EN ISO 23500-4:2019
(Main)Preparation and quality management of fluids for haemodialysis and related therapies - Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2019)
Preparation and quality management of fluids for haemodialysis and related therapies - Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2019)
This document specifies minimum requirements for concentrates used for haemodialysis and related therapies.
This document is addressed to the manufacturer of such concentrates. In several instances in this document, the dialysis fluid is addressed, which is made by the end user, to help clarify the requirements for manufacturing concentrates. 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.
This document includes concentrates in both liquid and powder forms. It also includes 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.
This document also specifies requirements for equipment used to mix acid and bicarbonate powders into concentrate at the user's facility.
Concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility are excluded from the scope of this document. Although references to dialysis fluid appear herein, this document does not address dialysis fluid as made by the end user. This document also excludes requirements for the surveillance frequency of water purity used for the making of dialysis fluid by the dialysis facility. This document does not address bags of sterile dialysis fluid or sorbent dialysis fluid regeneration systems that regenerate and recirculate small volumes of the dialysis fluid.
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.
This document does not cover haemodialysis equipment, which is addressed in IEC 60601-2-16:2012.
Herstellung und Qualitätsmanagement von Flüssigkeiten für die Hämodialyse und verwandte Therapien - Teil 4: Konzentrate für die Hämodialyse und verwandte Therapien (ISO 23500-4:2019)
Dieses Dokument legt die Mindestanforderungen an Konzentrate für die Hämodialyse und verwandte Therapien fest.
Dieses Dokument richtet sich an den Hersteller dieser Konzentrate. An mehreren Stellen in diesem Dokument wird die vom Endanwender hergestellte Dialysierflüssigkeit benannt, um die Anforderungen an die Konzentratherstellung zu präzisieren. Da der Hersteller des Konzentrates keine Kontrolle über die fertige Dialysierflüssigkeit hat, dient jede Referenz auf die Dialysierflüssigkeit der Präzisierung und ist keine Anforderung des Herstellers.
Dieses Dokument behandelt Konzentrate sowohl in Flüssig als auch in Pulverform. Ebenfalls abgehandelt werden Zusätze, auch Spikes genannt. Dies sind Chemikalien, die dem Konzentrat hinzuge¬fügt werden dürfen, um eine oder mehrere der im Konzentrat vorkommenden Ionen und somit auch in der fertigen Dialysierflüssigkeit zu erhöhen.
Dieses Dokument stellt auch Anforderungen an die Geräte zum Mischen von Säure und Bicarbonatpulver zur Herstellung von Konzentrat in der Einrichtung des Anwenders.
Konzentrate aus vorverpackten Salzen sowie Wasser in einer Dialyseeinrichtung zur Verwendung in ebendieser sind vom Anwendungsbereich dieses Dokuments ausgeschlossen. Obwohl in ihr Referenzen zu Dialysierflüssigkeiten auftauchen, behandelt dieses Dokumentkeine Dialysierflüssigkeiten, die vom Endan-wender hergestellt werden. Dieses Dokument umfasst auch keine Anforderungen an die Überwachungshäufigkeit der Wasserreinheit für Dialysierflüssigkeiten, die in einer Dialyseeinrichtung hergestellt werden. Dieses Dokument behandelt keine Beutel mit steriler Dialysierflüssigkeit oder sorbensbasierte Dialysierflüssigkeits Wiederaufbereitungssysteme, die geringe Mengen der Dialysierflüs-sigkeit wiederaufbereiten und wieder in Umlauf bringen.
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.
Dieses Dokument behandelt nicht die Geräte für Hämodialyse, die in IEC 60601 2 16:2012 dargestellt wer¬den.
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies annexes - Partie 4: Concentrés pour hémodialyse et thérapies apparentées (ISO 23500-4:2019)
Le présent document spécifie les exigences minimales relatives aux concentrés utilisés pour l'hémodialyse et les thérapies apparentées.
Le présent document est destiné aux fabricants de ces concentrés. Le présent document aborde à plusieurs endroits la question du liquide de dialyse produit par l'utilisateur final, afin de clarifier les exigences de production des concentrés. Étant donné que le fabricant du concentré n'a aucun contrôle sur le liquide de dialyse final, toute référence au liquide de dialyse est donnée à titre de clarification et ne constitue pas une exigence du fabricant.
Le présent document inclut les concentrés sous forme liquide et sous forme pulvérulente. Il traite également des 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.
Le présent document spécifie également des exigences relatives à l'appareil utilisé pour mélanger les poudres d'acide et de bicarbonate dans le concentré au sein de l'installation de l'utilisateur.
Les concentrés préparés à partir de sels préemballés et d'eau dans un centre de dialyse aux fins d'y être utilisés sont exclus du domaine d'application du présent document. Bien qu'il contienne des références au liquide de dialyse, le présent document ne concerne pas le liquide de dialyse produit par l'utilisateur final. Le présent document exclut également du domaine d'application les exigences relatives à la fréquence de surveillance de la pureté de l'eau utilisée pour la production du liquide de dialyse par le centre de dialyse. Le présent document ne traite pas des sacs de liquide de dialyse stériles ou des systèmes de régénération des liquides de dialyse à base de sorbant qui régénèrent et remettent en circulation de petits volumes de liquide de dialyse.
Le présent document ne concerne pas les liquides de dialyse utilisés pour la dialyse clinique des patients. Le liquide de dialyse est abordé 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.
De plus, le présent document ne concerne pas l'appareil d'hémodialyse, qui est abordé dans la IEC 60601‑2‑16:2012.
Priprava in vodenje kakovosti tekočin za hemodializo in podobne terapije - 4. del: Koncentrati za hemodializo in podobne terapije (ISO 23500-4:2019)
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, za namene pojasnitve zahtev za proizvodnjo koncentratov. Ker proizvajalec koncentrata nima nadzora nad končno dializno tekočino, so vsi sklici na dializno tekočino namenjeni pojasnitvi in ne pomenijo 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.
Dokument prav tako določa zahteve za opremo, ki se uporablja za mešanje 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 zajema
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
Frequently Asked Questions
EN ISO 23500-4:2019 is a standard published by the European Committee for Standardization (CEN). Its full title is "Preparation and quality management of fluids for haemodialysis and related therapies - Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2019)". This standard covers: This document specifies minimum requirements for concentrates used for haemodialysis and related therapies. This document is addressed to the manufacturer of such concentrates. In several instances in this document, the dialysis fluid is addressed, which is made by the end user, to help clarify the requirements for manufacturing concentrates. 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. This document includes concentrates in both liquid and powder forms. It also includes 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. This document also specifies requirements for equipment used to mix acid and bicarbonate powders into concentrate at the user's facility. Concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility are excluded from the scope of this document. Although references to dialysis fluid appear herein, this document does not address dialysis fluid as made by the end user. This document also excludes requirements for the surveillance frequency of water purity used for the making of dialysis fluid by the dialysis facility. This document does not address bags of sterile dialysis fluid or sorbent dialysis fluid regeneration systems that regenerate and recirculate small volumes of the dialysis fluid. 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. This document does not cover haemodialysis equipment, which is addressed in IEC 60601-2-16:2012.
This document specifies minimum requirements for concentrates used for haemodialysis and related therapies. This document is addressed to the manufacturer of such concentrates. In several instances in this document, the dialysis fluid is addressed, which is made by the end user, to help clarify the requirements for manufacturing concentrates. 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. This document includes concentrates in both liquid and powder forms. It also includes 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. This document also specifies requirements for equipment used to mix acid and bicarbonate powders into concentrate at the user's facility. Concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility are excluded from the scope of this document. Although references to dialysis fluid appear herein, this document does not address dialysis fluid as made by the end user. This document also excludes requirements for the surveillance frequency of water purity used for the making of dialysis fluid by the dialysis facility. This document does not address bags of sterile dialysis fluid or sorbent dialysis fluid regeneration systems that regenerate and recirculate small volumes of the dialysis fluid. 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. This document does not cover haemodialysis equipment, which is addressed in IEC 60601-2-16:2012.
EN ISO 23500-4:2019 is classified under the following ICS (International Classification for Standards) categories: 11.040.40 - Implants for surgery, prosthetics and orthotics. The ICS classification helps identify the subject area and facilitates finding related standards.
EN ISO 23500-4:2019 has the following relationships with other standards: It is inter standard links to EN ISO 13958:2015, EN ISO 23500-4:2024. Understanding these relationships helps ensure you are using the most current and applicable version of the standard.
You can purchase EN ISO 23500-4:2019 directly from iTeh Standards. The document is available in PDF format and is delivered instantly after payment. Add the standard to your cart and complete the secure checkout process. iTeh Standards is an authorized distributor of CEN standards.
Standards Content (Sample)
SLOVENSKI STANDARD
01-maj-2019
1DGRPHãþD
SIST EN ISO 13958:2016
3ULSUDYDLQYRGHQMHNDNRYRVWLWHNRþLQ]DKHPRGLDOL]RLQSRGREQHWHUDSLMHGHO
.RQFHQWUDWL]DKHPRGLDOL]RLQSRGREQHWHUDSLMH ,62
Preparation and quality management of fluids for haemodialysis and related therapies -
Part 4: Concentrates for haemodialysis and related therapies (ISO 23500-4:2019)
Leitfaden für die Vorbereitung und das Qualitätsmanagement von Konzentraten für die
Hämodialyse und verwandte Therapien - Teil 4: Konzentrate für die Hämodialyse und
verwandte Therapien (ISO 23500-4:2019)
Préparation et management de la qualité des liquides d'hémodialyse et de thérapies
annexes - Partie 4: Concentrés pour hémodialyse et thérapies apparentées (ISO 23500-
4:2019)
Ta slovenski standard je istoveten z: EN ISO 23500-4:2019
ICS:
11.120.99 Drugi standardi v zvezi s Other standards related to
farmacijo pharmaceutics
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
EN ISO 23500-4
EUROPEAN STANDARD
NORME EUROPÉENNE
March 2019
EUROPÄISCHE NORM
ICS 11.040.40 Supersedes EN ISO 13958:2015
English Version
Preparation and quality management of fluids for
haemodialysis and related therapies - Part 4: Concentrates
for haemodialysis and related therapies (ISO 23500-
4:2019)
Préparation et management de la qualité des liquides Leitfaden für die Vorbereitung und das
d'hémodialyse et de thérapies annexes - Partie 4: Qualitätsmanagement von Konzentraten für die
Concentrés pour hémodialyse et thérapies apparentées Hämodialyse und verwandte Therapien - Teil 4:
(ISO 23500-4:2019) Konzentrate für die Hämodialyse und verwandte
Therapien (ISO 23500-4:2019)
This European Standard was approved by CEN on 14 January 2019.
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, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey 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
© 2019 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 23500-4:2019 E
worldwide for CEN national Members.
Contents Page
European foreword . 3
European foreword
This document (EN ISO 23500-4:2019) 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 September 2019, and conflicting national standards
shall be withdrawn at the latest by September 2019.
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 13958:2015.
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, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
Endorsement notice
The text of ISO 23500-4:2019 has been approved by CEN as EN ISO 23500-4:2019 without any
modification.
INTERNATIONAL ISO
STANDARD 23500-4
First edition
2019-02
Preparation and quality 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 23500-4:2019(E)
©
ISO 2019
ISO 23500-4:2019(E)
© ISO 2019
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2019 – All rights reserved
ISO 23500-4:2019(E)
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 . 4
4.3 Systems for bulk mixing concentrate at a dialysis facility . 4
4.3.1 General. 4
4.3.2 Materials compatibility . 5
4.3.3 Disinfection protection . 5
4.3.4 Safety requirements . 5
4.3.5 Bulk storage tanks . 5
4.3.6 Ultraviolet irradiators . 6
4.3.7 Piping systems . 6
4.3.8 Electrical safety requirements . 6
5 Tests . 6
5.1 General . 6
5.2 Concentrates . 6
5.2.1 Physical state . 6
5.2.2 Solute concentrations . 7
5.2.3 Water . 7
5.2.4 Microbial contaminant test methods for bicarbonate concentrates . 7
5.2.5 Endotoxin levels . 8
5.2.6 Fill quantity . 8
5.2.7 Chemical grade . 8
5.2.8 Particulates . 8
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 . 9
5.4 Systems for mixing concentrate at a dialysis facility . 9
5.4.1 General. 9
5.4.2 Materials compatibility . 9
5.4.3 Disinfection protection . 9
5.4.4 Safety requirements .10
5.4.5 Bulk storage tanks .10
5.4.6 Ultraviolet irradiators .10
5.4.7 Piping systems .10
ISO 23500-4:2019(E)
5.4.8 Electrical safety requirements .10
6 Labelling .10
6.1 General .10
6.2 General labelling requirements for concentrates .11
6.3 Labelling requirements for liquid concentrate .12
6.4 Labelling requirements for powder concentrate .12
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 .14
Annex A (informative) Rationale for the development and provisions of this document .16
Bibliography .22
iv © ISO 2019 – All rights reserved
ISO 23500-4:2019(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see www .iso
.org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee
SC 2, Cardiovascular implants and extracorporeal systems.
This first edition cancels and replaces ISO 13958:2014, which has been technically revised. The main
changes compared to the previous edition are as follows:
— The document forms part of a revised and renumbered series dealing with the preparation and
quality management of fluids for haemodialysis and related therapies. The series comprise
ISO 23500-1 (previously ISO 23500), ISO 23500-2, (previously ISO 26722), ISO 23500-3, (previously
ISO 13959), ISO 23500-4, (previously ISO 13958), and ISO 23500-5, (previously ISO 11663).
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.
ISO 23500-4:2019(E)
Introduction
The requirements and goals established by this document will help ensure the effective, safe
performance of haemodialysis concentrates and related materials. 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 that could be reasonably achieved at the time of publication.
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 shall be merged.
The rationale for the development of this document is given in informative Annex A.
Throughout this document, requirements and recommendations are made to use ISO-quality water.
Therefore, it is recommended to refer to ISO 23500-3 along with this document.
For the purpose of this document, “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.
vi © ISO 2019 – All rights reserved
INTERNATIONAL STANDARD ISO 23500-4:2019(E)
Preparation and quality management of fluids for
haemodialysis and related therapies —
Part 4:
Concentrates for haemodialysis and related therapies
1 Scope
This document specifies minimum requirements for concentrates used for haemodialysis and related
therapies.
This document is addressed to the manufacturer of such concentrates. In several instances in this
document, the dialysis fluid is addressed, which is made by the end user, to help clarify the requirements
for manufacturing concentrates. 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.
This document includes concentrates in both liquid and powder forms. It also includes 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.
This document also specifies requirements for equipment used to mix acid and bicarbonate powders
into concentrate at the user's facility.
Concentrates prepared from pre-packaged salts and water at a dialysis facility for use in that facility
are excluded from the scope of this document. Although references to dialysis fluid appear herein,
this document does not address dialysis fluid as made by the end user. This document also excludes
requirements for the surveillance frequency of water purity used for the making of dialysis fluid by the
dialysis facility. This document does not address bags of sterile dialysis fluid or sorbent dialysis fluid
regeneration systems that regenerate and recirculate small volumes of the dialysis fluid.
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.
This document does not cover haemodialysis equipment, which is addressed in IEC 60601-2-16:2012.
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
ISO 23500-4:2019(E)
IEC 60601-1, Medical electrical equipment — Part 1: General requirements for basic safety and essential
performance
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 terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
3.1
batch system
apparatus in which the dialysis fluid is prepared in bulk before each dialysis session
Note 1 to entry: Dry sodium bicarbonate, without added sodium chloride, is also used in concentrate generators
to produce a concentrated solution of sodium bicarbonate used by the dialysis machine to make dialysis fluid.
3.2
bicarbonate dialysis fluid
dialysis fluid containing physiological or higher concentrations of bicarbonate
3.3
concentrate mixer
mixer for preparation of dialysis concentrate for dialysis fluid at a dialysis facility
4 Requirements
4.1 Concentrates
4.1.1 Physical state
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).
4.1.1.1 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 or shall be present according
to approved specifications by the local regulations. 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, or shall be present according to approved specifications by the local regulations. Where
concentrates include non-traditional constituents, such as antioxidants and iron compounds, these
constituents shall be present at nominal concentrations with ± 5 % tolerances or shall be present
according to approved specifications by the local regulations. 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 reflect this and the substitute chemicals shall be present at nominal concentrations
2 © ISO 2019 – All rights reserved
ISO 23500-4:2019(E)
with ± 5 % tolerances, or shall be present according to approved specifications by the local regulations.
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
confined to laboratory testing, mixing process or proportioning, dialysis water).
4.1.1.2 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 final 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 bacterial growth and as such, acid
concentrate need not be tested for bacterial 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 according to 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 according to 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
according to 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 according to 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 23500-4:2019(E)
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”
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).
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 powder and 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,
— the container will function with the machines as defined 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 © ISO 2019 – All rights reserved
ISO 23500-4:2019(E)
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, the residual level shall
be less than 3 mg/l; when sodium hypochlorite is used, the residual level shall be as specified per the
manufacturer’s instructions; when ozone is used, the residual level shall be less than 0,1 mg/l; when a
commercially available chemical germicide other than formaldehyde, sodium hypochlorite, or ozone is
used, the residual level shall be that recommended by the manufacturer of the specific germicide. When
recommending chemical disinfectants, the manufacturer shall also recommend methods for testing for
residual levels of the disinfectants.
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 chemical disinfectant, 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.
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.
ISO 23500-4:2019(E)
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
bacterial control, the following shall be complied with:
a) the ultraviolet irradiator shall emit radiation at a wave frequency of 254 nm;
b) the ultraviolet irradiator shall provide a dose of radiant energy of 16 mW∙s/cm if it is fitted with
a calibrated ultraviolet intensity meter, otherwise it shall provide a dose of radiant energy of
30 mW·s/cm ;
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
bacterial proliferation and biofilm formation that can contaminate susceptible concentrates. Frequent
disinfection of bicarbonate concentrate distribution systems is one way to minimize bacterial
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
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 defines 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 such methods have been appropriately validated and are comparable to the cited
methods.
5.2 Concentrates
5.2.1 Physical state
Conformity with the requirements of 4.1.1 shall be determined by visual inspection.
6 © ISO 2019 – All rights reserved
ISO 23500-4:2019(E)
5.2.2 Solute concentrations
5.2.2.1 Liquid solute concentrations
Conformity with the requirements of 4.1.1.1 for calcium, potassium, magnesium and sodium shall
[5]
be determined by using methods described by the American Public Health Association , methods
[6]
referenced by the U.S. Environmental Protection Agency , methods referenced in applicable
pharmacopoeia, or other equivalent validated analytical methods. Samples shall be collected in sealed
containers. Appropriate sample preparation, including using suitable mixing vessels and adjusting for
pH if necessary, shall be used to ensure accurate determinations.
Conformity with the requirements of 4.1.1.1 for new and non-traditional concentrate constituents shall
be determined by using appropriate and validated analytical methods.
The maximum contaminant levels referred to in ISO 23500-3 shall be used as a reference for
dialysis water.
Conformity with the requirements for the contents of the dialysis fluid shall be determined as described
in Table 1. Other test methods are permitted, provided it has been demonstrated that such methods
have been appropriately validated and are comparable to the cited methods.
Table 1 — Analytical tests for chemical components
Component Test methods
Acetate Gas chromatography, liquid chromatography, enzymatic, or potentiometric methods
Bicarbonate Acid titration and calculation, ion chromatography, or other method for total CO
EDTA titrimetric method, or atomic absorption (direct aspiration), inductively coupled
Calcium
plasma spectrometry (direct aspiration) or ion chromatography
Glucose Polarimetry, enzymatic, liquid chromatography, or chemical methods
Atomic absorption (direct aspiration), inductively coupled plasma spectrometry (di-
Magnesium
rect aspiration), or ion chromatography
Flame photometry method, atomic absorption (direct aspiration), inductively coupled
Potassium
plasm
...
記事のタイトル：EN ISO 23500-4:2019 - 血液透析と関連療法のための準備と品質管理-第4部：血液透析と関連療法のための濃縮液（ISO 23500-4:2019） 記事の内容：この文書は、血液透析と関連療法に使用される濃縮液の最低要件を指定しています。 この文書は、濃縮液の製造業者を対象としています。この文書のいくつかの箇所では、最終的にエンドユーザーが作成する透析液についても言及しており、これは濃縮液の製造要件を明確化するためのものです。濃縮液の製造業者は、最終的な透析液をコントロールすることはできないため、透析液に関する参照は明確化のためにあり、製造業者の要件ではありません。 この文書は液体および粉末形態の濃縮液を含みます。また、濃縮液に添加される化学物質である添加剤（スパイク）も含まれます。これは、既存のイオンの濃度を補完または増加させるために濃縮液に添加することができる化学物質です。 この文書は、酸と炭酸水素塩の粉末をユーザーの施設で濃縮液に混合するための装置の要件も指定しています。 施設内で使用されるために施設で事前にパッケージ化された塩と水から準備される濃縮液は、この文書の範囲外です。ここで透析液について言及があるように見えますが、この文書はエンドユーザーが作成する透析液については言及していません。また、透析施設で使用される透析液の水質の監視頻度に関する要件も除外します。また、滅菌された透析液の袋や小容量の透析液再生システムについても対象外です。 この文書は、臨床的に患者に使用される透析液をカバーしていません。透析液については、ISO 23500-5で取り扱われています。透析液の製造は、ユーザーのベッドサイドまたは中央の透析液供給システムで濃縮液と水の配合によって行われます。また、透析液のラベル要件は濃縮液のラベリングに記載されますが、適切な使用はユーザーの責任です。 この文書は、IEC 60601-2-16:2012で扱われている血液透析装置には該当しません。
The article discusses the requirements and specifications for concentrates used in haemodialysis and related therapies. It is intended for manufacturers of these concentrates. The document includes both liquid and powder forms of concentrates, as well as additives that can be added to increase the concentration of certain ions in the final dialysis fluid. It also specifies requirements for the equipment used to mix these concentrates. The document explicitly excludes concentrates prepared at dialysis facilities for use within that facility, as well as bags of sterile dialysis fluid and sorbent dialysis fluid regeneration systems. It also states that it does not address the dialysis fluid used in the clinical dialysis of patients, which is covered in a separate ISO standard. The article further clarifies that it does not cover haemodialysis equipment, as that is addressed in a different standard.
기사 제목: EN ISO 23500-4:2019 - 혈액투석 및 관련 치료를 위한 용액의 준비 및 품질 관리-제4부: 혈액투석 및 관련 치료용 농축액 (ISO 23500-4:2019) 기사 내용: 이 문서는 혈액투석 및 관련 치료에 사용되는 농축액에 대한 최소 요구 사항을 명시한다. 이 문서는 해당 농축액의 제조업체를 대상으로 한다. 이 문서의 여러 부분에서는 끝 사용자가 만드는 혈액투석 용액이 언급되는데, 이는 농축액의 제조 요구 사항을 명확히 하기 위한 것이다. 농축액의 제조업체는 최종 혈액투석 용액을 통제할 수 없으므로, 용액에 대한 어떠한 언급도 제조업체의 요구 사항은 아니다. 이 문서는 액체와 분말 형태의 농축액을 모두 포함한다. 또한, 농축액에 첨가되는 화학 물질인 첨가제도 포함된다. 첨가제는 농축액에 이미 존재하는 이온의 농도를 보조하거나 증가시키기 위해 농축액에 첨가될 수 있는 화학 물질이다. 이 문서는 사용자의 시설에서 산과 탄산염 분말을 농축액에 혼합하는 데 사용되는 장비에 대한 요구 사항도 명시한다. 해당 시설에서 혈액투석을 위해 사전 패키지된 염료와 물로 준비되는 농축액은 이 문서의 범위에서 제외된다. 여기에 혈액투석용 용액에 대한 언급이 있지만, 이 문서는 최종 사용자가 만드는 혈액투석 용액에 대한 것이 아니다. 이 문서는 또한 혈액투석 시설에서 사용하는 dialysis 용수의 정도 확인 주기에 대한 요구 사항도 제외한다. 이 문서는 멸균 혈액투석 용액 봉지나 작은 용량의 dialysis 용수 회생 시스템에 대해서도 다루지 않는다. 이 문서는 임상적으로 환자에게 사용되는 혈액투석 용액을 다루지 않는다. 혈액투석 용액은 ISO 23500-5에서 다루고 있다. 혈액투석 용액의 제조는 사용자의 침대 옆이나 중앙 dialysis 용수 공급 시스템에서 농축액과 물의 비율을 조절하여 이루어진다. 또한, 농축액의 라벨 요구 사항은 농축액의 라벨링에 기재되지만, 적절한 사용을 보장하는 것은 사용자의 책임이다. 이 문서는 IEC 60601-2-16:2012에서 다루는 혈액투석 장비에는 해당하지 않는다.
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