EN ISO 23500-4:2024
(Main)Preparation and quality management of fluids for haemodialysis and related therapies - Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2024)
Preparation and quality management of fluids for haemodialysis and related therapies - Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2024)
This document specifies the chemical and microbiological requirements for concentrates used for haemodialysis and related therapies and applies to the manufacturer of such concentrates.
This document is applicable to:
— concentrates in both liquid and powder forms;
— additives, also called spikes, which are chemicals that can be added to the concentrate to supplement or increase the concentration of one or more of the existing ions in the concentrate and thus in the final dialysis fluid;
— equipment used to mix acid and bicarbonate powders into concentrate at the user's facility.
This document does not apply to:
— concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility;
— pre-packaged and sterile dialysis fluid;
— sorbent dialysis fluid regeneration systems that regenerate and recirculate small volumes of the dialysis fluid;
— equipment to perform patient treatment; this is addressed IEC 60601-2-16.
This document does not cover the dialysis fluid that is used to clinically dialyse patients. Dialysis fluid is covered in ISO 23500-5. The making of dialysis fluid involves the proportioning of concentrate and water at the bedside or in a central dialysis fluid delivery system. Although the label requirements for dialysis fluid are placed on the labelling of the concentrate, it is the user's responsibility to ensure proper use.
Herstellung und Qualitätsmanagement von Flüssigkeiten für die Hämodialyse und verwandte Therapien - Teil 4: Konzentrate für die Hämodialyse und verwandte Therapien (ISO 23500-4:2024)
Dieses Dokument legt die chemischen und biologischen Anforderungen an Konzentrate für die Hämodialyse und verwandte Therapien fest und gilt für Hersteller dieser Konzentrate.
Dieses Dokument ist anwendbar für:
- Konzentrate sowohl in Flüssig als auch in Pulverform;
- Zusätze, auch Spikes genannt. Dies sind Chemikalien, die dem Konzentrat hinzugefügt werden können, um eine oder mehrere der im Konzentrat vorkommenden Ionen und somit auch in der fertigen Dialysierflüssigkeit zu ergänzen oder zu erhöhen:
- Geräte zum Mischen von Säure und Bicarbonatpulver zur Herstellung von Konzentrat in der Einrichtung des Anwenders.
Dieses Dokument ist nicht anwendbar für:
- Konzentrate aus vorverpackten Salzen sowie Wasser in einer Dialyseeinrichtung zur Verwendung in der Dialyseeinrichtung;
- vorverpackte Beutel mit steriler Dialysierflüssigkeit;
- sorbensbasierte Dialysierflüssigkeits Wiederaufbereitungssysteme, die geringe Volumen der Dialysierflüs¬sigkeit wiederaufbereiten und wieder in Umlauf bringen;
- Geräte für die Behandlung von Patienten. Dies ist Gegenstand der IEC 60601 2 16.
Dieses Dokument behandelt nicht die Dialysierflüssigkeit, die zur klinischen Dialyse bei Patienten verwendet wird. Dialysierflüssigkeit wird in ISO 23500 5 definiert. Die Herstellung von Dialysierflüssigkeit beinhaltet die Dosierung von Konzentraten und Wasser am Krankenbett oder in einem zentralen Dialysierflüssigkeits Zufuhrsystem. Obwohl die Etikettenanforderungen an Dialysierflüssigkeiten auf dem Etikett des Konzentrats vermerkt sind, liegt die Verantwortung für dessen sachgemäße Benutzung beim Anwender.
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies annexes - Partie 4: Concentrés pour hémodialyse et thérapies apparentées (ISO 23500-4:2024)
Le présent document spécifie les exigences chimiques et microbiologiques pour les concentrés utilisés à des fins d’hémodialyse et thérapies apparentées, et s’applique au fabricant de ces concentrés.
Le présent document est applicable à ce qui suit :
— les concentrés sous forme de liquide et de poudre ;
— les additifs, également appelés dopants, qui sont des substances chimiques pouvant être ajoutées au concentré pour enrichir ou augmenter la concentration d’un ou de plusieurs ions existants dans le concentré, et donc dans le liquide de dialyse final ;
— l’appareil utilisé pour mélanger les poudres d’acide et de bicarbonate dans le concentré au sein de l’installation de l’utilisateur.
Le présent document ne s’applique pas à ce qui suit :
— les concentrés préparés à partir d’eau de dialyse et de sels préemballés produits au centre de dialyse en vue d’être utilisés dans ce centre ;
— le liquide de dialyse stérile et préemballé ;
— les systèmes de régénération de liquide de dialyse sorbants qui régénèrent et recyclent de petites quantités de liquide de dialyse ;
— l’équipement nécessaire au traitement du patient, qui est couvert par l’IEC 60601-2-16.
Le présent document ne concerne pas les liquides de dialyse utilisés pour la dialyse clinique des patients. Le liquide de dialyse est traité dans l’ISO 23500-5. La production de liquides de dialyse implique le dosage de concentré et d’eau au chevet du patient ou dans un système de distribution de liquide de dialyse centralisé. Bien que les exigences d’étiquetage des liquides de dialyse portent sur l’étiquetage du concentré, il est de la responsabilité de l’utilisateur d’en garantir la bonne utilisation.
Priprava in vodenje kakovosti tekočin za hemodializo in podobne terapije - 4. del: Koncentrati za hemodializo in podobne terapije (ISO 23500-4:2024)
Ta dokument določa minimalne zahteve glede koncentratov za hemodializo in podobne terapije.
Ta dokument je namenjen proizvajalcem takšnih koncentratov. V nekaterih izdajah tega dokumenta je obravnavana dializna tekočina, ki jo pripravi končni uporabnik, da bi s tem pojasnili zahteve za proizvodnjo koncentratov. Ker proizvajalec koncentrata nima nadzora nad končno dializno tekočino, so vsi sklici na dializno tekočino namenjeni pojasnitvi in ne predstavljajo zahteve za proizvajalca.
Ta dokument zajema koncentrate v obliki tekočin in praškov. Zajema tudi aditive, imenovane tudi dodatki, ki so kemična sredstva za dodajanje h koncentratu, s čimer se dopolni ali poveča koncentracija enega ali več obstoječih ionov v koncentratu in s tem tudi v končni dializni tekočini.
Ta dokument podaja tudi zahteve za opremo za mešanje kislin in bikarbonatnih praškov v koncentrat v uporabnikovi opremi.
Koncentrati, pripravljeni v dializni opremi iz vnaprej pakiranih soli in vode, ki se uporabljajo v takšni opremi, ne spadajo na področje uporabe tega dokumenta. Čeprav se v tem dokumentu pojavljajo sklici na dializno tekočino, ta dokument ne obravnava dializne tekočine, kot jo pripravi končni uporabnik. Ta dokument prav tako ne vsebuje zahtev glede pogostosti nadzora za čistost vode, ki se uporablja za pripravo dializne tekočine v dializni opremi. Ta dokument ne obravnava vrečk v sistemih za regeneracijo sterilne dializne tekočine ali sorbentne dializne tekočine, ki regenerirajo in recirkulirajo majhne količine dializne tekočine.
Ta dokument ne zajema dializne tekočine, ki se uporablja pri klinični dializi bolnikov. Dializna tekočina je obravnavana v standardu ISO 23500-5. Priprava dializne tekočine vključuje določanje deleža koncentrata in vode v obposteljnih in centralnih sistemih dovajanja dializne tekočine. Čeprav so zahteve o označevanju za dializno tekočino navedene na etiketi koncentrata, je uporabnik odgovoren, da zagotovi pravilno uporabo.
Ta dokument ne zajema opreme za hemodializo, ki je obravnavana v standardu IEC 60601-2-16:2012.
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
01-julij-2024
Priprava in vodenje kakovosti tekočin za hemodializo in podobne terapije - 4. del:
Koncentrati za hemodializo in podobne terapije (ISO 23500-4:2024)
Preparation and quality management of fluids for haemodialysis and related therapies -
Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2024)
Herstellung und Qualitätsmanagement von Flüssigkeiten für die Hämodialyse und
verwandte Therapien - Teil 4: Konzentrate für die Hämodialyse und verwandte
Therapien (ISO 23500-4:2024)
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies
annexes - Partie 4: Concentrés pour hémodialyse et thérapies apparentées (ISO 23500-
4:2024)
Ta slovenski standard je istoveten z: EN ISO 23500-4:2024
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 23500-4
EUROPEAN STANDARD
NORME EUROPÉENNE
April 2024
EUROPÄISCHE NORM
ICS 11.040.40 Supersedes EN ISO 23500-4:2019
English Version
Preparation and quality management of fluids for
haemodialysis and related therapies - Part 4: Concentrates
for haemodialysis and related therapies (ISO 23500-
4:2024)
Préparation et management de la qualité des liquides Herstellung und Qualitätsmanagement von
d'hémodialyse et de thérapies annexes - Partie 4: Flüssigkeiten für die Hämodialyse und verwandte
Concentrés pour hémodialyse et thérapies apparentées Therapien - Teil 4: Konzentrate für die Hämodialyse
(ISO 23500-4:2024) und verwandte Therapien (ISO 23500-4:2024)
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 23500-4:2024 E
worldwide for CEN national Members.
Contents Page
European foreword . 3
European foreword
This document (EN ISO 23500-4:2024) 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 23500-4:2019.
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 23500-4:2024 has been approved by CEN as EN ISO 23500-4:2024 without any
modification.
International
Standard
ISO 23500-4
Second edition
Preparation and quality
2024-04
management of fluids for
haemodialysis and related
therapies —
Part 4:
Concentrates for haemodialysis and
related therapies
Préparation et management de la qualité des liquides
d'hémodialyse et de thérapies annexes —
Partie 4: Concentrés pour hémodialyse et thérapies apparentées
Reference number
ISO 23500-4:2024(en) © ISO 2024
ISO 23500-4:2024(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 23500-4:2024(en)
Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Requirements . 2
4.1 Concentrates .2
4.1.1 Physical state .2
4.1.2 Water .3
4.1.3 Bacteriology of concentrates .3
4.1.4 Endotoxin levels .3
4.1.5 Fill quantity . .3
4.1.6 Chemical grade . .3
4.1.7 Particulates .4
4.1.8 Additives — “Spikes” .4
4.1.9 Containers .4
4.1.10 Bulk-delivered concentrate .4
4.1.11 Concentrate generators .4
4.2 Manufacturing equipment .5
4.3 Systems for bulk mixing concentrate at a dialysis facility .5
4.3.1 General .5
4.3.2 Materials compatibility .5
4.3.3 Disinfection protection.5
4.3.4 Safety requirements .6
4.3.5 Bulk storage tanks .6
4.3.6 Ultraviolet irradiators .6
4.3.7 Piping systems.6
4.3.8 Electrical safety requirements .6
5 Tests . 7
5.1 General .7
5.2 Concentrates .7
5.2.1 Physical state .7
5.2.2 Solute concentrations .7
5.2.3 Water .8
5.2.4 Microbial contaminant test methods for bicarbonate concentrates.8
5.2.5 Endotoxin levels .8
5.2.6 Fill quantity . .9
5.2.7 Chemical grade . . .9
5.2.8 Particulates .9
5.2.9 Additives — “Spikes” .9
5.2.10 Containers .9
5.2.11 Bulk delivered concentrate .9
5.2.12 Concentrate generators .9
5.3 Manufacturing equipment .10
5.4 Systems for mixing concentrate at a dialysis facility .10
5.4.1 General .10
5.4.2 Materials compatibility .10
5.4.3 Disinfection protection.10
5.4.4 Safety requirements .10
5.4.5 Bulk storage tanks .10
5.4.6 Ultraviolet irradiators .10
5.4.7 Piping systems.11
5.4.8 Electrical safety requirements .11
iii
ISO 23500-4:2024(en)
6 Labelling .11
6.1 General .11
6.2 General labelling requirements for concentrates .11
6.3 Labelling requirements for liquid concentrate . 12
6.4 Labelling requirements for powder concentrate . 13
6.5 Additives . 13
6.6 Labelling requirements for concentrate generators . 13
6.7 Labelling for concentrate mixer systems.14
6.7.1 General .14
6.7.2 Product literature for concentrate mixers . 15
Annex A (informative) Rationale for the development and provisions of this document .16
Bibliography .22
iv
ISO 23500-4:2024(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 23500-4:2019), which has been technically
revised.
The main changes are as follows:
— alternatives to classic microbial analytical methods [endotoxin testing using rFC (tp)] have been
incorporated;
— further clarifications on the use of concentrates spikes and containers have been added.
A list of all parts of 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.
v
ISO 23500-4:2024(en)
Introduction
The requirements established in this document will help ensure the effective, safe performance of
haemodialysis concentrates and related materials. Haemodialysis concentrates are a mixture of chemicals
and water, or chemicals in the form of dry powder or other highly concentrated media, which are delivered
to the end user to make dialysis fluid used to perform haemodialysis and related therapies. In this document,
the dialysis fluid made by the end user mixing haemodialysis concentrate and water of the quality given in
ISO 23500-3 is discussed to help clarify the requirements for manufacturing concentrates. Therefore, it is
recommended to refer to ISO 23500-3 along with this document.
This document reflects the conscientious efforts of concerned physicians, clinical engineers, nurses,
dialysis technicians and dialysis patients, in consultation with device manufacturers and regulatory agency
representatives to develop a standard for performance levels. The term “consensus” as applied to the
development of voluntary medical device standards does not imply unanimity of opinion, but rather reflects
the compromise necessary in some instances when a variety of interests are merged.
Because the manufacturer of the concentrate does not have control over the final dialysis fluid, any reference
to dialysis fluid is for clarification and is not a requirement of the manufacturer, Furthermore, label
requirements for dialysis fluid are placed on the labelling of the concentrate, it is the user's responsibility to
ensure proper use.
The rationale for the development of this document is given in Annex A.
vi
International Standard ISO 23500-4:2024(en)
Preparation and quality management of fluids for
haemodialysis and related therapies —
Part 4:
Concentrates for haemodialysis and related therapies
1 Scope
This document specifies the chemical and microbiological requirements for concentrates used for
haemodialysis and related therapies and applies to the manufacturer of such concentrates.
This document is applicable to:
— concentrates in both liquid and powder forms;
— additives, also called spikes, which are chemicals that can be added to the concentrate to supplement
or increase the concentration of one or more of the existing ions in the concentrate and thus in the final
dialysis fluid;
— equipment used to mix acid and bicarbonate powders into concentrate at the user's facility.
This document does not apply to:
— concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility;
— pre-packaged and sterile dialysis fluid;
— sorbent dialysis fluid regeneration systems that regenerate and recirculate small volumes of the
dialysis fluid;
— equipment to perform patient treatment; this is addressed IEC 60601-2-16.
This document does not cover the dialysis fluid that is used to clinically dialyse patients. Dialysis fluid is
covered in ISO 23500-5. The making of dialysis fluid involves the proportioning of concentrate and water at
the bedside or in a central dialysis fluid delivery system. Although the label requirements for dialysis fluid
are placed on the labelling of the concentrate, it is the user's responsibility to ensure proper use.
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
ISO 23500-3, Preparation and quality management of fluids for haemodialysis and related therapies — Part 3:
Water for haemodialysis and related therapies
ISO 23500-5, Preparation and quality management of fluids for haemodialysis and related therapies — Part 5:
Quality of dialysis fluid for haemodialysis and related therapies
IEC 60601-1, Medical electrical equipment — Part 1: General requirements for basic safety and essential
performance
ISO 23500-4:2024(en)
IEC 61010-1, Safety requirements for electrical equipment for measurement, control, and laboratory use —
Part 1: General requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 23500-1 and the following 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
bicarbonate dialysis fluid
dialysis fluid containing physiological or higher concentrations of bicarbonate
Note 1 to entry: Dry sodium bicarbonate, without added sodium chloride, is also used in concentrate generators (3.3)
to produce a concentrated solution of sodium bicarbonate used by the dialysis machine to make dialysis fluid.
3.2
concentrate mixer
mixer for the preparation of dialysis concentrate for dialysis fluid at a dialysis facility
3.3
concentrate generator
system where the concentrate is delivered to the user as a powder in a container, suitable for attachment
to the dialysis machine with which it is intended to be used, and then the powder is converted into a
concentrated solution by the dialysis machine
Note 1 to entry: The solution produced by the concentrate generator is used by the dialysis machine to make the final
dialysis fluid delivered to the dialyser.
4 Requirements
4.1 Concentrates
4.1.1 Physical state
4.1.1.1 General
The concentrate for haemodialysis can be supplied in dry or aqueous form. Packaging can be for direct use
with a single dialysis machine or for use in systems supplying multiple dialysis machines (bulk use).
4.1.1.2 Liquid solute concentrations
All electrolytes identified on the label shall be present within ±5 % or ±0,1 mEq/l (expressed as dialysis
fluid concentrations), whichever is greater, of the stated concentration, with the exception of sodium, which
shall be present within ±2,5 % of the labelled concentration. If used, glucose shall be present within ±5 %
or ±0,05 g/l (when measured as properly diluted dialysis fluid), whichever is greater, of the labelled
concentration. Where concentrates include non-traditional constituents, such as antioxidants and iron
compounds, these constituents shall be present at nominal concentrations with ±5 % tolerances. If alternate,
locally approved tolerances are used, the tolerances shall be similarly stated and the rationale for their use
documented.
Most concentrates are manufactured with standard traditional chemicals such as sodium chloride,
potassium chloride, magnesium chloride, calcium chloride, acetic acid and glucose. New concentrates are
available which include additional chemicals or in which certain chemicals have been substituted by others;
for example, citric acid has been substituted for acetic acid. Where this occurs, the labelling shall correctly
ISO 23500-4:2024(en)
reflect this information and the substitute chemicals shall be present at nominal concentrations with ±5 %
tolerance. If alternate, locally approved tolerances are used, the tolerances shall be similarly stated and the
rationale for their use documented.
It is essential that the actual concentrations of the solutes contained in the concentrate be as close as
possible to the labelled amount since the final composition of the dialysis fluid will be subject to cumulative
variability from other sources within the process of dialysis fluid delivery (such as, but not limited to,
laboratory testing, mixing process or proportioning, dialysis water).
4.1.1.3 Solute concentrations based on powder
When concentrate is packaged in dry form or a combination of dry and liquid and is mixed according to the
manufacturer's instruction for use, the concentrate shall meet the requirements of 4.1.1.1.
4.1.2 Water
The quality of water used in the manufacture of the concentrate shall be in accordance with ISO 23500-3.
4.1.3 Bacteriology of concentrates
4.1.3.1 Bacteriology of acid concentrates
There are no published reports of acid concentrate supporting microbial growth and, as such, acid
concentrate need not be tested for microbial growth.
4.1.3.2 Bacteriology of bicarbonate concentrates
Concentrate containing bicarbonate supplied as a liquid shall be provided in a sealed container and
manufactured by a process validated to produce dialysis fluid meeting the microbiological requirements of
ISO 23500-5, when used in accordance with the manufacturer's instructions. Bicarbonate powder intended
for the preparation of concentrate at a dialysis facility shall be capable of producing dialysis fluid meeting
the microbiological requirements of ISO 23500-5, when used in accordance with the manufacturer's
instructions.
4.1.4 Endotoxin levels
The concentrate shall be formulated and packaged using a process validated to produce dialysis fluid meeting
the endotoxin requirements of ISO 23500-5 or the applicable pharmacopoeia when used in accordance with
the manufacturer's instructions.
4.1.5 Fill quantity
The excess fill volume of liquid containers and the excess fill weight of powder containers used with batch
systems for a single dialysis treatment shall be within 2 % of the labelled volume or weight. The fill weight of
bulk delivered powdered concentrate shall be such that, when mixed in accordance with the manufacturer’s
instructions, it produces liquid concentrate that meets the requirements of 4.1.1.1. The fill weight of a
concentrate generator shall be such that the device performs as intended. For all other applications, the fill
volume or weight shall be ≥100 % of the stated volume or weight.
4.1.6 Chemical grade
All chemicals shall meet the requirements of the applicable pharmacopoeia, including all applicable portions
of the general notices and of the general requirements for tests and assay. If all other requirements are
met, monograph limits for sodium, potassium, calcium, magnesium and/or pH can be exceeded provided
that correction is made, if necessary, for the presence of those ions in the final formulation. Also, any
pharmacopoeia requirements that the chemicals be labelled for use in haemodialysis need not be complied
with if the manufacturer is performing its own testing to meet the requirements of the applicable
pharmacopoeia.
ISO 23500-4:2024(en)
4.1.7 Particulates
The aqueous dialysis concentrate shall be filtered through a nominal 1 µm or finer particulate filter. The
particulate filter used shall have a non-fibre-releasing membrane that does not contain material of known
potential for human injury.
4.1.8 Additives — “Spikes”
The use of concentrate additives such as potassium chloride in a canister is not recommended. Due to
differences in density, homogeneous mixing is made more difficult and there is a risk of “island formation”,
i.e. areas with a high concentration of the concentrate additive. If the dialysis machine aspirates such areas,
this can lead to a serious patient risk.
If additives are supplied, the concentration, when properly diluted with water or concentrate, shall yield
values within ±5 % by weight of the labelled value.
NOTE The use of additives is not approved in some countries.
4.1.9 Containers
Containers, including the closures, shall not interact chemically or physically with the contents to alter the
strength, purity or quality of the concentrate during handling, storage and shipment. The containers shall
have closures that prevent contamination or loss of content. Each container shall be marked to indicate its
contents. One means of indicating the contents is to use an appropriate symbol (see Table 3).
Dialysis concentrates in canisters are usually intended for single use by the manufacturer and labelled
accordingly. If not completely used, sometimes canisters are reused by the user. In those cases, the user is
liable for any damage to health resulting from the reuse.
If the container or cannister is of a type which is suitable for use in multiple treatment sessions, an
appropriate risk control measure shall be introduced so that the use of the container and its contents beyond
the initial use does not introduce risks to the patient.
The following risks exist, among others:
— cross-contamination due to use of a contaminated canister contents with another patient, e.g. if the
canister was not used for the specific patient;
— changes in the chemical composition or the microbiological contamination due to storage, e.g. beyond
the next patient treatment day;
— contamination, evaporation and change in concentration of contents arising from incorrect re sealing of
the container.
4.1.10 Bulk-delivered concentrate
When concentrate is delivered in bulk form, the responsibility for ensuring conformity with this document
shall pass from the manufacturer to the user at the legal point of transfer of the shipment. Once the
concentrate is transferred from the manufacturer to the user, it becomes the user's responsibility to
maintain the product in a usable state with appropriate labels and non-tamper procedures.
4.1.11 Concentrate generators
Concentrate generator systems include systems that mix powder, or a highly concentrated liquid, into a
concentrate by forming a slurry or concentrated solution in a container designed to function with specific
dialysis machines. Mixing is accomplished by an automated dynamic proportioning system within the
dialysis fluid delivery system. Because these concentrates are delivered to the user as a powder or a
highly concentrated liquid in containers designed for specific machines, it is the concentrate generator
manufacturer's responsibility to ensure that
— all applicable clauses of this document dealing with powder are met,
ISO 23500-4:2024(en)
— the container will function with the machines as specified by the manufacturers of the machines, and
— undissolved powder is prevented from entering the dialysis fluid stream.
4.2 Manufacturing equipment
Any material components of the manufacturing equipment (e.g. piping, storage, and distribution systems)
that have contact with the final concentrate or any component of the concentrate shall not interact physically
or chemically with the product so as to significantly alter the strength, purity or quality of the concentrate
delivered to the user. Examples of materials that should not be used in manufacturing equipment include
copper, brass, zinc, galvanized metal or aluminium.
4.3 Systems for bulk mixing concentrate at a dialysis facility
4.3.1 General
The following requirements apply to systems, such as a central concentrate system, used to prepare acid or
bicarbonate concentrates from dialysis water and powder or other highly concentrated media at a dialysis
facility.
4.3.2 Materials compatibility
The materials of any components of concentrate mixing devices/systems (including storage and distribution
systems) that contact the concentrate solutions shall not interact chemically or physically so as to adversely
affect their purity or quality. Such components shall be fabricated from non-reactive materials (e.g. plastics)
or appropriate stainless steel. The use of materials that are known to cause toxicity in haemodialysis, such
as copper, brass, zinc, galvanized material or aluminium, are specifically prohibited.
4.3.3 Disinfection protection
4.3.3.1 General
When the manufacturer of the mixing system recommends chemical disinfectants [see 6.7.2 k)], means shall
be provided to restore the system to a safe condition relative to residual disinfectant prior to the system
being used to prepare a batch of concentrate.
When formaldehyde is used, residual levels can be determined by the Hantzsch reaction, Schiff's reagent, or
by an equivalent test. Residual levels shall not exceed 3 mg/l.
NOTE Local requirements can apply.
When ozone is used, the residual level shall be less than 0,1 mg/l; when sodium hypochlorite is used, test
strips with a minimum indication of 0 mg/l shall be used.
If other chemicals are used, appropriate testing in accordance with the manufacturer’s recommendations
shall be used.
When the manufacturer of the mixing system recommends high-temperature disinfection, a means shall be
provided to restore the system to a safe temperature prior to being used to prepare a batch of concentrate.
4.3.3.2 System lock out
When disinfection is accomplished automatically by a chemical disinfectant, such as ozone, or by high
temperature procedures, activation of the disinfection system shall result in activation of a warning system
and measures should be taken to isolate haemodialysis machines from the concentrate preparation and
distribution system.
ISO 23500-4:2024(en)
4.3.4 Safety requirements
Each concentrate mixing device/system shall exhibit the following minimum safety features:
a) operating controls shall be positioned so as to minimize inadvertent operation and resetting of
functions;
b) distribution controls shall be clearly labelled to minimize the possibility of error in the transfer of
concentrate.
4.3.5 Bulk storage tanks
When used for bicarbonate concentrate, storage tanks should have a conical or bowl-shaped base and should
drain from the lowest point of the base. Bicarbonate storage tanks should have a tight-fitting lid to prevent
ingress of contaminants and be vented through a hydrophobic 0,45 µm air filter.
Rigid, non-flexing acid concentrate storage tanks can have a flat bottom and should be vented in a way to
prevent dirt contamination of the concentrate.
Storage tanks should not have sight tubes, which can grow algae and fungi. Means shall be provided to
effectively disinfect any storage tank in a concentrate distribution system that is subject to microbiological
contamination.
The disinfection of acid concentrate tanks is normally not necessary. However, bicarbonate tanks should be
disinfected frequently. For acid concentrate storage, alternative bulk storage containers, such as bladders,
can be used.
4.3.6 Ultraviolet irradiators
When concentrate storage and distribution systems are provided with an ultraviolet irradiator for microbial
control, the following shall be complied with:
a) the ultraviolet irradiator shall emit radiation at a wavelength of 254 nm;
b) the ultraviolet irradiator shall provide a dose of radiant energy of 160 J/m if it is fitted with a calibrated
ultraviolet intensity meter, otherwise it shall provide a dose of radiant energy of 300 J/m ;
c) the ultraviolet irradiator shall be sized appropriately for the maximum flow rate;
d) the ultraviolet irradiator shall be equipped with an online monitor of radiant energy output or a
recommended frequency of lamp replacement shall be stated;
e) the ultraviolet irradiator shall be followed by an endotoxin retentive filter.
4.3.7 Piping systems
Concentrate distribution systems shall not contribute microbiological contaminants to the concentrate.
Concentrate distribution systems shall be designed and operated in a manner that minimizes microbial
proliferation and biofilm formation that can contaminate susceptible concentrates. Frequent disinfection
of bicarbonate concentrate distribution systems is one way to minimize microbial proliferation and biofilm.
The disinfection of piping systems for acid concentrate is normally not necessary because acid concentrates
are typically bacteriostatic.
4.3.8 Electrical safety requirements
Where there is a possibility of a sustainable fluid pathway to the patient which is capable of conducting
electrical current, the device shall meet the requirements of IEC 60601-1 with respect to electrical
ISO 23500-4:2024(en)
safety. Where the electrical system is isolated from the patient the device shall meet the requirements of
IEC 61010-1, with respect to electrical safety.
NOTE There is a possibility of a sustainable fluid pathway to the patient which is capable of conducting electrical
current. Its existence would depend on the distribution system and the manufacturer's instructions for use of the
concentrate mixing system. To maximize electrical safety two cases are presented:
a) where there is a possibility of a sustainable electrical pathway, and
b) where the electrical system is isolated from the patient.
5 Tests
5.1 General
Clause 5 specifies test methods by which conformity with the requirements of Clause 4 shall be verified. The
test methods listed do not represent the only acceptable test methods available but are intended to provide
examples of acceptable methods. Other test methods are permitted, provided it has been demonstrated that
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