FprEN ISO 18704

SLOVENSKI STANDARD
oSIST prEN ISO 18704:2024
01-december-2024
Molekularne diagnostične preiskave in vitro - Specifikacije za predpreiskovalne
procese pregleda urina in drugih telesnih tekočin - Izolirana brezcelična DNK
(ISO/DIS 18704:2024)
Molecular in vitro diagnostic examinations - Specifications for pre-examination processes
for urine and other body fluids - Isolated cell free DNA (ISO/DIS 18704:2024)
Molekularanalytische in-vitro-diagnostische Verfahren - Spezifikationen für
präanalytische Prozesse für Urin und andere Körperflüssigkeiten - Isolierte zellfreie DNA
(ISO/DIS 18704:2024)
Analyses de diagnostic moléculaire in vitro - Spécifications relatives aux processus
préanalytiques pour l’urine et d’autres liquides corporels - ADN libre extrait (ISO/DIS
18704:2024)
Ta slovenski standard je istoveten z: prEN ISO 18704
ICS:
11.100.10 Diagnostični preskusni In vitro diagnostic test
sistemi in vitro systems
oSIST prEN ISO 18704:2024 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

oSIST prEN ISO 18704:2024
oSIST prEN ISO 18704:2024
DRAFT
International
Standard
ISO/DIS 18704
ISO/TC 212
Molecular in vitro diagnostic
Secretariat: ANSI
examinations — Specifications
Voting begins on:
for pre-examination processes
2024-10-23
for urine and other body fluids —
Voting terminates on:
Isolated cell free DNA
2025-01-15
ICS: 11.100.10
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENTS AND APPROVAL. IT
IS THEREFORE SUBJECT TO CHANGE
AND MAY NOT BE REFERRED TO AS AN
INTERNATIONAL STANDARD UNTIL
PUBLISHED AS SUCH.
This document is circulated as received from the committee secretariat.
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NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
PROVIDE SUPPORTING DOCUMENTATION.
Reference number
ISO/DIS 18704:2024(en)
oSIST prEN ISO 18704:2024
DRAFT
ISO/DIS 18704:2024(en)
International
Standard
ISO/DIS 18704
ISO/TC 212
Molecular in vitro diagnostic
Secretariat: ANSI
examinations — Specifications
Voting begins on:
for pre-examination processes
for urine and other body fluids —
Voting terminates on:
Isolated cell free DNA
ICS: 11.100.10
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENTS AND APPROVAL. IT
IS THEREFORE SUBJECT TO CHANGE
AND MAY NOT BE REFERRED TO AS AN
INTERNATIONAL STANDARD UNTIL
PUBLISHED AS SUCH.
This document is circulated as received from the committee secretariat.
IN ADDITION TO THEIR EVALUATION AS
BEING ACCEPTABLE FOR INDUSTRIAL,
© ISO 2024
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
STANDARDS MAY ON OCCASION HAVE TO
ISO/CEN PARALLEL PROCESSING
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Website: www.iso.org
Published in Switzerland Reference number
ISO/DIS 18704:2024(en)
ii
oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3  Terms and definitions . 1
4 General requirements . 6
5 Outside the laboratory . 7
5.1 Specimen collection .7
5.1.1 Information about the patient or specimen donor .7
5.1.2 Selection of the body fluid collection device by the laboratory .7
5.1.3 Urine and other body fluid specimen collection from the patient/donor and
stabilization procedures .8
5.1.4 Information about the specimen storage requirements at the body fluid
collection facility .9
5.2 Transport requirements .11
5.2.1 General .11
5.2.2 Transport using urine and other body fluid collection devices with cfDNA
stabilizers .11
5.2.3 Transport using urine and other body fluid collection devices without cfDNA
stabilizers . 12
6 Inside the laboratory .12
6.1 Specimen/sample reception . 12
6.2 Specimen/sample storage after transport and reception . 12
6.3 Urine and other body fluid specimen/sample processing prior to cfDNA isolation . 13
6.4 Storage requirements for urine and other body fluid samples after processing . 13
6.5 Isolation of urine and other body fluid cfDNA . 13
6.5.1 General . 13
6.5.2 Using a commercial cfDNA isolation kit approved for diagnostic use .14
6.5.3 Using a laboratory developed cfDNA isolation procedure .14
6.6 Quantity and quality assessment of isolated cfDNA . 15
6.6.1 General . 15
6.6.2 Quantity assessment of cfDNA . 15
6.6.3 Quality assessment of cfDNA . 15
6.7 Storage of isolated urine and other body fluid cfDNA.16
6.7.1 General .16
6.7.2 Storage of isolated urine and other body fluid cfDNA, isolated with a
commercially available kit . .16
6.7.3 Storage of isolated urine and other body fluid cfDNA, isolated with the
laboratory's own procedure .17
Annex A (informative) Effects of pre-examination storage of unstabilized urine on cfDNA .18
Annex B (informative) Effects of pre-examination storage of unstabilized and stabilized urine
on the amount of a specific cfDNA target sequence.22
Bibliography .24

iii
oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
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 212, Medical laboratories and in vitro diagnostic
systems.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.

iv
oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
Introduction
Molecular in vitro diagnostics has enabled significant progress in medicine. Further progress has been
achieved and is still expected by new technologies used to examine profiles of nucleic acids, proteins, and
metabolites in human tissues and body fluids (e.g. genomic, epigenomic, transcriptomic, proteomic and
metabolomic profiling). However, the profiles of these molecules can change drastically during specimen
collection, transport, storage and processing. This can make the outcome from diagnostics or research
unreliable or even result in failure because the subsequent examination will not measure the genuine cfDNA
profile as it was in the patient, but a profile altered by the pre-examination process. Therefore, specifying,
developing, verifying and validating preanalytical workflows has become an essential part of examination
[1]
development .
Most of the DNA in the body is located within cells, but small amounts of DNA originating from cells can
also be found outside of cells (extracellular DNA). In case of circulating body fluids such as blood, this DNA
is called circulating cell-free DNA (ccfDNA) and in case of non-circulating body fluids such as urine, saliva,
cerebrospinal fluid, pleural effusion, ascites, and synovial fluid, the DNA is called cell-free DNA (cfDNA).
cfDNA is of specific interest, as for example cfDNA in urine originates from cells from the genitourinary
[2]
tract or from ccfDNA passing through glomerular filtration . cfDNA from cancerous or malignant cells in
[3],[4]
urine have been associated with cancer specific sequences, epigenetic and structural changes . Urine
is currently the most frequently used non-circulating body fluid for cfDNA examination because it is easily
obtained from patients. Although urine is often described as the major specimen type, in this document the
term body fluid is used for urine and other body fluids as defined in chapter 3.
Standardization of the entire workflow from specimen collection to the cfDNA examination is needed to
minimize post-collection release of DNA from cells into the fluid and degradation of cfDNA in the specimen,
which can change the original native cfDNA profile in the body fluid. Post collection microbial growth in
the specimen can further enhance the degradation of the cfDNA, e.g. in urine and saliva. Furthermore, the
isolation of cfDNA can lead to a cfDNA profile bias. Different methods to determine cfDNA yield and quality
can lead to additional variations and impacts.
Studies have been undertaken to determine the pre-examination sources of these and other variables, as
they can impact the cfDNA examination. This can compromise the specified examination performance
characteristics, such as sensitivity, specificity, linearity and reproducibility. It can also impact the
examination reliability which could lead to an erroneous examination result and misdiagnosis.
This document draws upon such work to codify and standardize the steps for cfDNA examination from body
fluids in what is referred to as the pre-examination phase.
In this document, the following verbal forms are used:
— “shall” indicates a requirement;
— “should” indicates a recommendation;
— “may” indicates a permission;
— “can” indicates a possibility or a capability.

v
oSIST prEN ISO 18704:2024
oSIST prEN ISO 18704:2024
DRAFT International Standard ISO/DIS 18704:2024(en)
Molecular in vitro diagnostic examinations — Specifications
for pre-examination processes for urine and other body fluids
— Isolated cell free DNA
1 Scope
This document specifies requirements and provides recommendations for the pre-examination phase of cell
free DNA (cfDNA) from body fluid specimens other than blood, including but not limited to the collection,
handling, storage, transport, processing and documentation of human body fluids, such as urine, pleural
effusions, ascites, cerebrospinal fluid (CSF), and saliva, intended for cfDNA examination. Processing includes
multiple steps, such as centrifugation for specimen purification and isolation of cfDNA.
This document is applicable to medical laboratories, health institutions including facilities collecting and
handling specimens, laboratory customers, in vitro diagnostic examination developers and manufacturers,
biobanks, institutions and organizations performing biomedical research, and regulatory authorities.
Dedicated measures that need to be taken for cytohistological analysis of body fluid derived nucleated cells
are not described in this document, neither are measures for preserving and handling of pathogens, and
other bacterial or whole microbiome DNA in body fluids described.
Different dedicated measures need to be taken for preserving circulating cell free DNA (ccfDNA) from blood.
These are not described in this document, but are covered in ISO 20186-3.
NOTE International, national or regional regulations or requirements can also apply to specific topics covered in
this document.
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 15189, Medical laboratories — Requirements for quality and competence
ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes
3  Terms and definitions
For the purposes of this document, the terms and definitions given below apply.
For medical laboratories additional terms and definitions described in ISO 15189 apply.
For IVD developers and manufacturers additional terms and definitions described in ISO 13485 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/

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
3.1
aliquot
portion of a larger amount of homogenous material, assumed to be taken with negligible sampling error
Note 1 to entry: The term is usually applied to fluids. Tissues are heterogeneous and therefore cannot be aliquoted.
Note 2 to entry: The definition is derived from [5], [6] and [7].
[SOURCE: ISO 20166-1:2018, 3.1]
3.2
analyte
component represented in the name of a measurable quantity
[SOURCE: ISO 17511:2020, 3.1 — Deleted example.]
3.3
examination performance
analytical test performance
analytical performance
includes but is not limited to accuracy, precision, specificity, sensitivity and limit of detection of a test to
examine the analyte of interest
Note 1 to entry: Other test performance characteristics such as robustness and repeatability can apply as well.
[SOURCE: ISO 20184-1:2018, 3.4, modified — added specificity and limit of detection to the definition.]
3.4
ascites
abnormal buildup of fluid in the abdomen that can cause swelling
Note 1 to entry: In late-stage cancer, tumour cells can be found in the fluid in the abdomen.
Note 2 to entry: Ascites also occurs in patients with liver disease.
Note 3 to entry: This definition was derived from [8].
3.5
body fluid
natural fluid or secretion that is produced by the body including, but not limited to, urine, saliva, semen,
mucus, vaginal secretions, breast milk, amniotic fluid, cerebrospinal fluid (CSF), synovial fluid, ascites,
pleural effusions and pericardial fluid
[SOURCE: ISO/TR 19591:2018, 3.23, modified — blood and faeces deleted, saliva, ascites and pleural
effusion added.]
Note 1 to entry: For the purpose of this document blood is not included.
3.6
body fluid collection device
tube or other container in which the body fluid (e.g. urine) specimen is collected
3.7
ccfDNA
circulating cell free DNA
extracellular human DNA present in blood and plasma
Note 1 to entry: ccfDNA can include DNA present in vesicles such as exosomes.
[SOURCE: ISO 20186-3:2019, 3.5]

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
3.8
cfDNA
cell free DNA
extracellular human DNA present in body liquids such as urine
[9]
Note 1 to entry: cfDNA can include DNA present in vesicles such as exosomes .
3.9
cfDNA profile
cell free DNA profile
amount of different cfDNA (3.8) molecules, present in a body fluid that can be measured in the absence of
any losses, inhibition and interference
3.10
closed system
non-modifiable system provided by the vendor including all necessary components for the analysis (i.e.,
hardware, software, procedures and reagents)
3.11
collection facility
any area where a human specimen is collected, such as physician’s office, patient’s home, hospital and clinic
3.12
CSF
cerebrospinal fluid
fluid that flows in and around the hollow spaces of the brain and spinal cord, and between two of the
meninges (the thin layers of tissue that cover and protect the brain and spinal cord)
Note 1 to entry: Cerebrospinal fluid is made by tissue called the choroid plexus in the ventricles (hollow spaces) in the brain.
Note 2 to entry: This definition was derived from [8].
3.13
DNA
deoxyribonucleic acid
polymer of deoxyribonucleotides occurring in a double-stranded (dsDNA) or single-stranded (ssDNA) form
[SOURCE: ISO 22174:2005, 3.1.2]
3.14
DNA stabilizer
compound, solution or mixture that is designed to minimize degradation and fragmentation of cfDNA as
well as release of genomic DNA from nucleated cells
3.15
examination
set of operations having the objective of determining the numerical value or characteristics of a property
Note 1 to entry: Processes that start with the isolated measurand and include all kinds of parameter testing or
chemical manipulation for quantitative or qualitative examination.
[SOURCE: ISO 15189:2022, 3.8, modified — Term and definition are used here without the original notes; the
term “text value” was removed.]
3.16
examination device manufacturer
entity that manufactures in vitro diagnostic or research examination devices, including measurement
systems, instruments, reagents, and instructions for use for a specific examination (3.15)
[SOURCE: ISO 20166-4:2021, 3.16]

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
3.18
genomic DNA
gDNA
genomic DNA present in nucleated cells
3.19
homogenous
uniform in structure and composition
3.20
interfering substance
endogenous or exogenous substance (e.g. stabilization solution) that can be present in specimens and that
can alter an examination (3.15) result
3.21
microorganism
entity of microscopic size, encompassing bacteria, fungi, protozoa and viruses
[SOURCE: ISO 11139:2018, 3.176]
3.22
pleural effusion
abnormal collection of fluid between the thin layers of tissue (pleura) lining the lung and the wall of the
chest cavity
Note 1 to entry: This definition was derived from [8].
3.23
pre-examination processes
pre-analytical phase
pre-analytical workflow
pre-examination phase
processes that start, in chronological order, from the user’s request and include but are not limited to the
examination (3.15) request, preparation and identification of the patient, collection of specimen(s) (3.24),
transportation to and within the laboratory, storage, isolation of analytes and usually end with the quality
assessment and storage of the analyte
[SOURCE: ISO 15189:2022, 3.24, modified — More details have been included and the phrase “and ending
when the examination begins” has been replaced by “and usually end with the quality assessment and
storage of the analyte”.]
3.24
specimen
primary sample
discrete portion of a body fluid or tissue or other sample associated with the human body taken for
examination (3.15), study or analysis of one or more quantities or characteristics to determine the character
of the whole
[SOURCE: ISO 15189:2022, 3.25, modified — The term and definition are used here without the original note.]
3.25
proficiency test
evaluation of participant performance against pre-established criteria by means of interlaboratory
comparisons
[SOURCE: ISO/IEC 17043:2023, 3.7, modified — Term and definition are used here without the original note.]
3.26
room temperature
temperature in the range of 18 °C to 25 °C
Note 1 to entry: Local or national regulations can have different definitions.

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
[SOURCE: ISO 20166-1:2018, 3.22]
3.27
sample
one or more parts taken from a primary sample (3.24)
[SOURCE: ISO 15189:2022, 3.28]
3.28
stability
ability of a sample material, when stored under specified conditions, to maintain a stated property value
within specified limits for a specified period of time
Note 1 to entry: The measurand constituent for the purpose of this document is isolated DNA.
[SOURCE: ISO Guide 30:2015, 2.1.15, modified — The words “characteristic of a reference material” were
replaced by “ability of a sample material”; “specified property value” replaced by “stated property value”.
Term and definition are used here without the original note.]
3.29
storage
prolonged interruption of the pre-analytical workflow of a sample or analyte respectively, or of their
derivatives, under appropriate conditions in order to preserve their properties
Note 1 to entry: Long-term storage typically occurs in laboratory archives or in biobanks.
[SOURCE: ISO 20184-1:2018, 3.22]
3.30
synovial fluid
transparent, sticky liquid produced in joints (i.e. places where two bones are connected) that allows the
bones and tendons to move smoothly
Note 1 to entry: In pathological situations the collected synovial fluid can have a different colour.
Note 2 to entry: This definition was derived from [10].
3.31
urine
liquid product of the human excretory system produced by the kidneys and expelled through the urethra via
urination (i.e. micturition)
[SOURCE: ISO 30500:2018, 3.1.2.3]
3.32
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended use
or application have been fulfilled
Note 1 to entry: The term “validated” is used to designate the corresponding status.
[SOURCE: ISO 9000:2015, 3.8.13, modified — Notes 1 and 3 to entry have been omitted.]
3.33
verification
confirmation, through the provision of objective evidence, that specified requirements have been fulfilled
Note 1 to entry: The term “verified” is used to designate the corresponding status.
Note 2 to entry: Confirmation can comprise activities such as:
— performing alternative calculations;
— comparing a new design specification with a similar proven design specification;

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
— undertaking tests and demonstrations; and
— reviewing documents prior to issue.
[SOURCE: ISO 9000:2015, 3.8.12, modified — Note 1 and Note 2 have been omitted.]
3.34
workflow
series of activities necessary to complete a task
[SOURCE: ISO 20166-1:2018, 3.30]
4 General requirements
For general statements on medical laboratory quality management systems and in particular on specimen
collection, reception and handling (including avoidance of cross contaminations) see ISO 15189 and
ISO/IEC 17020 or ISO/IEC 17025. ISO 20658 and ISO 20387 (for biobanking) can also apply. The requirements
on laboratory equipment, reagents, and consumables according to ISO 15189 shall be followed; ISO/IEC 17020
and ISO/IEC 17025 can also apply. For IVD developers and manufacturers ISO 13485 may apply instead.
All steps of the pre-examination, examination and post-examination processes (i.e. the entire workflow)
can influence the diagnosis or research study results, thus, this entire workflow shall be specified, verified
and validated during the development of the examination, including the development of in vitro diagnostic
(IVD) medical devices. This includes explicitly all pre-examination process steps such as the examination
request, preparation and identification of the patient, collection of the specimen(s), transport to and within
the laboratory, storage and isolation of analytes.
The stability of the cfDNA profile should be investigated throughout the complete pre-examination process.
The verification and validation shall account for the variability of the body fluid specimen's quality. cfDNA
profiles can change significantly after body fluid collection. The post-collection release of genomic DNA
from cells in the body fluid can change the cfDNA profile (see [11]). In some body fluids, such as urine, post-
collection growth of bacteria can cause additional changes to the cfDNA profile such as contaminating the
human cfDNA with bacterial DNA and causing degradation of target cfDNA. Post-collection conditions such
as large temperature variations and prolonged storage and/or transportation times can also result in cfDNA
degradation. Post-collection changes can vary individually in specimens from different donors or patients,
and they can also depend on pathophysiological conditions. This can impact the validity and reliability of the
examination results.
During the design and development of a cfDNA based examination, an appropriate risk assessment shall
be performed (see also ISO 14971, ISO 22367, ISO 35001). Mitigation measures for eliminating or reducing
identified risks shall be established where required for ensuring the performance of the examination. It
shall particularly be investigated and ensured that the cfDNA profile(s) intended to be examined is/are not
compromised during the pre-examination process in a manner impacting the examination performance.
To ensure the cfDNA profile is not compromised, it may be necessary to characterize whether and/or how
the profile intended to be examined changes during the pre-examination process steps (e.g. degradation
of target cfDNA, and the post-collection release of genomic DNA from present cells). This can be done, for
example by applying the intended examination to specimens/samples that have been subjected to pre-
examination steps such as transport and storage in time course studies (see Annex A). Measures can be
implemented to prevent or reduce impacts by the identified pre-examination variables, e.g. by using body
fluid collection devices with cfDNA stabilizers.
During the whole pre-examination process, precautions shall be taken to avoid cross contamination between
different specimens/samples (e.g. by using single-use material whenever feasible or appropriate cleaning
procedures between processing of different specimens/samples), and to avoid mixing up of specimens/
samples.
Safety instructions for the whole pre-examination process shall be in place and followed. Safety regulations
on specimen/sample transport and handling shall be considered (see ISO 15189, ISO 15190 and ISO 20658).
If transport is required over public areas, corresponding regulations or laws for packaging and transport
apply (e.g. International Air Transport Association (IATA) for air transport).

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
The manufacturer's material safety data sheet shall be considered before first use of any potentially
hazardous material (e.g. chemicals in stabilizers).
For all pre-examination steps, the examination manufacturer's instructions shall be followed, if provided.
Where, for justified reasons (e.g. unmet patient needs), a commercial product is not used in accordance with
the manufacturer's instructions, responsibility for its verification, validation, use and performance lies with
the laboratory.
5 Outside the laboratory
5.1 Specimen collection
5.1.1 Information about the patient or specimen donor
The documentation shall include the identity of the patient or specimen donor, which can be in the form of
the name or a code.
The documentation should include, but is not limited to:
a) the relevant health status (e.g. healthy, disease type, concomitant disease) and demographics of the
patient or specimen donor (e.g. age and gender);
b) the information about medical treatment and special treatment prior to body fluid collection (e.g.
anaesthetics, medications, fasting status, surgical or diagnostic procedures);
c) the type and the purpose of the examination requested;
d) the appropriate consent from the patient or specimen donor.
NOTE See ISO 15189 for further information. ISO 20658 provides additional general guidance on the entire
collection process.
5.1.2  Selection of the body fluid collection device by the laboratory
The cfDNA profile of body fluids can be influenced by e.g. inadequate collection procedures, inappropriate
storage/transport conditions, separation of contaminating cells as well as by cfDNA isolation procedures.
Specifically, the post-collection degradation can change the cfDNA profile in body fluids, e.g. in urine
[12],[13]
significantly . This can impact the validity of the examination results.
In order to prevent cfDNA degradation, bacterial growth and, where required, genomic DNA release from
cells, body fluid collection devices with cfDNA profile stabilizers, or devices without stabilizers with
immediate post-collection addition of stabilizers should be used. These stabilizers should also allow the
separation of nucleated cells from cfDNA in the body fluid, e.g. by centrifugation. Body fluid collection devices
without cfDNA profile stabilizers and workflows without immediate post-collection addition of cfDNA
stabilizers should only be used if the ordered examination specifications allow the non-use of stabilizers.
The examination manufacturer's instructions for use for the specimen collection shall be followed. Where
the cfDNA examination manufacturer requires usage of a dedicated body fluid collection device or body
fluid cfDNA stabilizer, these shall be used. This can include a transfer into a secondary container with a
stabilizer. The device's and stabilizers' catalogue and lot numbers shall be documented.
For specimens intended for extended storage in a biobank the individual human cfDNA examinations needed
are not always known in advance of extended storage. Therefore, body fluid collection devices with cfDNA
profile stabilizers or workflows with immediate post-collection addition of cfDNA stabilizers should be used
to enable the use of a wider range of examinations.

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
5.1.3  Urine and other body fluid specimen collection from the patient/donor and stabilization
procedures
5.1.3.1 General
The examination manufacturer shall specify, verify and validate the body fluid collection device for the
examination and shall provide instructions for use for the specimen collection procedure, either with or
where appropriate without stabilizers.
NOTE In some countries it is not a requirement of the examination manufacturer to provide such instructions for
use and to specify, verify and validate the body fluid collection device for the examination.
A cfDNA stabilizer should be used, to prevent any cfDNA profile changes during the pre-examination
process. This can be a collection device prefilled with a stabilizer or an external stabilizer can be added to
the collected urine or body fluid, e.g. from a bulk solution.
Where the specimen collection device is intended for self-collection and/or home collection, the collection
device manufacturer shall validate this device for these purposes. This shall include mitigating any potential
risks for the patient/donor from the cfDNA stabilizer where appropriate (see chapter 4).
The laboratory shall have written and/or visual instructions in place for body fluid collection. These shall
follow the examination manufacturer's instructions for use where provided.
Where the examination manufacturer's instructions are not provided (e.g. due to less stringent legal
frameworks), or where, for justified reasons (e.g. unmet patient needs), they require modifications, the
laboratory shall specify, verify and validate the body fluid collection device and collection procedure for
the intended examination and document this according to its quality management system requirements.
This shall include specifications for specimen storage and transport as required for the examination (see
5.1.4 and 5.2). Where the selected body fluid collection device manufacturer provides specified and verified
instructions (see 5.1.3.2 and 5.1.3.3) for the body fluid collection, these can serve as a basis for the laboratory
to verify this device for the examination.
Where the specifications given in the instructions for use of the selected body fluid collection device do not
meet the examination requirements during verification, they shall be modified to be fit for purpose, verified
and documented by the laboratory.
Where specimen self-collection is possible (e.g. saliva, urine), written and/or visual instructions, either
from the body fluid collection device manufacturer or the laboratory shall be supplied to the patient/
donor. Laboratory instructions shall be based on the body fluid collection device manufacturer's and/or the
examination manufacturer's requirements.
The instructions for body fluid specimen collection shall include:
1) Requirements and recommendations to follow before the collection, in particular related to e.g. drinking
and/or fasting before collection, or collection time, e.g. first midstream urine of the morning.
2) All requirements for patient identification, collection, storage and transport of the specimen to the
laboratory. For collection this shall include requirements
a) to collect the specimen within the specified volume range;
b) to mix the specimen with the stabilizer/s if required by the manufacturer, e.g. by immediate shaking
or inverting.
For self-collection, the patient/donor shall be provided with an appropriate body fluid collection device (e.g.
container, tube), identity tag(s) (e.g. label, RFID), and in general anything needed for the specimen collection,
preservation, storage and transport procedure for returning the specimen to laboratory.
The patient/donor shall also be provided with an option to confirm compliance with the supplied instructions
for the body fluid specimen collection, e.g. electronic, paper based.

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
The patient/donor or person collecting the specimen from the patient/donor shall confirm compliance with
the supplied instructions for the body fluid specimen collection.
The identity of any person other than the patient/donor collecting the specimen shall be documented. The
date and time of body fluid collection shall be documented.
For the labelling (sample/specimen identification) of the body fluid collection device, a routine procedure
(ISO 15189 for medical laboratories or ISO 20387 for biobanks) or a procedure with additional information
(e.g. 2D-barcode) shall be used.
Any alterations and/or additions to the specimen shall be documented.
5.1.3.2  Urine and other body fluid collection with cfDNA stabilizers
The cfDNA stabilizer manufacturer and, where the stabilizer is incorporated into a collection device, the
collection device manufacturer, shall specify, verify and validate the instructions for use for body fluid
collection and stabilization.
The specimen collection device manufacturer shall also specify and verify the specimen collection device
quality parameters, e.g. interference of device materials, stability of stabilizer during product shelf-life and
tightness of closures/caps.
The examination manufacturer shall determine the cfDNA target stability (see chapter 4).
The examination manufacturer's instructions and thereon built laboratory’s instructions for use can refer
to the instructions of the body fluid collection device and/or stabilizer provided by the manufacturer.
The person collecting the specimen from the patient/donor or the patient/donor self-collecting the specimen
shall follow the laboratory’s written instructions for use (see 5.1.3.1).
5.1.3.3  Urine and other body fluid collection without cfDNA stabilizers
The cfDNA profile can change rapidly post-collection and can thus impact the intended performance
characteristics of the examination. Therefore such collection devices shall only be used if they have been
specified, verified and validated for the specific examination.
The examination manufacturer's instructions and thereon built laboratory’s instructions for use can refer
to the instructions of the body fluid collection device without stabilizer provided by the manufacturer.
Where the manufacturer of the body fluid collection device without stabilizer does not provide such
instructions, the laboratory shall specify, verify and validate the instructions for use of the device for body
fluid collection for cfDNA examination. The laboratory shall write instructions for use and follow them.
The instructions can include cooling of the specimen to 2°C to 8°C or placing on wet ice, and transportation
to the laboratory without delay within a verified period of time. Otherwise microbial growth, cfDNA
degradation and contamination with genomic DNA, released from cells present in the body fluid can happen
and impact examination test results.
The person collecting the specimen from the patient/donor or the patient/donor self-collecting the specimen
shall follow the laboratory’s written instructions for use (see 5.1.3.1).
5.1.4  Information about the specimen storage requirements at the body fluid collection facility
5.1.4.1 General
The examination manufacturer shall specify, verify and validate the storage requirements and shall provide
instructions for specimen storage, either with (see 5.1.4.2) or where appropriate without stabilizers (see
5.1.4.3).
NOTE In several countries it is not a requirement to provide such instructions for use.

oSIST prEN ISO 18704:2024
ISO/DIS 18704:2024(en)
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