EN ISO 23500-3:2024
(Main)Preparation and quality management of fluids for haemodialysis and related therapies - Part 3: Water for haemodialysis and related therapies (ISO 23500-3:2024)
Preparation and quality management of fluids for haemodialysis and related therapies - Part 3: Water for haemodialysis and related therapies (ISO 23500-3:2024)
This document specifies the minimum chemical and microbiological quality requirements, for water used for preparation of dialysis fluids, concentrates, and for the reprocessing of haemodialysers, together with the necessary steps to ensure conformity with the requirements. The document also provides guidance for the ongoing monitoring of the purity of such water in terms of chemical and microbiological quality.
This document is applicable to
— water used in the preparation of dialysis fluids for haemodialysis, haemodiafiltration and haemofiltration and the reprocessing of haemodialysers, and
— water used in the preparation of concentrates.
This document does not apply to dialysis fluid regenerating systems.
The operation of water treatment equipment and the final mixing of treated water with concentrates to produce dialysis fluid are the sole responsibility of dialysis professionals.
Herstellung und Qualitätsmanagement von Flüssigkeiten für die Hämodialyse und verwandte Therapien - Teil 3: Wasser für die Hämodialyse und verwandte Therapien (ISO 23500-3:2024)
Dieses Dokument legt die Mindestanforderungen an die chemische und mikrobiologische Qualität von Wasser fest, das für die Zubereitung von Dialysierflüssigkeiten und -konzentraten sowie für die Wiederaufbereitung von Hämodialysatoren verwendet wird, sowie die notwendigen Schritte, um die Einhaltung der Anforderungen zu gewährleisten. Das Dokument gibt auch einen Leitfaden für die laufende Überwachung der Reinheit dieses Wassers in Bezug auf die chemische und mikrobiologische Qualität.
Dieses Dokument ist anwendbar für
- Wasser für die Zubereitung von Dialysierflüssigkeiten für die Hämodialyse, Hämodiafiltration und Hämofiltration sowie für die Wiederaufbereitung von Hämodialysatoren, und
- Wasser, das zur Herstellung von Konzentraten verwendet wird.
Dieses Dokument ist nicht anwendbar für Systeme zur Regeneration von Dialysierflüssigkeit.
Der Betrieb von Wasseraufbereitungsanlagen und die abschließende Vermischung von behandeltem Wasser mit Konzentraten zur Herstellung von Dialysierflüssigkeit liegen in der alleinigen Verantwortung der Dialysefachkräfte.
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies annexes - Partie 3: Eau pour hémodialyse et thérapies apparentées (ISO 23500-3:2024)
Le présent document spécifie les exigences minimales de qualité chimique et microbiologique applicables à l’eau utilisée pour la préparation des liquides de dialyse et des concentrés, ainsi que le traitement des hémodialyseurs. Il décrit également les étapes nécessaires pour garantir la conformité aux exigences. Le document fournit en outre des recommandations pour la surveillance continue de la pureté de cette eau à l’égard de la qualité chimique et microbiologique.
Le présent document est applicable à ce qui suit:
— l’eau utilisée pour la préparation des liquides de dialyse pour hémodialyse, hémodiafiltration et hémofiltration, ainsi que pour le retraitement des hémodialyseurs; et
— l’eau utilisée pour la préparation des concentrés.
Le présent document ne concerne pas les systèmes de régénération des liquides de dialyse.
Le fonctionnement de l’équipement de traitement de l’eau et le mélange final de l’eau traitée avec les concentrés pour produire le liquide de dialyse relèvent de l’entière responsabilité des néphrologues.
Priprava in vodenje kakovosti tekočin za hemodializo in podobne terapije - 3. del: Voda za hemodializo in podobne terapije (ISO 23500-3:2024)
Ta dokument določa minimalne zahteve glede vode, uporabljene pri hemodializi in podobnih terapijah.
Ta dokument zajema vodo za pripravo koncentratov, dializnih tekočin za hemodializo, hemodiafiltracijo in hemofiltracijo ter ponovno obdelavo v hemodializatorjih.
Ta dokument ne zajema postopka uporabe opreme za pripravo vode in končno mešanje pripravljene vode s koncentrati za proizvodnjo dializne tekočine. Za takšne postopke so izključno odgovorni strokovnjaki za dializo. Ta dokument se ne uporablja za sisteme za regeneracijo dializne tekočine.
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
01-julij-2024
Priprava in vodenje kakovosti tekočin za hemodializo in podobne terapije - 3. del:
Voda za hemodializo in podobne terapije (ISO 23500-3:2024)
Preparation and quality management of fluids for haemodialysis and related therapies -
Part 3: Water for haemodialysis and related therapies (ISO 23500-3:2024)
Herstellung und Qualitätsmanagement von Flüssigkeiten für die Hämodialyse und
verwandte Therapien - Teil 3: Wasser für die Hämodialyse und verwandte Therapien
(ISO 23500-3:2024)
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies
annexes - Partie 3: Eau pour hémodialyse et thérapies apparentées (ISO 23500-3:2024)
Ta slovenski standard je istoveten z: EN ISO 23500-3:2024
ICS:
11.040.40 Implantanti za kirurgijo, Implants for surgery,
protetiko in ortetiko prosthetics and orthotics
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
EN ISO 23500-3
EUROPEAN STANDARD
NORME EUROPÉENNE
April 2024
EUROPÄISCHE NORM
ICS 11.040.40 Supersedes EN ISO 23500-3:2019
English Version
Preparation and quality management of fluids for
haemodialysis and related therapies - Part 3: Water for
haemodialysis and related therapies (ISO 23500-3:2024)
Préparation et management de la qualité des liquides Herstellung und Qualitätsmanagement von
d'hémodialyse et de thérapies annexes - Partie 3: Eau Flüssigkeiten für die Hämodialyse und verwandte
pour hémodialyse et thérapies apparentées (ISO Therapien - Teil 3: Wasser für die Hämodialyse und
23500-3:2024) verwandte Therapien (ISO 23500-3:2024)
This European Standard was approved by CEN on 18 April 2024.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2024 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 23500-3:2024 E
worldwide for CEN national Members.
Contents Page
European foreword . 3
European foreword
This document (EN ISO 23500-3:2024) has been prepared by Technical Committee ISO/TC 150
"Implants for surgery" in collaboration with Technical Committee CEN/TC 205 “Non-active medical
devices” the secretariat of which is held by DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by October 2024, and conflicting national standards shall
be withdrawn at the latest by October 2024.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 23500-3:2019.
Any feedback and questions on this document should be directed to the users’ national standards
body/national committee. A complete listing of these bodies can be found on the CEN website.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the
United Kingdom.
Endorsement notice
The text of ISO 23500-3:2024 has been approved by CEN as EN ISO 23500-3:2024 without any
modification.
International
Standard
ISO 23500-3
Second edition
Preparation and quality
2024-04
management of fluids for
haemodialysis and related
therapies —
Part 3:
Water for haemodialysis and related
therapies
Préparation et management de la qualité des liquides
d'hémodialyse et de thérapies annexes —
Partie 3: Eau pour hémodialyse et thérapies apparentées
Reference number
ISO 23500-3:2024(en) © ISO 2024
ISO 23500-3:2024(en)
© ISO 2024
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
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Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii
ISO 23500-3:2024(en)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Requirements . 2
4.1 Dialysis water quality requirements .2
4.2 Chemical contaminant requirements.2
4.2.1 General .2
4.2.2 Organic carbon, pesticides and other chemicals .4
4.3 Dialysis water microbiological requirements .4
5 Tests for microbiological and chemical requirements . 4
5.1 Dialysis water microbiology .4
5.2 Microbial contaminant test methods .4
5.3 Chemical contaminants test methods .6
Annex A (informative) Rationale for the development and provisions of this document . 8
Bibliography .16
iii
ISO 23500-3:2024(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 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 150, Implants for surgery, Subcommittee
SC 2, Cardiovascular implants and extracorporeal systems, in collaboration with the European Committee for
Standardization (CEN) Technical Committee CEN/TC 205, Non-active medical devices, in accordance with the
Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This second edition cancels and replaces the first edition (ISO 23500-3:2019), which has been technically
revised.
The main changes are as follows:
— the use of WHO Drinking Water Guideline as the drinking water quality reference has replaced the
previously used EPA Water quality requirements;
— thallium has been removed from the list of contaminants of other trace elements in dialysis water as no
published study reports that this contaminant is of particular concern in the setting of haemodialysis;
— alternatives to classic microbial analytical methods (endotoxin testing using recombinant Factor C [rFC])
have been incorporated.
A list of all parts in the ISO 23500 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
ISO 23500-3:2024(en)
Introduction
Assurance of adequate water quality is one of the most important aspects of ensuring a safe and effective
delivery of haemodialysis, haemodiafiltration or haemofiltration.
This document contains the minimum chemical and microbiological requirements for the water to be used
for preparation of dialysis fluids and concentrates, and for the reprocessing of haemodialysers and the
necessary steps to ensure conformity with those requirements.
Haemodialysis and related therapies such as haemodiafiltration can expose the patient to more than
500 l of water per week across the semi-permeable membrane of the haemodialyser or haemodiafilter.
Healthy individuals seldom have a weekly oral intake above 12 l. This over 40-fold increase in exposure
requires control and regular surveillance of water quality to avoid excesses of known or suspected harmful
substances. Since knowledge of potential injury from trace elements and contaminants of microbiological
origin over long periods is still growing and techniques for treating drinking water are continuously
developed, this document will evolve and be refined accordingly. The physiological effects attributable to
the presence of organic contaminants in dialysis water are important areas for research, however, the effect
of such contaminants on patients receiving regular dialysis treatment is largely unknown, consequently no
threshold values for organic contaminants permitted in water used for the preparation of dialysis fluids,
concentrates and reprocessing of haemodialysers has been specified in this document.
Within this document, current measurement techniques at the time of publication have been cited. Other
standard methods can be used, provided that such methods have been appropriately validated and are
comparable to the cited methods.
The final dialysis fluid is produced from concentrates or salts manufactured, packaged and labelled
according to ISO 23500-4 mixed with water meeting the requirements of this document. The operation of
water treatment equipment and haemodialysis systems, including ongoing surveillance of the quality of
water used to prepare dialysis fluids, and handling of concentrates and salts are the responsibility of the
haemodialysis facility and are addressed in ISO 23500-1. Haemodialysis professionals make choices about
the various applications (haemodialysis, haemodiafiltration, haemofiltration) and should understand the
risks of each and the requirements for safety for fluids used for each.
This document is directed towards manufacturers and providers of water treatment systems and also to
haemodialysis facilities.
The rationale for the development of this document is given in Annex A.
v
International Standard ISO 23500-3:2024(en)
Preparation and quality management of fluids for
haemodialysis and related therapies —
Part 3:
Water for haemodialysis and related therapies
1 Scope
This document specifies the minimum chemical and microbiological quality requirements, for water used
for preparation of dialysis fluids, concentrates, and for the reprocessing of haemodialysers, together with
the necessary steps to ensure conformity with the requirements. The document also provides guidance for
the ongoing monitoring of the purity of such water in terms of chemical and microbiological quality.
This document is applicable to
— water used in the preparation of dialysis fluids for haemodialysis, haemodiafiltration and haemofiltration
and the reprocessing of haemodialysers, and
— water used in the preparation of concentrates.
This document does not apply to dialysis fluid regenerating systems.
The operation of water treatment equipment and the final mixing of treated water with concentrates to
produce dialysis fluid are the sole responsibility of dialysis professionals.
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 23500-1, Preparation and quality management of fluids for haemodialysis and related therapies — Part 1:
General requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 23500-1 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/
ISO 23500-3:2024(en)
4 Requirements
4.1 Dialysis water quality requirements
The quality of the dialysis water, as specified in 4.2 and 4.3, shall be verified upon installation of a water
treatment system. Regular surveillance of the dialysis water quality shall be carried out thereafter.
NOTE Throughout this document, it is assumed that the water undergoing treatment is potable water and
therefore meets the appropriate regulatory requirements for such water. If the water supply is derived from an
alternate source such as a privately-owned borehole or well, contaminant levels cannot be as rigorously controlled.
4.2 Chemical contaminant requirements
4.2.1 General
Dialysis water shall not contain chemicals at concentrations in excess of those listed in Tables 1 and 2.
Table 1 does not include any recommendation for organic carbon, pesticides and other chemicals such
as pharmaceutical products and endocrine disruptors that can be present in feed water. It is technically
difficult and costly to measure such substances on a routine basis. The effect of their presence on
haemodialysis patients is difficult to specify and consequences of exposure are probably of a long-term
nature. Furthermore, there is an absence of evidence of their widespread presence in water although it is
recognized that inadvertent discharges are possible. In view of this, it is not at present possible to specify
limits for their presence in water used in the preparation of dialysis fluid.
Nanofiltration and reverse osmosis are capable of significant rejection of many such compounds. Granular
activated carbon (GAC) is also highly effective at removing majority of these chemicals. However, as granular
activated carbon is widely used in the removal chlorine/chloramine, their use in the removal of organic
carbons, pesticides and other chemicals will be dependent upon the size of the carbon filters and/or beds
and users shall be aware of appropriate dimensioning since the majority of carbon valences can be already
occupied and not available for further removal activity.
NOTE 1 See Clause A.3 for an explanation of the values in Tables 1 and 2.
NOTE 2 The maximum allowable levels of contaminants listed in Tables 1 and 2 include the anticipated uncertainty
associated with the analytical methodologies listed in Table 4.
Where the dialysis water is used to reprocess haemodialysers (cleaning, testing and mixing of disinfectants),
the user is cautioned that the dialysis water shall meet the requirements of this document. The dialysis
water should be measured at the input to the dialyser reprocessing equipment.
ISO 23500-3:2024(en)
a
Table 1 — Maximum allowable levels of toxic chemicals and dialysis fluid electrolytes in dialysis water
b
Maximum concentration
Contaminant
mg/l
Contaminants with documented toxicity in haemodialysis
Aluminium 0,01
c
Total chlorine 0,1
Copper 0,1
Fluoride 0,2
Lead 0,005
Nitrate (as N) 2
Sulfate 100
Zinc 0,1
Electrolytes normally included in dialysis fluid
Calcium 2 (0,05 mmol/l)
Magnesium 4 (0,15 mmol/l)
Potassium 8 (0,2 mmol/l)
Sodium 70 (3,0 mmol/l)
a
A physician in charge of dialysis has the ultimate responsibility for ensuring the quality of water used for dialysis.
b
The reader is cautioned to refer to the latest edition of this document to ensure that there have been no changes to this table.
b
Unless otherwise indicated.
c
When chlorine is added to water, some of the chlorine reacts with organic materials and metals in the water and is not
available for disinfection (i.e. the chlorine demand of the water). The remaining chlorine is the total chlorine and is the sum of
free or non-bound chlorine and combined chlorine.
Total chlorine is usually measured on site by appropriately trained personnel in water prior to entering the treatment system.
Additional measurements in the treated water are not necessary provided that the pre-treatment concentration level is below
the permitted limit.
There is no direct method for the measurement of chloramine. It is generally established by measuring total and free chlorine
concentrations and calculating the difference. When total chlorine tests are used as a single analysis the maximum level for both
chlorine and chloramine shall not exceed 0,1 mg/l. Since there is no distinction between chlorine and chloramine, this safely
assumes that all chlorine present is chloramine.
NOTE The maximum allowable levels of contaminants listed include the anticipated uncertainty associated with the analytical
methodologies used to establish the values shown.
Table 2 — Maximum allowable levels of other trace elements in dialysis water
a
Contaminant Maximum concentration
mg/l
Antimony 0,006
Arsenic 0,005
Barium 0,1
Beryllium 0,000 4
Cadmium 0,001
Chromium 0,014
Mercury 0,000 2
Selenium 0,09
Silver 0,005
a
The reader is cautioned to refer to the latest edition of this document to ensure that no changes have been made to the
maximum concentrations shown.
NOTE The maximum allowable levels of contaminants listed in include the anticipated uncertainty associated with the
analytical methodologies to establish the values shown.
ISO 23500-3:2024(en)
4.2.2 Organic carbon, pesticides and other chemicals
The presence of organic compounds, such as pesticides, polycyclic aromatic hydrocarbons and other
chemicals such as pharmaceutical products and endocrine disruptors in respect of haemodialysis patients
are difficult to specify. Consequences of exposure are probably of a long-term nature and it is technically
difficult and costly to measure these substances on a routine basis. Furthermore, there is an absence of
evidence of their widespread presence in water although it is recognized that inadvertent discharges are
possible. In view of this, it is at present not possible to specify limits for their presence in water used in the
preparation of dialysis fluid.
4.3 Dialysis water microbiological requirements
Total viable microbial counts in dialysis water shall be less than 100 CFU/ml. An action level shall be set
based on knowledge of the microbial dynamics of the system. Typically, the action level will be 50 % of the
maximum allowable level.
Endotoxin content in dialysis water shall be less than 0,25 EU/ml. An action level shall be set, typically at
50 % of the maximum allowable level.
Fungi (yeasts and filamentous fungi) can coexist with bacteria and endotoxin in the dialysis water. Further
studies on the presence of fungi in haemodialysis water systems, their role in biofilm formation and their
clinical significance are required and in view of this, no recommendation in respect of permitted maximum
limits is made.
Some integrated, validated systems, and other new systems by alternative design can provide ultrapure
dialysis water with <0,1 CFU/ml and <0,03 EU/ml. By mixing with sterile and non-pyrogenic concentrates
and by utilising sterile and non-pyrogenic dialysis fluid pathway, ultrapure dialysis fluid can be produced in
such integrated and validated systems.
NOTE See Clause A.4 for a history of these requirements.
5 Tests for microbiological and chemical requirements
5.1 Dialysis water microbiology
Samples shall be collected where a dialysis machine connects to the water distribution loop, and from a
sample point in the distal segment of the loop or where such water enters a mixing tank.
Samples should be analysed as soon as possible after collection to avoid unpredictable changes in the
microbial population. If samples cannot be analysed within 4 h of collection, they should be stored at <10 °C
without freezing until ready to transport to the laboratory for analysis. Sample storage for more than 24 h
should be avoided and sample shipping should be done according to the laboratory’s instructions.
Total viable counts (standard plate counts) shall be obtained using conventional microbiological assay
procedures (pour plate, spread plate, membrane filter techniques). Membrane filtration is the preferred
method for this test. Other methods may be used, provided that such methods have been appropriately
validated and are comparable to the cited methods. The use of the calibrated loop technique is not acceptable.
5.2 Microbial contaminant test methods
Methodology to establish microbial contaminant levels is given in Table 3. Such methods provide only a
relative indication of the bioburden rather than an absolute measure.
Recommended methods and cultivation conditions can also be found in ISO 23500-4 and ISO 23500-5 as well
as this document (see Table 3). The methodology detailed uses tryptone glucose extract agar (TGEA) and
Reasoner’s agar no. 2 (R2A) incubated at 17 °C to 23 °C for 7 d and tryptic soy agar (TSA) at an incubation
[17]
temperature of 35 °C to 37 °C and an incubation time of 48 h. The background for the inclusion of TSA for
dialysis water and dialysis fluid used for standard dialysis is explained in Clause A.4.
ISO 23500-3:2024(en)
Different media types and incubation periods can result in varying colony concentrations and types of
[18]-[21]
microorganisms recovered. Furthermore, the use of R2A has been shown to result in higher colony
counts than TSA for dialysis water and dialysis fluids samples. In a more recent publication, the authors
indicated that there were no significant differences when comparing the microbial burden of dialysis water
and dialysis fluid used for the standard dialysis fluid yielding colony counts ≥50 CFU/ml when assayed using
[17]
R2A incubated at 17 °C to 23 °C for 7 d and TSA incubated at 35 °C to 37 °C for 48 h.
Historic studies with TGEA incubated at 17 °C to 23 °C for a period of 7 d also yielded higher colony counts
[17]
than TSA. Maltais et al. in their comparison of TGEA with TSA showed that the proportion of dialysis
water samples yielding colony counts ≥50 CFU/ml was significantly different from that found using TSA at
an incubation temperature of 35 °C to 37 °C and an incubation time of 48 h (p = 0,001). The proportions of
dialysis fluid samples in which microbial burden was ≥50 CFU/ml were not significantly different on the two
media and incubation conditions.
The culture medium and incubation times selected should be based on the type of fluid to be analysed for
example, standard dialysis fluid, water used in the preparation of standard dialysis fluid, ultrapure dialysis
fluid, water used for the preparation of ultrapure dialysis fluid or fluid used for online therapies such as
haemodiafiltration. The method selected, should be based on the analysis of the advantages, disadvantages
and sensitivity, of each of the methods detailed above in this subclause. According to the United States
Pharmacopeia (USP), the decision to use longer incubation times should be made after balancing the need
for timely information and the type of corrective actions required when the alert or action level is exceeded
with the ability to recover the microorganisms of interest. The advantages gained by incubating for longer
times namely recovery of injured microorganisms, slow growers, or more fastidious microorganisms, should
be balanced against the need to have a timely investigation and take corrective action, as well as the ability
of these microorganisms to detrimentally affect products or processes (e.g. patient safety). Other methods
may be used, provided that such methods have been appropriately validated and are comparable to the cited
methods. Blood agar and chocolate agar shall not be used.
Currently, there are no requirements for routine surveillance for the presence of fungi (i.e. yeasts and
filamentous fungi) which can coexist with other microbial species, however if an indication of their
presence is required, membrane filtration is the preferred method to provide a sample suitable for analysis.
Culture media used should be Sabouraud or malt extract agar (MEA) media. Other methods may be used,
provided that such methods have been appropriately validated and are comparable to the cited methods.
An incubation temperature of 17 °C to 23 °C and an incubation time of 168 h (7 d) are recommended. Other
incubation times and temperatures can be used, provided it has been demonstrated that such methods have
been appropriately validated and are comparable to the cited methods.
Microbial endotoxins are assayed using the Limulus amoebocyte lysate (LAL) test. Current pharmacopoeias
(USP, European and Japanese pharmacopoeias) acknowledge different testing techniques.
The most frequently used test for microbial endotoxins, the LAL test is based on the humoral coagulation
cascade of the horseshoe crab Limulus polyphemus. The first enzyme in this coagulation cascade reacts with
endotoxin and is called Factor C. This factor is now produced recombinantly (i.e. using biotechnology) and
offered as the rFC test by several manufacturers for the determination of microbial endotoxins. Compared
to the LAL test, the rFC test has proven to be at least as sensitive and reliable, but less susceptible to certain
interfering factors and batch fluctuations. Due to biotechnological production, no live animals are required
as blood donors.
This new method has been incorporated into the European Pharmacopoeia (Ph.Eur) (<2.6.32> Endotoxins
[44]
using recombinant factor C) , the Japanese Pharmacopeia ( Bacterial Endotoxins Test and
[45]
Alternative Methods using Recombinant Protein-reagents for Endotoxin Assay) and the USP and the
National Formulary (USP–NF) (<1085.1> Use of Recombinant Reagents in the Bacterial Endotoxins Test -
[46]
Photometric and Fluorometric Methods Using Recombinantly Derived Reagents) .
ISO 23500-3:2024(en)
Table 3 — Culture techniques
Culture medium Incubation temperature Incubation time
TGEA 17 °C to 23 °C 7 d
R2A 17 °C to 23 °C 7 d
a
Sabouraud or malt extract agar 17 °C to 23 °C 7 d
b
TSA 35 °C to 37 °C 48 h
a
Intended for the quantification of yeasts and filamentous fungi. Currently, there are no requirements in this document for their routine
surveillance; they have been included for completeness.
b [11]
The use of TSA has only been validated for dialysis water and standard dialysis fluid.
5.3 Chemical contaminants test methods
Conformity with the requirements listed in Table 1 and 2 can be shown by using the chemical analysis
methods detailed in Table 4 or by any other equivalent validated analytical method. Where testing for the
individual trace elements listed in Table 2 is not available, and the source water can be demonstrated to
[16]
meet the standards for potable water as specified by the WHO , an analysis for total heavy metals can be
used with a maximum allowable level of 0,1 mg/l. If neither of these options is available, conformity with
the requirements of Table 2 can be met by using water that can be demonstrated to meet the potable water
requirements of the WHO and a reverse osmosis system with a rejection of >90 % based on conductivity,
resistivity or TDS. Samples shall be collected at the end of the water purification cascade or at the most
distal point in each water distribution loop.
Table 4 — Analytical test methods for chemical contaminants
Contaminant Analytical technique Reference, method
Inductively coupled plasma mass spectrometry (ICP-MS) or atomic absorption
[4] [14]
Aluminium ISO 17294-2 , APHA Method 3113
(electrothermal)
[4] [9]
Antimony ICP-MS or atomic absorption (platform) ISO 17294-2 , EPA Method 200.7
[4] [14]
Arsenic ICP-MS or atomic absorption (gaseous hydride) ISO 17294-2 , APHA Method 3114
[4] [14]
Barium ICP-MS or atomic absorption (electrothermal) ISO 17294-2 , APHA Method 3113
[4] [9]
Beryllium ICP-MS or atomic absorption (platform) ISO 17294-2 , EPA Method 200.7
[4] [14]
Cadmium ICP-MS or atomic absorption (electrothermal) ISO 17294-2 , APHA Method 3113
[4] [14]
ICP-MS or ethylene diamine tetraacetic acid (EDTA) titrimetric method or ISO 17294-2 , APHA Method 3500-Ca D ,
Calcium
[14]
atomic absorption (direct aspiration) or ion specific electrode APHA Method 3111B
N-diethyl-p-phenylenediamine (DPD) ferrous titrimetric method or DPD
[14]
APHA Method 4500-Cl F ,
Total chlorine colorimetric method or Thio-Michler’s Ketone (TMK/MTK) colorimetric
[14]
APHA Method 4500-Cl G
method
[4] [14]
Chromium ICP-MS or atomic absorption (electrothermal) ISO 17294-2 , APHA Method 3113
[4] [14]
ISO 17294-2 , APHA Method 3111 ,
Copper ICP-MS or atomic absorption (direct aspiration) or neocuproine method
[14]
APHA Method 3500-Cu D
[2] [3]
Ion chromatography or ion selective electrode method or sodium 2- ISO 10304-1 , ISO 10359-1 ,
- [14]
Fluoride (parasulfophenylazo)-1,8-dihydroxy-3,6-naphthalenedisulfonate (SPADNS) APHA Method 4500-F C ,
- [14]
method APHA Method 4500-F D
[4] [14]
Lead ICP-MS or atomic absorption (electrothermal) ISO 17294–2 , APHA Method 3113
[4] [14]
ISO 17294–2 , APHA Method 3111 , EPA
Magnesium ICP-MS or atomic absorption (direct aspiration) or ion chromatography
[8]
300.7
[14]
Mercury Flameless cold vapour technique (atomic absorption) APHA Method 3112
[2] [1]
Ion chromatography or spectrophotometric method using sulfosalicylic acid or ISO 10304–1 , ISO 7890-3 ,
Nitrate
[14]
cadmium reduction method APHA Method 4500-NO E
[3] [14]
ISO 17294-2 , APHA Method 3111 ,
Inductively coupled plasma mass spectrometry or atomic absorption
[14]
Potassium APHA Method 3500-K D ,
(direct aspiration) or flame photometric method or ion specific electrode
[14]
APHA Method 3500-K E
[4] [14]
ICP-MS or atomic absorption (gaseous hydride) ISO 17294-2 , APHA Method 3114 ,
Selenium
[14]
or atomic absorption (electrothermal) APHA Method 3113
Inductively coupled plasma mass spectromety
[4] [14]
Silver ISO 17294-2 , APHA Method 3113
or atomic absorption (electrothermal)
[4] [14]
ICP-MS or atomic absorption (direct aspiration) or flame photometric method ISO 17294-2 , APHA Method 3111 ,
Sodium
[14]
or ion specific electrode APHA method 3500-Na D
ISO 23500-3:2024(en)
TTaabblle 4 e 4 ((ccoonnttiinnueuedd))
Contaminant Analytical technique Reference, method
[3] 2- [14]
Sulfate Ion chromatography or turbidimetric method ISO 10304-1 , APHA Method 4500-SO E
[13]
European Pharmacopoeia, 5.20 ,
Total heavy
[13]
Colorimetric method European Pharmacopoeia 2.4.20 ,
metals
[10] [11]
USP–NF <232> , USP–NF <233>
[4] [14]
ISO 17294-2 , APHA Method 3111 ,
Zinc ICP-MS or atomic absorption (direct aspiration) or dithizone method
[14]
APHA Method 3500-Zn D
ISO 23500-3:2024(en)
Annex A
(informative)
Rationale for the development and provisions of this document
A.1 General
Water treated according to the requirements of this document is predominantly used for the preparation of
dialysis fluid but can also be used for other applications such as the reprocessing of haemodialysers intended
for multiple use. When dialysis water is mixed with concentrated electrolyte solutions manufactured
according to ISO 23500-4, the requirements detailed in ISO 23500-5 apply.
A.2 Feed water
The water used in the preparation of dialysis fluid usually originates as potable water from a municipal
water supply, although in some instances the water can be from a local borehole or well. Potable water
complies with the WHO Guidelines for drinking water, or its local equivalent. These requirements specify
the permitted water contaminants and their levels. As dialysis patients are exposed to larger volumes of
water than the general population, the water needs to undergo additional treatment to reduce any risk from
water contaminants and to meet the appropriate requirements detailed in 4.2 and 4.3.
If the feed water to the water treatment infrastructure is via an indirect feed, for example, a hospital water
system, disinfectants and antimicrobial agents can be added to supress the development of legionella
within the water system. Commonly used agents include hydrogen peroxide and silver stabilized hydrogen
peroxide. Unintended exposure to both have resulted in adverse events in dialysis patients as remaining
residues cannot be removed by reverse osmosis and rely on the use of activated carbon.
If drinking water has chlorine and/or chloramine added to minimize bacterial content, both of these
compounds are toxic to dialysis patients and are removed by the water treatment system as outlined in
ISO 23500-2. Removal of those compounds renders the water susceptible to microbial proliferation and
biofouling unless appropriate preventative measures are taken as outlined in ISO 23500-1.
While the majority of bacteria in the feed water are faecal in origin and the measures that the water
utility takes are intended to minimize their proliferation, the feed water can also contain other microbial
compounds such as cyanotoxins that occur in the presence of cyanobacteria or blue green algae.
Cyanotoxins are considered natural contaminants that occur worldwide. Specific classes of cyanotoxins
have shown regional prevalence. The Americas encompassing North Central and South America often show
high concentrations of microcystin, anatoxin-a and cylindrospermopsin in freshwater, whereas those in
Australia often show high concentrations of microcystin, cylindrospermopsin and saxitoxins. Other less
frequently reported cyanotoxins include lyngbyatoxin A, debromoaplysiatoxin and beta-N-methylamino-L-
[17]
alanine. Cyanobacterial blooms usually occur according to a combination of environmental factors, for
example, nutrient concentration, water temperature, light intensity, salinity, water movement, stagnation
and residence time, as well as several other variables. Cyanotoxins are primarily produced intracellularly
during the exponential growth phase. Release of toxins into water can occur during cell death or senescence
but can also be due to evolutionary-derived or environmentally-mediated circumstances such as allelopathy
[22]
or relatively sudden nutrient limitation .
In many countries, cyanotoxins have been viewed primarily as a recreational water issue. However, there is
a growing awareness of the public health risk they pose in drinking water and thus the need to monitor and
remove cyanotoxins in the drinking water treatment process. The WHO has established a suggested drinking
water guideline value of 1 μg/l and a recreational exposure guideline value of 10 μg/l for microcystin-LR.
Health Canada has also published a drinking water standard of 1,5 μg/l for microcystin-LR, while in the
United States, the EPA has developed health advisory recommendations for concentrations of cyanotoxins in
ISO 23500-3:2024(en)
drinking water, namely that for adults, the recommended levels for drinking water are at or below 1,6 μg/l
for microcystins and 3,0 μg/l for cylindrospermopsin.
Currently, water utilities do not regularly look for cyanobacterial toxins in the water supply unless
cyanobacteria are present in the source water. Once cyanobacteria are detected in the water supply,
treatment can remove them using a variety of different methods, such as clarification or membrane filtration,
adsorption on activated carbon or reverse osmosis and chemical oxidation by ozonation or chlorination.
A.3 Chemical contaminants in dialysis water
A.3.1 General
Chemical contaminants present in potable water can pose a risk to the patient receiving dialysis treatment.
Contaminants identified as needing restrictions on their allowable level compared with potable water have
been divided into three groups for the purposes of this document:
a) chemicals known to cause toxicity in dialysis patients,
b) physiological substances that can adversely affect the patient if present in the dialysis fluid in excessive
amounts, and
c) trace elements.
A.3.2 Chemicals known to cause toxicity in dialysis patients
Chemicals known to cause toxicity to dialysis patients include those which are added to drinking water for
public health benefits. Fluoride can be present naturally in potable water or be added in low concentrations
to minimize dental caries. The maximum limit for this compound in drinking water is set at 1,5 mg/l. The
toxicity of fluoride in dialysis patients at the levels present in fluoridated water, is questionable. In the
absence of a consensus on fluoride's role in uraemic bone disease, it was initially thought prudent to restrict
the fluoride level of dialysis fluid. Isolated cases of acute exposure of dialysis patients to elevated levels
of fluoride has been described in the scientific literature. Fluoride levels of up to 50 mg/l were found in
water used for dialysis that was treated only with a water softener. In another case, where deionizers were
allowed to exhaust, 12 of 15 patients became acutely ill from fluoride intoxication and three of the patients
died from ventricular fibrillation. In another publication, the death of one patient was reported as a result of
[23]
accidental over fluoridation of a municipal water supply .
Aluminium is toxic to haemodialysis patients. Salts of aluminium, such as alum, are added to drinking
water in order to facilitate chemical precipitation and flocculation of colloidal particles (turbidity). In
[24]
haemodialysis patients, exposure to aluminium can result i
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