC 276 - Biotechnology
• Drafting Committee: ISO/TC 276/WG 3 - Analytical methods
• Current Stage: 6060 - International Standard published
• Start Date: 31-May-2023
• Due Date: 11-Jun-2023
• Completion Date: 31-May-2023

Standards Content (Sample)

INTERNATIONAL ISO
STANDARD 24190
First edition
2023-05
Biotechnology — Analytical methods
— Risk-based approach for method
selection and validation for rapid
microbial detection in bioprocesses
Biotechnologie — Méthodes d'analyse — Approche basée sur
les risques pour la sélection et la validation de méthodes pour la
détection microbienne rapide dans les bioprocédés
Reference number
ISO 24190:2023(E)
© ISO 2023

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ISO 24190:2023(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2023
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: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii
  © ISO 2023 – All rights reserved

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ISO 24190:2023(E)
Contents Page
Foreword .v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations .7
5 Risk management for microbiological contamination. 7
5.1 Risk management in manufacturing process . 7
5.2 Risk management in microbial testing . 8
6 Selection of a fit-for-purpose assay .9
6.1 General . 9
6.2 Assay selection . 10
6.3 Kit or system selection . 10
6.4 Considerations for various test types . 11
6.5 User requirement specifications .12
6.5.1 General .12
6.5.2 Speed .12
6.5.3 Sample volume .12
6.5.4 In-process versus final release testing .12
6.5.5 Specificity . 12
6.5.6 Sensitivity . 13
7 Validation . .13
7.1 General concepts . 13
7.2 Selection of microorganisms for validation . 14
7.3 Quality by design of method validation . 15
7.4 Revalidation method . 15
7.5 System validation . 16
7.6 Use of reference material in validation . 16
7.7 Acceptance criteria of targeted validation parameters . 16
7.8 Precision . . . 17
7.9 Detection limit . 17
7.10 Accuracy . 17
7.11 Robustness . 18
7.12 Ruggedness . 18
8 Use and application of rapid microbial tests .18
8.1 Number and type of samples . 18
8.2 Testing environment . 18
8.3 Sensitivity . 19
8.4 Analytical specificity (microorganism detection) . 19
8.5 Comparable test data . 19
9 Investigation of positive sterility results .20
10 Training .20
11 Documentation .21
12 Test report .21
Annex A (informative) Exemplary framework for identifying microbial contamination .22
Annex B (informative) Risk analysis with cellular therapeutic products related to input
materials — Donor selection .23
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ISO 24190:2023(E)
Annex C (informative) Risk analysis with cellular therapeutic products related to input
materials — Cell transformation and expansion .24
Annex D (informative) Risk analysis with cellular therapeutic products related to input
materials — Packaging storage and administration .26
Annex E (informative) Risk-based classification for monitoring practices for cellular
therapeutic product manufacturing .27
Annex F (informative) Validation of rapid microbial test methods .28
Annex G (informative) Microorganisms for validation of rapid microbial test methods .30
Annex H (informative) Methods for rapid microbial testing .34
Annex I (informative) Environmental control .41
Bibliography .42
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ISO 24190:2023(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 document should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use
of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed
patent rights in respect thereof. As of the date of publication of this document, ISO had not received
notice of (a) patent(s) which may be required to implement this document. However, implementers are
cautioned that this may not represent the latest information, which may be obtained from the patent
database available at www.iso.org/patents. ISO shall not be held responsible for identifying any or all
such patent rights.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO’s adherence to
the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 276, Biotechnology.
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.
v
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ISO 24190:2023(E)
Introduction
Patient safety is essential in providing cell-based therapies. However, novel cell-based therapies
present many challenges with respect to the timely assessment of microbial contamination. Since
many cell-based therapies have short shelf lives, they are administered to patients within hours after
formulation. In addition to final product testing, testing on cell banks and product intermediates is
common. Microbiological testing includes bacteria, fungi, mycoplasma and viral adventitious agents.
Culture-based testing methods (e.g. pharmacopeia methods) have been widely adopted by industry.
However, culture-based testing methods can take days to weeks to obtain a result. More rapid methods
for microbiological testing are needed to ensure patient safety prior to product administration. The
development and use of rapid, validated methods that are sensitive and accurate, and that allow for the
detection of a broad range of microorganisms are therefore desired and supported by this document.
vi
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INTERNATIONAL STANDARD ISO 24190:2023(E)
Biotechnology — Analytical methods — Risk-based
approach for method selection and validation for rapid
microbial detection in bioprocesses
1 Scope
This document provides guidance, a framework and a risk-based approach for the selection and
validation of methods for rapid microbial detection in cellular therapeutic product manufacturing.
This document provides a flexible risk-based framework for the detection of microbial contamination
in cellular therapeutic products and cellular intermediates.
This document provides general requirements and risks associated with cellular therapeutic product
manufacturing, with flexibility to address differences in specific manufacturing processes of each
unique cellular therapeutic product.
This document primarily addresses sterility testing in cellular therapeutic product manufacturing.
This document is applicable to other cell-derived therapeutic product manufacturing.
This document focuses on rapid microbial test methods (RMTMs) used for both in-process and final
product testing.
Viral testing in cellular therapeutic product manufacturing is not included in this document.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
acceptance criteria
numerical limits, ranges, or other attributes or variables meeting predefined performance for the
assays described
Note 1 to entry: Acceptance criteria are specified by the user requirement specifications (3.30).
3.2
accuracy
measurement accuracy
closeness of agreement between a measured quantity value and an assigned quantity value of a
measurand
Note 1 to entry: The concept “measurement accuracy” is not a quantity and is not given a numerical quantity
value. A measurement is said to be more accurate when it offers a smaller measurement error.
1
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ISO 24190:2023(E)
Note 2 to entry: The term “measurement accuracy” should not be used for measurement trueness and the term
measurement precision should not be used for “measurement accuracy”, which, however, is related to both these
concepts.
Note 3 to entry: “Measurement accuracy” is sometimes understood as closeness of agreement between measured
quantity values that are being attributed to the measurand.
[SOURCE: ISO 16140-1:2016, 2.2]
3.3
analytical sensitivity
quotient of the change in measurement indication and the corresponding change in value of a quantity
being measured
Note 1 to entry: Analytical sensitivity should not be used to mean detection limit (3.8) or quantitation limit and
should not be confused with diagnostic sensitivity (3.9).
[SOURCE: ISO 18113-1:2022, 3.2.4, modified — Admitted term “sensitivity of a measurement procedure”
deleted. Notes 1 to 3 to entry deleted. Note 4 to entry renumbered as Note 1 to entry.]
3.4
analytical specificity
capability of a measuring system, using a specified measurement procedure, to provide measurement
results for one or more measurands which do not depend on each other nor on any other quantity in the
system undergoing measurement
Note 1 to entry: Lack of analytical specificity is called analytical interference.
Note 2 to entry: Analytical specificity should not be confused with diagnostic specificity (3.10).
Note 3 to entry: ISO/IEC Guide 99:2007 uses the term “selectivity” for this concept instead of “specificity”.
[SOURCE: ISO 18113-1:2022, 3.2.5, modified — Admitted term “selectivity of a measurement procedure”
deleted. Notes to entry replaced.]
3.5
aseptic
conditions and procedures used to exclude the introduction of microbial contamination
[SOURCE: ISO 18362:2016, 3.3, modified — “aseptic” replaced “aseptic technique” as the term.]
3.6
cellular therapeutic product
product containing cells as the active substance
EXAMPLE Cell and gene therapy products, tissue engineered products, drug products.
Note 1 to entry: Products produced from cells for gene therapies are included in the definition of cellular
therapeutic product, as cells are not necessarily the active substance for all gene therapies.
Note 2 to entry: Recombinant proteins are not included in this definition of cellular therapeutic product.
[SOURCE: ISO 20399:2022, 3.9, modified — “used for cell therapy or gene therapy” deleted from the
definition.]
3.7
design qualification
DQ
process for verification (3.32) that the proposed specification for the facility, equipment or system of
the assay meets the expectation for the user requirement specifications (URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.1, modified — Abbreviated term “DQ” and “of the assay” added. “user
requirement specifications (URS)” replaced “intended use”.]
2
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ISO 24190:2023(E)
3.8
detection limit
limit of detection
measured quantity value, obtained by a given measurement procedure, for which the probability of
falsely claiming the absence of a component in a material is β, given a probability α of falsely claiming
its presence
Note 1 to entry: IUPAC recommends default values for α and β equal to 0,05.
Note 2 to entry: The abbreviation LOD is sometimes used.
Note 3 to entry: The term “sensitivity” is discouraged for “detection limit”.
[SOURCE: ISO/IEC Guide 99:2007, 4.18]
3.9
diagnostic sensitivity
ability of an in vitro diagnostic examination procedure to identify the presence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent positivity in samples where the target marker is known to be present.
Note 2 to entry: Diagnostic sensitivity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 × the number of true positive values (TP) divided by the sum of the number of true positive
values (TP) plus the number of false negative values (FN), or 100 × TP/(TP + FN). This calculation is based on a
study design where only one sample is taken from each subject.
Note 3 to entry: For microbial detection, diagnostic sensitivity represents the fraction of target organisms that
were detected correctly.
[SOURCE: ISO 18113-1:2022, 3.2.17, modified — “identify the presence of a target marker” replaced
“have positive results”. Second sentence of Note 1 to entry deleted. Note 3 to entry replaced.]
3.10
diagnostic specificity
ability of an in vitro diagnostic examination procedure to recognize the absence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent negativity in samples where the target marker is known to be absent.
Note 2 to entry: Diagnostic specificity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 × the number of true negative values (TN) divided by the sum of the number of true negative
values (TN) plus the number of false positive values (FP), or 100 × TN/(TN+FP). This calculation is based on a
study design where only one sample is taken from each subject.
[SOURCE: ISO 18113-1:2022, 3.2.18, modified — “recognize the absence of a target marker associated
with a” replaced “have negative results associated with an absence of”. Second sentence of Note 1 to
entry deleted. Note 3 to entry deleted.]
3.11
false negative
result indicated by the test method to be negative (3.15) which has subsequently been shown to contain
the target microorganisms
[SOURCE: ISO 13843:2017, 3.14, modified — “microorganisms” replaced “organism”.]
3.12
false positive
result indicated by the test method to be positive (3.19) which was subsequently shown not to contain
the target microorganisms
[SOURCE: ISO 13843:2017, 3.15, modified — “microorganisms” replaced “organism”.]
3
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ISO 24190:2023(E)
3.13
fit for purpose
in line with prearranged requirements for an intended use
[SOURCE: ISO 20387:2018, 3.24, modified — Admitted term “fitness for the intended purpose” and Note
1 to entry deleted.]
3.14
installation qualification
IQ
process of establishing by objective evidence that all key aspects of the process equipment and ancillary
system for the assay instrument installation comply with the approved user requirement specifications
(URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.2, modified — “for the assay instrument” added and “user requirement
specifications (URS)” replaced “specification”.]
3.15
negative
test result indicating the absence of the analyte in a given test portion as defined by the procedure of
the method
[SOURCE: ISO 16140-1:2016, 2.43, modified — “negative” replaced “negative test result” as the term.
“the absence of the analyte” replaced “the analyte was not detected” and “qualitative” deleted before
“method”.]
3.16
nucleic acid amplification techniques
NAT
biochemistry and molecular biology methods that involve the in vitro synthesis of many copies of DNA
or RNA from one original template
Note 1 to entry: NAT is characterized by existence of reverse transcription, amplification method and type of
determination (qualitative or quantitative)
Note 2 to entry: Examples of amplification methods are PCR and iso thermal amplification (NEAR, TMA, LAMP,
HAD, CRISPER, SDA)
3.17
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment operates within predetermined
limits when used in accordance with its operational procedures
[SOURCE: ISO 11139:2018, 3.220.3]
3.18
performance qualification
PQ
process of establishing by objective evidence that the assay process, under anticipated conditions,
consistently produces a result which meets all predetermined user requirement specifications (URS)
(3.30)
[SOURCE: ISO 11139:2018, 3.220.4, modified — “assay” added before “process”, “result” replaced
“product” and “user requirement specifications (URS)” replaced “requirements”.]
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ISO 24190:2023(E)
3.19
positive
test result indicating the presence of the analyte in a given test portion as defined by the procedure of
the method
Note 1 to entry: When the reference method or alternative method provides a preliminary positive test result
requiring further testing to confirm this result, this test result can be considered as a presumptive positive test
result. If the further testing specified by the method’s procedure confirms that the test result can indeed be
considered as being positive, the test result can be considered as a confirmed positive test result.
[SOURCE: ISO 16140-1:2016, 2.50, modified — “positive” replaced “positive test result” as the term.]
3.20
precision
closeness of agreement between indications or measured quantity values obtained by replicate
measurements on the same or similar objects under specified conditions
Note 1 to entry: Measurement precision is usually expressed numerically by measures of imprecision, such as
standard deviation, variance, or coefficient of variation under the specified conditions of measurement.
Note 2 to entry: The “specified conditions” can be, for example, repeatability conditions of measurement,
intermediate precision conditions of measurement, or reproducibility conditions of measurement (see
ISO 5725-1).
[SOURCE: ISO/IEC Guide 99:2007, 2.15, modified — “precision” replaced “measurement precision” as
the term. Notes 3 and 4 to entry deleted.]
3.21
qualification
activities undertaken to demonstrate that utilities, equipment and methods are suitable for their
intended use and perform properly
Note 1 to entry: Qualification of either equipment or processes, or both, generally includes installation qualification
(3.14), operational qualification (3.17) and performance qualification (3.18).
[SOURCE: ISO 11139:2018, 3.220, modified — “or modes” deleted after “methods”.]
3.22
rapid microbial test method
RMTM
analytical method that allows the user to get microbiology test results faster compared with traditional
visual observation methods using direct inoculation and culture-plating
Note 1 to entry: Generally, this means in a significantly reduced time as compared with the traditional method
(e.g. hours or days).
3.23
reference material
material, sufficiently homogeneous and stable with reference to specified properties, which has been
established to be fit for its intended use in measurement or in examination of nominal properties
[SOURCE: ISO/IEC Guide 99:2007, 5.13, modified — Abbreviated term “RM”, notes to entry and examples
deleted.]
3.24
risk assessment
overall process of risk identification, risk analysis and risk evaluation
[SOURCE: ISO Guide 73:2009, 3.4.1]
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ISO 24190:2023(E)
3.25
risk control
process in which decisions are made and measures implemented by which risks are reduced to, or
maintained within, specified levels
[SOURCE: ISO 14971:2019, 3.21]
3.26
risk-based approach
methodology that allows the prioritization of activities based on a previous analysis of data and
according to the biosafety level
3.27
robustness
measure of a test method’s capacity to remain unaffected by small, but deliberate, variations in method
parameters and to provide an indication of its reliability during normal usage
[11]
[SOURCE: ICH Q2(R1) ]
3.28
shelf life
period of time after production during which a product that is kept under specified conditions retains
its specified properties
[SOURCE: ISO 1382:2020, 3.485, modified — The term “storage life” deleted. “material or” deleted
before “product” and “that is” added.]
3.29
sterility
state of being free from viable microorganisms (3.33)
Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be proven.
[SOURCE: ISO 11139:2018, 3.274]
3.30
user requirement specifications
URS
requirements specific to a user or requirements that are not covered in general req
...

© ISO 2023 – All rights reserved
ISO/FDIS 24190:2023(E)
Date: 2023-01-0302-15
ISO/TC 276/WG 3
Secretariat: DIN
Biotechnology — Analytical methods — Risk-based approach for
method selection and validation for rapid microbial detection in
bioprocesses

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ISO/FDIS 24190:2023(E)
© ISO 2023
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-1214 Vernier, Geneva
Phone: + 41 22 749 01 11
Email: [e-mail]
Website: www.iso.org
Published in Switzerland.
ii © ISO 2023 – All rights reserved

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ISO/FDIS 24190:2023(E)
Contents
Foreword . v
Introduction. vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 7
5 Risk management for microbiological contamination . 8
5.1 Risk management in manufacturing process . 8
5.2 Risk management in microbial testing . 10
6 Selection of a fit-for-purpose assay . 10
6.1 General . 10
6.2 Assay selection . 11
6.3 Kit or system selection . 12
6.4 Considerations for various test types . 12
6.5 User requirement specifications . 13
6.5.1 General . 13
6.5.2 Speed . 13
6.5.3 Sample volume . 14
6.5.4 In-process versus final release testing . 14
6.5.5 Specificity . 14
6.5.6 Sensitivity . 14
7 Validation . 15
7.1 General concepts . 15
7.2 Selection of microorganisms for validation . 16
7.3 Quality by design of method validation . 17
7.4 Revalidation method . 17
7.5 System validation . 17
7.6 Use of reference material in validation . 18
7.7 Acceptance criteria of targeted validation parameters . 18
7.8 Precision . 19
7.9 Detection limit . 19
7.10 Accuracy . 19
7.11 Robustness . 20
7.12 Ruggedness . 20
8 Use and application of rapid microbial tests . 20
8.1 Number and type of samples . 20
8.2 Testing environment . 20
8.3 Sensitivity . 21
8.4 Analytical specificity (microorganism detection) . 21
8.5 Comparable test data . 21
9 Investigation of positive sterility results . 22
10 Training . 22
11 Documentation . 23
12 Test report . 23
Annex A (informative) Exemplary framework for identifying microbial contamination . 25
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ISO/FDIS 24190:2023(E)
Annex B (informative) Risk analysis with cellular therapeutic products related to input
materials — Donor selection . 26
Annex C (informative) Risk analysis with cellular therapeutic products related to input
materials — Cell transformation and expansion . 27
Annex D (informative) Risk analysis with cellular therapeutic products related to input
materials — Packaging storage and administration . 29
Annex E (informative) Risk-based classification for monitoring practices for cellular
therapeutic product manufacturing . 30
Annex F (informative) Validation of rapid microbial test methods . 31
Annex G (informative) Microorganisms for validation of rapid microbial test methods . 33
Annex H (informative) Methods for rapid microbial testing . 37
Annex I (informative) Environmental control . 44
Bibliography . 45
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ISO/FDIS 24190:2023(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 276, Biotechnology.
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 2023 – All rights reserved v

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ISO/FDIS 24190:2023(E)
Introduction
Patient safety is essential in providing cell-based therapies. However, novel cell-based therapies present
many challenges with respect to the timely assessment of microbial contamination. Since many cell-based
therapies have short shelf lives, they are administered to patients within hours after formulation. In
addition to final product testing, testing on cell banks and product intermediates is common.
Microbiological testing includes bacteria, fungi, mycoplasma and viral adventitious agents. Culture-based
testing methods (e.g. pharmacopeia methods) have been widely adopted by industry. However, culture-
based testing methods can take days to weeks to obtain a result. More rapid methods for microbiological
testing are needed to ensure patient safety prior to product administration. The development and use of
rapid, validated methods that are sensitive and accurate, and that allow for the detection of a broad range
of microorganisms are therefore desired and supported by this document.
vi © ISO 2023 – All rights reserved

---------------------- Page: 6 ----------------------
FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 24190:2023(E)

Biotechnology — Analytical methods — Risk-based approach
for method selection and validation for rapid microbial
detection in bioprocesses
1 Scope
This document provides guidance, a framework and a risk-based approach for the selection and
validation of methods for rapid microbial detection in cellular therapeutic product manufacturing.
This document provides a flexible risk-based framework for the detection of microbial
contamination in cellular therapeutic products and cellular intermediates.
This document provides general requirements and risks associated with cellular therapeutic
product manufacturing, with flexibility to address differences in specific manufacturing processes
of each unique cellular therapeutic product.
This document primarily addresses sterility testing in cellular therapeutic product manufacturing.
This document is applicable to other cell-derived therapeutic product manufacturing.
This document focuses on rapid microbial test methods (RMTMs) used for both in-process and
final product testing.
Viral testing in cellular therapeutic product manufacturing is not included in this document.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https://www.iso.org/obp
— IEC Electropedia: available at https://www.electropedia.org/
3.1
acceptance criteria
numerical limits, ranges, or other attributes or variables meeting predefined performance for the
assays described
Note 1 to entry: Acceptance criteria are specified by the user requirement specifications (3.2830).
3.2
accuracy
measurement accuracy
closeness of agreement between a measured quantity value and an assigned quantity value of a
measurand
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ISO/FDIS 24190:2023(E)
Note 1 to entry: The concept ‘“measurement accuracy’accuracy” is not a quantity and is not given a
numerical quantity value. A measurement is said to be more accurate when it offers a smaller measurement
error.
Note 2 to entry: The term ‘“measurement accuracy’accuracy” should not be used for measurement trueness
and the term measurement precision should not be used for ‘“measurement accuracy’,accuracy”, which,
however, is related to both these concepts.
Note 3 to entry: ‘“Measurement accuracy’accuracy” is sometimes understood as closeness of agreement
between measured quantity values that are being attributed to the measurand.
[SOURCE: ISO 16140-1 and JCGM, 2021, modified — Term “accuracy of measurement”
deleted.]:2016, 2.2]
3.3
analytical sensitivity
quotient of the change in measurement indication and the corresponding change in value of a
quantity being measured
Note 1 to entry: Analytical sensitivity should not be used to mean detection limit (3.8) or quantitation limit,
and should not be confused with diagnostic sensitivity (3.9)).
[SOURCE: ISO 18113-1:2009, A.2022, 3.32.4, modified — Note Admitted term “sensitivity of a
measurement procedure” deleted. Notes 1 to 3 to entry was reviseddeleted. Note 4 to entry
renumbered as Note 1 to entry.]
3.4
analytical specificity
capability of a measuring system, using a specified measurement procedure, to provide
measurement results for one or more measurands which do not depend on each other nor on any
other quantity in the system undergoing measurement
Note 1 to entry: Lack of analytical specificity is call analytical interference
Note 2 to entry: Analytical specificity should not be confused with diagnostic specificity (3.10)
Note 3 to entry: ISO/IEC Guide 99:2007 uses the term “selectivity” for histhis concept instead of “specificity”.
[SOURCE: ISO 18113-1:2009, A.2022, 3.152.5, modified — Admitted term “selectivity of a
measurement procedure” deleted. Notes to entry were revisedreplaced.]
3.5
aseptic
conditions and procedures used to exclude the introduction of microbial contamination
[SOURCE: ISO 18362:2016, 3.3, modified — “aseptic” replaced “aseptic technique” as the term.]
3.6
cellular therapeutic product
product containing cells as the active substance
EXAMPLE Cell and gene therapy products, tissue engineered products, drug products.
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ISO/FDIS 24190:2023(E)
Note 1 to entry: Products produced from cells for gene therapies are included in the definition of cellular
therapeutic productsproduct, as cells are not necessarily the active substance for all gene modified
therapies.
Note 2 to entry: Recombinant proteins are not included in this definition of cellular therapeutic product.
[SOURCE: ISO 20399:2022, 3.9], modified — “used for cell therapy or gene therapy” deleted from
the definition.]
3.7
design qualification
DQ
process for verification (3.32) that the proposed specification for the facility, equipment or system
of the assay meets the expectation for the user requirement specifications (URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.1, modified — Abbreviated term “DQ” and “of the assay” added.
“user requirement specifications (URS)” replaced “intended use”.]
3.8
detection limit
limit of detection
measured quantity value, obtained by a given measurement procedure, for which the probability
of falsely claiming the absence of a component in a material is β, given a probability α of falsely
claiming its presence
Note 1 to entry: IUPAC recommends default values for α and β equal to 0,05.
Note 2 to entry: The abbreviation LOD is sometimes used.
Note 3 to entry: The term “sensitivity” is discouraged for “detection limit”.
[SOURCE: ISO/IEC Guide 99:2007, 4.18]
3.9
diagnostic sensitivity
ability of an in vitro diagnostic examination procedure to identify the presence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent positivity in samples where the targetarget marker is known to be
present.
Note 2 to entry: Diagnostic sensitivity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 x× the number of true positive values (TP) divided by the sum of the number of true
positive values (TP) plus the number of false negative values (FPFN), or 100x100 × TP/(TP + FN). This
calculation is based on a study design where only one sample is taken from each subject.
Note 3 to entry: For microbial detection, diagnostic sensitivity represents the fraction of target organisms
that were detected correctly.
[SOURCE: ISO 18113-1:2009, A.2022, 3.152.17, modified — Notes“identify the presence of a target
marker” replaced “have positive results”. Second sentence of Note 1 to entry were reviseddeleted.
Note 3 to entry replaced.]
3.10
diagnostic specificity
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ISO/FDIS 24190:2023(E)
ability of an in vitro diagnostic examination procedure to recognise the absence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent negativity in samples where the target marker is known to be
absent.
Note 2 to entry: Diagnostic specificity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 x × the number of true negative values (TN) divided by the sum of the number of true
negative values (TN) plus the number of false positive values (FP), or 100 x × TN/(TN+FP). This calculation
is based on a study design where only one sample is taken from each subject.
[SOURCE: ISO 18113-1:2009, A.2022, 3.162.18, modified — Notes“recognise the absence of a
target marker” replaced “have negative results”. Second sentence of Note 1 to entry were
revised]deleted. Note 3 to entry deleted.]
3.11
false negative
result indicated by the test method to be negative (3.15) which has subsequently been shown to
contain the target microorganisms
[SOURCE: ISO 13843:2017, 3.14, modified — “microorganisms” replaced “organism”.]
3.12
false positive
result indicated by the test method to be positive (3.19) which was subsequently shown not to
contain the target microorganisms
[SOURCE: ISO 13843:2017, 3.15, modified — “microorganisms” replaced “organism”.]
3.13
fit for purpose
in line with prearranged requirements for an intended use
[SOURCE: ISO 20387:2018, 3.24, modified — TermAdmitted term “fitness for the intended
purpose” and Note 1 to entry deleted.]
3.14
installation qualification
IQ
process of establishing by objective evidence that all key aspects of the process equipment and
ancillary system for the assay instrument installation comply with the approved user requirement
specifications (URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.2, modified — “for the assay instrument” was added and “user
requirement specifications (URS)” replaced “specification”.]
3.15
negative
test result indicating the absence of the analyte in a given test portion as defined by the procedure
of the method
[SOURCE: ISO 16140-1:2016, 2.43, modified — “negative” replaced “negative test result” as the
term,. “the absence of the analyte” replaced “the analyte was not detected” and “qualitative” was
deleted before “method”.]
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ISO/FDIS 24190:2023(E)
3.16
nucleic acid amplification techniques
NAT
biochemistry and molecular biology methods that involve the in vitro synthesis of many copies of
DNA or RNA from one original template
Note 1 to entry: NAT is characterisedcharacterized by existence of reverse transcription, amplification
method, and Typetype of determination (qualitative or quantitative)
Note 2 to entry: Examples of amplification methods are PCR, and iso thermal amplification (NEAR, TMA,
LAMP, HAD, CRISPER, SDA, and so on)
3.17
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment operates within
predetermined limits when used in accordance with its operational procedures
[SOURCE: ISO 11139:2018, 3.220.3]
3.18
performance qualification
PQ
process of establishing by objective evidence that the assay process, under anticipated conditions,
consistently produces a result which meets all predetermined user requirement specifications
(URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.4, modified — “assay” was added before “process”, “result”
replaced “product” and “user requirement specifications (URS)” replaced “requirements”.]
3.19
positive
test result indicating the presence of the analyte in a given test portion as defined by the procedure
of the method
Note 1 to entry: When the reference method or alternative method provides a preliminary positive test
result requiring further testing to confirm this result, this test result can be considered as a presumptive
positive test result. If the further testing specified by the method’s procedure confirms that the test result
can indeed be considered as being positive, the test result can be considered as a confirmed positive test
result.
[SOURCE: ISO 16140-1:2016, 2.50, modified — “positive” replaced “positive test result” as the
term.]
3.20
precision
closeness of agreement between indications or measured quantity values obtained by replicate
measurements on the same or similar objects under specified conditions
Note 1 to entry: Measurement precision is usually expressed numerically by measures of imprecision, such
as standard deviation, variance, or coefficient of variation under the specified conditions of measurement.
Note 2 to entry: The “specified conditions” can be, for example, repeatability conditions of measurement,
intermediate precision conditions of measurement, or reproducibility conditions of measurement (see
ISO 5725-1).
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ISO/FDIS 24190:2023(E)
[SOURCE: ISO/IEC Guide 99:2007, 2.15, modified — “precision” replaced “measurement
precision” as the term. Notes 3 and 4 to entry were deleted.]
3.21
qualification
activities undertaken to demonstrate that utilities, equipment and methods are suitable for their
intended use and perform properly
Note 1 to entry: Qualification of equipment and/or processes generally includes installation qualification
(3.14), operational qualification (3.17) and performance qualification (3.18).
[SOURCE: ISO 11139:2018, 3.220, modified — “or modes” was deleted after “methods”.]
3.22
rapid microbial test method
RMTM
analytical method that allows the user to get microbiology test results faster compared with
traditional visual observation methods using direct inoculation and culture-plating
Note 1 to entry: Generally, this means in a significantly reduced time as compared with the traditional
method (e.g. hours or days).
3.23
reference material
material, sufficiently homogeneous and stable with reference to specified properties, which has
been established to be fit for its intended use in measurement or in examination of nominal
properties
[SOURCE: ISO/IEC Guide 99:2007, 5.13, modified — Abbreviated term “RM”, notes to entry and
examples were deleted.]
3.24
risk assessment
overall process of risk identification, risk analysis and risk evaluation
[SOURCE: ISO Guide 73:2009, 3.4.1]
3.25
risk control
process in which decisions are made and measures implemented by which risks are reduced to,
or maintained within, specified levels
[SOURCE: ISO 14971:2019, 3.21]
3.26
risk-based approach
methodology that allows the prioritization of activities based on a previous analysis of data and
according to the biosafety level
3.27
robustness
measure of a test method’s capacity to remain unaffected by small, but deliberate, variations in
method parameters and to provide an indication of its reliability during normal usage
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ISO/FDIS 24190:2023(E)
[11]
[SOURCE: ICH Q2(R1) ]
3.28
shelf life
period of time after production during which a product that is kept under specified conditions
retains its specified properties
[SOURCE: ISO 1382:2020, 3.485, modified — The term “storage life” was deleted,. “material or”
was deleted before “product” and “that is” was added.]
3.29
sterility
state of being free from viable microorganisms (3.33)
Note 1 to entry: In practice, no such absolute statement regarding the absence of microorganisms can be
proven.
[SOURCE: ISO 11139:2018, 3.274]
3.30
user requirement specifications
URS
requirements specific to a user or requirements that are not covered in general requirements
3.31
validation
confirmation, through the provision of objective evidence, that the requirements for a specific
intended use or application have been fulfilled
deleted.]
[SOURCE: ISO 9000:2015, 3.8.13, modified — Notes to entry were
3.32
verification
confirmation, through the provision of objective evidence, that specified requirements have been
fulfilled
[SOURCE: ISO 9000:2015, 3.8.12, modified — Notes to entry were deleted.]
3.33
viable microorganism
microorganism within a sample that has at least one attribute of being alive (e.g. metabolically
active, capable of reproduction, possession of an intact cell membrane, with the capacity to
resume these functions) defined based on the intended measurement purpose
4 General considerations
Prior to patient administration, cellular therapeutic products should be tested for microbial
contamination. Many of these products rely on the activity of viable cells for a therapeutic effect.
Viable cells cannot be terminally sterilized and rely on a combination of aseptic techniques and
closed-system manufacturing to ensure sterility of the final product. These products typically have
a relatively short shelf life and are manufactured as single lots or small lots, presenting challenges
[57-
for utilizing compendial or culture-based methods for detecting microbial contamination
60] [35][36][37][38]
..
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-----
...

FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 24190
ISO/TC 276
Biotechnology — Analytical methods
Secretariat: DIN
— Risk-based approach for method
Voting begins on:
2023-03-02 selection and validation for rapid
microbial detection in bioprocesses
Voting terminates on:
2023-04-27
RECIPIENTS OF THIS DRAFT ARE INVITED TO
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPOR TING
DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO-
ISO/FDIS 24190:2023(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN-
DARDS TO WHICH REFERENCE MAY BE MADE IN
NATIONAL REGULATIONS. © ISO 2023

---------------------- Page: 1 ----------------------
ISO/FDIS 24190:2023(E)
FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 24190
ISO/TC 276
Biotechnology — Analytical methods
Secretariat: DIN
— Risk-based approach for method
Voting begins on:
selection and validation for rapid
microbial detection in bioprocesses
Voting terminates on:
COPYRIGHT PROTECTED DOCUMENT
© ISO 2023
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.
RECIPIENTS OF THIS DRAFT ARE INVITED TO
ISO copyright office
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
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THEY ARE AWARE AND TO PROVIDE SUPPOR TING
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DOCUMENTATION.
Phone: [phone]
IN ADDITION TO THEIR EVALUATION AS
Reference number
Email: [e-mail]
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO­
ISO/FDIS 24190:2023(E)
Website: www.iso.org
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
Published in Switzerland
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN­
DARDS TO WHICH REFERENCE MAY BE MADE IN
ii
  © ISO 2023 – All rights reserved
NATIONAL REGULATIONS. © ISO 2023

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ISO/FDIS 24190:2023(E)
Contents Page
Foreword .v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations .7
5 Risk management for microbiological contamination. 7
5.1 Risk management in manufacturing process . 7
5.2 Risk management in microbial testing . 9
6 Selection of a fit-for-purpose assay .9
6.1 General . 9
6.2 Assay selection . 10
6.3 Kit or system selection . 10
6.4 Considerations for various test types . 11
6.5 User requirement specifications .12
6.5.1 General .12
6.5.2 Speed .12
6.5.3 Sample volume .12
6.5.4 In-process versus final release testing .12
6.5.5 Specificity . 12
6.5.6 Sensitivity . 13
7 Validation . .13
7.1 General concepts . 13
7.2 Selection of microorganisms for validation . 14
7.3 Quality by design of method validation . 15
7.4 Revalidation method . 15
7.5 System validation . 16
7.6 Use of reference material in validation . 16
7.7 Acceptance criteria of targeted validation parameters . 16
7.8 Precision . . . 17
7.9 Detection limit . 17
7.10 Accuracy . 17
7.11 Robustness . 18
7.12 Ruggedness . 18
8 Use and application of rapid microbial tests .18
8.1 Number and type of samples . 18
8.2 Testing environment . 18
8.3 Sensitivity . 19
8.4 Analytical specificity (microorganism detection) . 19
8.5 Comparable test data . 19
9 Investigation of positive sterility results .20
10 Training .20
11 Documentation .21
12 Test report .21
Annex A (informative) Exemplary framework for identifying microbial contamination .22
Annex B (informative) Risk analysis with cellular therapeutic products related to input
materials — Donor selection .23
iii
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ISO/FDIS 24190:2023(E)
Annex C (informative) Risk analysis with cellular therapeutic products related to input
materials — Cell transformation and expansion .24
Annex D (informative) Risk analysis with cellular therapeutic products related to input
materials — Packaging storage and administration .26
Annex E (informative) Risk-based classification for monitoring practices for cellular
therapeutic product manufacturing .27
Annex F (informative) Validation of rapid microbial test methods.28
Annex G (informative) Microorganisms for validation of rapid microbial test methods .30
Annex H (informative) Methods for rapid microbial testing .34
Annex I (informative) Environmental control .41
Bibliography .42
iv
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ISO/FDIS 24190:2023(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 non­governmental, 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 276, Biotechnology.
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.
v
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ISO/FDIS 24190:2023(E)
Introduction
Patient safety is essential in providing cell-based therapies. However, novel cell-based therapies
present many challenges with respect to the timely assessment of microbial contamination. Since
many cell-based therapies have short shelf lives, they are administered to patients within hours after
formulation. In addition to final product testing, testing on cell banks and product intermediates is
common. Microbiological testing includes bacteria, fungi, mycoplasma and viral adventitious agents.
Culture-based testing methods (e.g. pharmacopeia methods) have been widely adopted by industry.
However, culture-based testing methods can take days to weeks to obtain a result. More rapid methods
for microbiological testing are needed to ensure patient safety prior to product administration. The
development and use of rapid, validated methods that are sensitive and accurate, and that allow for the
detection of a broad range of microorganisms are therefore desired and supported by this document.
vi
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FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 24190:2023(E)
Biotechnology — Analytical methods — Risk-based
approach for method selection and validation for rapid
microbial detection in bioprocesses
1 Scope
This document provides guidance, a framework and a risk­based approach for the selection and
validation of methods for rapid microbial detection in cellular therapeutic product manufacturing.
This document provides a flexible risk-based framework for the detection of microbial contamination
in cellular therapeutic products and cellular intermediates.
This document provides general requirements and risks associated with cellular therapeutic product
manufacturing, with flexibility to address differences in specific manufacturing processes of each
unique cellular therapeutic product.
This document primarily addresses sterility testing in cellular therapeutic product manufacturing.
This document is applicable to other cell­derived therapeutic product manufacturing.
This document focuses on rapid microbial test methods (RMTMs) used for both in-process and final
product testing.
Viral testing in cellular therapeutic product manufacturing is not included in this document.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
acceptance criteria
numerical limits, ranges, or other attributes or variables meeting predefined performance for the
assays described
Note 1 to entry: Acceptance criteria are specified by the user requirement specifications (3.30).
3.2
accuracy
measurement accuracy
closeness of agreement between a measured quantity value and an assigned quantity value of a
measurand
Note 1 to entry: The concept “measurement accuracy” is not a quantity and is not given a numerical quantity
value. A measurement is said to be more accurate when it offers a smaller measurement error.
1
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ISO/FDIS 24190:2023(E)
Note 2 to entry: The term “measurement accuracy” should not be used for measurement trueness and the term
measurement precision should not be used for “measurement accuracy”, which, however, is related to both these
concepts.
Note 3 to entry: “Measurement accuracy” is sometimes understood as closeness of agreement between measured
quantity values that are being attributed to the measurand.
[SOURCE: ISO 16140­1:2016, 2.2]
3.3
analytical sensitivity
quotient of the change in measurement indication and the corresponding change in value of a quantity
being measured
Note 1 to entry: Analytical sensitivity should not be used to mean detection limit (3.8) or quantitation limit and
should not be confused with diagnostic sensitivity (3.9).
[SOURCE: ISO 18113-1:2022, 3.2.4, modified — Admitted term “sensitivity of a measurement procedure”
deleted. Notes 1 to 3 to entry deleted. Note 4 to entry renumbered as Note 1 to entry.]
3.4
analytical specificity
capability of a measuring system, using a specified measurement procedure, to provide measurement
results for one or more measurands which do not depend on each other nor on any other quantity in the
system undergoing measurement
Note 1 to entry: Lack of analytical specificity is call analytical interference
Note 2 to entry: Analytical specificity should not be confused with diagnostic specificity (3.10)
Note 3 to entry: ISO/IEC Guide 99:2007 uses the term “selectivity” for this concept instead of “specificity”.
[SOURCE: ISO 18113-1:2022, 3.2.5, modified — Admitted term “selectivity of a measurement procedure”
deleted. Notes to entry replaced.]
3.5
aseptic
conditions and procedures used to exclude the introduction of microbial contamination
[SOURCE: ISO 18362:2016, 3.3, modified — “aseptic” replaced “aseptic technique” as the term.]
3.6
cellular therapeutic product
product containing cells as the active substance
EXAMPLE Cell and gene therapy products, tissue engineered products, drug products.
Note 1 to entry: Products produced from cells for gene therapies are included in the definition of cellular
therapeutic product, as cells are not necessarily the active substance for all gene therapies.
Note 2 to entry: Recombinant proteins are not included in this definition of cellular therapeutic product.
[SOURCE: ISO 20399:2022, 3.9, modified — “used for cell therapy or gene therapy” deleted from the
definition.]
3.7
design qualification
DQ
process for verification (3.32) that the proposed specification for the facility, equipment or system of
the assay meets the expectation for the user requirement specifications (URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.1, modified — Abbreviated term “DQ” and “of the assay” added. “user
requirement specifications (URS)” replaced “intended use”.]
2
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ISO/FDIS 24190:2023(E)
3.8
detection limit
limit of detection
measured quantity value, obtained by a given measurement procedure, for which the probability of
falsely claiming the absence of a component in a material is β, given a probability α of falsely claiming
its presence
Note 1 to entry: IUPAC recommends default values for α and β equal to 0,05.
Note 2 to entry: The abbreviation LOD is sometimes used.
Note 3 to entry: The term “sensitivity” is discouraged for “detection limit”.
[SOURCE: ISO/IEC Guide 99:2007, 4.18]
3.9
diagnostic sensitivity
ability of an in vitro diagnostic examination procedure to identify the presence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent positivity in samples where the target marker is known to be present.
Note 2 to entry: Diagnostic sensitivity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 × the number of true positive values (TP) divided by the sum of the number of true positive
values (TP) plus the number of false negative values (FN), or 100 × TP/(TP + FN). This calculation is based on a
study design where only one sample is taken from each subject.
Note 3 to entry: For microbial detection, diagnostic sensitivity represents the fraction of target organisms that
were detected correctly.
[SOURCE: ISO 18113-1:2022, 3.2.17, modified — “identify the presence of a target marker” replaced
“have positive results”. Second sentence of Note 1 to entry deleted. Note 3 to entry replaced.]
3.10
diagnostic specificity
ability of an in vitro diagnostic examination procedure to recognise the absence of a target marker
associated with a particular disease or condition
Note 1 to entry: Also defined as percent negativity in samples where the target marker is known to be absent.
Note 2 to entry: Diagnostic specificity is expressed as a percentage (number fraction multiplied by 100),
calculated as 100 × the number of true negative values (TN) divided by the sum of the number of true negative
values (TN) plus the number of false positive values (FP), or 100 × TN/(TN+FP). This calculation is based on a
study design where only one sample is taken from each subject.
[SOURCE: ISO 18113-1:2022, 3.2.18, modified — “recognise the absence of a target marker” replaced
“have negative results”. Second sentence of Note 1 to entry deleted. Note 3 to entry deleted.]
3.11
false negative
result indicated by the test method to be negative (3.15) which has subsequently been shown to contain
the target microorganisms
[SOURCE: ISO 13843:2017, 3.14, modified — “microorganisms” replaced “organism”.]
3.12
false positive
result indicated by the test method to be positive (3.19) which was subsequently shown not to contain
the target microorganisms
[SOURCE: ISO 13843:2017, 3.15, modified — “microorganisms” replaced “organism”.]
3
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ISO/FDIS 24190:2023(E)
3.13
fit for purpose
in line with prearranged requirements for an intended use
[SOURCE: ISO 20387:2018, 3.24, modified — Admitted term “fitness for the intended purpose” and Note
1 to entry deleted.]
3.14
installation qualification
IQ
process of establishing by objective evidence that all key aspects of the process equipment and ancillary
system for the assay instrument installation comply with the approved user requirement specifications
(URS) (3.30)
[SOURCE: ISO 11139:2018, 3.220.2, modified — “for the assay instrument” added and “user requirement
specifications (URS)” replaced “specification”.]
3.15
negative
test result indicating the absence of the analyte in a given test portion as defined by the procedure of
the method
[SOURCE: ISO 16140-1:2016, 2.43, modified — “negative” replaced “negative test result” as the term.
“the absence of the analyte” replaced “the analyte was not detected” and “qualitative” deleted before
“method”.]
3.16
nucleic acid amplification techniques
NAT
biochemistry and molecular biology methods that involve the in vitro synthesis of many copies of DNA
or RNA from one original template
Note 1 to entry: NAT is characterized by existence of reverse transcription, amplification method and type of
determination (qualitative or quantitative)
Note 2 to entry: Examples of amplification methods are PCR and iso thermal amplification (NEAR, TMA, LAMP,
HAD, CRISPER, SDA)
3.17
operational qualification
OQ
process of obtaining and documenting evidence that installed equipment operates within predetermined
limits when used in accordance with its operational procedures
[SOURCE: ISO 11139:2018, 3.220.3]
3.18
performance qualification
PQ
process of establishing by objective evidence that the assay process, under anticipated conditions,
consistently produces a result which meets all predetermined user requirement specifications (URS)
(3.30)
[SOURCE: ISO 11139:2018, 3.220.4, modified — “assay” added before “process”, “result” replaced
“product” and “user requirement specifications (URS)” replaced “requirements”.]
4
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ISO/FDIS 24190:2023(E)
3.19
positive
test result indicating the presence of the analyte in a given test portion as defined by the procedure of
the method
Note 1 to entry: When the reference method or alternative method provides a preliminary positive test result
requiring further testing to confirm this result, this test result can be considered as a presumptive positive test
result. If the further testing specified by the method’s procedure confirms that the test result can indeed be
considered as being positive, the test result can be considered as a confirmed positive test result.
[SOURCE: ISO 16140-1:2016, 2.50, modified — “positive” replaced “positive test result” as the term.]
3.20
precision
closeness of agreement between indications or measured quantity values obtained by replicate
measurements on the same or similar objects under specified conditions
Note 1 to entry: Measurement precision is usually expressed numerically by measures of imprecision, such as
standard deviation, variance, or coefficient of variation under the specified conditions of measurement.
Note 2 to entry: The “specified conditions” can be, for example, repeatability conditions of measurement,
intermediate precision conditions of measurement, or reproducibility conditions of measurement (see
ISO 5725­1).
[SOURCE: ISO/IEC Guide 99:2007, 2.15, modified — “precision” replaced “measurement precision” as
the term. Notes 3 and 4 to entry deleted.]
3.21
qualification
activities undertaken to demonstrate that utilities, equipment and methods are suitable for their
intended use and perform properly
Note 1 to entry: Qualification of equipment and/or processes generally includes installation qualification (3.14),
operational qualification (3.17) and performance qualification (3.18).
[SOURCE: ISO 11139:2018, 3.220, modified — “or modes” deleted after “methods”.]
3.22
rapid microbial test method
RMTM
analytical method that allows the user to get microbiology test results faster compared with traditional
visual observation methods using direct inoculation and culture­plating
Note 1 to entry: Generally, this means in a significantly reduced time as compared with the traditional method
(e.g. hours or days).
3.23
reference material
material, sufficiently homogeneous and stable with reference to specified properties, which has been
established to be fit for its intended use in measurement or in examination of nominal properties
[SOURCE: ISO/IEC Guide 99:2007, 5.13, modified — Abbreviated term “RM”, notes to entry and examples
deleted.]
3.24
risk assessment
overall process of risk identification, risk analysis and risk evaluation
[SOURCE: ISO Guide 73:2009, 3.4.1]
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ISO/FDIS 24190:2023(E)
3.25
risk control
process in which decisions are made and measures implemented by which risks are reduced to, or
maintained within, specified levels
[SOURCE: ISO 14971:2019, 3.21]
3.26
risk-based approach
methodology that allows the pr
...