Aami Iso CDV-1

DOCUMENT: AAMI/ISO/CDV-1 (ISO/DIS) 23500-1, Guidance for the
preparation and quality management of fluids for

haemodialysis and related therapies — Part 1: General
requirements (revision of ANSI/AAMI 23500:2014)
Public Review Draft Designation: AAMI/ISO/CDV-1 23500-1
AAMI has circulated this draft to committee members for comment and vote.
Consensus on this draft will be developed by AAMI/RD, Renal Disease and
Detoxification Committee. Interested parties may submit public review
comments, in writing, to:
AAMI
4301 N Fairfax Dr
Ste 301
Arlington, VA 22203-1633
ATTN: Cliff Bernier
Fax: 703-276-0793; Email: [email protected]
COMMENT DEADLINE: 1 May 2017

INSTRUCTIONS FOR COMMENTING:
Comments should be received by AAMI by the above deadline (earlier if possible) to ensure their
consideration by the Committee.
Comments should be set forth as follows:
a. Section number, section heading, and page number of document;
b. Comments/objection;
c. Rationale for comment/objection; and,
d. Suggested alternative text to resolve comment/objection.
NOTE–The above format is not required for comments concerning typographical errors; simply
identify the nature and location of the error (e.g, by page, paragraph, and line number). Failure to
comply fully with these instructions may cause comments to be considered nonpersuasive.
An electronic Public Reviewer form is available from the AAMI website:
WORD97 http://www.aami.org/standards/downloadables/aamirevf.docx
Acrobat (pdf) http://www.aami.org/standards/downloadables/aamirevf.pdf
Please be sure to identify the document by designation: 'AAMI/ISO/CDV-1 23500-1,

Guidance for the preparation and quality management of fluids for haemodialysis and related
therapies — Part 1: General requirements,' and include your name, address, phone number, fax
number and email address in the event we need to contact you about your comments.
© 2017. All rights reserved.

DRAFT INTERNATIONAL STANDARD
ISO/DIS 23500-1
ISO/TC 150/SC 2 Secretariat: ANSI

Voting begins on: Voting terminates on:
2017-04-07
Guidance for the preparation and quality management of

fluids for haemodialysis and related therapies —
Part 1:
General requirements
Directives concernant la préparation et le management de la qualité des fluides d’hémodialyse et de
thérapies annexes —
Partie 1: Exigences générales
ICS: 11.040.40
THIS DOCUMENT IS A DRAFT CIRCULATED

FOR COMMENT AND APPROVAL. IT IS
This document is circulated as received from the committee secretariat.
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
BEING ACCEPTABLE FOR INDUSTRIAL, ISO/CEN PARALLEL PROCESSING
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN Reference number
NATIONAL REGULATIONS.
ISO/DIS 23500-1:2017(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
Licensed to: Team ANSI ISO
TO SUBMIT, WITH THEIR COMMENTS,
Downloaded:
NOTIFICATION OF ANY RELEVANT PATENT 2017-02-09
RIGHTS OF WHICH THEY ARE AWARE
SingleAND TO licence only, copying
user and networking prohibited
PROVIDE SUPPORTING DOCUMENTATION. © ISO 2017
ISO/DIS 23500-1:2017(E)

COPYRIGHT PROTECTED DOCUMENT

© ISO 2017, Published in Switzerland
All rights reserved. Unless otherwise specified, 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
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
[email protected]
www.iso.org Licensed to: Team ANSI ISO
Downloaded: 2017-02-09
Single user licence only, copying and networking prohibited
ii © ISO 2017 – All rights reserved
ISO/DIS 23500-1
Contents Page
Foreword .........................................................................................................................................................................iii
Introduction ................................................................................................................................................................... iv
1 Scope .................................................................................................................................................................... 2
2 Normative references .................................................................................................................................... 2
3 Terms and definitions ................................................................................................................................... 3
4 Summary of quality requirements of ISO 23500-4, ISO 23500-3 and ISO 23500-5 ............. 10
5 Critical aspects of system design ............................................................................................................ 15
6 Validation of system performance ......................................................................................................... 18
7 Quality management ................................................................................................................................... 21
8 Strategies for microbiological control .................................................................................................. 28
9 Location of and access to water treatment system .......................................................................... 33
10 Personnel ........................................................................................................................................................ 34
Annex A (informative) Rationale for the development and provisions of this
International Standard .............................................................................................................................. 36
Annex B (informative) Equipment ........................................................................................................................ 41
Annex C (informative) Monitoring guidelines for water treatment equipment,
distribution systems, and dialysis fluid ............................................................................................... 60
Annex D (informative) Strategies for microbiological control ................................................................... 65
Annex E (informative) Validation .......................................................................................................................... 73
Annex F (informative) Special considerations for home haemodialysis ................................................ 76
Annex G (informative) Special considerations for acute haemodialysis ................................................ 83
Bibliography ................................................................................................................................................................. 88

ii © ISO 2017 – All rights reserved.
ISO/DIS 23500-1
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 on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO's adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 150, Implants for surgery, Subcommittee SC 2,
Cardiovascular implants and extracorporeal systems.
This third edition cancels and replaces the second edition (ISO 23500:2014), which has been technically
revised and forms part of a revised and renumbered series dealing with water treatment (ISO 23500-2,
previously ISO 26722), water quality (ISO 23500-3, previously ISO 13959), concentrates used for the
preparation of dialysis fluid (ISO 23500-4, previously ISO 13958), and dialysis fluid quality (ISO 23500-
5, previously ISO 11663).

© ISO 2017 – All rights reserved iii

ISO/DIS 23500-1
Introduction
This International Standard was developed by ISO/TC 150/SC 2. It is the base standard for a number of
other standards dealing with water treatment equipment (ISO 23500-2 replacing ISO 26722:2014),
water quality (ISO 23500-3 replacing ISO 13959:2014), concentrates (ISO 23500-4 replacing ISO
13958:2014) and the quality of dialysis fluid (ISO 23500-5 replacing ISO 11663:2014)
The objective of these standards is to provide users with guidance for handling water and concentrates
and for the production and monitoring of dialysis fluid used for haemodialysis. The need for such
guidance is based on the critical role of dialysis fluid quality in providing safe and effective
haemodialysis, and the recognition that day-to-day dialysis fluid quality is under the control of the
healthcare professionals who deliver dialysis therapy.
This International Standard does not address clinical issues that might be associated with inappropriate
usage of the water, dialysis water, concentrates, or dialysis fluid. Healthcare professionals involved in
the provision of treatment for kidney failure should make the final decision regarding the applications
with which these fluids are used, for example, haemodialysis, haemodiafiltration, high-flux
haemodialysis, and the reprocessing of dialysers, and need to be aware of the issues that the use of
inappropriate fluid quality raises in each of the therapies.
The equipment used in the various stages of dialysis fluid preparation is generally obtained from
specialized vendors. Dialysis practitioners are generally responsible for maintaining that equipment
following its installation. Therefore, this International Standard provides guidance on monitoring and
maintenance of the equipment to ensure that dialysis fluid quality is acceptable at all times. At various
places throughout this International Standard, the user is advised to follow the manufacturer's
instructions regarding the operation and maintenance of equipment. In those instances in which the
equipment is not obtained from a specialized vendor, it is the responsibility of the user to validate the
performance of the equipment in the haemodialysis setting and to ensure that appropriate operating
and maintenance manuals are available. Annex B provides a general description of the system
components that are used for water treatment, concentrate, and dialysis fluid preparation at a dialysis
facility. These descriptions are intended to provide the user with a basis for understanding why certain
equipment might be required and how it should be configured; they are not intended as detailed design
standards. Requirements for water treatment equipment are provided in ISO 23500-2 (previously ISO
26722)
Increasingly, self-contained, integrated systems designed and validated to produce water and dialysis
fluid are becoming available and used clinically. The provisions included in this International Standard
apply to systems assembled from individual components. Consequently, some of the provisions in ISO
23500-1 and ISO 23500-2 might not apply to integrated systems, however such systems are required to
comply with the requirements of ISO 23500-3, ISO 23500-4, and ISO 23500-5. In order to ensure
compliance when using such systems, the user shall follow the manufacturer's instructions regarding
the operation, testing, and maintenance of such systems in order to ensure that the system is being
operated under the validated conditions.
The verbal forms used in this International Standard conform to usage described in Annex H of the
ISO/IEC Directives, Part 2:2004. For the purposes of this International Standard, the auxiliary verb:
— “shall” means that compliance with a requirement or a test is mandatory for compliance with this
International Standard;
— “should” means that compliance with a requirement or a test is recommended but is not mandatory
for compliance with this International Standard;

iv © ISO 2017 – All rights reserved.
ISO/DIS 23500-1
— “may” is used to describe a permissible way to achieve compliance with a requirement or test.
This International Standard reflects the conscientious efforts of healthcare professionals, patients, and
medical device manufacturers to develop recommendations for handling water and concentrates and
for the production and monitoring of dialysis fluid for haemodialysis. This International Standard is
directed towards the healthcare professionals involved in the management or routine care of
haemodialysis patients and responsible for the quality of dialysis fluid. The recommendations contained
in this International Standard might not be applicable in all circumstances and they are not intended for
regulatory application.
The guidance provided by this International Standard is aimed at protecting haemodialysis patients
from adverse effects arising from known chemical and microbial contaminants that might be found in
improperly prepared dialysis fluid. However, the physician in charge of dialysis has the ultimate
responsibility for ensuring that the dialysis fluid is correctly formulated and meets the requirements of
all applicable quality standards.
The concepts incorporated in this International Standard should not be considered inflexible or static.
The recommendations presented here should be reviewed periodically in order to assimilate increased
understanding of the role of dialysis fluid purity in patient outcomes and technological developments.

© ISO 2017 – All rights reserved v

ISO/DIS 23500-1
Guidance for the preparation and quality management of fluids

for haemodialysis and related therapies — Part 1: General
requirements
1 Scope
1.1 General
This International Standard provides dialysis practitioners with guidance on the preparation of dialysis
fluid for haemodialysis and related therapies and substitution fluid for use in online therapies, such as
haemodiafiltration and haemofiltration. As such, this International Standard functions as a
recommended practice.
1.2 Inclusions
This International Standard addresses the user's responsibility for dialysis fluid once the equipment
used in its preparation has been delivered and installed.
For the purposes of this International Standard, dialysis fluid includes:

a) dialysis water (see 3.18 for definition) used for the preparation of dialysis fluid and substitution
fluid,
b) dialysis water used for the preparation of concentrates at the user's facility,
c) concentrates,
d) the final dialysis fluid and substitution fluid.
The scope of this International Standard includes
a) the quality management of equipment used to treat and distribute water used for the
preparation of dialysis fluid and substitution fluid, from the point at which municipal water enters
the dialysis facility to the point at which the final dialysis fluid enters the dialyser or the point at
which substitution fluid is infused,
b) equipment used to prepare concentrate from powder or other highly concentrated media at a
dialysis facility, and
c) preparation of the final dialysis fluid or substitution fluid from dialysis water and concentrates.
NOTE Because water used to prepare dialysis fluid can also be used to reprocess dialysers not marked
intended for single use, this aspect of water use is also covered by this International Standard.
1.3 Exclusions
This International Standard does not apply to sorbent-based dialysis fluid regeneration systems that
regenerate and recirculate small volumes of dialysis fluid, systems for continuous renal replacement
therapy that use pre packaged solutions, and systems and solutions for peritoneal dialysis.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest editionLicensed
of the referenced document
to: Team ANSI ISO (including any amendments) applies.
© ISO 2017 – All rights reserved 2

ISO/DIS 23500-1
ISO 23500-5, Guidance for the preparation and quality management of fluids for haemodialysis and
related therapies – Part 5: Quality of dialysis fluid for haemodialysis and related therapies
related therapies – Part 4: Concentrates for haemodialysis and related therapies
related therapies – Part 3: Water for haemodialysis and related therapies
related therapies – Part 2: Water treatment equipment for haemodialysis applications and related
therapies
3 Terms and definitions

For the purposes of this document, the following terms and definitions apply.
3.1
acetate concentrate
concentrated solution of salts containing acetate, which, when diluted with dialysis water, yields
bicarbonate-free dialysis fluid for use in dialysis
Note 1 to entry: Acetate concentrate may contain glucose.
Note 2 to entry: Sodium acetate is used to provide buffer in place of sodium bicarbonate.
Note 3 to entry: Acetate concentrate is used as a single concentrate.
3.2
acid concentrate
A-concentrate
acidified concentrated mixture of salts that, when diluted with dialysis water and bicarbonate
concentrate, yields dialysis fluid for use in dialysis
Note 1 to entry: The term “acid” refers to the small amount of acid (for example, acetic acid or citric acid) that is
included in the concentrate.
Note 2 to entry: Acid concentrate may contain glucose.
Note 3 to entry: Acid concentrate may be in the form of a liquid, a dry powder, other highly concentrated media, or
some combination of these forms.
3.3
action level
concentration of a contaminant at which steps should be taken to interrupt the trend toward higher,
unacceptable levels
3.4
additive
spike
small amount of a single chemical that, when added to the concentrate, will increase the concentration
of a single existing chemical by a value labelled on the additive packaging
3.5
bicarbonate concentrate
B-concentrate Licensed to: Team ANSI ISO

ISO/DIS 23500-1
concentrated preparation of sodium bicarbonate that, when diluted with dialysis water and acid
concentrate, makes dialysis fluid used for dialysis
Note 1 to entry: Sodium bicarbonate is also known as sodium hydrogen carbonate.
Note 2 to entry: Some bicarbonate concentrates also contain sodium chloride.
Note 3 to entry: Bicarbonate concentrate may be in the form of a liquid or a dry powder.
Note 4 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.
3.6
biofilm
microbially-derived sessile community characterized by cells that are irreversibly attached to a
substratum or interface or to each other, are imbedded in a matrix of extracellular polymeric
substances that they have produced, and exhibit an altered phenotype with respect to growth rate and
gene transcription
Note 1 to entry: The matrix, a slimy material secreted by the cells, protects the bacteria from antibiotics and
chemical disinfectants.
Note 2 to entry: A certain amount of biofilm formation is considered unavoidable in dialysis water systems. When
the level of biofilm is such that the action levels for microorganisms and endotoxins in the dialysis water are
routinely reached or exceeded, the operation of the system is compromised from a medical and technical point of
view. This level of biofilm formation is often referred to as biofouling..
3.7
bulk delivery
delivery of large containers of concentrate to a dialysis facility
Note 1 to entry: Bulk delivery includes containers such as drums, which can be pumped into a storage tank
maintained at the user's facility. Alternatively, the drums can be left at the facility and used to fill transfer
containers to transfer the concentrate to the dialysis machines. Bulk delivery can also include large containers for
direct connection to a central concentrate supply system.
Note 2 to entry: Bulk delivery also includes dry powder concentrates intended to be used with an appropriate
concentrate mixer.
3.8
central concentrate system
system that prepares and/or stores concentrate at a central point for subsequent distribution to its
points of use
3.9
central dialysis fluid delivery system
system that produces dialysis fluid from dialysis water and concentrate or powder at a central point
and distributes the dialysis fluid from the central point to individual dialysis machines
3.10
chlorine, combined
chlorine that is chemically combined, such as in chloramine compounds
Note 1 to entry: There is no direct test for measuring combined chlorine, but it can be measured indirectly by
measuring both total and free chlorine and calculating the difference.
3.11
chlorine, free Downloaded: 2017-02-09

ISO/DIS 23500-1
chlorine present in water as dissolved molecular chlorine (Cl), hypochlorous acid (HOCl), and
hypochlorite ion (OCl−)
Note 1 to entry: The three forms of free chlorine exist in equilibrium.
3.12
chlorine, total
sum of free and combined chlorine
Note 1 to entry: Chlorine can exist in water as dissolved molecular chlorine, hypochlorous acid, and/or
hypochlorite ion (free chlorine) or in chemically combined forms (combined chlorine). Where chloramine is used
to disinfect water supplies, chloramine is usually the principal component of combined chlorine.
3.13
colony-forming unit
CFU
measure of bacterial or fungal cell numbers that theoretically arise from a single cell when grown on
solid media
Note 1 to entry: Colonies can also form from groups of organisms when they occur in aggregates.
3.14
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.
3.15
dialysis fluid
dialysate
dialysis solution
aqueous fluid containing electrolytes and, usually, buffer and glucose, which is intended to exchange
solutes with blood during haemodialysis and haemodiafiltration
Note 1 to entry: The term “dialysis fluid” is used throughout this International Standard to mean the fluid made
from dialysis water and concentrates that is delivered to the dialyser by the dialysis fluid delivery system. Such
phrases as “dialysate” or “dialysis solution” are used in place of dialysis fluid in some countries; however, that
usage is discouraged to avoid confusion.
Note 2 to entry: The dialysis fluid entering the dialyser is referred to as “fresh dialysis fluid”, while the fluid
leaving the dialyser is referred to as “spent dialysis fluid”.
Note 3 to entry: Dialysis fluid does not include prepackaged parenteral fluids used in some renal replacement
therapies, such as haemodiafiltration and haemofiltration.
3.16
dialysis fluid delivery system
device that prepares dialysis fluid online from dialysis water and concentrates or that stores and
distributes premixed dialysis fluid; circulates the dialysis fluid through the dialyser; monitors the
dialysis fluid for temperature, conductivity (or equivalent), pressure, flow, and blood leaks; and,
prevents dialysis during disinfection or cleaning modes
Note 1 to entry: The term includes reservoirs, conduits, proportioning devices for the dialysis fluid, and monitors
and associated alarms and controls
Licensed assembled
to: Team as a system for the purposes listed above.
ANSI ISO

ISO/DIS 23500-1
Note 2 to entry: The dialysis fluid delivery system may be an integral part of the single-patient dialysis machine or
a centralized preparation system which feeds multiple bedside monitoring systems.
Note 3 to entry: Dialysis fluid delivery systems are also known as proportioning systems and dialysis fluid supply
systems.
3.17
dialysis water
water that has been treated to meet the requirements of ISO 23500-3 and which is suitable for use in
haemodialysis applications, including the preparation of dialysis fluid, reprocessing of dialysers,
preparation of concentrates and preparation of substitution fluid for online convective therapies
3.18
disinfection
destruction of pathogenic and other kinds of microorganisms by thermal or chemical means
Note 1 to entry: Disinfection is a less lethal process than sterilization because it destroys most recognized
pathogenic microorganisms but does not necessarily destroy all microbial forms.
Note 2 to entry; Appropriate disinfection strategies need to include: disinfection type, disinfectant concentration,
exposure time and temperature
3.19
empty-bed contact time
EBCT
time taken by a fluid to pass through an empty volume equal to the volume of a particle bed
Note 1 to entry: EBCT (min) is calculated from the following formula:
EBCT = V/Q
where
V is the volume of the particle bed, in cubic metres (m3);

Q is the flow rate of water through the bed, in cubic metres per minute (m3/min).
Note 2 to entry: EBCT is used as an indirect measure of how much contact occurs between particles, such as
activated carbon, and water as the water flows through a bed of particles.
3.20
endotoxin
major component of the outer cell wall of gram-negative bacteria
Note 1 to entry: Endotoxins are lipopolysaccharides, which consist of a polysaccharide chain covalently bound to
lipid A. Endotoxins can acutely activate both humoral and cellular host defences, leading to a syndrome
characterized by fever, shaking, chills, hypotension, multiple organ failure, and even death if allowed to enter the
circulation in a sufficient dose. [See also pyrogen (3.36)].
3.21
endotoxin-retentive filter
ETRF
membrane filter used to remove endotoxins and microorganisms from dialysis water or dialysis fluid
Note 1 to entry: The performance of an endotoxin-retentive filter is usually expressed as the logarithmic reduction
value (LRV), defined as log10(inlet concentration)/(outlet concentration).
Note 2 to entry: Endotoxin-retentive filters

Licensed may be
to: Team configured
ANSI ISO in a cross-flow or dead-end mode. Some endotoxin-
retentive filters also remove endotoxins by adsorption.

ISO/DIS 23500-1
3.22
endotoxin units
EU
units assayed by the Limulus amoebocyte lysate (LAL) test when testing for endotoxins
Note 1 to entry: Because activity of endotoxins depends on the bacteria from which they are derived, their activity
is assessed by reference to a standard endotoxin.
Note 2 to entry: In some countries, endotoxin concentrations are expressed in international units (IU). Since the
harmonization of endotoxin assays, EU and IU are equivalent.
3.23
feed water
water supplied to a water treatment system or to an individual component of a water treatment system
Note 1 to entry: the water supplied to the water treatment system is potable water that meets drinking water
requirements.
3.24
germicide
agent that kills microorganisms
3.25
haemodiafiltration
form of renal replacement therapy in which waste solutes are removed from blood by a combination of
diffusion and convection through a high-flux membrane
Note 1 to entry: Diffusive solute removal is achieved using a dialysis fluid stream as in haemodialysis. Convective
solute removal is achieved by adding ultrafiltration in excess of that needed to obtain the desired weight loss; fluid
balance is maintained by infusing a replacement solution into the blood either before the dialyser (predilution
haemodiafiltration), after the dialyser (postdilution haemodiafiltration), or a combination of the two (mixed
dilution haemodiafiltration).
3.26
haemodialysis
form of renal replacement therapy in which waste solutes are removed primarily by diffusion from
blood flowing on one side of a membrane into dialysis fluid flowing on the other side
Note 1 to entry: Fluid removal that is sufficient to obtain the desired weight loss is achieved by establishing a
hydrostatic pressure gradient across the membrane. This fluid removal provides some additional waste solute
removal, particularly for solutes with higher molecular weight.
3.27
haemofiltration
form of renal replacement therapy in which waste solutes are removed from blood by convection
Note 1 to entry: Convective transport is achieved by ultrafiltration through a high-flux membrane. Fluid balance is
maintained by infusing a replacement solution into the blood either before the haemofilter (predilution
haemofiltration), after the haemofilter (postdilution haemofiltration), or a combination of the two (mixed dilution
haemofiltration).
Note 2 to entry: There is no dialysis fluid stream in haemofiltration.
3.28
heterotrophic
not self-sustaining, i.e. a type of nutrition in which organisms derive energy from the oxidation of
organic compounds by either consumption or absorption of other organisms

ISO/DIS 23500-1
3.29
Limulus amoebocyte lysate test
LAL test
assay used to detect endotoxin
Note 1 to entry: The detection method uses the chemical response of an extract from blood cells of a horseshoe
crab (Limulus polyphemus) to endotoxins.
Note 2 to entry: Amebocyte lysate from a second horseshoe crab, Tachypleus tridentatus, may also be used to
detect endotoxin.
3.30
manufacturer
entity that designs, makes, fabricates, assembles, or processes a particular item or object.
Note 1 to entry: Manufacturer includes, but is not limited to, those who perform the functions of contract
sterilization, installation, relabelling, remanufacturing, repacking, or specification development, and initial
distributions of foreign entities performing these functions.
Note 2 to entry: Manufacturer does not cover the preparation of concentrates from pre packaged dry chemicals at
a dialysis facility or the handling of bulk concentrates at a dialysis facility after responsibility for the concentrate is
transferred from the manufacturer to the user.
3.31
microbiological contamination
contamination with any form of microorganism (e.g. bacteria, yeast, fungi, and algae) or with the by-
products of living or dead organisms, such as endotoxins, exotoxins, and cyanobacterial toxins (derived
from blue-green algae)
3.32
non pyrogenic
not eliciting a pyrogen reaction
Note 1 to entry: This definition is applicable for fluids produced by online techniques, e.g. substitution and
priming fluids.
Note 2 to entry: Historically, the threshold pyrogenic dose of 5 EU/kg/h (the minimum dose that produces fever)
has been used to set endotoxin limits of devices and injectable medications.
Note 3 to entry: The volume of fluid administered should not exceed the volume that would result in a total dose
of endotoxin of ≥5 EU/kg/h. Additionally, the maximum allowable level for endotoxin should be < 0,03 EU/ml.
Note 4 to entry: The commonly used gel clot method has a sensitivity limit of 0,03 EU/ml.
3.33
product water
water produced by a water treatment system or by an individual device thereof
3.34
proportioning system
apparatus that proportions dialysis water and haemodialysis concentrate to prepare dialysis fluid
3.35
pyrogen
fever-producing substance
Note 1 to entry: Pyrogens are most often lipopolysaccharides of gram-negative bacterial origin [see also endotoxin
(3.21)]. Downloaded: 2017-02-09

ISO/DIS 23500-1
3.36
sodium hypochorite
chemical used for disinfection of haemodialysis systems
Note 1 to entry: Commercially available solutions of sodium hypochlorite are known in different countries by
terms such as bleach and javel. These solutions are used for disinfection at concentrations recommended by
equipment manufacturers.
3.37
source water
water entering a dialysis facility from an external supplier, such as a municipal water supply
Note 1 to entry: Source water, sometimes referred to as feed water, is potable water meeting the requirements for
drinking water
3.38
sterile
free from viable microorganisms
Note 1 to entry: “Sterile” can be used to describe a packaged solution that was prepared using a terminal
sterilization process validated according to the methods of the applicable pharmacopoeia. A terminal sterilization
process is commonly defined as one that achieves a sterility assurance level (SAL) of 10−6, i.e. assurance of less
than one chance in a million that viable microorganisms are present in the sterilized article.
Note 2 to entry: Alternatively, “sterile” can be used to describe a solution prepared for immediate use by a
continuous process, such as filtration, that has been validated according to the methods of the appropriate
sections of the applicable pharmacopoeia to produce a solution free from microorganisms for the validated life of
the filter.
3.39
storage tank
tank at the user's facility for storage of dialysis water or concentrate from bulk deliveries, or for
concentrate prepared in bulk at the user's facility from powder and dialysis water
3.40
substitution fluid
fluid used in haemofiltration and haemodiafiltration treatments which is infused directly into the
patient's blood as a replacement for the fluid that is removed from the blood by ultrafiltration
Note 1 to entry: Substitution fluid is also referred to as substitution solution or replacement solution.
Note 2 to entry: Substitution fluid can also be used for bolus administration, for priming of an extracorporeal
blood circuit, and for returning blood to the patient at the end of a treatment.
3.41
total dissolved solids
TDS
sum of all ions in a solution, often approximated by means of electrical conductivity or resistivity
measurements
Note 1 to entry: TDS measurements are commonly used to assess the performance of reverse osmosis units. TDS
values are often expressed in terms of CaCO3, NaCl, KCl, or 442 equivalents, in milligrams per litre (mg/l). [442 is
a solution of sodium sulfate (40 %), sodium bicarbonate (40 %), and sodium chloride (20 %) that closely
represents the conductivity to concentration relationship, on average, for naturally occurring fresh water.]
3.42
ultrapure dialysis fluid
highly purified dialysis fluid that 2017-02-09
Downloaded: can be used in place of conventional dialysis fluid

ISO/DIS 23500-1
Note 1 to entry: A widely accepted specification of ultrapure dialysis fluid is <0,1 CFU/ml and <0,03 EU/ml.
3.43
user
responsible physician, their representative, or healthcare professional with a responsibility for the
prescription, production, and delivery of dialysis fluid.
Note 1 to entry: In this context the user refers to the decision maker who is accountable for the medical decision
for the care of the patients.
3.44
validation
process of documenting that the dialysis water treatment and dialysis fluid production systems, when
installed and operated according to the manufacturer's recommendations, consistently produce dialysis
water or dialysis fluid meeting the stipulated quality levels
Note 1 to entry: In this context, validation also includes demonstrating that the system is “fit for purpose”.
Note 2 to entry: The term “verification” is also used and refers to demonstrating that the system complies with
applicable regulations, specifications, or other conditions. A dialysis facility might be interested in both validation
and verification of its fluid production systems.
3.45
water treatment system
collection of water treatment devices and associated piping, pumps, valves, gauges, etc., that together
produce water for dialysis meeting the requirements of ISO 23500-3 for haemodialysis applications and
deliver it to the point of use.
4 Summary of the quality requirements of ISO 23500-4 (previously ISO 13958),

ISO 23500-3 (previously ISO 13959) and ISO 23500-5 (previously ISO 11663)
The quality requirements set forth in this clause are reproduced from ISO 23500-4, ISO 23500-3, and
ISO 23500-5. The latest editions of these International Standards should be consulted to ascertain if
there have been any changes to quality requirements before implementing the recommendations of this
International Standard.
4.1 Dialysis water

4.1.1 General
The requirements contained in this clause apply to dialysis water at its point of use. As such, these
requirements apply to the water treatment system as a whole and not to each of the devices that make
up the system. However, collectively, the individual devices shall produce water that, at a minimum,
meets the requirements of this clause.
4.1.2 Chemical contaminants in dialysis water
Dialysis water shall not contain substances at levels greater than those listed in ISO 23500-3
(see Tables 1 and 2). The manufacturer or supplier of a complete water treatment system should
recommend a system that is capable of meeting these requirements based on a feed water analysis. The
system design should reflect possible seasonal variations in feed-water quality. The manufacturer or
supplier of a complete water treatment and distribution system should demonstrate that the complete
water treatment, storage, and distribution system is capable of meeting the requirements of ISO 23500-
3 at the time of installation.
NOTE The maximum allowable levels

Licensed of contaminants
to: Team ANSI ISO listed in Tables 1 and 2 include the anticipated
uncertainty associated with the analytical methodologies
Downloaded: 2017-02-09 listed in Table 3 of ISO 23500-3. Other analytical

ISO/DIS 23500-1
methods can be used, provided that such methods have been appropriately validated and compared to the cited
methods.
Following installation of a water treatment, storage, and distribution system, the user is responsible for
regular monitoring of the levels of chemical contaminants in the dialysis water and for complying with
the requirements of this International Standard.
Tables 1 and 2 are reproduced from ISO 23500-3
Table 1 — Maximum allowable levels of toxic chemicals and dialysis fluid electrolytes in dialysis
watera,b
Contaminant Maximum concentration (mg/L)

c
Contaminants with documented toxicity in haemodialysis

Aluminium 0,01
Total chlorinee 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 dialysis facility’s Medical Director has the ultimate responsibility for ensuring
the quality of dialysis water.
b The reader is cautioned to refer to the latest version of ISO 23500-3 to ensure that
there have been no changes to this table.
c Unless otherwise noted.
d.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 (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.
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 should not exceed 0.1 mg/L. Since there is no
distinction between chlorine and chloramine, this safely assumes that all chlorine
present is chloramine.
e When verifying disinfectant removal from the dialysis equipment, effluent, free
chlorine measurement is acceptable to the limits specified by the manufacturer


ISO/DIS 23500-1
Table 2 — Maximum allowable levels of other trace elements in dialysis watera
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
Thallium 0,002
a The reader is cautioned to refer to the latest version of ISO 23500-3 to ensure that
no changes have been made to the maximum concentrations shown.
No limits in respect of organic compounds are included in the above table. Currently, there is limited
documentary evidence to suggest that exposure impacts on patients wellbeing. A suggested starting
point to assess whether such compounds are of concern is the National Drinking Water requirement for
organic compounds.
Since organic compounds can be effectively removed by the use activated carbon beds or filters, the
dialysis facility should consider carefully their dimensioning to ensure that there is sufficient capacity to
remove organic compounds should the need arise.
4.1.3 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 hemodialysis
patients are difficult to define. 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 not at present possible to define 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 or organic carbons, pesticides and other chemicals will be dependant upon the size of the
carbon filters and/or beds and users must be aware of appropriate dimensioning since majority of
carbon valences may be already occupied and not available for further removal activity.
4.1.4 Microbiological contaminants in dialysis water
The total viable microbial count and endotoxin concentration in dialysis water shall comply with the
maximum allowable levels specified in ISO 23500-3 (see Table 3). Action levels for the total viable
microbial count and endotoxin concentration
Licensed shall
to: Team ANSI ISOalso be set, based on knowledge of the microbial
dynamics of the system. Typically, the action level is set at 50 % of the maximum allowable level for

ISO/DIS 23500-1
bacteria and endotoxins. If a total viable microbial count or endotoxin concentration at or above the
action level is observed in the dialysis water, corrective measures should be taken promptly to reduce
the level. The manufacturer or supplier of a complete water treatment and distribution system should
demonstrate that the complete water treatment, storage, and distribution system is capable of meeting
the requirements of ISO 23500-3 at the time of installation.
Following installation of a water treatment, storage and distribution system, the user is responsible for
regular monitoring of the microbiology of the system and for complying with the requirements of this
International Standard, including those requirements related to action levels.
In association with the presence of bacteria and endotoxin in the water, yeast and filamentous fungi
may also be present. No specific recommendations have been made in respect of the routine
measurement of such contaminants, nor have action limits been set.
Table 3 is adapted from ISO 23500-3.
Table 3 — Maximum allowable levels for total viable microbial count (TVC) and endotoxins in
dialysis watera
Contaminant Maximum allowable level Typical action levelb

TVC <100 CFU/ml 50 CFU/ml
Endotoxin <0,25 EU/ml 0,125 EU/ml
a The reader is cautioned to refer to the latest version of ISO 23500-3 to ensure that there have been no
changes to the values presented in this table.
b Typically set at 50 % of the maximum allowable level. Other values may be set.
4.2 Requirements for concentrate

4.2.1 Chemical and microbiological contaminants in concentrate
Concentrates used to prepare dialysis fluid shall comply with the quality requirements specified in
ISO 23500-4.
Bicarbonate concentrate can grow bacteria and caution should be used to limit the bacterial levels in
bicarbonate concentrate.
4.2.2 Water used to prepare concentrate
Water used to prepare concentrates at a dialysis facility shall meet the requirements of ISO 23500-3.
Any concentrate prepared at a dialysis facility shall permit the dialysis machine to prepare dialysis fluid
meeting the requirements of ISO 23500-5.
4.3 Requirements for dialysis fluid

4.3.1 General
The requirements contained in this clause apply to a sample of the dialysis fluid collected as close as
practicable to the inlet to the dialyser.
ISO 23500-5 defines three levels of dialysis fluid: standard dialysis fluid, ultrapure dialysis fluid, and
online-prepared substitution fluid used for haemodiafiltration.

ISO/DIS 23500-1
Standard dialysis fluid shall be regarded as the minimum acceptable quality. Ultrapure dialysis fluid is a
step forward in improving biocompatibility, reducing inflammation and preventing dialysis related
complications.
Tests for bacterial growth and endotoxins are not required if the dialysis machine fluid pathway is fitted
with an appropriate capacity bacteria retentive and endotoxin-retentive filter validated by the
manufacturer and operated and monitored according to the manufacturer's instructions, unless the
manufacturer requires such tests in the instructions for use.
4.3.2 Microbiological requirements for standard dialysis fluid
The total viable microbial count and endotoxin concentration in standard dialysis fluid shall comply
with the maximum allowable levels specified in ISO 23500-5 and reproduced in Table 4. Action levels
for the total viable microbial count and endotoxin concentration shall also be set, based on knowledge
of the microbial dynamics of the system as specified in ISO 23500-5. Typically, the action level is set at
50 % of the maximum allowable level for total viable microbial count and endotoxins. If total viable
microbial counts or endotoxin concentrations at or above the action levels are observed in the dialysis
fluid, corrective measures, such as disinfection and retesting, should promptly be taken to reduce the
levels.
Table 4 is adapted from ISO 23500-5.
Table 4 — Maximum allowable levels for total viable microbial count (TVC) and endotoxins in
standard and ultrapure dialysis fluida
Standard dialysis fluid Ultrapure dialysis fluid

Contaminant Maximum allowable Maximum allowable
level Action levelb level
TVC <100 CFU/ml 50 CFU/ml <0,1 CFU/ml
Endotoxin <0,5 EU/ml 0,25 EU/ml <0,03 EU/ml
a The reader is cautioned to refer to the latest version of ISO 23500-5 to ensure that there have been no changes to this
table.
b Typically set at 50 % of the maximum allowable level. Other values may be set.
4.3.3 Microbiological requirements for ultrapure dialysis fluid
The total viable microbial count and endotoxin concentration in ultrapure dialysis fluid shall comply
with the maximum allowable levels specified in ISO 23500-5 and reproduced in Table 4. If those limits
are exceeded in ultrapure dialysis fluid, corrective measures should be taken to reduce the levels into
an acceptable range. The user is responsible for monitoring the dialysis fluid bacteriology of the total
system following installation.
Tests for bacterial growth and endotoxins are not required if the dialysis machine fluid pathway is fitted
with an appropriate capacity bacteria retentive and endotoxin-retentive filter validated by the
manufacturer and operated and monitored according to the manufacturer's instructions, unless the
manufacturer requires such tests in the instructions for use.


ISO/DIS 23500-1
4.3.4 Microbiological requirements for online-prepared substitution fluid
The recommendations contained in this clause apply to substitution fluid as it enters the patient's
blood.
This fluid shall be sterile and nonpyrogenic according to the recommendations of ISO 23500-5.
Substitution fluid for convective therapies, such as haemodiafiltration and haemofiltration, or for
priming the extracorporeal circuit or bolus administration of fluid during a treatment, may be produced
online by a process of ultrafiltration with endotoxin-retentive filters. This online process shall be
validated by the manufacturer to produce substitution fluid that is sterile and nonpyrogenic.
The user shall follow the manufacturer's instructions for the installation, use, maintenance, and
monitoring of the validated system. The function of the validated system shall be verified according to
the manufacturer's instructions at the time of installation and confirmed by the user with regular
monitoring. Monitoring shall include confirmation that the dialysis water and concentrates used by the
validated system to prepare the substitution fluid continue to meet the specifications of ISO 23500-4
and ISO 23500-3.
4.4 Record retention
Records of installation, monitoring, maintenance, and disinfection of the water treatment and dialysis
fluid preparation systems, medical observation, and personnel education shall be kept according to
national regulations. In the absence of national regulations, it is recommended that these records
should be retained for the same period as clinical records.
5 Critical aspects of system design

The preparation of dialysis fluid, from inlet municipal water and acquisition of concentrates to
discharge of spent dialysis fluid into the drain system, involves numerous components that, together,
form a dialysis fluid handling system.
The technical features of the water treatment component of that system should be based on the criteria
listed in ISO 23500-2, with special regard to the aspects related to the dialysis water quality,
disinfection and maintenance. In addition to the general specifications the system design should also
comply with local water and building regulations. The treatment of water for haemodialysis
applications is an energy and resource intensive process and in designing the system, appropriate
consideration should also be given to ensure optimal use of resources e.g water and energy.
Concentrates used with the treated water to prepare dialysis fluid may be obtained from a supplier in a
ready-to-use form or prepared at the dialysis facility from dialysis water and prepackaged salts. The
technical features of the concentrate preparation and distribution component of the system should be
based on the criteria listed in ISO 23500-4.
In general, the spent or used dialysis fluid is discharged into the public sewage system without
treatment. Sterilants may also be similarly discharged. The risks to public health and the environment
from such discharges are negligible, however such discharges may impact on the effectiveness of
domestic aneorobic digestion systems
5.1 Technical aspects
In accordance with the requirements listed in ISO 23500-2, the system design should specifically
address the following points:
a) The choice of the water treatment system should consider the following aspects concerning the
feed-water supply:

ISO/DIS 23500-1
i. full chemical analysis of the feed water and silt density index (SDI);
ii. microbiological load, which may require the introduction of an additional chlorination step;
iii. flow rates, pressure, and temperature;
iv. treatment techniques used by the provider of the feed water (for example, addition of
chloramine, fluoride, aluminium sulfate, etc.). Because treatment techniques can change,
ongoing communication with the provider of the feed water is recommended;
NOTE 1 Source water is assumed to be potable water meeting National Drinking Water Requirements.
NOTE 2 If the water supply to the treatment system, is not directly from the municipal distribution
network, but comes via an existing hospital water supply, there should be awareness of the potential risks
that may arise from the introduction of chemicals into the hospital water supply by hospital engineering staff.
To prevent the occurrence of adverse effects arising from such actions, the introduction or addition of
chemicals into the hospital water supply should only be undertaken after prior consultation with renal
services. It should be further noted, that if such chemicals are introduced, it may necessitate additional
monitoring prior to water being used for dialysis applications.
b) product water capacity during sanitization:
if heat sanitization is planned for the system, the distribution loop is sanitized along with the links from
the distribution loop to the dialysis machines. The demand for water during such sanitization is higher
than required by the dialysis machines during operation;
c) product water capacity during the winter months:
commonly, reverse osmosis systems capacity is rated at a specified incoming water temperature. There
should be awareness that such temperatures may not be achieved during the winter months, and the
efficiency of the system will reduce. To meet the required water demand there may be a need to pre
heat the feed water or to install a plant with increased capacity to compensate for the reduction in
reverse osmosis efficiency during the winter months;
d) sanitization of the system:
disinfection is the only effective method of diminishing and inactivating microflora: First and foremost,
the frequency of disinfection is important. Disinfection should be performed on a regular basis to limit
biofouling within the fluid pathways of the system. Second, all surfaces in the circuit should be included
in the disinfection procedure. This includes the reverse osmosis membranes (especially the clean side),
the distribution piping, the inlet lines to the dialysis machines (located before the disinfection circuit of
the dialysis machine), and the dialysis machines (which have their own disinfection circuit and
programme). Third, the disinfection procedure, when applied with a given frequency and with inclusion
of all critical areas, should be capable of minimizing the effects of biofouling.
Disinfection can be performed using heat or chemicals. UV lamps can be used to inactivate planktonic
cells but are of no value against any biofilm that has formed in the system.
Hot water may be used to control bacterial proliferation in dialysis water storage and distribution
systems. The exposure time should be according to the manufacturer’s instructions. The water heater of
a hot water disinfection system should be capable of delivering hot water at the temperature and for
the exposure time specified by the manufacturer to any site in the dialysis water storage and
distribution system. The manufacturer’s instructions for using hot water disinfection systems should
be followed.
If chemical sanitization is to be used, the period of down time should be sufficient to enable the
chemicals to be rinsed completely from the
Downloaded: system prior to the commencement of the next dialysis shift.
2017-02-09

ISO/DIS 23500-1
If it is possible to sanitize the haemodialysis machines at the same time as the distribution ring, then
this should be performed since this is the easiest and simplest..
e) compliance with mandatory local water and building regulations:
f) provision for adequate process monitoring;
g) service and maintenance.
If the entire fluid handling system is not obtained from a single supplier, then the user becomes
responsible for ensuring that the separate parts of the system are compatible. For example, it is
important that the pre treatment section of the water treatment system be designed to supply the main
purification device (usually reverse osmosis) with feed water meeting the specifications for that device,
i.e. pressure, temperature, flow, and quality (for example, elimination of chemicals which cannot be
effectively removed by the main purification device or that could damage it).
5.2 Microbiological aspects
The required microbiological quality of the dialysis water and dialysis fluid is achieved by paying
adequate attention to the entire water treatment and dialysis fluid preparation cascade. For this reason,
the system should be designed to reduce, as much as possible, potential sources of contamination and to
allow effective monitoring and disinfection of the critical parts.
When applicable, equipment should be operated on a regular basis to reduce stagnation.
The distribution system should be designed to maintain dialysis water or dialysis fluid quality and,
therefore, should fulfil the following criteria:
— the distribution loop should be of the minimum length, and avoid multiple branches and dead ends;
— materials shall be compatible with the different operational conditions (i.e. supply, disinfection,
cleaning);
— there should be no release of chemicals and nutrients for microorganisms;
— temperature increases or exposure to sunlight should be minimized.
Suitable sampling ports should be available at the start and the end of the distribution loop.
5.3 Environmental impact
The environmental aspect of haemodialysis is considerable in terms of the resources used. e.g water
and electricity). In planning the water treatment, consideration should be given to minimizing the
water that is rejected by the reverse osmosis system, for example by the use of a dual pass RO systems
in which the rejected water passes through a second RO system to improve recovery and/or the use of
rejected water for applications that do not require drinking water, e.g flushing toilets.
Treatment of patients may take place in a hospital, clinic or a home environment. When the patient is
receiving treatment in their home, there should be awareness that the discharge of large volumes of
fluid associated with dialysis treatment in the form of used dialysis fluid, or disinfection products
associated with the water treatment maintenance may impact on the effectiveness of a domestic
anaerobic digestion system. Furthermore, there may be local regulations in place limiting such
discharges into public sewage systems.


ISO/DIS 23500-1
6 Validation of system performance

The validation process should provide documentary evidence that the system will consistently produce
dialysis water, dialysis fluid, or substitution fluid meeting the quality requirements of ISO 23500-3 or
ISO 23500-5. An example of the validation process is presented schematically in Figure 1.
Key
IQ • installation qualification
OQ • operational qualification
PQ • performance qualification
Figure 1—Example of a validation process for a fluid preparation and distribution system
The rationale for the validation process is given in Annex E.
The validation process consists of the following:
— assignment of operational responsibility;
— assignment of clinical responsibility;

— assignment of legal responsibility;

ISO/DIS 23500-1
— validation plan;
— installation and operational qualification;
— performance qualification;
— revalidation as it relates to routine monitoring.
6.1 Validation plan
The validation plan should be a clear and concise document covering the following:
— description of relevant systems, equipment, or processes;
— current status of those systems, equipment, or processes;
— procedures for making changes to systems, equipment, or processes;
— planning and scheduling, including the addition of new systems, activities driven by change, and
periodic review.
The validation plan should be approved by the person at the dialysis facility with overall responsibility
for dialysis fluids.
6.2 Installation and operational qualification
The installation qualification defines and provides the documented proof that the system is installed in
accordance with the approved plans and the manufacturer's technical requirements and specifications.
Full system documentation should be available on completion of this procedure, including system flow
diagrams and layout, log books, and operator's manuals. The installation should be carried out by
qualified personnel in accordance with the manufacturer's documented recommendations.
The installation qualification should be followed by an operational qualification that verifies the proper
operation of the system, including range of operation, set point and interlock testing, and functional
testing, and that compares the system performance with the functional specifications of the system. On
completion of this phase, the following information should be available:
— test records;
— set-up record;
— calibration schedule;
— sampling procedures;
— maintenance (e.g. disinfection, filter changes, etc.) and monitoring (e.g. conductivity,
microbiological analysis) plans;
— record of operator(s) training.
6.3 Performance qualification
The performance qualification should demonstrate the consistency and robustness of the system under
local operational conditions. During this phase, information about system behaviour should be collected
and action levels should be reviewed
Licensed or defined.
to: Team ANSI ISO On completion of the performance qualification, the
following informationSingle
should be available:
user licence only, copying and networking prohibited

ISO/DIS 23500-1
— test records;
— chemical and microbial analyses;
— key performance indicators [for example, pretreatment efficiency, reverse osmosis (RO)
recovery/rejection rate, etc.];
— (initial) trend analysis.
For newly installed systems, the person with overall clinical responsibility for dialysis (possibly
supported by technical experts) may authorize use of dialysis fluid for patient treatments once chemical
and microbiological analyses are available that show full compliance with the quality requirements of
Clause 4, the manufacturer's specifications, and any applicable regulatory requirements.
In some instances the schematic approach shown in Figure 1 cannot be followed, and concurrent
validation may be appropriate e.g following major refurbishment of an already existing system. The
person with overall clinical responsibility for dialysis (supported by technical experts) may authorize
use of dialysis fluid for patient treatments provided an appropriate risk assessment has been performed
and recorded.
6.4 Routine monitoring and revalidation
This sub clause describes the monitoring activities to be conducted as part of the quality control and
quality assurance process.
Routine monitoring should begin following the performance qualification (see 6.3) to ensure ongoing
compliance with the dialysis water and dialysis fluid quality requirements set forth in Clause 4. Trend
analysis of monitoring data should be used to provide advanced information on system performance,
thus enabling a preventive rather than a reactive approach to system maintenance.
Monitoring is achieved with online and offline measurements. Online monitoring of suitable parameters
(such as conductivity) provides immediate identification of deviations from normal operating
conditions and can identify potential problems in their early stages, and could trigger specific additional
offline measurements. A purely time-based offline sampling regime has inherent limitations for the
monitoring of a continuous production process since deviations can occur between samples.
Fluid sampling for microbiological testing should be performed before disinfection or no sooner than
24 h after disinfection (to avoid false-negative results). When disinfection is performed on consecutive
days, or more frequently, samples should be taken before, and as close as practicable, to a disinfection
procedure.
Samples for routinely scheduled microbiology monitoring should be obtained in as short a possible time
before the scheduled disinfection.
Guidance on parameters that should be monitored is provided in Annex C, Table C.1.
A revalidation should be performed following:
— modification of the maintenance and monitoring plans;
— modification of the system;
— changes in the requirements for dialysis fluid quality.
In the absence of system modification, regular revalidation is still required. This revalidation consists of
a retrospective assessment of the routine
Licensed results
to: Team of the previous year (no additional tests are required
ANSI ISO
for the revalidation process). The purpose of this review is to prove the adequacy of the maintenance

ISO/DIS 23500-1
and monitoring plan under the local operating conditions. The revalidation should include a report
submitted to, and approved by, the person with overall clinical responsibility for dialysis.
7 Quality management
7.1 General
Quality control and quality assurance procedures should be established to ensure on going
conformance to policies and procedures regarding fluid quality. This clause defines some of the
monitoring activities to be performed at the dialysis facility as part of the quality assurance process.
The test methods described in 7.2 are intended to provide examples of acceptable methods. Other test
methods, provided that they have been appropriately validated and compared to the methods cited in
7.2 and have demonstrated equivalence to the results obtained by the cited methods may also be used.
The frequency of monitoring is generally recommended by the equipment manufacturer or by local
organizations that oversee dialysis facilities. In the absence of a manufacturer's recommendations,
guidance on tests to include in a quality assurance monitoring programme can be found in Annex C.
This guidance can also be used to supplement the manufacturer's recommendations.
Water utility companies’ primary obligation is to provide the domestic user with water which meets the
requirements of national or local drinking water regulations. In order to meet these requirements, the
water company may introduce new methods of treatment or sanitization without prior consultation.
Whilst the impact of any such change is unlikely to impact on the normal user, the changes can impact
on patients receiving dialysis treatment. In view of this, the clinic should establish robust
communications with the feed-water supplier so that the feed-water supplier is aware that the feed
water is used for the production of dialysis fluid [i.e. for life-saving treatment on end-stage renal disease
(ESRD) patients] and request the establishment of formal procedures to provide the clinic with correct
and timely information about any change in the supplied water quality (for example, change of source
or type of raw water treatment) or delivery (e.g. water supply interruptions). If such procedures cannot
be established, additional monitoring of feed-water quality is highly desirable to maximize patient
safety.
7.2 Monitoring of fluid quality

7.2.1 Monitoring of dialysis water quality
Dialysis water quality shall be monitored on a regular basis for the chemical and microbiological
contaminants listed in 4.1.2 and 4.1.3. The monitoring schedule shall be based on the results of the
system validation. For an established water treatment system operating under stable conditions,
chemical contaminants in dialysis water should be monitored at least annually. The exception is for
total chlorine, which should be monitored as described in 7.3.5.
Methods for monitoring chemical and microbiological contaminants in dialysis water are given in
ISO 23500-3 (see also 8.3).
For water treatment and distribution systems that are integrated into a single system and that have
been validated to produce water meeting the quality requirements of ISO 23500-3, the manufacturer's
recommendations for monitoring may be followed for the manufacturer's recommended maximum
period of use according to the instructions for use, provided that there is assurance that the system is
being operated under the validated conditions.
7.2.2 Monitoring of concentrate quality
Users do not have to test concentrates to demonstrate compliance with the requirements of ISO 23500-
4 when using commercially available packaged chemicals intended for use in preparing liquid
concentrates at a dialysis facility or when using commercially available liquid concentrates, provided
that the concentratesLicensed to: Team ANSI ISO
are manufactured in accordance with the requirements of ISO 23500-4. If the user

ISO/DIS 23500-1
prepares concentrate from raw chemicals, the resulting concentrate should meet the requirements of
ISO 23500-4.
7.2.3 Monitoring of dialysis fluid quality
Dialysis fluid quality shall be monitored on a regular basis for the microbiological contaminants listed in
4.3.2 as described in 8.3.1. Methods for monitoring microbiological contaminants in dialysis fluid are
described in 8.3.
NOTE 1 Tests for bacterial growth and endotoxins are not required if the dialysis machine fluid pathway is fitted
with an appropriate capacity bacteria retentive and endotoxin-retentive filter validated by the manufacturer and
operated and monitored according to the manufacturer's instructions, unless the manufacturer requires such
tests in the instructions for use.
NOTE 2 It is not practical to monitor compliance with the microbial quality requirements for substitution
solutions using currently available culturing methods,without an increased risk of exogenous contamination.
Because dialysis fluid is prepared from dialysis water and concentrates meeting the quality
requirements of ISO 23500-3 and ISO 23500-4, respectively, and since the dialysis water distribution
system and dialysis fluid delivery system are required to be constructed of materials that do not
contribute chemical contaminants to the water, routine monitoring of chemical contaminants in the
dialysis fluid is not required.
7.3 Monitoring of water treatment equipment

7.3.1 General
The following requirements relate to and help explain the guidance provided in Annex C. A brief
description of the individual water treatment devices is provided in Annex B.
7.3.2 Monitoring of sediment filters
There is no easy test to determine the effectiveness of a sediment filter; however, pressure drop (∆P)
across the filter can be used to determine when the filter is retaining particulate matter to the point that
the filter will no longer allow the required water flow without an excessive reduction in pressure at the
outlet of the filter. A backwash cycle is used as a preventive measure to remove particulate matter from
the sediment filter and avoid the development of an excessive pressure drop. The frequency of
backwashing should follow the manufacturer's recommendations. Sediment filter monitoring should
include verification that the timer used to initiate backwashing cycles is set to the correct time of day. A
log sheet should be developed to record the pressure drop measurements and timer verifications.
7.3.3 Monitoring of cartridge filters
Cartridge filters should be monitored on a regular basis. There is no easy test to determine the
effectiveness of a cartridge filter in removing particulate matter; however, pressure drop (∆P) across
the filter can be used to determine when the filter is retaining particulate matter to the point that the
filter will no longer allow the required water flow without an excessive reduction in pressure at the
outlet of the filter. A marked decrease in ∆P without a corresponding decrease in flow rate can indicate
a loss of filter integrity. Cartridges are usually replaced when ∆P increases to some specified value or at
a predetermined interval. A log sheet should be developed to record the pressure drop measurements.
7.3.4 Monitoring of softeners
Softener monitoring consists of the following: testing softened water for residual hardness; for
automatically regenerating Licensed
softeners, checking
to: Team that the brine tank contains a sufficient supply of
ANSI ISO
undissolved sodium chloride;
Single user licence only, copyingsofteners,
and, for time-controlled checking
and networking that the timer indicates the
prohibited

ISO/DIS 23500-1
correct time of day. The frequency of monitoring should be based on the hardness of the feed water and
the capacity of the softener. When reverse osmosis is used, monitoring should be used to ensure that
hardness limits established by the reverse osmosis machine manufacturer are not exceeded. A
temporary rise in hardness will have a minimal effect on the performance of the reverse osmosis
system, as calcium and magnesium are removed by reverse osmosis.
Testing for hardness should be performed using an ethylenediaminetetraacetic acid (EDTA) titration
test, with “dip and read” test strips, or a similar method. Online hardness monitors are also available. If
an online monitor is used, it should be used and maintained in accordance with the manufacturer's
instructions. Regardless of the method chosen, users should ensure that test accuracy and sensitivity
are sufficient to satisfy the hardness monitoring requirements of the reverse osmosis machine
manufacturer when the softener is used as pre treatment for a reverse osmosis system.
When timer-controlled softeners are used, it is recommended that the hardness of the water exiting the
softener be measured as near as practicable to the end of the duty cycle. The hardness test at the end of
the duty cycle will indicate the overall effectiveness of the water softener under worst-case conditions
and will ensure that the softener is sized properly and that the regeneration schedule is adequate.
Timers should be checked at the beginning of each day. For volume-controlled duplex softeners, testing
for hardness can be performed at any time of the day.
The softener brine tank should be monitored on a regular basis to ensure that enough salt is present in
the brine tank to form saturated salt solution of sufficient volume for a minimum of one regeneration
cycle. Salt used for regeneration should meet the specifications of the softener manufacturer. In
particular, salt designated as rock salt should not be used for softener regeneration since it is not
refined and typically contains sediments and other impurities that can damage O-rings and pistons and
clog orifices in the softener control head. The frequency of monitoring should be based on the length of
the duty cycle.
Water softeners should be fitted with a mechanism to prevent water containing the high concentrations
of sodium chloride used during regeneration from entering the product-water line during regeneration.
Water hardness test results and verification of timer settings and the presence of salt pellets should be
recorded in a water-softener log.
7.3.5 Monitoring of carbon media
The performance of carbon beds is monitored by measuring the total chlorine concentration in the
water exiting the carbon bed, or exiting the first carbon bed when a series‐connected pair of beds is
used. The total chlorine level should not exceed 0,1 mg/L. Alternately, if free chlorine is used this
should not exceed 0,5 mg/L
Testing for total chlorine can be accomplished using the N,N‐diethyl‐p‐phenylenediamine (DPD)‐based
test kits, dip‐and‐read test strips based on Michler's thioketone (MTK or TMK), or other methods where
comparable sensitivity and specificity can be demonstrated. Online monitors can also be used to
measure total chlorine concentrations. If an online monitor is used, it should be used and maintained in
accordance with the manufacturer's instructions. Whichever test system is used, it should have
sufficient sensitivity and specificity to resolve the maximum levels described in 4.1.2 (see Table 1).
When offline tests are used, testing for total chlorine should be performed at the beginning of each
treatment day prior to the patient's initiating treatment. Where chloramine is used to disinfect the
potable water supply at a level of 1 mg/L or more, testing should be repeated prior to the beginning of
each patient shift; if there are no set patient shifts, testing should be performed approximately every 4 h
during operation. More frequent monitoring could be appropriate during temporary operation with a
single carbon bed, which can occur following breakthrough of the first bed. In such instances, testing is
performed on water exiting the second carbon bed in a series‐connected pair. The decision to change
the frequency of monitoring should
Downloaded: be based on the past performance of the system and on whether
2017-02-09

ISO/DIS 23500-1
changes in feed‐water quality have occurred. The system should be flushed for a sufficient period of
time to ensure that water sampled is representative of the water to be used for treatment. Sufficient
flushing is necessary to ensure that sampled water has not been resident in the removal system
between treatments, such that it would under‐represent the chloramine level that would be delivered
during normal operation. The minimum flush time should be 15 minutes unless otherwise directed by
the manufacturer of the equipment. The analysis should be performed onsite since total chlorine levels
will decrease if the sample is not assayed promptly.
Results of monitoring should be recorded on a log sheet.
7.3.6 Monitoring of chemical injection systems
Systems for chemical injection should be monitored according to the manufacturer's instructions. If a
facility designs its own chemical injection system, procedures should be developed to ensure proper
preparation of the chemical, adequate mixing of the injected chemical with the water flowing through
the pretreatment cascade, and reduction to a safe level of the concentration of any chemical residuals
before the point of water use. The facility should also verify that the injected chemical does not degrade
the performance of downstream devices, such as the reverse osmosis system. Verification can be
accomplished by testing samples from the chemical reservoir and the water line after the point of
injection for at least three batches of chemical.
When the chemical to be injected is prepared at a facility from powder or by dilution of a liquid
concentrate, the chemical injection reservoir should be labelled with the name of the chemical and its
concentration, the date the solution was prepared, and the name of the person who mixed the solution.
Each batch of chemical should be tested for correct formulation before use. A batch of chemical should
not be used or transferred to the injection system reservoir until all tests are completed. The test
results, and verification that they meet all applicable criteria, should be recorded and signed by the
trained personnel performing the tests.
Protective clothing and an appropriate environment, including ventilation adequate to meet applicable
environmental exposure limits, and national standards or regulations should be provided when
chemicals for injection are prepared in a dialysis facility.
7.3.7 Monitoring of reverse osmosis
Reverse osmosis systems should be monitored using continuously-reading monitors that measure
product-water conductivity [sometimes displayed as total dissolved solids (TDS)]. The measurements
can be used to calculate rejection of solutes by the reverse osmosis membrane and provide a measure of
equipment performance. Per cent rejection is calculated using the Formula (1):
Feed water conductivity − Permeate conductivity

Rejection ( % ) × 100
Feed water conductivity (1)
Many reverse osmosis systems have a direct reading for per cent rejection.
The permeate conductivity and rejection are both affected by a number of factors, such as the salinity
and composition of the feed water, the water temperature, the level of dissolved gases, and the pressure
in the system. Therefore, neither of them should be regarded as a true indicator of the water's
suitability for dialysis. No limits are therefore set for these parameters in ISO 23500-3. Instead, they
should be used to monitor changes in performance over time rather than an absolute measure of the
quality. This can only be established by performing a chemical analysis of the product water in
accordance with ISO 23500-3.
NOTE 1 For two-stage reverse osmosis systems, the per cent rejection of the second stage will be lower than
that of the first stage because ofLicensed
physicochemical phenomena.
to: Team ANSI ISO

ISO/DIS 23500-1
Other parameters that should be measured include product and reject stream flow rates and various
internal pressures to the extent permitted by the system's instrumentation. Although these parameters
are not directly indicative of treated water quality, monitoring them can help ensure that the system is
operating within the manufacturer's specifications and, thus, will aid in maintaining the performance of
the reverse osmosis membranes. Flow rates can be used to calculate the per cent recovery of the
reverse osmosis system using Formula (2):
Permeate water flow rate

Recovery ( % ) × 100
Permeate water flow rate + Reject water flow rate (2)
NOTE 2 The per cent recovery is also known as the “water conversion factor”. The terms are equivalent if none
of the reject water stream is recycled to the feed-water stream (see B.2.7). If some of the reject water stream is
recycled, Formula (2) provides a measure of overall water utilization by the reverse osmosis system, rather than
the recovery of water during a single pass through the membrane module.
NOTE 3 The permeate water flow rate varies with operating pressure and temperature. To enable comparisons
to be made under different operating conditions, a normalized permeate flow rate can be calculated. Methods for
calculating the normalized permeate flow rate are available from reverse osmosis membrane manufacturers or
can be found in ASTM D4516–00 (2010).[168]
When reverse osmosis is the final process in the water treatment system for removing chemical
contaminants, analysis for the contaminants listed in Tables 1 and 2 should be done when the reverse
osmosis system is installed to ensure that the limits specified in 4.1.2 are met. It is also recommended
that chemical analyses be done when the following situations occur:
— information is obtained from the water supplier that significant changes in the source water, such
as seasonal variations, have occurred;
— significant deviations are observed in process parameters, such as pH, conductivity, chlorine
concentration and hardness, that can affect the performance of components of the water treatment
system;
— reverse osmosis rejection rates decrease by more than 10 %.
All results of measurements of reverse osmosis performance should be recorded daily in an operating
log that permits trending and historical review.
7.3.8 Monitoring of deionization
Deionizers shall be monitored continuously using resistivity monitors that compensate for
temperatures up to 25° C and that are equipped with audible and visual alarms. Resistivity monitors
shall have a minimum sensitivity of 1 MΩ·cm (1 μS/cm or 0,1 mS/m). If the resistivity of the water at
the outlet of a deionizer is less than 1 MΩ·cm, the water shall not be used for dialysis. When
deionization is employed as the primary method for removing inorganic contaminants (reverse osmosis
is not employed), or when deionization is necessary to polish reverse-osmosis-treated water, chemical
analyses to ensure that the requirements of 4.1.2 are met should be performed when the system is
installed. Resistivity monitor readings should be recorded on a log sheet twice each treatment day.
7.3.9 Monitoring of endotoxin-retentive filters
The performance of endotoxin-retentive filters in dialysis water distribution, bicarbonate concentrate

distribution, or dialysis fluid delivery systems can be monitored by testing the fluid that is directly
exiting the filter for bacteria and endotoxins. Endotoxin-retentive filters should be fitted with a means
of assessing filter integrity and fouling. One suitable means is to monitor the pressure drop (∆P) across
the filter at a given product fluid flow rate using pressure gauges on the inlet (feed) and outlet (product)
streams. Alternatively, product
Licensed fluidANSI
to: Team flow
ISOrate can be measured at a given pressure drop. Such
monitoring can indicate when membrane fouling has progressed to the point that membrane

ISO/DIS 23500-1
replacement or cleaning is needed. Monitoring is also necessary to ensure that the device is being
operated in accordance with the manufacturer's instructions. Endotoxin-retentive filters operated in
the cross-flow mode should also be monitored in terms of the flow rate of fluid being directed to drain
at a given pressure drop. Results of pressure measurements and bacteria and endotoxin levels should
be recorded on a log sheet.
7.4 Monitoring of dialysis water storage and distribution

NOTE 7.4.1 to 7.4.3 relate to and help explain Table C.1.
7.4.1 Monitoring of water storage tanks
For a system that distributes dialysis water to single-patient proportioning systems, routine monitoring
of water storage tank for total viable microbial count and endotoxin concentration is generally
accomplished indirectly by monitoring the dialysis water at the first outlet to the distribution loop. For
routine monitoring of a storage tank that supplies dialysis water to a central dialysis fluid delivery
system, or when direct monitoring of a dialysis water storage tank is performed as part of a
troubleshooting process, the total viable microbial count and endotoxin concentration should be
determined using samples drawn from a port at the outlet of the storage tank. When a change has been
made to an existing storage tank, more frequent testing should be considered to verify that bacteria or
endotoxin levels are consistently within the allowed limits. The need for additional testing should be
based on the original validation plan (see 6.1) and a risk analysis of the likely impact of the change on
system performance. All total viable microbial counts and endotoxin results should be recorded on a log
sheet and should be subject to trend analysis.
7.4.2 Monitoring of the water distribution systems
Distribution piping systems used for dialysis water should be monitored for total viable microbial count
and endotoxin concentration to demonstrate the adequacy of the disinfection programme described in
8.2. The total viable microbial count and endotoxins shall not exceed the levels specified in 4.1.3.
Monitoring should be accomplished by taking samples from the last outlet of the distribution loop and
the outlets supplying reuse equipment and bicarbonate concentrate mixing tanks. If the results of this
testing are unsatisfactory, the disinfection programme should be re-evaluated and additional testing
(for example, endotoxin-retentive filter inlet and outlet, reverse osmosis product water, and storage
tank outlet) should be undertaken as part of a troubleshooting strategy to identify the source of
contamination, after which appropriate corrective actions can be taken. Total viable microbial counts
and endotoxin testing should be conducted on a regular schedule according to system validation data
and local regulations and in accordance with 8.3.3 and 8.3.4. When a change has been made to an
existing system, more frequent testing should be considered to verify that bacteria or endotoxin levels
are consistently within the allowed limits. The need for additional testing should be based on the
original validation plan (see 6.1) and a risk analysis of the likely impact of the change on system
performance. All bacteria and endotoxin results should be recorded on a log sheet to permit
identification of trends and the need for corrective action.
7.4.3 Monitoring of bacterial control devices
7.4.3.1 Monitoring of ultraviolet irradiators
Ultraviolet irradiators intended for use as a direct means of bacterial control should be monitored for
radiant energy output. UV irradiators are available equipped with radiant energy intensity sensors.
Either a visual alarm or an output meter is acceptable for determining if the UV lamp is emitting
sufficient radiant energy. UV irradiators should be monitored at the frequency recommended by the
manufacturer. Because the radiant energy decreases with time, annual lamp replacement is typically
required. Periodic cleaning of the quartz sleeve may also be required, depending on the water quality. A
log sheet should be used to indicate that monitoring has been performed.

ISO/DIS 23500-1
7.4.3.2 Monitoring of ozone generators
Ozone generators should be monitored for ozone output at a level specified by the manufacturer. The
output of the ozone generator should be measured by determining the ozone concentration in the water
at the most distal point from the ozone generator. A test based on indigo trisulfonate chemistry, DPD, or
the equivalent, or ozone-in-water test strips should be used to measure the ozone concentration. It is
recommended that ozone concentration be measured each time disinfection is performed. An ozone-in-
ambient-air test should be conducted on a periodic basis, as recommended by the manufacturer, to
ensure compliance with National Standards and regulations for the permissible exposure limit. A log
sheet should be used to indicate that monitoring has been performed.
7.4.3.3 Monitoring of hot water disinfection systems
Hot water disinfection systems should be monitored for temperature and time of exposure to hot water,
as specified by the manufacturer. The temperature of the water should be recorded at a point farthest
from the water heater; that is, where the lowest water temperature is likely to occur. It is recommended
that the water temperature be measured each time a disinfection cycle is performed. A record that
verifies successful completion of the heat disinfection should be maintained. Successful completion is
defined as meeting the temperature and time requirements specified by the equipment manufacturer.
7.5 Monitoring of concentrate preparation

7.5.1 Monitoring of mixing systems
Systems for preparing either bicarbonate or acid concentrate from powder or other highly concentrated
media at a dialysis facility should be monitored according to the mixing system manufacturer's
instructions to ensure appropriate dissolution. If a facility designs its own system, procedures should be
developed and demonstrated to ensure proper mixing of the concentrate, including establishment of
acceptable limits for tests of proper concentration. In this case, verification can be accomplished by
testing a sample from each batch prepared over a three-day period.
Acid and bicarbonate concentrates may be tested by measuring conductivity, density with a density
meter, or specific gravity with a hydrometer according to the manufacturer's instructions. Although not
required, some manufacturers of concentrate powder or other highly concentrated media may provide
allowable ranges for either the conductivity, density, or the specific gravity of concentrates prepared
from their powder. The use of pH, alone, as an indicator of proper dissolution is inappropriate for both
acid and bicarbonate concentrates because large variations in concentration do not produce significant
changes in pH. Concentrates should not be used or transferred to holding tanks or distribution systems
until all tests are completed. The test results and verification that they meet all applicable criteria
should be recorded and signed by the individuals performing the tests.
7.5.2 Monitoring of additives
When additives are prescribed for a specific patient, the container holding the prescribed concentrates
should be labelled with the name of the patient, the final concentration of the added electrolyte, the date
and time when the prescribed concentrate was mixed, and the name of the person who mixed the
additive. This information should also be recorded in accordance with the requirements of 4.4. The
label should be affixed to the container when the mixing process begins.
7.6 Monitoring of concentrate distribution
A daily check to ensure that the appropriate acid and bicarbonate concentrate is connected to the
corresponding concentrate delivery line is recommended if the storage tank is not permanently
connected to its distribution piping.
Once a bicarbonate distribution system

Licensed to: Team ANSIhas
ISObeen activated, dialysis fluid should be monitored weekly
until sufficient data have been obtained
Downloaded: to demonstrate the adequacy of the disinfection programme for
2017-02-09

ISO/DIS 23500-1
the bicarbonate distribution system. The frequency of monitoring may then be reduced, but monitoring
should be performed at least monthly. If elevated total viable microbial counts or endotoxin levels are
found in the dialysis fluid, the disinfection programme for all systems involved in dialysis fluid
preparation, including the bicarbonate concentrate distribution system, should be evaluated and
revised. The frequency of monitoring should then be increased until it can be demonstrated that the
revised disinfection programme is adequate to provide concentrate that allows preparation of dialysis
fluid meeting the quality requirements of ISO 23500-5.
There are no published reports of acid concentrate supporting bacterial growth; therefore, it is not
necessary to perform routine testing for total viable microbial count and endotoxins on those systems.
However, it should be possible to disinfect these systems.
7.7 Monitoring of dialysis fluid proportioning
Dialysis fluid proportioning should be monitored following the procedures specified by the equipment
manufacturer. When the user has specific requirements for monitoring dialysis fluid proportioning,
such as when dialysis machine settings are changed to allow the use of concentrates with a different
proportioning ratio, the user should develop procedures for the routine monitoring of dialysis fluid
electrolyte values, such as by monitoring of sodium (Na+), potassium (K+), ,or dialysis fluid
conductivity.
8 Strategies for microbiological control

8.1 General
The strategy for controlling the proliferation of microorganisms in haemodialysis systems primarily
involves appropriate system design and operation, and regular disinfection of the entire fluid system.
This includes the reverse osmosis membranes (especially the clean side), the distribution piping, the
inlet lines to the dialysis machines (located before the disinfection circuit of the dialysis machine), and
the dialysis machines (which have their own disinfection circuit and programme). A key concept in
ensuring compliance with the requirements of 4.1.3 and 4.3 is that disinfection schedules should be
designed to prevent microbial proliferation, rather than being designed to eliminate microorganisms
once they have proliferated to an unacceptable level. With this strategy, monitoring levels of
microorganisms and endotoxin serves to demonstrate that the disinfection programme is effective, not
to indicate when disinfection should be performed.
Microorganisms in fluid colonize surfaces resulting in biofilm formation, even when levels of microbial
contamination are low. Microorganisms living within biofilms produce an extracellular polysaccharide
or slime matrix, which protects them against disinfection. Microorganisms also excrete both simple and
complex metabolites. Their effect on patients, and whether or not they are removed by endotoxin-
retentive filters, is largely unknown. All strategies for microbial control of the system should, therefore,
be proactive in order to limit biofouling (microbial growth and biofilm formation). It is of utmost
importance that the disinfection procedure is applied from the start of the operation of the
haemodialysis system as once formed, biofilm is difficult, if not impossible, to eradicate.
The combined efforts of disinfection and employing strategies for bacterial control make it possible to
minimize microbiological growth and biofilm formation.
The information given in this guidance is valid for the following:
— water systems;
— dialyser reprocessing systems;
— central dialysis fluid delivery systems;


ISO/DIS 23500-1
— central sodium bicarbonate concentrate preparation and distribution systems.
8.2 Disinfection
Disinfection is the only effective method of diminishing and inactivating microflora.
First, and most of all, the frequency of disinfection is important. Disinfection should be performed on a
regular basis to limit biofouling within the fluid pathways of the system. Depending on the
circumstances, different levels of disinfection may be required to comply with the fluid quality
requirements of Clause 4.
Second, all surfaces in the circuit should be included in the disinfection procedure. This includes the
reverse osmosis membranes (especially the clean side), the distribution piping, the inlet lines to the
dialysis machines (located before the disinfection circuit of the dialysis machine), and the dialysis
machines (which have their own disinfection circuit and programme).
Third, the disinfection procedure, when applied with a given frequency and with inclusion of all critical
areas, should be capable of minimizing the effects of biofouling.
Disinfection can be performed using heat or chemicals. UV lamps can be used to inactivate planktonic
cells but are of no value against any biofilm that has formed in the system.
8.2.1 Microbiological aspects of fluid system design
The circuit downstream of the reverse osmosis system, including the clean side of the reverse osmosis
membranes, the distribution piping, tanks and filters in the distribution piping, and the inlet lines to the
dialysis machines are to be maintained and disinfected so that it is possible to fulfil the microbiological
requirements of ISO 23500-5 and ISO 23500-3.
Examples of good system design include
— use of a recirculation-type system,
— avoidance of dead ends and dead space areas,
— a high-quality finish to joints and connections,
— use of materials compatible with the planned methods of disinfection, and
— avoidance of storage tanks. If a storage tank is necessary it should be designed and constructed in
such a manner that it can be cleaned and disinfected.
Once the water treatment system has been installed, water flow should be maintained to limit biofilm
formation.
NOTE 1 Biofilm formation on a surface is a function of both surface roughness and flow velocity.
Experimental studies have demonstrated that a Reynolds number (Re) of 3,000 in a piping system is
able to minimize but not totally eliminate the formation of biofilm. A Reynolds number of ~ 3 000 is
obtained with a flow velocity of about 0,15 m/s in a 2 cm diameter pipe (0,5 ft/s in a 3/4” diameter
pipe).
NOTE 2 In dialysis facilities, there might not be continuous flow through the system, since patients may
not be treated overnight or the system is undergoing maintenance. Consequently it is not feasible to
specify a minimum flow velocity that is effective in reducing biofilm formation and bacterial
contamination. Furthermore, the use of such a flow velocity would not provide a substitute for regular
disinfection of the distribution
Licensed to:system.
Team ANSI ISO

ISO/DIS 23500-1
The system design should also take into consideration preventive maintenance of the fluid distribution
system, as well as education and training of staff in order to create awareness about disinfection and
microbiological control.
The disinfection programme could compensate for a weakness in system design but will not totally
prevent the formation of biofilm, which can become difficult to eradicate.
8.2.2 Disinfection frequency
8.2.2.1 General
A key concept in ensuring compliance with the requirements of 4.1.3, 4.2.1, and 4.3.2 is that disinfection
schedules should be designed to prevent bacterial proliferation, rather than being designed to eliminate
bacteria once they have proliferated to an unacceptable level (i.e. above the action level). With this
strategy, monitoring levels of bacteria and endotoxins serves to demonstrate that the disinfection
programme is effective, not to indicate when disinfection should be performed.
Disinfection strategy is preventive and should be applied from the start of operation of the system. The
disinfection frequency may be modified, based on results obtained during validation monitoring and
revalidation activities. Any such modification should be appropriately documented.
8.2.2.2 Dialysis water storage and distribution systems
Storage and distribution systems should be disinfected on a schedule that allows the water quality
recommendations of 4.1.3 to be met routinely. For integrated treatment and distribution systems, the
manufacturer's instructions for disinfection should be followed, provided routine monitoring shows
that they are adequate to meet the requirements of 4.1.3. For systems assembled from individual
components, the frequency of disinfection necessary to minimize biofouling will vary with the design of
the system and, in the case of existing systems, the extent to which any biofouling has already occurred.
8.2.2.3 Concentrate mixing systems
Concentrate mixing equipment should be either
a) completely emptied, cleaned, and/or disinfected according to the manufacturer's instructions, or
b) cleaned and/or disinfected using a procedure demonstrated by the facility to be effective in

routinely producing concentrate that allows the recommendations of 4.2.1 to be met.
The mixing and disinfection data should be recorded for each mix and disinfection cycle using a
dedicated log.
8.2.2.4 Concentrate distribution systems
Piped bicarbonate concentrate distribution systems should be disinfected either according to the
manufacturer's instructions or using a procedure that has been demonstrated by the facility to be
effective in routinely producing concentrate that allows the recommendations of 4.2.1 to be met. If the
manufacturer does not supply disinfection procedures, the user should develop and validate a
disinfection protocol. It is recommended that monitoring of concentrate distribution systems be
performed on a routine basis.
When centrally produced bicarbonate concentrate is decanted into reusable concentrate containers, the
containers and pick-up tubes should be disinfected at least weekly or at a frequency required by local
regulatory requirements. Bicarbonate concentrate containers and concentrate pick up tubes should be
rinsed with treated water allowed to air dry and stored inverted at the end of each treatment day.
Because there are no published reports
Licensed of acid
to: Team concentrate
ANSI ISO supporting bacterial growth, disinfection of

ISO/DIS 23500-1
acid concentrate distribution systems is not normally required. However, it should be possible to
disinfect these systems.
8.3 Microbiological monitoring methods

8.3.1 General
The fluid system shall be routinely monitored in order to verify that the microbiological quality
indicators (bioburden represented by total plate count and endotoxin concentration) are being met.
The frequency of sampling should meet applicable local recommendations. If no such recommendations
exist, the following are recommended.
a) Water system: The number of samples and positions of sampling should be based on the complexity
and size of the water system. The frequency will depend on the analysis of the data collected during
the validation and revalidation activities. Monthly monitoring is most frequently adopted but less
frequent monitoring may be possible based on data collected during the validation and
revalidation.
b) Dialysis fluid/haemodialysis machines without a validated bacteria- and endotoxin-retentive filter:

Machines should be sampled on a regular basis to provide verification of the effectiveness of the
disinfection process. The schedule of sampling will depend on the type of disinfection process being
used. Each machine should be sampled at least once per year and different machines should be
sampled on each occasion. Monthly monitoring is most frequently adopted.
c) It is not necessary to take samples of ultrapure dialysis fluid or substitution fluids if their
production paths are fitted with bacteria- and endotoxin-retentive filters validated by the
manufacturer and operated and monitored according to the manufacturer's instructions. It could be
necessary to sample the dialysis fluid entering such bacteria- and endotoxin-retentive filters
depending on the manufacturer's instructions for use of the filters; for example, when the
instructions for use specify the quality of the fluid entering the filter. (See also Annexes D and E.)
The results of testing should be subjected to trend analysis. When results exceed the action levels, or in
the case of a patient's pyrogenic reaction or suspected bacteremia/fungemia, an investigation and
follow-up should be initiated. This investigation could include additional sampling and extra
disinfection procedures carried out as per the manufacturer's recommendations.
8.3.2 Sample collection
8.3.2.1 Dialysis water sample sites
Samples are to be taken at outlets of the distribution system, according to the sampling instructions
provided by the manufacturer. In the absence of manufacturers instructions, the following may be used
to ensure that the sample taken is not contaminated by any microbial growth at the point of sampling:
Any hose attached to the sampling point removed, and the port cleaned with a sterile gauze or cotton
swab wetted with alcohol, or as recommended by the manufacturer. Bleach or other disinfectant
solutions should not be used. The sampling port is opened and fluid allowed to run to waste for at least
60s unless the port manufacturer instructions for use state otherwise, prior to the aseptic collection of
the sample. The sample volume collected should be 5-1000mL depending upon the test to be run
and/or as specified by the laboratory performing the test. The containers used for the samples to be
cultured should be sterile and endotoxin free.
Other sampling methods may be used provided they have been validated.


ISO/DIS 23500-1
8.3.2.2 Dialysis fluid samples
Samples should be collected from the dialysis fluid line according to the sampling instructions provided
by the manufacturer of the dialysis fluid delivery system. If not specified, the exterior of the sample port
(not the lumen) may be disinfected by wiping with alcohol, 70% ethanol or isopropanol (isopropyl
alcohol). Bleach or other disinfectant solutions should not be used. The sample should not be collected
until all the alcohol has evaporated so as to leave no disinfectant residual in the sample.
The sample volume collected should be 5-1000mL depending upon the test to be performed and/or as specified
by the laboratory performing the test.
Containers used for samples to be cultured should be sterile and endotoxin free.
NOTE Where the dialysis fluid delivery system is equipped with a dialysis fluid sampling port that can be
accessed using a syringe, the sample port can be disinfected with alcohol and allowed to air dry. A sterile syringe
can then be used to aspirate dialysis fluid out of and into the port before filling the syringe. The filled syringe is
discarded and a fresh sample of dialysis fluid collected using a new sterile syringe. For sample ports consisting of a
simple septum penetrated with a needle, the use of a second syringe is not necessary.
Alternatively, if the haemodialysis machine permits, samples can be collected immediately after the dialyser by
disconnecting the effluent connector and aseptically collecting a “free/clean” catch sample after allowing dialysis
fluid to run for at least 60 s
8.3.3 Heterotrophic plate count
8.3.3.1 Storage of samples
Microbial analysis of any fluid sample should be conducted as soon as possible after collection to avoid
unpredictable changes in the microbial population. If samples cannot be analysed within 4 h of
collection, the laboratory's instructions for shipping shall be followed. Samples intended for colony
counts should not be frozen but kept at a temperature of <10°C until ready for shipping or collection by
the laboratory. If samples cannot be analysed within 4 h of collection, they should be stored at <10 °C
during transit to the laboratory. Sample storage for more than 24 h should be avoided
Storage of samples for endotoxin analysis may be different from what is given above, provided the
complete procedure follows the manufacturer's instructions for use of the LAL assay.
8.3.3.2 Analytical methods
The recommended methods (e.g., membrane filtration, spread plate, pour plate,), media, and incubation
ranges allow each dialysis center to accommodate their facility with a monitoring program.
The culture medium and incubation times selected should be based on the type of fluid to be analysed
e,g 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 on line therapies such as
haemodiafiltration. The method selected, should be based on the analysis of the advantages,
disadvantages and sensitivity, of each of the suggested methods. It should also ensure that the patient
is provided with the necessary safeguards within any constraints imposed by local laboratory working
practices and reimbursement.
8.3.3.2.1 Membrane filtration
Membrane filtration is filtration of the sample through a membrane filter with pore diameter of 0,45 µm
or less. Membrane filtration is a method used when the sample is to be concentrated to detect low levels
of contamination (usually <1 CFU/ml), and can also be used for quantification of yeast and filamentous
fungi should this be required. The volume to be filtered should be determined by the suspected level of
contamination and should beLicensed
between to:10 ml ANSI
Team and 1ISO
000 ml.

ISO/DIS 23500-1
NOTE Alternate membrane filtration techniques may be used provided that they have been appropriately
validated and the results compared to the analytical methods outlined in this section.
8.3.3.2.2 Spread-plate technique
A pipette is used to apply 0,1 ml to 0,3 ml of a sample to a Petri dish (typically 90 mm in diameter)
containing agar medium and spread over the surface of the agar. The detection limit of this technique is
5 CFU/ml when 0,2 ml of sample is used as the inoculum.
NOTE New methods may become available. Such methods may be used provided that they have been
appropriately validated and the results compared to the analytical methods outlined in this section.
8.3.3.2.3 Pour-plate technique
A sample (typically 1 ml) is placed in a Petri dish and 15 ml to 20 ml of molten medium is added. The
sample and medium are mixed carefully by gentle rotation and allowed to set. The time between
addition of the sample and addition of the molten medium should not exceed 15 min. The plate is
inverted and incubated. If 1 ml of sample is used, the detection limit of this technique is 1 CFU/ml.
Molten media should be <45 °C at the time the plate is poured.
NOTE New methods may become available. Such methods may be used provided that they have been
appropriately validated and the results compared to the analytical methods outlined in this section.
8.3.3.2.4 Dip samplers
Currently available dip samplers are not suitable for use in dialysis applications.
8.3.3.3 Cultivation methods and conditions
The recommended methods and cultivation conditions can be found in ISO 23500-3, ISO 23500-4 and
ISO 23500-5. The methodologies detailed use Tryptone Glucose Extract Agar (TGEA) or Reasoner’s Agar
No. 2 (R2A) incubated at 17°C -23° C for a period of 7 days, or Tryptic Soy Agar incubated at 35°C for 48
hours for the culturing of standard dialysis fluid and dialysis water. The rationale for the use of TSA and
its inclusion in the most recent revision of the standard is explained in ISO 23500-3 Annex A.3.
Culture results obtained using the methods outlined are only a relative indicator of the bioburden and
do not provide a measure of the absolute bacterial burden. Different media types and incubation
periods can result in varying colony concentrations and types of microorganisms recovered. (128,126,132)
The use of Reasoner’s 2A agar (R2A) has been reported in previous studies to result in higher colony
counts than tryptic soy agar (TSA) for water samples and dialysis fluids.(132,138,135) In a more recent
publication, 2016, the authors indicated that there were no significant differences when bacterial
burden in standard dialysis water and standard dialysis fluid were compared using >50CFU/ml as the
action limit when assayed using R2A and TSA at the conditions stated above. (128)
Tryptone glucose extract agar (TGEA), also yielded higher colony counts than TSA (126). Maltais et al
(128)in their comparison of this medium with TSA also showed that the proportion of standard dialysis
water samples yielding colony counts >50 CFU/mL was significantly different from that found using
TSA (p=0.001), with each mediium using the respective incubation conditions stated above. 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 the assay method conditions selected should be based on the type of fluid to be
analysed e,g 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 on line
therapies such as haemodiafiltration and the purpose of the analysis. It should also ensure that patient

ISO/DIS 23500-1
safety is safeguarded and allow for consideration of local laboratory working practices, and that local
regulatory and reimbursement requirements can be met.
8.3.4 Bacterial endotoxin test
Bacterial endotoxins are assayed using the Limulus amoebocyte lysate (LAL) test. Current
pharmacopoeias [United States (USP), European, and Japanese pharmacopoeias] acknowledge six
different testing techniques.
Endotoxin testing requires training and should be performed by fully trained personnel.
Valid tests have to follow official applicable requirements and manufacturer's instructions.
NOTE It is important to use correct types of sample containers, labelled or validated for storage of endotoxin
samples. Appropriate containers are usually specified by the testing laboratory or the manufacturer of the LAL
testing kit.
8.3.5 Determination of yeast and mould
Currently there is no requirement for the routine monitoring for yeast and mould. If quantification of
such species is required, the culture media used should be Sabouraud or Malt Extract Agar, with a 7d
incubation period at 20° C -22° C. Alternate techniques validated against Sabouraud or Malt Extract
Agar, with a 7d incubation period at 20° C -22° C, can also be used.
9 Location of and access to water treatment system

The water treatment and storage system should be located in a secure locked area, accessible only by
personnel authorized by the dialysis facility. An up to date list with contact details should be held
centrally. Spare keys to the facility should be kept in a secure location.
The location for the water treatment system should be chosen with a view to minimizing the length and
complexity of the distribution system. Access to the treatment system should be restricted to
individuals responsible for monitoring and maintenance of the system.
The layout of the water treatment system should provide easy access to all components of the system,
including all meters, gauges, and sampling ports used for monitoring system performance. An area for
processing samples and performing onsite tests is also recommended. Critical alarms, such as those
associated with deionizer exhaustion or low water levels in a storage tank, should be configured to
notify staff in the patient treatment area, as well as in the water treatment room.
Water systems should include schematic diagrams that identify components, valves, sample ports and
flow direction. Additionally, piping should be labelled to indicate the contents of the pipe and direction
of flow. The use of text labels, such as “RO Water”, and colour-coded “arrow tape” provides a convenient
means of identifying the pipe content and flow direction. Sampling points should be marked as such and
identified in schematic diagrams.
If water system manufacturers have not done so, users should identify major water system components
and describe their function. How performance is verified, and what actions to take in the event that
performance is not within an acceptable range, should be readily available to the user.
10 Personnel
Policies and procedures that are understandable and accessible are mandatory, along with a training
programme that includes quality testing, the risks and hazards of improperly prepared concentrate, and
bacterial issues. Operators should be trained in the use of the equipment by the manufacturer or should
be trained using materials provided
Licensed to:by the ANSI
Team manufacturer.
ISO Additional training may be provided using
materials from other sources. The training should be specific to the functions performed (i.e. mixing,

ISO/DIS 23500-1
disinfection, maintenance, and repairs). Periodic audits of the operator’s compliance with procedures
should be performed. The user should establish an ongoing training programme designed to maintain
the operator's knowledge and skills.


ISO/DIS 23500-1
Annex A
(informative)
Rationale for the development and provisions of this

International Standard
A.1 Scope
This clause provides the rationale for the requirements in Clause 1. It has long been known that
chemical and microbiological contamination of dialysis fluid places haemodialysis patients at risk of
acute and chronic adverse events. From the beginning, it was recognized that there was a problem with
including fluid quality requirements in an International Standard directed at manufacturers of water
treatment equipment or haemodialysis machines. Although a manufacturer might be responsible for
providing equipment that, when assembled as a system, provides water, concentrate, or dialysis fluid
that meets certain quality requirements, that manufacturer has no control over the equipment once it is
installed. For example, the treated water quality could change if a water treatment system is not well
maintained or if there is some change in the municipal water feeding the system. Therefore, fluid
quality standards were established independent of the standards for the equipment used to prepare
those fluids. Since the day-to-day responsibility for maintaining fluid quality lies with the healthcare
professionals at each dialysis facility under the leadership of the facility's Medical Director, this
International Standard was prepared to provide guidance to those healthcare professionals on how to
manage fluid preparation systems so as to comply with the requirements of the fluid quality standards.
A.2 Chemical contaminants

This clause provides the rationale for the requirements in 4.1.2. ISO 23500-3 sets forth maximum levels
of chemical contaminants for dialysis water in three groups: chemicals with documented toxicity in
haemodialysis patients, electrolytes normally included in dialysis fluid, and trace elements. The
rationale for including particular chemicals in ISO 23500-3, and for setting their maximum levels, is set
forth in Annex A of ISO 23500-3.
Hazards to patients receiving haemodialysis treatment associated with the presence of organic
compounds such as pesticides, polycrylic aromatic hydrocarbons and other chemical products present
in the water are difficult to define. Consequences are probably of a long term nature and routine
measurement of such substances is difficult and costly. In view of this, no recommendation in respect of
such compounds is made in this version of the standard.
The ability of water treatment systems to remove such compounds depends on the chemical structure
and the concentration of the contaminant. Microfiltration and ultrafiltration are less effective than
nanofiltration and reverse osmosis. Granular activated carbon (GAC) is on the other hand highly
effective in removing such chemical contaminats. Compounds with a high degree of hydrophilicity may
breach activated carbon faster than hydrophobic compounds. Backwashing cycles also play an
important role in this process. Since granular activated carbons provide the primary method for the
removal of chlorine and chloramine from the feed water, proper dimensioning of the carbon beds or
filters is essential to ensure that the majority of the carbon valences are not already occupied limiting
the removal of organic contaminants should there be a requirement to remove such compounds.


ISO/DIS 23500-1
A.3 Microbiological contaminants

This clause provides the rationale for the requirements in 4.1.3. ISO 23500-3 sets forth maximum levels
of bacteria and endotoxins in dialysis water, along with action levels for these contaminants. The
rationale for the maximum levels of bacteria and endotoxins is set forth in Annex A of ISO 23500-3
A.4 Requirements for concentrate

The rationale in this clause addresses the requirements in 4.2. Requirements for commercially available
concentrates are given in ISO 23500-4. It was decided not to recommend limits on bacteria and
endotoxins for concentrate prepared at a facility, even for bicarbonate concentrate. This decision was
based on the difficulty of performing cultures and endotoxin assays in samples with high concentrations
of salts. High concentrations of bicarbonate require special culturing techniques and are inhibitory in
the LAL assay. It was determined that it was unreasonable to require an individual dialysis facility to
meet the special conditions required for proper testing of bicarbonate concentrate and that patients
would be adequately safeguarded by the quality recommendations for the water used to prepare the
concentrate and for the final dialysis fluid. For users who are interested in determining bacterial levels
and endotoxin concentrations as part of a troubleshooting investigation, guidelines on performing
cultures and endotoxin assays in bicarbonate concentrate are included in 8.3.3.3 and A.10.
A.5 Microbiological contaminants in dialysis fluid

The rationale in this clause addresses the requirements in 4.3. ISO 23500-5 sets forth maximum levels
of bacteria and endotoxins in three categories of dialysis fluid: standard dialysis fluid, ultrapure dialysis
fluid, and online-prepared substitution fluid. Where appropriate, action levels for bacteria and
endotoxins are also given. The rationale for the maximum levels of bacteria and endotoxins is set forth
in Annex A of ISO 23500-5.
ISO 23500-3 sets a maximum allowable level for endotoxins in dialysis water of 0,25 EU/ml, while
ISO 23500-5 sets a maximum allowable level for endotoxins in dialysis fluid of 0,5 EU/ml. The level for
dialysis fluid is set higher than that for dialysis water in recognition that powder concentrates can
contribute endotoxins, but not volume, to the final dialysis fluid. No such accommodation is made for
bacteria since most bacteria will not survive in a viable form in powder concentrate.
A.6 Monitoring of carbon media

The rationale in this clause addresses the requirements in 7.3.5. Intensive monitoring of carbon beds is
recommended because of the long history of adverse events related to chloramine contamination of
dialysis fluid.[37.38] Chloramine concentrations in municipal water can change from day to day and the
capacity of carbon beds to remove chloramine can vary with the pH and temperature of the water, the
nature of the chloramine compounds present, and the presence of other substances in the water. The
dependence of chloramine removal on multiple factors makes the performance of carbon beds
unpredictable. Therefore, patient safety can only be ensured by intensively monitoring the performance
of the carbon bed. Configuring carbon beds in series and sampling from a port located between the two
beds provides one margin of protection against chloramine breakthrough. When chloramine is first
detected in the effluent from the first bed, the second bed will still have some capacity for chloramine
removal. This reserve capacity allows the user to conveniently replace the exhausted bed without risk
to patients. The exhausted bed is discarded, the second bed is moved into the first position, and a new
bed is placed in the second position. A new bed of virgin carbon should be used for replacement.
Continuous monitoring with an online monitor provides the best protection of the patient. The online
monitor should be capable of activating a means of diverting the water from the reverse osmosis
system, for example by shutting down the reverse osmosis system, should the total chlorine level
exceed 0,1 mg/L.
In situations where chloramine is notANSI

Licensed to: Team usedISOto disinfect the water, and the ammonia level in the water is
low, one carbon bed or a carbon cartridge filter with a shorter EBCT could be sufficient. Carbon cannot

ISO/DIS 23500-1
be regenerated in a dialysis facility, and the use of regenerated carbon is prohibited. Backwashing of
carbon beds does not regenerate the carbon, although it can allow more efficient use of the bed's
capacity by removing channels that can form in the bed during routine operation. The recommendation
that the water purification system should operate for at least 15 min, before samples of water from a
carbon bed are drawn, is to guard against inadvertently sampling water that has been in the bed for an
extended period.
A.7 Strategies for microbiological control

The rationale in this clause addresses the requirements in 8.1. All microbial growth in a fluid system
involves growth on surfaces. In most cases, the microbial growth starts on surfaces and consequently
little or nothing of the microbial development in the fluid system is recorded by taking fluid samples.
The surface growth occurs in patches in the earlier stages and is difficult to analyse.
No testing is able to show a complete picture of bacterial growth and the tests described and referred to
in this International Standard do not measure many microbial contaminants, including: cell wall
fragments from microorganisms; nucleic acids DNA and RNA; and metabolites of various kinds.
For this reason, a proactive disinfection programme is recommended to combat bacterial growth in the
dialysis water and dialysis fluid systems.
A.8 Heterotrophic plate count

The rationale in this clause addresses the requirements in 8.3.3.
Sensitive culturing methods should be used to measure the low total viable microbial counts permitted
for water used for haemodialysis applications. The membrane filter technique is particularly suited for
this application because it permits large fluid volumes to be assayed. Because the membrane filter
technique might not be readily available in clinical laboratories, the spread plate assay or the pour plate
assay can be used as an alternative for water and standard dialysis fluid.[112] If the spread plate assay is
used, a calibrated loop should not be used to apply sample to the plate. The sensitivity of an assay
performed with a calibrated loop is low. A standard calibrated loop transfers 0,001 ml of sample to the
culture medium so that the minimum sensitivity of the assay is 1 000 CFU/ml. This sensitivity is
unacceptable when the maximum allowable limit for microorganisms is 100 CFU/ml. Therefore, when
the spreadplate method is used, a pipette should be used to place 0,1 ml to 0,3 ml of water or dialysis
fluid on the culture medium. The pour-plate method may be used as an alternative method to the
spread-plate method. If a sample volume of 1 ml is used, the detection limit of the pour-plate method is
1 CFU/ml.
Culture results obtained using any of the methods outlined in this International Standard are only a
relative indicator of the bioburden in dialysis water or dialysis fluid and do not provide a measure of
the absolute bacterial burden. The original clinical observations on which the microbiological
requirements were based used standard methods agar (SMA), a medium containing relatively few
nutrients.[75] Later, the use of trypticase soy agar (TSA), a general-purpose medium for isolating and
cultivating fastidious organisms was added. Several studies have shown that the use of nutrient-poor
media, such as tryptone glucose extract agar (TGEA) or Reasoner's agar No. 2 (R2A), results in an
increased recovery of bacteria from water.[110][113][115][116] Extending the culturing time up to 7 d
and using incubation temperatures of 23 °C to 28 °C have also shown an increase the recovery of
bacteria compared to incubation for 48 h at 35 °C to 37 °C.[110][113][116]
The use of Reasoner’s 2A agar (R2A) and Tryptone glucose extract agar (TGEA) has been reported in
some publications to result in higher colony counts than tryptic soy agar (TSA) for culturing of water
samples and dialysis fluids.( 126, 132, 135, 138) In a more recent publication (2016), the authors
indicated that there were no significant differences for comparisons of bacterial burden in the
proportion of standard water and to:
Licensed standard dialysis
Team ANSI ISO fluid yielding colony counts >50CFU/ml when
assayed using R2A and TSA at the conditions
Downloaded: stated above. (128)
2017-02-09

ISO/DIS 23500-1
Maltais et al (128) in their comparison of this medium (TGEA) with TSA when quantifying the microbial
burden in water and dialysis fluid used for standard dialysis showed that the proportion of water
samples yielding colony counts >50 CFU/mL incubated at 17°C -23° C for a period of 7 days was
significantly different from the proportion established by TSA at an incubation temperature of 35°C -
37° C and an incubation time of 48 hours (p=0.001). The proportions of dialysis fluid samples in which
microbial burden was >50 CFU/mL were not significantly different.
The TSA method balances the increased recovery against the shorter time for actionable results.
Tryptone Glucose Extract Agar (TGEA) or Reasoner’s Agar No. 2 (R2A) incubated at 17° C -23° C for a
period of 7 days, or Tryptic Soy Agar incubated at 35° C for 48 hours are all validated and acceptable
methods. The user should determine which of these methodologies is appropriate for the circumstance,
taking into account the advantages of each.
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 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]. [USP
<1231>][179].
The culture medium and incubation times selected should also be based on the type of fluid to be
therapies such as haemodiafiltration. The method selected, should be based on the analysis of
the advantages, disadvantages and sensitivity of each of the suggested methods. It should also ensure
that the patient is provided with the necessary safeguards within any constraints imposed by local
laboratory working practices and reimbursement.
When monitoring for microbial contamination in ultrapure dialysis fluid, the maximum allowable level
of bacteria requires that culturing be performed using the membrane filtration method with a minimum
of 10 ml of ultrapure dialysis fluid being passed through the filter. The use of larger volumes (up to
1 000 ml) will provide greater sensitivity, but the improved sensitivity needs to be balanced against the
increased risk of contamination in collecting and handling the sample. Even with these more sensitive
techniques, compliance with the stringent requirement that online-prepared substitution fluid be
sterile cannot be demonstrated by culturing; it has to be ensured by use of a validated process.
Monitoring of the production of online-prepared substitution fluid will depend on the production
system and should be performed according to the manufacturer's instructions.
Furthermore, the culturing conditions recommended in this International Standard could fail to identify
the presence of some organisms. Specifically, the recommended methods might not detect the presence
of various non tuberculous mycobacteria that have been associated with several outbreaks of infection
in dialysis units.[76][95] Also, the recommended methods will not detect fungi and yeast, which have been
shown to contaminate water used for haemodialysis applications.[90]
The microbiological purity of packaged liquid concentrates and dry powder cartridges is the
responsibility of the manufacturer. Monitoring of bicarbonate concentrate produced at a dialysis facility
from powder and water, though not required routinely, may be undertaken as part of a troubleshooting
investigation.. The sodium content of TSA is sufficient for use in culturing bicarbonate concentrate
without supplementation. Salt tolerance studies showed that optimal growth of organisms found in
bicarbonate concentrate occurred when the sodium chloride concentration was approximately 3 % to 6
%. [75] Therefore, if a low-salt medium, such as Reasoner's 2A or TGEA, is used to monitor microbial
contamination in bicarbonate concentrate, it should be supplemented by the addition of 4 % sodium
bicarbonate.

ISO/DIS 23500-1
A.9 Cultivation conditions

The rationale in this clause addresses the requirements in 8.3.3.3. Since dialysis is not stopped between
sampling and obtaining the results of the tests, a long incubation time of 7d is of no disadvantage.
Significant contamination might be detected earlier by performing intermediate counts (e.g. every 2d).
A.10 Bacterial endotoxin test

The rationale in this clause addresses the requirements in 8.3.4. Bicarbonate concentrate inhibits the
LAL assay. Inhibition is caused by the high concentration of solutes in the concentrate and the pH. In the
gel-clot assay, this inhibition results in a failure of the positive control to clot. In kinetic assays,
inhibition results in a failure to recover the positive control to within −50 % to +200 % of the nominal
value.
Dilution of the bicarbonate concentrate with water is the usual method for overcoming inhibition. A
minimum dilution of 1:16 is necessary; however, higher dilutions are recommended for more sensitive
assays. For example, a 1:20 dilution is recommended when using an assay with a sensitivity of
0,03 EU/ml. Dilution reduces the detection limit of the assay. In kinetic methods, the sensitivity is the
lowest concentration used to construct the standard curve. A kinetic assay is recommended for
monitoring the quality of online-prepared substitution fluid because kinetic assays generally are more
sensitive than gel-clot assays.
Standard gel-clot tests are incubated at 37 °C for the time recommended by the manufacturer. At the
end of the recommended time, the tubes are inverted to detect the presence of a clot. A positive test will
have a clot, which will remain in the end of the tube as long as it is not shaken or bumped. A negative
test will not have a clot and will tend to flow out of the tube, when inverted. A clot that is semisolid and
flows slowly is classified as a negative clot. For example, when bicarbonate concentrate is tested using a
gel-clot assay with a sensitivity of 0,03 EU/ml and the concentrate is diluted 1:20 (1,0 ml concentrate
plus 19 ml LAL reagent water or equivalent), the positive control sample should clot, indicating that
there is no inhibition of the assay. If the diluted bicarbonate concentrate sample clots, it indicates that
the sample contains at least 0,6 EU/ml of endotoxins. A new version of the gel-clot assay has a matched
positive control, which simplifies the testing and increases the reliability of the results.


ISO/DIS 23500-1
Annex B
(informative)
Equipment
B.1 General
This annex provides a brief description of the different components that may be included in systems to
treat and distribute dialysis water and dialysis fluid and to prepare and distribute concentrates for
haemodialysis applications. Two types of systems are used: systems in which dialysis water is
distributed to a dialysis machine at an individual patient treatment station, which prepares and controls
the dialysis fluid for use at that station; and central dialysis fluid delivery systems, which prepare
dialysis fluid centrally and supply it to multiple-patient treatment stations. Since feed-water quality and
product-water requirements can vary from facility to facility, not all of the components described in the
following clauses will be necessary in every water treatment and distribution system. Also, not every
dialysis facility will prepare concentrate at the dialysis facility. Requirements for water treatment
equipment used for haemodialysis and related therapies can be found in ISO 23500-2 and the
requirements for equipment used to prepare concentrates at a dialysis facility can be found in
ISO 23500-4.
Routine dialysis requires a well-functioning water treatment and distribution system, since dialysis
cannot be performed without an adequate supply of water. In addition, certain components of the water
treatment and distribution system are critical to its operation. An example of such a critical component
is the circulating pump in an indirect feed system. A dialysis facility should develop contingency plans
to cover the failure of its water treatment and distribution system or a critical component of that
system. Such contingency plans should describe how to deal with events that completely prevent
dialysis from being performed, such as failure of the facility's municipal water supply or electrical
service following a natural disaster or water main break. Other plans should address how to deal with
sudden changes in municipal water quality, as well as with failure of a critical component of the water
treatment and distribution system. Similar contingency plans should be developed to deal with the
failure of concentrate preparation systems.
B.2 Water treatment systems

B.2.1 General
Water treatment systems consist of three basic sections: a pretreatment section that conditions the
water supplied to the primary purification device, which may be followed by other devices that increase
final water quality. The pretreatment section commonly includes a sediment filter, cartridge filters
capable of retaining particles of various sizes, a softener, and carbon beds. The primary purification
process most commonly used is reverse osmosis, which may be followed by deionization and
ultrafiltration for polishing the product water from the reverse osmosis system. Whether a particular
device is included in an individual water treatment system will be dictated by local conditions.
This clause provides a brief description of the principal equipment used to purify water used in
haemodialysis applications. Devices used to treat water for haemodialysis should comply with the
requirements of ISO 23500-2, including certain design and performance specifications for individual
water treatment devices.
B.2.2 to B.2.9 provide general information. Design and instrumentation of individual water treatment
devices may vary from these to:
Licensed general descriptions.
Team ANSI ISO For example, softeners may be configured as a single
resin bed that is regenerated outside
Downloaded: the normal operating hours of the dialysis unit, or they may have a
2017-02-09

ISO/DIS 23500-1
dual-bed configuration that allows one bed to be regenerated while the other is used to provide water
for normal dialysis operations.
Depending on the feed-water quality and product-water requirements, not every component in this
clause might be required in a given facility. Likewise, additional components can be required in certain
circumstances. For example, carbon might not provide adequate chloramine removal if the water
contains substances, such as polyphosphates, that mask the reactive sites on the carbon particles. In
those circumstances, other processes, such as infusion of sodium bisulfite, can be required to achieve
product water that meets the requirements of 4.1.2.
Users are encouraged to obtain detailed descriptions of all water treatment components, together with
operating manuals and maintenance procedures, from the manufacturer or the supplier of the water
treatment and distribution system.
B.2.2 Sediment filters
Permanent, backwashable sediment filters, also known as “bed filters”, are frequently located at or near
the beginning of haemodialysis water treatment systems and are intended to remove relatively coarse
particulate materials from incoming water. Although a single filtration medium may be used, bed filters
known as multimedia filters are more commonly selected. These units contain multiple layers, each
layer retaining progressively smaller particles. In this way, the bed is used to its fullest extent; the
largest particles are removed in the first layer contacted by the water and the smallest in the final layer.
As the bed accumulates particulate material, open passages begin to clog and resistance to the water
flowing through the filter increases. Ultimately, the increased resistance to flow will lead to a reduction
in water supply to downstream components. To prevent this situation from occurring, bed filters are
cleaned by periodic backwashing, which is accomplished either manually or by using a timer-activated
control valve. Sediment filters should have an opaque housing or other means to inhibit proliferation of
algae. Bed filters should be fitted with gauges to measure the hydrostatic pressure at the filters' inlet
and outlet. These values can be used to determine the dynamic pressure drop across the filter (delta
pressure or ΔP), which serves as an index of resistance to flow and provides a basis, together with the
manufacturer's recommendations, for setting the frequency of backwashing.
B.2.3 Cartridge filters
Cartridge filters consist of a cylindrical cartridge of the filter medium with a central drainage core. The
cartridge is contained within a filter housing with seals to separate the feed and product-water streams.
In the pretreatment cascade, transparent filter housings can be useful because they allow any carbon or
resin leakage to be seen without the need to break the integrity of the system. The housing can be
cleaned to remove any algae growth when the filter cartridge is changed. For this reason, use of opaque
housings for cartridge filters is recommended, but not required. If transparent housings are used, they
should not be exposed to natural light, in order to minimize proliferation of algae. Cartridge filters
should be fitted with gauges to measure the hydrostatic pressure at the filters' inlet and outlet.
Although cartridge filters may be installed at the inlet to a water treatment system, their usual
application is as a final filtration step prior to reverse osmosis. Resistance to flow through the filter
increases as the cartridge accumulates particulate material, as indicated by an increase in ΔP. When the
maximum ΔP recommended by the filter manufacturer is reached, the cartridge should be replaced
according to the manufacturer's instructions.
B.2.4 Softeners
Water that contains calcium or magnesium can form relatively hard deposits and is called “hard water”.
Water that has had these elements replaced by sodium ion exchange is called “soft water”, hence the
term “softener” is used. Softeners also remove other polyvalent cations, most notably iron and
manganese, although they are somewhat limited in this regard. However, if significant concentrations of
iron and manganese are present, special
Downloaded: procedures should be implemented in order to reduce those
2017-02-09

ISO/DIS 23500-1
concentrations to levels that do not interfere with the softening process or cause membrane fouling.
The primary use of softeners in haemodialysis water systems is to prevent hard water deposits from
fouling reverse osmosis membranes.
A softener is a cylinder or vessel that contains insoluble spheres or beads, called “resin”, to which
sodium ions are attached. During operation, exchangeable sodium ions in the resin are progressively
replaced by calcium and magnesium ions. When all the sodium ions have been used, the resin bed has
reached a condition referred to as “exhaustion”. Prior to exhaustion, softeners should be restored; that
is, new exchangeable sodium ions are placed on the resin by a process known as “regeneration”, which
involves exposure of the resin bed to a highly concentrated sodium chloride solution. The concentrated
sodium chloride solution is prepared in a separate brine tank, from which the solution is drawn during
the regeneration process. A control valve on the softener regulates the regeneration and service cycles.
Automatically regenerated water softeners should be fitted with a mechanism to prevent water
containing the high concentration of sodium chloride used during regeneration from entering the
product-water line during regeneration. For softeners with a time-controlled regeneration cycle, the
face of the timer should be visible to the user. Operating controls should be positioned so as to minimize
inadvertent resetting.
B.2.5 Carbon media
Carbon systems, often referred to as carbon filters, are the principal means of removing both free
chlorine and chloramine. Removal of chloramine to a maximum level of 0,1 mg/L and removal of free
chlorine to a maximum level of 0,5 mg/L are necessary to protect haemodialysis patients from red
blood cell haemolysis. In addition, free chlorine can also degrade some reverse osmosis membranes,
depending on the membrane material. Determining the level of chloramine typically involves measuring
both total chlorine and free chlorine and assigning the difference in concentrations to chloramine. To
permit a single test to be used, a maximum allowable level for total chlorine was set at the maximum
allowable level for chloramine (0,1 mg/L).
In addition to removing free chlorine and chloramine, carbon also adsorbs a wide variety of other
substances, including both naturally occurring and synthetic organic compounds. The capacity of
carbon to remove free chlorine and chloramine can be reduced when other substances “mask” reactive
sites on the carbon media. In addition, the rate of free chlorine and chloramine removal is reduced as
pH increases or as temperature decreases. The net effect of those variables is that the finite capacity of
carbon beds to remove free chlorine and chloramine cannot be predicted with any certainty. Therefore,
their performance needs to be monitored frequently.
Carbon systems should be adapted specifically to the maximum anticipated water flow rate of the
system. When carbon is used for the removal of chloramine at a level of 1 mg/L or more, two carbon
beds should be installed in a series configuration. A means should be provided to sample the product
water from the first bed. A sampling port should also be installed following the second bed for use in the
event of total chlorine breaking through the first bed. In situations where chloramine is not used to
disinfect the water, and the ammonium level in the water is low, one carbon bed or carbon cartridge
filters could be sufficient. Exhausted carbon media should be discarded and replaced with new media,
according to a replacement schedule determined by regular monitoring. For example, when testing
between the beds shows that the first bed is exhausted, the second bed should be moved into the first
position, the second bed replaced with a new bed, and the exhausted bed discarded. When samples
from the first sampling port are positive for total chlorine, operation may be continued for a short time
(up to 72 h) until a replacement bed is installed, provided that samples from the second sampling port
remain negative. It was recognized that it might not be practical to rotate the bed positions in
installations that use large, backwashable carbon beds. However, there was concern that the capacity of
the second bed could decrease unpredictably and no longer provide adequate backup if there was
breakthrough of the first bed. For this reason, replacing both beds if bed rotation was not possible was
recommended. Licensed to: Team ANSI ISO

ISO/DIS 23500-1
Granular activated carbon with an iodine number greater than 900 is considered optimal for
chlorine/chloramine removal. When granular activated carbon is used as the medium for the removal
of chloramine from water containing >1 mg/L chloramine, each bed should have an empty-bed contact
time (EBCT) of at least 5 min at the maximum product-water flow rate (a total EBCT of at least 10 min).
Some source waters, such as those with a high organic content, could require alternative types of
carbon that are more resistant to organic fouling. These types of carbon may have iodine numbers less
than 900. When other forms of carbon or granular activated carbon with an iodine number of less than
900 are used, the manufacturer should provide performance data to demonstrate that each bed has the
capacity to reduce the total chlorine concentration in the feed water to less than 0,1 mg/l when
operating at the maximum anticipated flow rate for the maximum time interval between scheduled
testing of the product water for total chlorine. Regenerated carbon should not be used. Some granular
activated carbon contain aluminium, which can elute from the carbon and add to the burden of
aluminium to be removed by reverse osmosis or ion exchange. The use of acid-washed carbon
minimizes this source of aluminium in the water.
Where practical, portable dialysis systems supplied with water known to contain chloramine should
include two carbon beds in series, which together provide a 10 min EBCT. Where that is not practical,
alternative technologies can be used provided there is a redundant means of chloramine removal and
that a total chlorine concentration of less than 0,1 mg/L is verified in a sample collected after the
primary device before each treatment. Possible alternatives include: a granular activated carbon bed
followed by a dense carbon block; and two carbon block filters in series.
Carbon beds used for free chlorine and chloramine removal are sometimes arranged as series-
connected pairs of beds so that they need not be overly large. The beds within each pair are of equal
size and water that flows through them are parallel. For removal of chloramine from water
containing >1 mg/L, each pair of beds should have a minimum empty bed contact time of 5 min at the
maximum flow rate through the bed. When series-connected pairs of beds are used, the piping should
be designed to minimize differences in the resistance to flow from inlet and outlet between each
parallel series of beds to ensure that an equal volume of water flows through all beds.
Although treatment of water by carbon is the method usually used to meet the requirement of 4.1.2 for
total chlorine, it was recognized that, in certain situations, carbon might not adequately remove
chloramine. Inadequate removal of chloramine might occur when chloramines in the form of naturally
occurring N-chloramines are present or when practices such as the use of high pH or the inclusion of
orthophosphate or polyphosphates are used. If the pH of the incoming water is out of the range
specified by the manufacturer, the carbon might not function properly and deplete rapidly. In other
situations, such as acute dialysis with portable water treatment systems, it could be impractical to use
the volume of carbon required to ensure adequate chloramine removal. In such circumstances, other
strategies for chloramine removal may be needed to supplement carbon. Acid injection can be used to
decrease pH (see B.2.6), anion exchangers (also known as organic scavengers) can be installed before
carbon beds to remove organic matter and other substances that might foul carbon beds, and
dealkalizers can be used to reduce alkalinity. It is known that adding sodium bisulfite prior to the
reverse osmosis system has been successful in eliminating chloramine in haemodialysis applications.
Ascorbic acid has also been added to the acid concentrate used to eliminate chloramine from the final
dialysis fluid.[38] It should be noted that a minimum contact time is required for ascorbic acid to
neutralize chloramine in water. If ascorbic acid is being used to neutralize chloramine, and if
unexplained red blood cell destruction or anaemia occurs, the effectiveness of the ascorbic acid
neutralization of chloramine should be investigated. Other means of removing chloramine, such as
redox alloy media and ultraviolet irradiation, are used in the pharmaceutical and electronics industries.
These processes are currently being evaluated for haemodialysis applications. The final choice of a
system for chloramine removal in haemodialysis settings will depend on local conditions and might
need to include more than one of the processes outlined above.


ISO/DIS 23500-1
B.2.6 Chemical injection systems
Chemical injection systems may be used in the pretreatment section of a water purification system to
supplement the physical purification processes described in the previous clauses. Applications of
chemical injection include the addition of sodium bisulfite to remove chloramine and the addition of
acid to adjust pH.
Chemical injection systems consist of a reservoir that contains the chemical to be injected, a metering
pump, and a mixing chamber located in the main water line. Chemical injection systems also include
some means of regulating the metering pump to control the addition of a chemical. This system should
be designed to tightly control the addition of the chemical. The control system should ensure that a
chemical is added only when water is flowing through the pretreatment cascade and that it is added in
fixed proportion to the water flow or based on some continuously monitored parameter, such as pH,
using an automated control system. If an automated control system is used to inject the chemical, the
controlling parameter should be independently monitored. There should also be a means of verifying
that the concentrations of any residuals arising from the chemical added to the water are reduced to a
safe level before the water reaches its point of use.
When acid is added to adjust pH, a mineral acid should be used; organic acids can act as a nutrient and
allow bacteria to proliferate.
Reservations were expressed about the addition of chemicals to the water. However, it was recognized
that the addition of chemicals could be necessary, in some circumstances, if a facility is to meet the
maximum contaminant levels set forth in 4.1.2. For example, if the municipal water contains high levels
of N-chloramines or chloramine in the presence of orthophosphate or polyphosphate, injection of
sodium bisulfite can be one of the few options available for chloramine removal.
If chemical injection is used in the pretreatment cascade, users should ensure that the addition of the
chemical does not interfere with the operation of subsequent purification processes, including the
primary purification process. For example, the performance of thin-film composite reverse osmosis
membranes might be affected by the pH of the feed water. At pH levels below 7, the rejection of fluoride
can be substantially reduced, compared to its rejection at a pH of 8.
B.2.7 Reverse osmosis
Reverse osmosis (RO) systems have become widely used in haemodialysis water treatment systems,
largely because these devices remove dissolved inorganic and organic solutes, as well as bacteria and
bacterial endotoxins.
The following requirements apply to reverse osmosis systems.
a) When used to prepare water for haemodialysis applications, either alone or as the last chemical
purification stage in a water treatment system, reverse osmosis systems should be shown to be
capable, at installation, of meeting the requirements of ISO 13959, when tested with the typical feed
water of the user.
b) Reverse osmosis devices should be equipped with online monitors that allow the determination of
rejection rates and product-water conductivity. The product-water conductivity monitor should
activate audible and visual alarms when the product-water conductivity exceeds the preset alarm
limit. The alarms should be capable of notifying staff in the patient care area when reverse osmosis
is the last chemical purification process in the water treatment system. Monitors that measure
resistivity may be used in place of conductivity monitors.
The RO membrane separation process components are a semipermeable membrane, typically in a

spiral-wound configuration, a pump, and various flow and pressure controls to direct the flow of water
through the system. In operation,2017-02-09
Downloaded: feed water is pressurized by the RO pump and is then directed along

ISO/DIS 23500-1
the surface of the semipermeable membrane. A portion of the water is forced through the membrane; a
process that removes inorganic and organic solutes, bacteria and bacterial endotoxins. The remainder
of the water continues along the membrane surface and is directed to the drain. Water passing through
the membrane is referred to as “product water” or “permeate”. The water that flows along the
membrane surface and to the drain is known as “reject water” or “concentrate”. This flow configuration,
known as “cross-flow filtration”, prevents a progressive build-up of materials on the membrane surface
that would eventually lead to fouling and membrane failure. In some reverse osmosis systems, a portion
of the reject water stream is recycled to the feed-water stream. This recycling allows higher velocities
across the membrane surface, which can help reduce membrane fouling, as well as allowing higher
overall use of water. RO systems may operate in a single-stage or two-stage (double-pass) configuration
depending on feed-water quality and/or local requirements and preferences. In a two-stage RO, the
product water from the first stage acts as the feed water for the second stage.
NOTE The rejection rate of the second stage in a two-stage reverse osmosis system can be significantly lower
than the rejection rate of the first stage. One reason for the difference in rejection rates is due to dissolved CO2.
RO systems may also be fitted with flowmeters, usually in the product water and the rejected water
streams, to monitor the output of the RO system and gauges to monitor the pressure at various points in
the system. Although not indicative of treated water quality, monitoring flow rates and pressures can
help ensure that the system is operating within the manufacturer's specifications and thus will help
ensure RO reliability.
In addition, it is recommended that, when a reverse osmosis system is the last chemical purification
process in the water treatment system, means should be incorporated to prevent patient exposure to
unsafe product water in the event of a product-water conductivity alarm. Such means could include
diversion of the product water to the drain, in addition to activating the audible and/or visual alarms
that should be situated to ensure a prompt response by personnel in the patient care area.
Depending on membrane configuration and materials of construction, RO systems are sensitive to

various feed-water conditions that can lead to diminished performance or premature failure. To avoid
such problems, users should carefully follow the manufacturer's instructions for feed-water treatment
and monitoring to ensure that the RO is operated within its design parameters.
B.2.8 Deionization
Deionization (DI) is an ion exchange process that removes both anions (negatively charged ions) and
cations (positively charged ions) from water. During the exchange process, hydroxyl ions replace other
feed-water anions, and hydrogen ions replace other feed-water cations; the hydroxyl and hydrogen ions
then combine to form pure water. DI systems may contain anion and cation resin in separate vessels,
known as “dual-bed systems”, or may have both resin types mixed together in a single vessel, known as
“mixed-bed” or “unibed systems”.
Deionizers are an effective means of removing ionic contaminants from water. However, they do not
remove nonionic contaminants and they can contribute bacterial contaminants to the water rather than
remove them. The inability of deionizers to remove nonionic contaminants could limit aluminium
removal by deionization, since aluminium is an amphoteric substance that changes from being cationic
to being anionic as the pH varies from acidic to basic.[20] At neutral pH, aluminium is present mostly as
colloidal aluminium, which does not carry a charge and is not removed by deionization.[4] Furthermore,
deionizers have a finite capacity for contaminant removal. Once the deionizer is depleted of hydrogen
and hydroxyl ions, the next least avidly bound ions will be displaced by more avidly bound ions. For
example, once the hydroxyl ions are depleted, anionic contaminants in the water will displace fluoride
ions from the anion exchange resin.[26] This phenomenon has led to high levels of fluoride in the product
water, with subsequent patient injury and death.[23][27] Deionization, even in combination with an
endotoxin-retentive filter, does not remove certain low-molecular-weight toxic bacterial products, such
as microcystins. For the above reasons,
Licensed useANSI
to: Team of deionization
ISO as the primary means of treating water
supplying multiple dialysis Downloaded:
machines is strongly discouraged. Deionization may be used to polish
2017-02-09

ISO/DIS 23500-1
product water from a reverse osmosis system or may be used as a standby if the reverse osmosis
system fails. Many believe that a two-stage reverse osmosis system operated in a redundant
configuration is preferable to a combination of reverse osmosis and deionization.
The most common configuration for DI is to have two mixed beds in series, with resistivity monitors
being placed downstream of each bed. Upon exhaustion of the first bed, reliance for water of sufficiently
high resistivity shifts to the second bed, and dialysis operations may be continued for a short time until
a replacement bed is installed, provided that the product water from the second tank has a specific
resistivity of 1 MΩ·cm or greater.
DI has a finite capacity that, when exceeded, will cause dangerously high levels of contaminants in the
product water. Therefore, DI systems, when used to prepare water for haemodialysis applications,
should be monitored continuously to produce water of 1 MΩ·cm or greater specific resistivity (or
conductivity of 1 µS/cm or less) at 25 °C. An audible and visual alarm should be activated when the
product-water resistivity falls below this level and the product-water stream should be prevented from
reaching any point of use, for example by being diverted to drain. The alarm should be capable of
notifying staff in the patient care area. Under no circumstances should DI be used when the product
water of the final bed has a resistivity below 1 MΩ·cm.
Feed water for deionization systems should be pretreated with activated carbon, or a comparable
alternative, to prevent nitrosamine formation.
If a deionization system is the last process in a water treatment system, it should be followed by an
endotoxin-retentive filter or other bacteria- and endotoxin-reducing device. The tendency for
deionizers to contribute bacterial contaminants to the water is greater when deionizers are kept as a
backup for a reverse osmosis system, particularly if there is no flow through the deionizers. Some
facilities counter this tendency by connecting the deionizers in parallel to the main water line and by
maintaining a low flow through them. An alternative approach is to contract with a local supplier to
provide backup deionizers on demand.
NOTE The requirements given above for deionization might not apply to electrodeionization (EDI)
technology, which can be used as an alternative to deionization following reverse osmosis in haemodialysis
applications.
B.2.9 Endotoxin-retentive filters
Endotoxin-retentive filters are membrane-based separation devices that may be used to remove both
bacteria and endotoxins. Endotoxin-retentive filters should be placed in dialysis water systems at
locations downstream of deionization. They may also be used at the end of the purification cascade and
in dialysis water or central dialysis fluid distribution systems. Endotoxin-retentive filters can also be
used in the dialysis fluid line of individual dialysis machines as a final barrier against bacteria and
endotoxins. These filters are considered part of the dialysis machine and might not be subject to all the
recommendations that follow.
NOTE Endotoxin-retentive filters do not remove low-molecular-weight microbial metabolites.
Endotoxin-retentive membranes used for haemodialysis applications are typically in either a spiral-
wound configuration or a hollow-fibre configuration. Spiral-wound ultrafilters are usually operated in a
cross-flow mode, with a fraction of the feed water being forced through the membrane and the
remainder being directed along the membrane surface to drain. As with reverse osmosis, cross-flow
filtration is intended to minimize membrane fouling. Hollow-fibre endotoxin-retentive filters are
typically housed in vessels similar to those used for cartridge sediment filters and may be operated in a
cross-flow or a dead-end (no cross-flow) mode. When used in a water purification system for
haemodialysis applications, an endotoxin-retentive filter should be shown to reduce the concentrations
of bacteria and endotoxins entering the filter by factors at least as great as those specified in the
manufacturer's labelling.

ISO/DIS 23500-1
Endotoxin-retentive filters should be fitted with a means of assessing filter integrity and fouling. One
suitable means is to monitor the pressure drop (ΔP) across the filter at a given product-water flow rate
using pressure gauges on the inlet (feed) and outlet (product) water lines. Alternatively, product-water
flow rate can be measured at a given pressure drop. Such monitoring will indicate when membrane
fouling has progressed to the point at which membrane replacement or cleaning is needed. Monitoring
also ensures that the device is being operated in accordance with the manufacturer's instructions.
Endotoxin-retentive filters should be included in routine disinfection procedures to prevent
uncontrolled proliferation of bacteria in the filter. If bacterial proliferation is not controlled, bacteria
can “grow through” the membrane and contaminate the product-water compartment of the filter.
Endotoxin-retentive filters operated in the cross-flow mode should also be fitted with a flowmeter to
monitor the flow rate of water being directed to the drain.
B.3 Dialysis Water storage and distribution

B.3.1 General
The function of the water storage and distribution system is to distribute dialysis water from the
treatment cascade to its points of use, including individual haemodialysis machines, proportioning
systems used to prepare dialysis fluid centrally, dialyser reprocessing equipment, and concentrate
preparation systems. A water storage and distribution system typically contains a large volume of water
exposed to a large surface area of piping and storage tank walls. Because chlorine and chloramine are
removed in the purification process, the water does not contain a bacteriostatic agent. This combination
of circumstances predisposes wetted surfaces to bacterial proliferation and biofilm formation.
Therefore, any dialysis water storage and distribution system should be designed specifically to
facilitate bacterial control, including measures to prevent bacterial colonization and to allow for easy
and frequent disinfection.
B.3.2 Water storage
When used, storage tanks should have a conical or bowl-shaped base and should drain from the lowest
point of the base. Storage tanks should have a tight-fitting lid and be vented through a hydrophobic
0,22 µm to 0,45 µm air filter. The filter should be changed on a regular schedule according to the
manufacturer's instructions or if it becomes wet. A means should be provided to effectively disinfect
any storage tank installed in a water distribution system. Internal spray mechanisms can facilitate
effective disinfection and rinsing of a storage tank.
B.3.3 Water distribution
Two types of water distribution systems are used: direct feed systems and indirect feed systems. In a
direct feed system, dialysis water flows directly from the last stage of the purification cascade to the
points of use. In an indirect feed system, dialysis water flows from the end of the purification cascade to
a storage tank. From there, it is distributed to the points of use. The water storage and distribution
system chosen for a particular situation should provide the simplest possible flow path and contain the
smallest volume of water consistent with the operating needs of the dialysis unit. The simplest system is
generally a direct feed system. However, direct feed systems can be impractical. For example, the
pressure at the end of the purification cascade could be insufficient to provide adequate flow and
pressure at the points of use without a booster pump. If a direct feed system is used, it is also necessary
to size the water treatment cascade to provide sufficient water to meet the peak demand. For these
reasons, an indirect feed system with a storage tank may be used. Since storage tanks provide a large
surface area for potential biofilm formation, their volume should be kept to a minimum in order to
maximize water turnover in the tank. Whichever type of system is used, water distribution systems
should be configured as a continuous loop and designed to minimize bacterial proliferation and biofilm
formation (see Clause 8). A centrifugal pump made of inert materials is necessary to distribute the
dialysis water and aid in effective disinfection. A multistage centrifugal pump is preferred for this
purpose. Licensed to: Team ANSI ISO

ISO/DIS 23500-1
Direct feed distribution systems typically return unused dialysis water to the feed side of the reverse
osmosis unit. If the pressure at the end of the distribution loop decreases to a value below the water
pressure at the inlet to the reverse osmosis pressurizing pump, retrograde flow of untreated water into
the distribution loop can occur. To minimize this risk, it is recommended that dual check valves or a
break tank at the inlet to the reverse osmosis system with an air gap on the lines from the pretreatment
cascade and the distribution loop be used to prevent retrograde flow and that the pressure at the end of
the distribution loop be monitored.
Distribution systems for dialysis water should be constructed of materials that do not contribute
chemicals, such as aluminium, copper, lead, and zinc, or bacterial contaminants to dialysis water. The
choice of materials used for a water distribution system will also depend on the proposed method of
disinfection. Table B.1 provides some guidance on the compatibility of different materials and
disinfection agents. Whatever material is used, care should be taken to select a product with properties
that provide the least favourable environment for bacterial proliferation, such as smooth internal
surfaces.
Table B.1 — Guidance on piping materials used in dialysis water distribution systems
and their compatibility with common disinfectants
Sodium
Material hypochlorite Peracetic acid Formaldehyde Hot water Ozonea
(bleach)
PVC X X X X
CPVC X X X X
PVDF X X X X X
PEX X X X X X
SS X X X X
PP X X X X
PE X X X X
ABS X
PTFE X X X X X
Glass X X X X X
NOTE 1 X denotes probable compatibility.
NOTE 2 PVC = polyvinylchloride, CPVC = chlorinated polyvinylchloride, PVDF = polyvinylidene fluoride, PEX = cross-linked
polyethylene, SS = stainless steel, PP = polypropylene, PE = polyethylene, ABS = acrylonitrile butadiene styrene,
PTFE = polytetrafluoroethylene.
a Ozone refers to ozone dissolved in water, not ozone gas.
Table B.1 is not intended as an exhaustive compilation of all possible compatible combinations of piping
material and disinfectant. Considerations of compatibility should include any joint materials and pipe
fittings, as well as the actual piping material. The concentration of germicide and the duration,
frequency, and conditions (flow, pressure, temperature) of exposure should also be taken into account.
Users should verify compatibility between a given germicide and the materials of a piping system with
the supplier of that piping system and/or the disinfectant supplier before using the germicide.
B.3.4 Bacterial control devices
B.3.4.1 General

ISO/DIS 23500-1
Traditionally, chemical disinfection has been used to prevent bacterial proliferation in dialysis water
storage and distribution systems. One consequence of the increased attention being paid to bacterial
control in the dialysis water storage and distribution system is an interest in alternatives to traditional
chemical disinfection, including ultraviolet irradiators, ozone generators, and hot water disinfection
systems. Both ozone and hot water can allow more frequent disinfection of the dialysis water storage
and distribution system because prolonged rinsing is not needed to remove residual disinfectant from
the system before dialysis is recommenced. The use of ozone or hot water is possible only if the systems
are constructed from appropriately resistant materials. This limitation applies not only to the piping
and any storage tank that may be in the system but also to all pumps, valves, and other fittings,
including any O-rings and seals they may contain. Ultraviolet irradiation can be used to kill planktonic
cells, but it has no impact on bacteria located in biofilm. In order to achieve an effective and preventive
disinfection with the respective system, the user should refer to the recommendations given by the
manufacturer of the device or system.
B.3.4.2 Ultraviolet irradiators
When used to control bacterial proliferation in dialysis water storage and distribution systems, UV
irradiation devices should be fitted with a low-pressure mercury lamp which emits light at a
wavelength of 254 nm and provides a dose of radiant energy of 30 mW·s/cm2. If the irradiator includes
a calibrated ultraviolet intensity meter, the minimum dose of radiant energy should be at least
16 mW·s/cm2. The device should be sized for the maximum anticipated flow rate according to the
manufacturer's instructions. It is recommended that UV irradiators be followed by an endotoxin-
retentive filter to remove pyrogens.
The recommendations provided in this clause concern UV irradiator used specifically for bacterial
control. UV irradiators may also be used for other applications in a water purification and distribution
system.
Ultraviolet irradiation can also be used to control bacteria in the pretreatment section of a water
treatment system, such as the following carbon beds to reduce the bacterial burden presented to a
reverse osmosis unit.
UV irradiators should be equipped with a calibrated ultraviolet intensity meter, as described above, or
with an online monitor of radiant energy output that activates a visible alarm, which indicates that the
lamp should be replaced. Alternatively, the lamp should be replaced on a predetermined schedule
according to the manufacturer's instructions to maintain the recommended radiant energy output.
When ultraviolet irradiators are dipped in the storage tank to control bacteria, they should be designed
to keep the required energy at the farthest position in the tank, considering the flow situation during
operation.
B.3.4.3 Ozone disinfection systems
When used to control bacterial proliferation in dialysis water storage and distribution systems, an
ozone disinfection system should be capable of delivering ozone at the concentration and for the
exposure time specified by the manufacturer. When ozone disinfection systems are used, it is
recommended that an ambient air ozone monitor be installed in the area of the ozone generator.
Ozone generators convert oxygen to ozone using a corona discharge or ultraviolet irradiation. The
ozone is then injected into the water stream. An ozone concentration of 0,2 mg/L to 0,5 mg/L, combined
with a contact time of 10 min, measured at the end of the distribution loop, is capable of killing bacteria,
bacterial spores, viruses, moulds, and yeast in water. Destruction of established biofilm could require
longer exposure times and/or higher concentrations of ozone. Ozone can also degrade endotoxins.


ISO/DIS 23500-1
Ozone can degrade many plastic materials, including PVC and elastomeric O-rings and seals. Therefore,
ozone can be used for bacterial control only in systems constructed from ozone-resistant materials
(see B.3.3).
B.3.4.4 Hot water disinfection systems
Hot water may be used to control bacterial proliferation in dialysis water storage and distribution
systems. The exposure time should be according to the manufacturer's instructions. The water heater of
a hot water disinfection system should be capable of delivering hot water at the temperature and for
the exposure time specified by the manufacturer at any site in the dialysis water storage and
distribution system. The manufacturer's instructions for using hot water disinfection systems should be
followed. If no manufacturer's instructions are available, the effectiveness of the system can be
demonstrated by verifying that the system maintains a specified temperature for a specified time and
by performing ongoing surveillance with bacterial cultures and endotoxin testing.
NOTE 1 The ability of hot water to disinfect a distribution system is a function of water temperature and time
of exposure. For example, the minimum exposure time for hot water disinfection at 80 °C is 10 min.
NOTE 2 The concept Ao can be used for quantification of heat disinfection between 65 °C to 100 °C (see
ISO 15883-1; Washer-disinfectors -- Part 1: General requirements, terms and definitions and tests). Temperature
and time can be combined to yield a number representing a dose capable of achieving the required reduction in
viable organisms.
Ao = ∑10(T-80)/z · ∆t
where
T is the temperature in °C;

z is equal to 10 °C;
∆t is the selected time period in seconds.
An Ao value of 1 is defined as an exposure to 80 °C for 1 s. Thus, Ao = 600 represents 10 min at 80 °C, 1 min at
90 °C, or 100 min at 70 °C.
Hot water disinfection systems can be used only in systems constructed from heat-resistant materials,
such as PVDF (polyvinylidene fluoride), PEX (cross-linked polyethylene), SS (stainless steel), PP
(polypropylene), and PTFE (polytetrafluoroethylene) (see B.3.3).
B.4 Concentrate preparation

B.4.1 General
Dialysis fluid is customarily prepared from two concentrates: the bicarbonate concentrate, which
contains sodium bicarbonate (and sometimes additional sodium chloride), and the acid concentrate,
which contains all remaining ions, acetic acid, and sometimes glucose. Some systems have also been
developed that prepare acid concentrate from individual components, such as from a sodium chloride
cartridge and a concentrated solution of the remaining minor electrolytes.
Acid concentrate can be supplied by the manufacturer in bulk or in single-use containers. In some cases,
the manufacturer will pump the acid concentrate from bulk delivery containers into a holding tank at
the dialysis facility. Systems have recently been introduced that allow a user at a dialysis facility to
prepare acid concentrate from packaged powder and dialysis water using a mixer. If the acid
concentrate is pumped into a bulk storage tank at the dialysis facility, the user is responsible for
maintaining the concentrate in its original state and to ensure that the correct formula is used according
to the patient's prescription. Acid concentrate prepared at the dialysis facility from powder and dialysis
water is also the responsibility
Licensed to:of the ANSI
Team user. ISO

ISO/DIS 23500-1
Bicarbonate concentrate can be supplied by the manufacturer in one of the following three ways:
a) in powder cartridges that are used to prepare concentrate online at the time of dialysis;
b) as packaged powder that is mixed with dialysis water at the dialysis facility;
c) in single-treatment containers of liquid concentrate.
Dialysis fluid can also be prepared from a single concentrate that contains acetate. which is metabolized
by the patient to yield bicarbonate. Acetate-based dialysis fluid is rarely used in routine clinical practice.
In general, acetate-based concentrate is handled in a similar manner to that of acid concentrate, except
that acetate-based concentrate systems use only one concentrate which is mixed with dialysis water.
The labels of acetate-based concentrate are colour-coded white.
B.4.2 Materials compatibility
All components used in concentrate preparation systems (including mixing and storage tanks, pumps,
valves, and piping) should be fabricated from materials (e.g. plastics or appropriate stainless steel) that
do not interact chemically or physically with the concentrate to affect its purity, or with the germicides
or germicidal procedure used to disinfect the equipment. The use of materials that are known to cause
toxicity in haemodialysis, such as copper, brass, zinc, galvanized material, lead, and aluminium, are
specifically prohibited.
B.4.3 Labelling
B.4.3.1 General
Labelling strategies should permit positive identification by anyone using the contents of concentrate
mixing tanks, bulk storage/dispensing tanks, and small containers intended for use with a single
haemodialysis machine. Requirements for such positive identification will vary among facilities,
depending on the differences between concentrate formulations used and on whether single or multiple
dialysis fluid proportioning ratios are used. The use of multiple dialysis fluid proportioning ratios in a
single facility is strongly discouraged.
In addition to the container labelling described below, there should be permanent records of all batches
of concentrate produced at a dialysis facility. These records should include the concentrate formula
produced, the volume of the batch, the lot numbers of powdered concentrate packages, the
manufacturer of the powdered concentrate, the date and time of mixing, any test results, the person
performing the mixing, the person verifying mixing and test results, and the expiration date, if
applicable.
Although it is the responsibility of facilities to develop and use labelling to positively identify the
contents of mixing tanks, bulk storage/dispensing tanks, and concentrate containers, the guidelines in
the following subclauses are suggested.
B.4.3.2 Mixing tanks
Prior to batch preparation, a label should be affixed to the mixing tank that includes the date of
preparation and the chemical composition or formulation of the concentrate being prepared. This
labelling should remain on the mixing tank until the tank has been emptied. Using a photocopy of the
concentrate manufacturer's package label provides a convenient and comprehensive means of
identifying the chemical composition or formulation of the concentrate; however, the lot number and
expiration date should be marked out because they apply only to the dry powder.


ISO/DIS 23500-1
B.4.3.3 Bulk storage/dispensing tanks
These tanks should be permanently labelled to identify the chemical composition or formulation of
their contents. As with mixing tanks, bulk storage/dispensing tank labelling can be conveniently
accomplished by affixing a copy of the concentrate manufacturer's package label.
B.4.3.4 Concentrate containers
Concentrate containers may be nondisposable vessels provided by haemodialysis machine

manufacturers and having a capacity sufficient for one or two haemodialysis sessions. The extent of
labelling for these containers depends on the variety of concentrate formulations used and on whether
the facility uses dialysis machines with different proportioning ratios; the latter practice is strongly
discouraged.
At a minimum, concentrate containers should be labelled with sufficient information to differentiate the
contents from other concentrate formulations used at the facility. If a chemical spike is added to an
individual container to increase the concentration of an electrolyte, the label should show the added
electrolyte, the date and time added, and the name of the person making the addition (see B.4.5). The
additional information may be simple or extensive, but in all cases it should permit users to positively
identify the container's contents.
B.4.4 Concentrate mixing systems
B.4.4.1 General
Concentrate mixing systems require a source of dialysis water, a suitable drain, and a ground-fault-
protected electrical outlet. Protective measures should be used to ensure a safe work environment. For
example, ventilation and personal protective equipment should be used to handle any residual dust that
is introduced into the atmosphere as powdered concentrates are added to the system and to handle any
additional heat produced by the device. Structural issues, such as the facility's weight-bearing capacity,
should be addressed if systems are to be installed above ground level. Operators should at all times use
appropriate personal protective equipment, such as face shields, masks, gloves, gowns, and shoe
protectors, as recommended by the manufacturer.
If a concentrate mixing system is used, the preparer should follow the manufacturer's instructions for
mixing the powder with the correct amount of dialysis water. The number of bags or the weight of
powder added should be determined and recorded.
The manufacturer's recommendations should be followed regarding any preventive maintenance and
disinfection procedures. Records should be maintained indicating the date, time, person performing the
procedure, and results (if applicable).
B.4.4.2 Acid concentrate mixing systems
Acid concentrate mixing tanks should be designed to allow the inside of the tank to be completely
emptied and rinsed according to the manufacturer's instructions when concentrate formulas are
changed. Use of a tank with a sloping bottom that drains from the lowest point is one means of
facilitating this process. Because concentrate solutions are highly corrosive, mixing systems should be
designed and maintained to prevent corrosion. Acid concentrate mixing tanks should be emptied
completely and rinsed with dialysis water before mixing another batch of concentrate. If another batch
of concentrate is not to be mixed promptly, the mixing tank should be rinsed again with dialysis water
before the next batch is mixed.


ISO/DIS 23500-1
B.4.4.3 Bicarbonate concentrate mixing systems
Bicarbonate concentrate mixing tanks should be designed to drain completely; for example, they should
have a sloping bottom and a drain at the lowest point. High- and low-level alarms can prevent
overfilling and air damage to the pump. Because concentrate solutions are highly corrosive, mixing
systems should be designed and maintained to prevent corrosion. Mixing tanks should have a tight-
fitting lid and should be designed to allow all internal surfaces to be disinfected and rinsed. A
translucent tank allows users to see the liquid level; the use of sight tubes is not recommended because
of the potential for microbial growth, such as bacteria, algae, and fungi.
Once mixed, bicarbonate concentrate should be used within the time specified by the manufacturer of
the concentrate. The concentrate should be shown to routinely produce dialysis fluid meeting the
recommendations of 4.3.2. Overagitating or overmixing of bicarbonate concentrate should be avoided,
as this can cause CO2 loss and can increase pH. (Systems designed for mixing dry acid concentrates may
use methods that are too vigorous for dissolving dry bicarbonate.)
The mixing tank should be either
— completely emptied and disinfected according to the manufacturer's instructions, or
— disinfected using a procedure demonstrated by the facility to be effective in routinely producing

dialysis fluid that allows the recommendations of 4.3.2 to be met.
B.4.5 Additives
Manufacturers provide acid concentrates with a wide range of electrolyte compositions for different
proportioning ratios. Most typical dialysis fluid prescriptions can be obtained by using one or more of
these commercially available concentrates. If particular formulations are not available, manufacturers
provide additives that can be used to adjust the level of potassium or calcium in the dialysis fluid. These
additives are commonly referred to as “spikes”.
NOTE The use of additives is not approved in some countries.
Concentrate additives should be mixed with liquid acid concentrates according to the manufacturer's
instructions, taking care to ensure that the additive is formulated for use in concentrates of the
appropriate dilution ratio. When liquid additives are used, the volume contributed by the additive
should be considered when calculating the effect of dilution on the concentration of the other
components in the resulting concentrate. When powder additives are used, care should be taken to
ensure that the additive is completely dissolved and mixed before the concentrate is used.
B.5 Concentrate storage and distribution

All components used in concentrate distribution systems (including concentrate containers, storage
tanks, and piping) that contact the fluid should be fabricated from nonreactive materials (e.g. plastics or
appropriate stainless steel) that do not interact chemically or physically with the concentrate to affect
its purity. The use of materials that are known to cause toxicity in haemodialysis, such as copper, brass,
zinc, galvanized material, lead, and aluminium, are specifically prohibited.
B.5.2 Bulk storage tanks (acid concentrate)
Procedures should be in place to control the transfer of the acid concentrate from the delivery container
to the storage tank to prevent the inadvertent mixing of different concentrate formulations. If possible,
the tank and associated plumbing should form an integral system to prevent contamination of the acid

ISO/DIS 23500-1
concentrate. The storage tanks and inlet and outlet connections, if remote from the tank, should be
secure and labelled clearly.
B.5.3 Distribution systems
Concentrate may be distributed from a central preparation point using reusable concentrate containers
that contain sufficient concentrate for one to two treatments, or it may be distributed through a piping
system that provides concentrate connections at each treatment station. A combination of these two
systems may also be used, with some concentrates distributed by concentrate container and others
through a piping system. Two common configurations used for distributing concentrate through a
piping system are gravity feed and pressurized. Gravity feed systems require an elevated tank;
pressurized systems deliver the concentrate using a pump and motor and do not require an elevated
tank. The maximum allowable concentrate delivery pressure is specified by the manufacturer of the
dialysis fluid delivery machine and should not be exceeded.
Elevated tanks are usually smaller than those used for preparing concentrates. Elevated tanks for
bicarbonate concentrate distribution should be equipped with conical or bowl-shaped bottoms, tight-
fitting lids, a spray mechanism, and high- and low-level alarms. Any air vents should have 0,45 µm
hydrophobic vent filters.
B.5.3.1 Acid concentrate distribution systems
Acid concentrate delivery piping should be labelled and colour-coded red at the point of use (at the
container filling station or the dialysis machine connection). More than one type of acid concentrate
may be delivered, and each line should clearly indicate the type of acid concentrate it contains. Even
though there are no published reports of acid concentrate supporting bacterial growth, every effort
should be made to keep the system closed to prevent contamination and evaporation. If the acid system
remains intact, no rinsing or disinfection is necessary.
B.5.3.2 Bicarbonate concentrate distribution systems
Bicarbonate concentrate delivery piping should be colour-coded blue at the point of use (at the
concentrate container filling station or dialysis machine connection). All joints should be sealed to
prevent leakage of concentrate.
Because bicarbonate concentrates provide excellent media for bacterial proliferation,[80][81] bicarbonate
concentrate delivery systems should be disinfected on a regular basis to ensure that the dialysis fluid
routinely achieves the level of bacteriological purity recommended in 4.3.2. The manufacturer's
instructions can provide an initial disinfection schedule. However, this schedule might need to be
adjusted on the basis of the user's bacteriological monitoring. For piped distribution systems, the entire
system, including patient station ports, should be purged of bicarbonate concentrate before
disinfection. Each patient station port should be opened and flushed with disinfectant and then rinsed;
otherwise, it would be a “dead leg” in the system. Also, prompt use of bicarbonate concentrates
prepared in dialysis facilities from powder and dialysis water is strongly recommended.
When reusable concentrate containers are used to distribute bicarbonate concentrate, they should be
rinsed free of residual concentrate before disinfection.
All chemical disinfectants (e.g. sodium hypochlorite and peracetic acid products) that are compatible
with dialysis machines can be used to disinfect bicarbonate concentrate distribution systems. However,
some disinfectants attack biofilm better than others. Appropriate dwell times and concentrations
should be used as recommended by the manufacturer of the concentrate system. If this information is
not available, sodium hypochlorite solutions, such as bleach, may be used at a dilution of 1:100 and
proprietary disinfectants at the concentration recommended by the manufacturer for disinfecting
piping systems. In the event that precipitation or salt build-up impedes flow through a piping system,
cleaning with a 1:34Downloaded:
solution of2017-02-09
5 % acetic acid (e.g. distilled white vinegar) is recommended. Some

ISO/DIS 23500-1
manufacturers supply bicarbonate concentrate systems with UV irradiation or ozone systems for
bacterial control.
UV irradiation devices that are used to control bacterial proliferation in the pipes of bicarbonate
concentrate distribution systems should be fitted with a low-pressure mercury lamp that emits light at
a wavelength of 254 nm and provides a dose of radiant energy of 30 mW·s/cm2. The device should be
sized for the maximum anticipated flow rate according to the manufacturer's instructions and be
equipped with an online monitor of radiant energy output that activates a visual alarm indicating that
the lamp should be replaced. Alternatively, the lamp should be replaced on a predetermined schedule
according to the manufacturer's instructions to maintain the recommended radiant energy output. It is
recommended that UV irradiators be followed by an endotoxin-retentive filter. Disinfection of the
bicarbonate concentrate distribution system should continue to be performed routinely.
When used to disinfect the pipes of a bicarbonate concentrate distribution system, an ozone generator
should be capable of delivering ozone at the concentration and for the exposure time specified by the
manufacturer. When ozone disinfection systems are used, ambient air should be monitored for ozone
according to national standards and regulations.
When heat is used to disinfect the bicarbonate distribution system, the time and temperatures should
be validated by the manufacturer.
Overagitation or mixing of bicarbonate concentrate can result in loss of CO2 from the solution. Loss of
CO2 results in an increase in pH and favours the formation of carbonate that can lead to precipitation of
calcium carbonate in the fluid pathways of the dialysis machine following dialysis fluid proportioning.
B.5.3.3 Concentrate outlets
For piped concentrate distribution systems, each treatment station is equipped with a concentrate
outlet for bicarbonate, one or more outlets for acid concentrate, and a dialysis water outlet for
connection to the inlet line of the dialysis machine (optional). To prevent mix-ups with delivery of two
or more types of acid concentrate, each concentrate should have its own outlet. Concentrate outlets
should be compatible with the dialysis machine and have a means of minimizing the risk that the wrong
concentrate will be connected to an outlet. The dispensing outlets should be labelled with the
appropriate symbol (see Table B.2) indicating the proportioning ratio for the dialysis machine, if
required, and should be colour-coded blue for bicarbonate and red for acid.
B.6 Dialysis fluid proportioning

Historically, dialysis fluid was buffered with acetate. For acetate buffered dialysis fluid, dialysis water is
mixed with an acetate containing concentrate to produce the dialysis fluid. In such a system, the pH can
vary depending on the supply water. Although a single concentrate is used to prepare acetate dialysis
fluid, consideration should be given to checking both conductivity and pH because mix-ups involving
acid concentrate and other chemicals can result in an acceptable conductivity with an incorrect pH.
One of the functions of the dialysis fluid is to correct metabolic acidosis present in patients undergoing
dialysis treatment. With acetate buffered dialysis fluid, the acetate is converted by the body to
bicarbonate, acetate intolerance can be present and is characterized by vasodilation and smooth muscle
relaxation leading to hypotension. Current haemodialysis treatments utilize proportionating or mixing
technology which uses two separate concentrates mixed with dialysis water; an acid concentrate, and a
bicarbonate concentrate. It is important that the acid and bicarbonate concentrates are matched with
respect to the proportioning ratio and with the model and setup configuration of the dialysis machine.
Several types of three-stream concentrates are available, with different ratios of acid concentrate to
bicarbonate concentrate to dialysis water (see Table B.2). The different proportioning types are not
compatible with one another. Generally,
Licensed to: Team bicarbonate
ANSI ISO is available in one or two forms for each
proportioning type (in liquid, cartridge,2017-02-09
Downloaded: or dry powder, and in various sizes). Each proportioning type

ISO/DIS 23500-1
has numerous acid concentrate formulations (“codes”) with different amounts of potassium, calcium,
and magnesium ions, plus glucose. To help differentiate between concentrates of different
proportioning types, ISO 23500-4 recommends that the manufacturer include a geometric symbol on
the labels, along with acid/base colour coding.
Table B.2 — Symbols and colour coding for different concentrate proportioning ratios
Acid proportioning Bicarbonate

concentrate
Concentrate type ratioa Geometric symbol
(blue colour
Comments
(red colour coding) coding)
35X 1+34a Square Dry, liquid, or
cartridge
36,83X 1+35,83a Circle Dry or liquid Bicarbonate
concentrate contains
some NaCl.
45X 1+44a Triangle Dry, liquid, or
cartridge
36,1X 1+35,1a Diamond Cartridge Powder cartridges
may be used for other
proportioning ratios,
except for 36,83X, in
which the bicarbonate
concentrate also
contains NaCl.
NOTE Acetate-containing concentrate is colour-coded white.
a Acid+bicarbonate + water.
Different manufacturers of dialysis machines use different methods of controlling the proportions of the
concentrates. Such control may be: “fixed proportioning” or “servo-control”. With both methods, the
operator can select a desired sodium and bicarbonate level, or conductivities corresponding to defined
sodium and bicarbonate levels, and the machine will make the necessary adjustments to achieve the
selected levels. Both types use a redundant system of controls and monitoring. With fixed proportioning
systems, the pumps are set to established volumes, and the final conductivity is verified. With servo-
control machines, the individual concentrates are added until the conductivity achieves the expected
value. A final redundant conductivity monitor monitors the conductivity. Some machines also monitor
the pH of the dialysis fluid as an additional safeguard against gross errors in dialysis fluid formulation.
A different type of machine with a batch tank and dedicated concentrates is also available.
Depending on the type of acidified concentrate in use, the acid component may be in the form of sodium
acetate, sodium di-acetate or citric acid. Acetate is metabolized to bicarbonate in a 1:1 ratio, whilst
citric acid generates bicarbonate in a 3:1 molar ratio.
In selecting the dialysis fluid bicarbonate, the physician should consider all sources of buffer delivered
to the patient during the dialysis treatment, including the bicarbonate in the bicarbonate concentrate,
the acetate, citrate or lactate in the acid concentrate which, when metabolized form bicarbonate. In
selecting the bicarbonate prescription, the physician should consider the patient’s nutritional status,
assessed by history, physical examination, anthropometrics, serum albumin and protein nitrogen
appearance, since individuals whose metabolism results in a small acid load are at higher risk of
developing metabolic alkalosis following treatment. Decisions regarding the bicarbonate prescription
should also take into account changes in serum potassium, magnesium and calcium concentrations
during dialysis, and the presence and severity of heart disease.

ISO/DIS 23500-1
Some models of dialysis machines use a fixed proportionating ratio, whilst others may be set up or
calibrated for use with concentrates of more than one proportioning ratio. (Note that changing from
one proportioning ratio to another requires recalibration for some models of dialysis machines.) Thus,
for such machines, the type of concentrate should be labelled on the machine or clearly indicated by the
machine display. It is strongly recommended that facilities configure every machine to use only one
type of concentrate.
Injuries related to incorrect dialysis fluid composition are rare, but they can and do happen when all
procedures are not followed. Frequently, when the error occurs, several patients have been exposed
before the facility recognizes the mistake. For example, because one of the concentrates is acidic and the
other is basic, connecting the wrong concentrates to the machine could result in dialysis fluid that could
harm the patient. Thus, it is necessary for the operator to follow the manufacturer's instructions
regarding dialysis fluid conductivity, including measuring the approximate pH with an independent
method before starting the treatment of the next patient, if recommended by the dialysis machine
manufacturer. More recently, systems have been developed that use three concentrates (bicarbonate,
sodium chloride, and an acid concentrate containing the remaining electrolytes) to allow more
sophisticated variation of the dialysis fluid composition during dialysis.
B.7 Central dialysis fluid storage and delivery systems

B.7.1 General
Dialysis fluid may be prepared centrally and distributed to dialysis consoles at the treatment stations
using a central dialysis fluid delivery system (CDDS). Central dialysis fluid delivery systems incorporate
many of the features found in dialysis water storage and distribution systems (see B.3) and concentrate
preparation systems (see B.4) and most of the recommendations in those clauses are applicable to
central dialysis fluid delivery systems; however, there are additional factors to be considered.
B.7.2 Design and maintenance
Central dialysis fluid delivery systems are usually designed as single-pass systems, although a
distribution loop can also be used.
If a distribution loop is used, it is necessary to pay attention to preventing calcium carbonate

precipitation and an increase in pH resulting from loss of CO2 and an increase in temperature as the
dialysis fluid is circulated.
Central dialysis fluid delivery systems should be disinfected daily to limit biofilm formation using a
chemical disinfectant or hot water. Such disinfection should include the tubing connection to the
haemodialysis console as well as the dialysis console.
Microbiological monitoring of central dialysis fluid delivery systems should be similar to that described
in 8.3. Monitoring should include the dialysis consoles located at each treatment station, as well as the
dialysis fluid distribution system. Sampling should include samples collected from the inlet to dialysis
fluid proportioning system and the inlet to dialysis consoles. The frequency of monitoring should meet
applicable local recommendations; if no such recommendations exist the following are suggested.
a) Water system: The number of samples and positions of sampling should be based on the complexity
and size of the water system. The frequency will depend on the analysis of the data collected during
the validation and revalidation activities. Monthly monitoring is most frequently adopted but less
frequent monitoring may be possible based on data collected during the validation and
revalidation.
b) Dialysis fluid/haemodialysis machines without a validated bacteria- and endotoxin-retentive filter:

Machines should be sampled onto:a Team
Licensed regular basis
ANSI ISO to provide verification of the effectiveness of the
disinfection process. TheDownloaded:
schedule of2017-02-09
sampling will depend on the type of disinfection process being

ISO/DIS 23500-1
used. Each machine should be sampled at least once per year and different machines should be
sampled on each occasion. Monthly monitoring is most frequently adopted.
c) It is not necessary to take samples of ultrapure dialysis fluid or substitution fluids if their
production paths are fitted with bacteria- and endotoxin-retentive filters validated by the
manufacturer and operated and monitored according to the manufacturer's instructions. It could be
necessary to sample the dialysis fluid entering such bacteria- and endotoxin-retentive filters
depending on the manufacturer's instructions for use of the filters; for example, when the
instructions for use specify the quality of the fluid entering the filter. (See also Annexes D and E.)
The results of testing should be subjected to trend analysis. When results exceed the action levels, or in
the case of a patient's pyrogenic reaction or suspected bacteremia/fungemia, an investigation and
follow-up should be initiated. This investigation could include additional sampling and extra
disinfection procedures carried out as per the manufacturer's recommendations.
B.7.3 Dialysis fluid storage
Central dialysis fluid delivery systems usually include a dialysis fluid storage tank. The tank should be
designed to drain completely; for example, it should have a sloping bottom and a drain at the lowest
point, and be ventilated through a hydrophobic 0,45 µm air filter.
All components used in dialysis fluid storage and delivery systems (including storage tanks, pumps,
valves and piping) should be fabricated from materials (e.g. plastics or appropriate stainless steel) that
do not interact chemically or physically with the dialysis fluid to affect its purity, or with the germicides
or germicidal procedure used to disinfect the system. The use of materials that are known to cause
toxicity in haemodialysis, such as copper, brass, zinc, galvanized material, lead, and aluminium, is
specifically prohibited.


ISO/DIS 23500-1
Annex C
(informative)
Monitoring guidelines for water treatment equipment, distribution systems,

and dialysis fluid
C.1 Monitoring systems

Table C.1 provides guidelines on monitoring systems used for preparing and distributing dialysis fluid.
The recommendations given in Table C.1 can be used as a starting point for developing a quality
management programme for dialysis fluid when the manufacturer or supplier of the system does not
provide adequate instructions. Not every item listed in Table C.1 will be required in all dialysis facilities
and the frequency of monitoring may differ depending on the nature of the water supplied to the
dialysis facility; for example, whether or not the water supply is disinfected using chloramine. The
actual quality management programme for a given facility will depend on the components used in that
facility's water treatment system, the purposes for which the fluids are to be used, the results of
validation procedures, and any applicable local regulations.
NOTE Refer to footnotes a and b for an explanation of the use of Xs in the “Typical range of values” column.
Table C.1 — Suggested framework for monitoring water treatment equipment,

distribution systems, and dialysis fluid
Item to monitor What to monitor Typical range of values Typical interval Comments
Sediment filter Pressure drop across the Pressure drop less than XXXX Daily NA
filter (see 7.3.2)
Sediment filter Backwash cycle timer Backwash clock set to XX:XX Daily NA
backwashing cycle setting (see 7.3.2)
Cartridge filter Pressure drop across the Pressure drop less than XXXX Daily NA
filter (see 7.3.3)
Water softener Residual hardness of Hardness as specified by the Daily NA
product water (see 7.3.4) manufacturer of the reverse
osmosis equipment.
Water softener Level of undissolved salt Salt level at XXX Daily NA
brine tank in tank (see 7.3.4)
Water softener Regeneration cycle timer Regeneration cycle timer set to Daily NA
regeneration cycle setting (see 7.3.4) XX:XX


ISO/DIS 23500-1
Carbon beds Product-water total ≤0,1 mg/l of total chlorine Daily Prior to each
chlorine between the patient shift if
beds (see 7.3.5) chloramine is
present in the
feed water at
1 mg/l or more
(see 7.3.5 for
exceptions to
these typical
intervals). (Note
that use of an
online monitor
can provide
continuous
monitoring and
avoid the need
for offline
monitoring.)
Chemical injection Level of chemical in the Chemical level in reservoir ≥ XXX; Daily (continuous NA
system reservoir, injector controlling parameter in range XX monitoring is
function, value of the to XX preferable)
controlling parameter
(e.g. pH) (see 7.3.6)
Reverse osmosis Product water Rejection ≥ XX % Daily (continuous NA
conductivity, total Conductivity < XX μS/cm monitoring is
dissolved solids (TDS), or preferable)
resistivity and calculated
rejection (see 7.3.7)
Reverse osmosis Product and reject flow Product water flow rate ≥ X,X l/min Daily (continuous NA
rates, and calculated XX % < recovery < XX % monitoring is
recovery (see 7.3.7) preferable)
Deionizers Product water resistivity Resistivity ≥ 1 MΩ·cm Continuous NA
or conductivity Conductivity ≤ 1 μS/cm monitoring
(see 7.3.8)
Endotoxin- Pressure drop across the Pressure drop less than XXXX or Daily NA
retentive filters filter at a fixed flow rate flow rate greater than XXX
or product-water flow
rate at a fixed pressure
drop (see 7.3.9)
Water system Chemical contaminants Maximums as listed in Tables 1 and Yearly These
chemical as listed in Tables 1 and 2 2 recommendation
contaminants of ISO23500-3 The parameters to be monitored s apply to dialysis
should be defined by the validation water. However,
process on the basis of the expected chemical analysis
contaminants. of source water
(or analysis
results from the
water supplier) is
necessary to
evaluate the
overall
performance of
the water
treatment
system.


ISO/DIS 23500-1
Dialysis water Bacterial growth and Total viable microbial Monthly, or as Specific testing at
storage tanks endotoxins (see Clause 8) count < action level (typically defined by the this location is
50 CFU/ml); (see 4.1.3) results of the performed to
Endotoxin < action level (typically validation process troubleshoot
0,125 EU/ml); (see 4.1.3) for storage tanks contamination of
supplying a central the distribution
dialysis fluid system for tanks
delivery system connected to a
water
distribution
piping system
until a pattern of
consistent
compliance with
limits can be
demonstrated.
Water distribution Bacterial growth and Total viable microbial Monthly, or as NA
piping system endotoxins (see 4.1.3) count < action level (typically defined by the
50 CFU/ml); (see 4.1.3) validation process
Endotoxin < action level (typically results
0,125 EU/ml); (see 4.1.3)
UV irradiators Energy output and/or the Light output > XXX Monthly NA
lamp life span Lamp life span < XXXX
(see 7.4.3.1)
Ozone generators Concentration in the Ozone concentration > XXX During each NA
water and contact time Contact time > XXX disinfection
(see 7.4.3.2)
Residual ozone after
disinfection < X,XX mg/l
Hot water Temperature and time of Temperature not less than XX °C; During each This information
disinfection exposure of the system to minimum exposure time at disinfection might be
systems hot water (see 7.4.3.3) temperature ≥ XX min available from
the data logs of
automated
systems.
Chemical Concentration of Germicide During each NA
disinfection germicide in water and concentration > X,X mg/l; residual disinfection
systems contact time germicide
concentration < X,XX mg/l after
rinsing
Dialysis fluid Conductivity, pH, XX,X mS/cm < conductivity < XX,X In accordance with pH monitoring is
electrolyte mS/cm local regulations or necessary only if
concentrations pH in the range 6,9 to 8,0 for as specified by the recommended by
dialysis fluid containing manufacturer of the the manufacturer
bicarbonate, or as otherwise dialysis fluid of the dialysis
specified by the manufacturer delivery system fluid delivery
(continuous system.
monitoring for
proportioning
systems)
Standard dialysis Bacterial growth and Total viable microbial Monthly, rotated The sample
fluid endotoxin concentration count < action level (typically among machines so should be
in standard dialysis fluid 50 CFU/ml); (see 4.3.2) that each machine is collected at
(see 4.3.2) Endotoxin < action level (typically tested at least once worst-case time
0,25 EU/ml); (see 4.3.2) per year and (for example,
different machines Monday
are sampled on each morning) if
occasion possible.


ISO/DIS 23500-1
Ultrapure dialysis Bacterial growth and Total viable microbial Before the first use NA
fluid endotoxins in the count < 0,1 CFU/ml; to validate the
ultrapure dialysis fluid as endotoxin < 0,03 EU/ml (see 4.3.3) system and monthly
it enters the dialyser (see (see 8.3.1 and Annex E) thereafter
4.3.3)
Substitution fluid Bacterial growth and Sterile and nonpyrogenic (see 8.3.1 NA
endotoxins in the and Annex E)
ultrapure dialysis fluid as
it enters the dialyser (see
8.3.1 and Annex E)
a It is not possible to specify universally acceptable operating ranges for each device listed in the table since some of the
specifications will be system-specific. In those cases, the facility should define an acceptable operating range based on the
manufacturer's instructions or measurements of system performance.
b The actual interval for monitoring, testing, cleaning, and/or disinfection should be based on the results of the validation
process and on going trend analysis (see Clause 6 and 8.2.2).
C.2 Cleaning/disinfection strategies

See Table C.2.
NOTE Refer to the manufacturer's instructions for more detail prior to referring to the “Typical interval”
column.
Table C.2 — Summary of cleaning/disinfection strategies for dialysis water treatment systems,
dialysis water storage and distribution systems, concentrate distribution systems, and dialysis
fluid distribution systems
Item for
Element(s) to be Cleaning/
cleaning/ Typical interval Comments
cleaned/disinfected disinfection
disinfection
Reverse osmosis The membrane module Disinfection Monthly, or The product side of the membrane
should be disinfected, according to is considered to be a part of the
paying particular manufacturer’s dialysis water distribution system.
attention to the product instructions It should be disinfected at an
side (See D.1) interval sufficient to routinely
(See 8.1, 8.2) produce dialysis water meeting the
quality requirements of Clause 4.
(See D.1, 3rd paragraph.) If needed,
the feed side of the membrane
should be cleaned periodically to
remove foulants that can degrade
membrane performance.
Water storage Tanks and pipes Disinfection Monthly, or More frequent disinfection might
tanks (See 8.2.2.2) according to be necessary if indicated by
manufacturer’s microbiological testing results.
instructions
Water Piping system Disinfection Monthly, or More frequent disinfection might
distribution (See 8.1, 8.2, D.1) according to be necessary if indicated by
piping system manufacturer’s microbiological testing results.
instructions
UV irradiators Quartz sleeve Periodic cleaning
(See 7.4.3.1) (See 7.4.3.1)


ISO/DIS 23500-1
Concentrate Tanks and piping Cleaning and/or Disinfection is usually not needed
mixing systems (See 8.2.2.3) disinfection for acid concentrate mixing
systems.
Concentrate Tanks and piping Disinfection Weekly If using sodium hypochlorite for
distribution (See 8.2.2.4, B.5.3.2) (See D.1, last disinfection, a concentration of
systems paragraph) 0,5 % to 1 % is recommended.
(bicarbonate) If cleaning with acetic acid, a
concentration of approximately
0,15 % acetic acid is recommended.
(See B.5.3.2, 4th paragraph.)
Disinfection is usually not needed
for acid concentrate distribution
systems.
Dialysis machine System Disinfection According to By its own disinfection circuit and
(See 8.1) manufacturer's programme. (See 8.2, 3rd
instructions paragraph.)
Central dialysis Dialysis fluid delivery Disinfection Daily Use chemical disinfectant or hot
fluid delivery system (See B.7.2) water. (See B.7.2, 3rd paragraph.)
system, CDDS Dialysis console
(See B.7.2)
NOTE The actual interval for cleaning and/or disinfection should be based on the results of the validation process and
ongoing trend analysis (see Clause 6 and 8.2.2).


ISO/DIS 23500-1
Annex D
(informative)
Strategies for microbiological control
D.1 General
The strategy for controlling the proliferation of microorganisms in haemodialysis systems primarily
involves proper system design and operation, and regular disinfection of water treatment system and
haemodialysis machines. A key concept in ensuring compliance with the requirements of 4.1.3 and 4.3
is that disinfection schedules should be designed to prevent bacterial proliferation, rather than being
designed to eliminate bacteria once they have proliferated to an unacceptable level. With this strategy,
monitoring levels of bacteria and endotoxins serves to demonstrate that the disinfection programme is
effective, not to indicate when disinfection should be performed. Gram-negative water bacteria, their
associated lipopolysaccharides (bacterial endotoxins), and nontuberculous mycobacteria (NTM) most
frequently come from the community water supply, and levels of those bacteria can be amplified
depending on the water treatment system, dialysis fluid distribution system, type of dialysis machine,
and method of disinfection.
All components of dialysis water treatment and distribution systems, and dialysis fluid preparation and
distribution systems, can serve as reservoirs of microbial contamination. Dialysis water distribution
systems frequently use pipes that are of larger diameter and longer than are needed to handle the
required flow. Oversized piping increases both the total fluid volume and the wetted surface area of the
system. Gram-negative bacteria in fluids remaining in pipes overnight multiply rapidly and colonize the
wet surfaces, thus producing bacterial populations and endotoxin quantities in proportion to the
volume and surface area. Such colonization results in the formation of protective biofilm that is difficult
to remove once formed and that provides a barrier between the bacteria and germicide during
disinfection.
Biofilm is a community of microorganisms consisting of cells that are irreversibly attached to a surface
or interface or to each other.[116] Biofilms can occur at solid-liquid, solid-air, and liquid-air interfaces.
Most microorganisms can form biofilms and more than 99 % of all microorganisms live in such
aggregates.[132] A feature of all biofilms is that the organisms are embedded in a matrix of microbial
origin, consisting of extracellular polymeric substances (EPS). The EPS comprises mainly
polysaccharides and proteins, which form hydrogel matrices.[118] The structure of biofilm, and the
physiological attributes of biofilm organisms, confer an inherent resistance to antimicrobial agents,
whether those agents are antibiotics, disinfectants or germicides.
Mechanisms responsible for resistance can include
— delayed penetration of the antimicrobial agent through the biofilm matrix,
— altered growth rate of biofilm organisms, and
— other physiological changes related to the mode of growth of the biofilm.
A certain amount of biofilm formation is considered unavoidable in dialysis water systems. When the
level of biofilm is such that the action levels for microorganisms and endotoxins in the dialysis water
cannot be routinely achieved, the operation of the system is compromised from a medical and technical
point of view. This level of biofilm formation is often referred to as biofouling. The key to avoiding
biofouling is to minimize biofilm
Licensed to: Teamdevelopment.
ANSI ISO The extent of biofilm growth is dependent on the
availability of nutrients. Classic 2017-02-09
Downloaded: biocidal approaches usually do not limit nutrient availability. In fact,

ISO/DIS 23500-1
some biocides increase nutrient availability by oxidizing recalcitrant organics and making them more
bioavailable.[134]
Routine disinfection should be performed to control bacterial contamination of distribution systems.

The frequency of disinfection will vary with the design of the system and the extent to which biofilm has
already formed in existing systems. Sodium hypochlorite and ozone are generally the most effective
agents against biofilm, and their use might be more efficacious if the pipes are treated first with a
descaling agent. However, in some cases, complete or partial replacement of a distribution system
might be the only way to re-establish control over mature biofilm.
It is commonly believed that maintaining flow through piping systems at all times minimizes biofilm
formation. However microbial growth and biofilm formation in hydraulic systems cannot be controlled
by the fluid velocity .[119] Data from the semiconductor industry show that a Reynolds number of 3 000
in a piping system is insufficient to prevent bacterial contamination in the water as biofilm was found
on the internal surfaces of pipes.[127] [A Reynolds number of approximately 3 000 is obtained with a
flow velocity of 0,15 m/s in a 2-cm-diameter pipe (0,5 ft/s in a 3/4” diameter pipe]
Even if it were possible to specify a minimum flow velocity that was effective in reducing biofilm
formation and bacterial contamination, use of such a minimum flow velocity would not provide a
substitute for regular disinfection of the distribution system. Other measures can also help protect
pipes from contamination. A mechanism should be incorporated in a distribution system to ensure that
disinfectant does not drain from pipes during the disinfection period. Dead-end pipes and unused
branches and taps that can trap fluid should be eliminated because they act as reservoirs of bacteria
and are capable of continuously inoculating the entire volume of the system. Joints between sections of
piping and between piping and fittings should be formed in a manner that minimizes the formation of
crevices and other voids that might serve as sites for bacterial colonization. Pipes should not be cut with
a hacksaw. Any burrs should be removed before the joint is formed. These measures also minimize the
possibility that pockets of residual disinfectant could remain in the piping system after disinfection.
A storage tank in the dialysis water or dialysis fluid distribution system greatly increases the volume of
fluid and surface area available and can serve as a niche for water bacteria. Storage tanks are therefore
not recommended for use in dialysis water or dialysis fluid distribution systems unless they are
frequently drained and adequately disinfected. It could be necessary for the user to scrub the sides of
the tank to remove bacterial biofilm if the tank design and maintenance are not adequate to prevent
bacterial proliferation. A bacteria- and endotoxin-retentive filter, distal to the storage tank, or some
other form of bacterial control device, is recommended.
For most haemodialysis machines, routine disinfection with hot water or with a chemical germicide
connected to a disinfection port on the machine does not disinfect the line between the outlet from the
dialysis water distribution system and the back of the dialysis machine. Users should establish a
procedure for regular disinfection of this line. One approach is to rinse the haemodialysis machines
with water containing germicide or hot water when the dialysis water distribution loop is disinfected. If
this procedure is used with a chemical germicide, each haemodialysis machine should be rinsed and
tested for the absence of residual germicide following disinfection.
Storage times for bicarbonate concentrate should be minimized (normally less than 24 h), as well as the
mixing of fresh bicarbonate concentrate with unused portions of concentrate from a previous batch.
The manufacturer's instructions should be followed if they are available. Facilities that reuse
concentrate containers for bicarbonate concentrate should disinfect the containers at least weekly.
Bicarbonate concentrate can support prolific growth of microorganisms. Containers and pick up tubes
can be disinfected with household sodium hypochlorite solutions (300 mg/L to 600 mg/L free
chlorine), with a contact time of about 30 min or according to another nationally approved standard or
regulation, or according to the manufacturer's instructions.
The containers and pick-up Licensed

tubes should beANSI
to: Team disinfected
ISO at least weekly or at a frequency required by
local regulatory requirements. Following
Downloaded: disinfection, the bicarbonate concentrate containers and
2017-02-09

ISO/DIS 23500-1
concentrate pick up tubes should be rinsed with treated water, allowed to air dry and stored inverted at
the end of each treatment day.
D.2 Microbial monitoring methods

D.2.1 General
The microbial quality of dialysis water shall be monitored regularly to validate the effectiveness of the
disinfection programme. The frequency of monitoring should be determined during the process of
system validation. In the absence of a formal determination of frequency, monitoring is usually
performed monthly. Monitoring can be accomplished by direct plate counts, in conjunction with the
measurement of bacterial endotoxins.
Samples of dialysis water shall be collected from several places to give an indication of the microbial
quality of the water throughout the dialysis water distribution system. For routine monitoring, samples
should be collected from the last outlet of the dialysis water distribution loop, where dialysis water
enters equipment used to reprocess dialysers, and where dialysis water enters equipment used to
prepare bicarbonate concentrate or from the bicarbonate concentrate mixing tank. Additional testing,
such as at the end of the water treatment cascade and at the outlet of the storage tank, if one is used, can
be necessary during qualification of a newly installed system or when troubleshooting the cause of
contamination within the dialysis water distribution loop. For central dialysis fluid distribution
systems, samples should be collected from the last outlet of the dialysis fluid distribution loop.
For dialysis machines that are not fitted with validated endotoxin-retentive filters, dialysis fluid
samples should be collected from enough machines so that each machine is tested at least once per
year. For dialysis machines fitted with validated endotoxin-retentive filters, samples should be collected
according to the filter manufacturer's instructions. If testing of any haemodialysis machine reveals a
level of contamination above the action level, an investigation should be conducted. The investigation
should be based on the presumption that other haemodialysis machines might also be contaminated. It
should include a review of compliance with disinfection and sampling procedures and an evaluation of
microbiological data for the previous three months to look for trends. The offending machine should be
retested and an additional sample of machines tested to determine if the contamination was limited to a
single machine or more widespread. The person in charge should also be notified.
Cultures should be repeated when bacterial counts exceed the allowable levels. If culture growth
exceeds permissible standards, samples from the dialysis water distribution system or dialysis fluid
distribution system and haemodialysis machines should be cultured weekly until acceptable results are
obtained. Additional samples should be collected when there is a clinical indication of a pyrogenic
reaction or septicaemia, and following a specific request by the clinician or the infection control
practitioner.
Samples shall always be collected before sanitization/disinfection or no sooner than 24 h after

disinfection. For systems disinfected daily, samples should be collected before, and as close as
practicable to, the next disinfection. Samples from haemodialysis machines should always be collected
before disinfection. Culture dialysis water and dialysis fluid weekly for new systems until a pattern has
been established. For established systems, culture monthly unless a greater frequency is dictated by
historical data at a given institution. If biofouling is suspected, for example due to erratic
microbiological test results, it could be necessary to check for the presence of biofilm (see D.2.3).
D.2.2 Sample collection
Samples shall be collected directly from sampling ports situated in different parts of the dialysis water
or dialysis fluid distribution system. In general, the sampling ports should be opened and the dialysis
water or dialysis fluid should be allowed to run for at least 60 s unless the sampling port manufacturer
instructions for use state otherwise,
Licensed to: Team before a sample is collected in a sterile, endotoxin-free container.
ANSI ISO
Containers validated Downloaded:
for collection of endotoxin samples should be used to collect samples. The sample
2017-02-09

ISO/DIS 23500-1
volume collected should be 5-1000mL depending upon the test to be run and/or as specified by the
laboratory performing the test. Sampling ports should be disinfected using a cotton swab or sterile
gauze wetted with alcohol, or as recommended by the port manufacturer. The sample should be
collected only when no disinfectant residual is present.
Dialysis fluid samples should be collected from a sampling port in the dialysis fluid inlet line to the
dialyser, or from the dialysis fluid outlet port of the dialyser, or from a sampling port in the dialysis fluid
outlet line of the dialyser. In some newer haemodialysis machines, dialysis fluid flow stops when the
dialysis fluid lines are disconnected from the port. In these instances, the machines are equipped with
dialysis fluid sampling ports that can be accessed using a syringe. Sampling ports may be disinfected
with alcohol and allowed to air dry. A sterile syringe should be used to aspirate at least 10 mL of dialysis
fluid out of the sampling port and discarded. A new appropriately sized sterile syringe should be
attached and used to draw the sample. The sample volume collected should be 5-1000mL depending
upon the test to be run and/or as specified by the laboratory performing the test.
Containers used for samples to be cultured should be sterile and endotoxin free.
D.2.3 Heterotrophic plate count
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 during transit to the laboratory. Sample storage for more than 24 h should be avoided.
The reference method for culturing is the membrane filtration technique. With this method, a known
volume of sample or diluted sample is filtered through_ a 0,45 μm membrane filter and the membrane
filter is aseptically transferred to the surface of an agar plate. The spread-plate technique may also be
used. With this method, an inoculum of at least 0,1 ml of sample is spread equally over the surface of the
agar plate. Use of a calibrated loop to apply the sample to the agar plate is not permitted. The pour-plate
technique may also be used. A sample volume of 1 ml is usually used with this method. Dip samplers
should not be used. The culture medium used should be selected based on the type of fluid to be
therapies such as haemodiafiltration,. Blood and chocolate agars should not be used.
Validated media selections, incubation times and temperatures are specified in ISO 23500-3, ISO
23500-4 and ISO 23500-5. During incubation, the plates can be sealed or kept in a plastic bag to avoid
desiccation of the agar if that is a concern, e.g. for methods requiring 7 day incubation.. Colonies should
be counted using a magnifying device. If a more accurate count from plates containing fewer than 30
colonies or more than 300 colonies is desired, larger or smaller volumes may be cultured. Smaller
volumes can be obtained by making 1:10 serial dilutions in sterile phosphate buffer. If larger volumes
are required, the membrane filtration method should generally be used.
It is virtually impossible to keep a dialysis water or dialysis fluid distribution system sterile;
microorganisms will always be present on surfaces waiting for nutrients which, in the case of
lithotrophic organisms, can even be inorganic.[117] Heterotrophic plate counts do not provide a good
measure of the presence of biofilm. Fluid samples give no information about the site, extent, or
composition of a biofilm. Although biofilms contaminate the fluid in a distribution system, they do so
only very irregularly. Erratic colony counts might indicate the presence of biofouling since clusters of
cells might be sloughed from the biofilm with release of bacteria into flowing fluid. Currently, few
practical methods are available for the routine detection of biofilm. Conventional methods rely on
sampling-defined surface areas or on exposure of test surfaces (coupons) with subsequent analysis in
the laboratory. A classic example is the so-called “Robbins device”,[125] which consists of plugs inserted
flush with pipe walls, thereby experiencing the same shear stress as the wall itself. After given periods
of time, they are removed and analysed in the laboratory for all biofilm-relevant parameters. The
disadvantage of such systems is the
Licensed to: time-lag
Team ANSIbetween
ISO analysis and result. Jacobs et al. (1996)[123]
described a simple spectrophotometric
Downloaded: monitoring
2017-02-09 method, using a nucleotide-specific fluorescent stain

ISO/DIS 23500-1
(4′,6-diamidino-2-phenylindole), and automated measurement. Other methods which report biofilm

growth online, non-destructively and in real time have been invented. They are all based on physical
methods. If careful attention is paid to routine disinfection, routine monitoring for biofilm is not
necessary. However, when the level of biofilm leads to a biofouling situation, it might be necessary to
determine the level of biofilm in the system using the methods currently available.
D.3 Interpreting the results of microbial monitoring

Microbial monitoring or culture results are dependent upon three basic parameters: culture medium,
culture temperature, and culture duration. Recommended methods and cultivation conditions can be
found in ISO 23500-3, ISO23500-4 and ISO 23500-5. Accurate microbiological surveillance is important
in establishing the microbial content of the water and dialysis fluid. Culture results obtained using the
methods outlined in this International Standard are only a relative indicator of the bioburden in dialysis
water or dialysis fluid and do not provide a measure of the absolute bacterial burden.
Tryptone Glucose Extract Agar (TGEA) or Reasoner’s Agar No. 2 (R2A) incubated at 17° C -23° C for a
period of 7 days, or Tryptic Soy Agar incubated at 35° C for 48 hours are all validated and acceptable
methods. The user should determine which of these methodologies is appropriate for the circumstance,
taking into account the advantages of each. 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
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]. [USP <1231>][179].
It should be further noted that measurements, reflect the presence of planktonic organisms in a fluid
storage and distribution system. However, more than 99 % of all microorganisms in such a system live
in biofilms on the surfaces of the system.[115] Thus, care should be taken in interpreting culture results
since a low bacterial count might be obtained even though a system was contaminated with an
established biofilm if the sample was taken at a point in time after disinfection, but before a biofilm
shedding event re-established a population of planktonic organisms.
The primary approach in respect of interpretation of microbiological test results is the use of trend
analysis. This enables the point at which corrective action should be taken to be identified. A suggested
algorithm in respect of actions to be taken, in the event of endotoxin levels >0.25EU/ml and a bacterial
content of >100CFU/ml is outlined in Figure 2.


ISO/DIS 23500-1


ISO/DIS 23500-1


ISO/DIS 23500-1
A. Microbial parameters assessed according to system validation results
B. Extraordinary disinfection (might involve the need to change disinfection methods).

Samples shall be collected no sooner than 24 hours after disinfection.
B. Additional measures might involve the need to change disinfection methods, changing of components
(e.g. RO membrane). Samples shall be collected no sooner than 24 hours after disinfection.
D. Interruption of the treatment must always be agreed with the medical responsible on the basis of the
risk analysis. Furthermore the assessment of the dialysis fluid must be taken into account in this
analysis.
Reproduced with permission from:
Good Dialysis practice: Water and Dialysis fluids: Boccato C, Evans D Lucena R,
Vienken J . Pabst Publishers Lengerich, Germany, ISBN 978-3-95853-111-6.
Figure 2 - Evaluation of microbial monitoring results and relevant (corrective) actions


ISO/DIS 23500-1
Annex E
(informative)
Validation
E.1 General and background

This annex provides background for Clauses 6 and 8 as well as for Annex C.
The dialysis fluid and the substitution fluid used for online convective therapies are the result of an
online process and are used immediately after their production. For this reason, the use of “batch
control” techniques based on testing at fixed intervals is not the most effective way to ensure the
required quality level is continuously reached. Periodic assessment of the chemical and microbial fluid
quality might not identify a potential problem; for example, if that problem arose just after a test sample
was collected.
Furthermore, compliance with the requirement that substitution fluid used for online convective
therapies be sterile cannot be demonstrated by culturing but has to be ensured by the application of a
validated and adequately monitored process.
The monitoring plan of the overall system (i.e. including the steps from the dialysis water production to
the generation of the dialysis fluid and substitution fluid) is based on the knowledge acquired with the
validation plan for the specific dialysis water or dialysis fluid production system and the monitoring
strategies applicable to the dialysis fluid production devices as validated by the manufacturer.
Moreover, when using a validated and monitored process for removal of bacteria and endotoxins at the
dialysis machine, sampling of the substitution fluid is not needed. The presence in the system of parts
and equipment (e.g. dialysis machine or endotoxin-retentive filters) that have already been validated by
the manufacturer is sufficient to ensure fluid quality, provided those parts and equipment are operated
in accordance with the manufacturer's instructions. Sampling of the dialysis water or dialysis fluid
should be performed if required by the manufacturer of the validated process.
For these reasons, and under the above-mentioned conditions, an effective monitoring strategy should
be based on the direct sampling of the dialysis and/or dialysis fluid and on monitoring of the process
parameters as recommended by the manufacturer and defined by knowledge of the water treatment or
dialysis fluid preparation system acquired during the validation phase.
E.2 Validation programme

E.2.1 General
The performance of the dialysis water or dialysis fluid production system should be verified to
demonstrate that the system is “fit for purpose”. The validation procedure should provide documentary
evidence that the process will consistently produce dialysis water, dialysis fluid, or substitution fluid
meeting the quality requirements of ISO 23500-3 and/or ISO 23500-5.
E.2.2 Validation steps
As described in Clause 6, validation consists of the following:
— validation plan;
— installation and operational qualification;


ISO/DIS 23500-1
— performance qualification;
— revalidation through the data collected during routine monitoring.
E.2.3 Validation plan
The validation plan is the road map for successful validation and provides a complete picture of the
dialysis facility's validation activities.
The validation plan defines and lists all necessary activities and documentation for
— installation and operational qualification,
— performance qualification, and
— revalidation.
The level of detail in the plan should reflect the risk, complexity and novelty of the system. The
validation plan should define all responsibilities during validation and subsequent system operation.
E.2.4 Performance qualification
As described in Clause 6, the aim of performance qualification is to establish that the system, as a whole,
functions consistently to produce water and dialysis fluid of the required quality when operated in
accordance with the defined procedures and with an incoming water supply of defined characteristics.
The prerequisites for performance qualification are as follows:
— a demonstration that the plant has been installed in accordance with the design plans and following
the manufacturer's procedures for installation (i.e. installation qualification);
— a demonstration that the system performs all the required actions and can be operated in
accordance with relevant technical manuals (i.e. operational qualification).
Performance qualification includes periodic assessment of a set of physical, chemical, and

microbiological parameters to demonstrate that a consistent performance pattern can be achieved for
the specific system design and performance requirements.
The sampling and testing pattern can be relaxed during the monitoring phase (normal operation)
provided it can be demonstrated that the system consistently yields high quality results over an
extended period and that continuously monitored parameters provide full surveillance of the system
performance.
Under these assumptions, the following pattern for performance qualification can be adopted.
The first phase requires a full chemical and microbiological analysis of the dialysis water or
microbiological analysis of the dialysis fluid, followed by regular microbiological analyses to
demonstrate consistent quality in the interval between disinfections. During this period, all the
information about the system behaviour should be collected and fine-tuning of the action levels
performed.
In this phase, the testing frequency of the microbiological parameters is kept at a higher level to create a
“trend analysis” and to identify any deviations to ensure the patients' safety.
The achievement of at least three consecutive results, consistently below the action level, allows the
start of the second phase where theto:final
Licensed Teamfrequency
ANSI ISO of testing of microbiological parameters and the
final frequency of disinfection are implemented.
Downloaded: Sampling should be performed prior to disinfection or,
2017-02-09

ISO/DIS 23500-1
alternatively, not sooner than 24 h after the disinfection process, to avoid false-negative results and to
demonstrate adequate system behaviour. Samples taken after disinfection are used to demonstrate the
effectiveness of the disinfection procedure; they should be taken at least once after the first disinfection
and following any significant deviations in the microbiological quality of the dialysis water or dialysis
fluid.
Attainment of two consecutive results within the action level allows the successful completion of
performance qualification and the start of routine monitoring operations.
E.3 Consequences for the monitoring strategy

As a result of the validation process for the water treatment or dialysis fluid preparation system,
adequate maintenance and routine monitoring plans are established. Based on these regimes, system
monitoring starts after performance qualification and ensures ongoing conformance to quality criteria
regarding dialysis fluid and in-house produced concentrates.
Trend analysis through monitoring should be used as a source of advanced information on system
performance, thus enabling a proactive approach to system maintenance with consequential
operational and financial benefits.
Monitoring is achieved with online and offline measurements. With current technology, the majority of
parameters have to be measured offline.
The online monitoring of suitable parameters (such as conductivity) provides immediate identification
of deviations from normal operating conditions, offering the following advantages:
— timely identification of potential problems in their early stage;
— quick and easy diagnosis of the root causes (incoming water quality/technical malfunction);
— implementation of necessary countermeasures;
— triggering of specific offline measurements.
As mentioned above, a purely time-based offline sampling regime has inherent limitations for the
monitoring of a continuous production process since deviations might occur during the sampling
intervals.
Table C.1 lists possible monitoring parameters and related frequencies of measurement.


ISO/DIS 23500-1
Annex F
(informative)
Special considerations for home haemodialysis
F.1 General
The quality of dialysis water used to prepare concentrate and dialysis fluid is as important for home
haemodialysis as it is for in-centre haemodialysis. This International Standard is written principally to
address equipment used for in-centre haemodialysis. While many of the provisions of this International
Standard are also applicable to home haemodialysis, the latter treatment might pose some special
challenges not encountered with in-centre haemodialysis. Similarly, home haemodialysis might require
some departures from the provisions of this guidance regarding dialysis fluid preparation. Because of a
renewed interest in home haemodialysis and, in particular, the use of more frequent treatment
schedules, this annex was included in this International Standard to address some of the concerns
particular to the home haemodialysis setting. The recommendations included in this annex apply to
water treatment systems assembled from individual components. Some of the recommendations in this
annex might not apply to systems for home haemodialysis containing integrated water treatment
equipment designed and validated to produce water and dialysis fluid of the quality required by
ISO 23500-3 and ISO 23500-5. Validated systems require assurance that the system is being operated
under the validated conditions. Also, the recommendations of this annex do not apply to sorbent-based
dialysate regeneration systems, which are excluded from the scope of this International Standard.
Home haemodialysis differs from in-centre haemodialysis in that the patient or a helper will be
responsible for day-to-day operation and maintenance of the water treatment and other dialysis
equipment. In general, these individuals will not have formal technical training in haemodialysis.
Therefore, the dialysis centre should provide training in the operation and maintenance of the
equipment and require a demonstration of competence in those areas before home treatments are
begun.
F.2 Fluid quality

Dialysis water, concentrate, and dialysis fluid used for home haemodialysis applications should meet
the quality requirements set forth in Clause 3 of ISO 23500-3,, Clause 4 of ISO 23500-4, and Clause 4 of
ISO 23500-5
F.3 Utilities
To incorporate a haemodialysis machine in a home, the home will need a water supply, a drain
connection, and a dedicated power source. It is recommended that the utility companies providing
water and power to the patient's home be notified that home dialysis is being performed at that location
and that restoring service following any interruption should be considered a priority.
F.3.1 Water supply
If the water is supplied by a municipal water system, it should meet the applicable standards for
drinking water. Periodic evaluation of source water should be performed to confirm that it meets this
International Standard.
If the water is not supplied by a municipal water system, but obtained from a private well, applicable
drinking water standards can differ,to:
Licensed depending
Team ANSIupon
ISO the number of households that the well supplies.
Furthermore, there may alsoDownloaded:
be different legal requirements in respect of monitoring. In view of this,
2017-02-09

ISO/DIS 23500-1
the source water should be analysed more frequently than in a hospital based dialysis unit especially if
the location is rural. The water source in such situations may be subject to seasonal changes, such as
heavy rain or flood and contamination from septic tanks, underground fuel storage tanks, or
agricultural waste and chemicals.
If home haemodialysis is performed utilizing an integrated water treatment equipment designed and
validated to produce dialysis water and dialysis fluid of the quality required by ISO 23500-3 and
ISO 23500-5, there should be adequate pretreatment, to ensure that the water produced meets the
requirements and to protect components such as the reverse osmosis membrane.
The water supply should support the maximum demand of the water treatment components. The
piping to a single-patient system should be at least 1 cm in diameter. The water pressure should meet
the minimum requirements of the water treatment system, typically at least 150 kPa (approximately 20
psi or 1,5 bar). Other components in the home that use water can temporarily reduce the water
pressure if activated. These components include showers, toilets, clothes washers and dishwashers. A
loss of water pressure could cause the RO system used for dialysis water treatment to shut down,
thereby triggering the dialysis machine's low-water-pressure alarm. If fluctuations in water pressure
become an issue, a bladder tank may be installed in the line supplying water to the water treatment
system to allow the system to continue operation during periods of low water pressure. Homes with an
individual well supply might need to increase the pressure setting of the well pump, increase the size of
the pump, or install a booster pump to ensure adequate pressure is maintained at times of heavy water
utilization within the household.
In isolated rural locations, water temperature of the feed water might be an issue, particularly during
winter. The performance of an RO system is temperature dependent, with the product-water flow rate
decreasing as the temperature decreases. Removal of chloramine by activated carbon is also
temperature dependent, with the efficiency of removal decreasing as the temperature decreases.
Finally, the treated water temperature needs to meet the minimum requirement for the dialysis
machine, typically 10 °C. If the water temperature decreases below 10 °C, the heater in the dialysis
machine might be unable to increase the temperature to the desired dialysate temperature. A
tempering valve could be needed to ensure a consistent supply of water of an adequate temperature. If
a tempering valve is installed, it should meet the requirements of ISO 23500-2, 4.2.3, and the water
heater should be capable of delivering the amount of hot water needed to provide water of the desired
temperature for the duration of the dialysis treatment. Alternatively, the demand for treated water may
be reduced during periods of reduced water temperature by decreasing the dialysis fluid flow rate.
Backflow protection should be installed before the start of the water treatment system in compliance
with any requirements of the local plumbing code. These devices should be inspected at the frequency
specified by the local plumbing code.
F.3.2 Drain
The drain should be capable of supporting the maximum flow from the dialysis machine, RO system,
and any water pretreatment equipment. Typically, a 2,5 cm or larger diameter drain pipe is needed. The
drain should incorporate some means of protecting against back siphon, such as an air break in the
wastewater stream, to avoid backflow from the drain system into the haemodialysis machine or any
water treatment component with a drain line.
If the home is serviced by a septic tank, the tank should be able to process the volume of water from the
haemodialysis procedure. Depending upon the volume of the tank, it might not be possible to perform
daily nocturnal haemodialysis over an extended period (8 h). Another potential limitation is that the
septic system will be exposed to disinfectant chemicals (sodium hypochlorite, peracetic acid, hydrogen
peroxide, etc.), which could impair functional efficiency.


ISO/DIS 23500-1
F.3.3 Electrical wiring and power supply
When haemodialysis equipment is used in the home, consideration should be given to the requirements
of IEC/TR 62653; Guidelines for the safe use of medical products in dialysis treatment with respect to
wiring. The power source used for the haemodialysis equipment should comply with the requirements
of IEC 60601-2-16; Medical electrical equipment - Part 2-16: Particular requirements for basic safety and
essential performance of haemodialysis, haemodiafiltration and haemofiltration equipment
F.4 Environment
Haemodialysis involves large volumes of water and waste dialysate. Loose tubing connections or
equipment malfunction might produce leaks that can cause damage to the home. If water treatment or
dialysis equipment is located on an upper floor, leaking fluids might seep through the floor and damage
ceilings on lower levels. It is recommended that areas where water is treated for dialysis, and in which
dialysis is performed, be designed to contain fluid spills when they occur. The flooring material should
be appropriately water resistant and be capable of easy cleaning. For these reasons, the use of carpeting
or wooden flooring in the room intended for dialysis is not recommended.
Home haemodialysis also requires an area for storage of supplies, including dialysis concentrate. That
area should provide a year-round environment that meets the manufacturer's recommendations for
storage of such supplies or consumables.
F.5 Equipment
F.5.1 General
The equipment selected for home haemodialysis should be simple to operate. The patient/helpers in
the home should be formally trained in the proper operation and maintenance of the haemodialysis and
supporting water treatment equipment by the dialysis centre or its designee.
The final configuration of the water treatment system will depend on the quality of the feed water. As
with in-centre dialysis, the water treatment system should be designed to produce dialysis water of the
quality set forth in Clause 3 of ISO 23500-3, when supplied with water containing contaminants at the
highest anticipated level. Water treatment equipment may include sediment filters, softeners, carbon
beds, reverse osmosis (RO) system, or deionizers (DI). Depending on the contaminants in the water,
additional water treatment equipment may include iron filters, dealkalinizers, and nitrate filters. Unless
specified otherwise in ISO 23500-2 or in this International Standard, water treatment equipment for
home haemodialysis should meet the requirements of ISO 23500-2.
F.5.2 Softener
A water softener might be needed to prevent calcium and magnesium from forming scale on the
membranes of a reverse osmosis system. For water with a high level of hardness, removal of calcium
and magnesium with a softener can be necessary if the reverse osmosis system is to produce dialysis
water that meets the requirements of ISO 23500-3 for calcium and magnesium. A softener typically is
not needed to support a deionization system.
Softeners should be regenerated or exchanged on a regular basis. Only sodium chloride should be used
to regenerate a softener. Potassium chloride should not be used for softener regeneration. Also, salt
designated as rock salt should not be used for regeneration since it is not refined and typically contains
sediments and other impurities that might damage O-rings and pistons and clog orifices in the softener
control head. Single tank softeners can be set to regenerate automatically on set days or after they have
processed a designated amount of water; alternatively, regeneration can be initiated manually.
Softeners used for haemodialysis applications that regenerate automatically are fitted with a
mechanism to prevent waterLicensed
from entering
to: Teamthe product
ANSI ISO line during regeneration. Typically, the timer on
the softener is not interlocked to stop 2017-02-09
Downloaded: the reverse osmosis system when regeneration occurs. If the

ISO/DIS 23500-1
dialysis machine is producing dialysis fluid at that time, a low water pressure alarm will occur. For that
reason, attention should be paid to setting the time for softener regeneration, particularly when daily
nocturnal haemodialysis is being performed.
F.5.3 Carbon media
At least one carbon bed or filter should be installed even if the water supply is from a well and no
chlorine is present. In addition to chlorine, carbon can remove organic contaminants from ground water,
including solvents, pesticides, industrial wastes, and substances leaking from underground storage
tanks. If chlorine is not present in the water, the carbon should be changed on a routine schedule.
When water is obtained from a municipal water supply containing 1 mg/L or more of chloramine, a
chlorine removal process incorporating safety redundancy for chloramine removal per ISO 233500-2
4.2.8 is required.
F.5.4 Reverse osmosis
Since the product flow rate will decrease with decreasing water temperature, a reverse osmosis system
installed without a tempering valve to ensure constant feed-water temperature needs to be sized so
that it will deliver the quantity of water required by the dialysis machine with the coldest anticipated
water temperature.
F.5.5 Deionization
Deionization systems for home haemodialysis should have a means of preventing product water from
reaching the point of use if the resistivity of the water is 1 MΩ·cm or less).
F.5.6 Dialysis water distribution
For home haemodialysis, a direct feed system will typically be used to distribute dialysis water to its
points of use. The water-contacting surfaces of the distribution system should not be constructed of
materials containing aluminium, copper, lead or zinc. Because systems used for home haemodialysis
operate intermittently, the distribution system should be designed and maintained to minimize
bacterial proliferation. The reverse osmosis system should be disinfected according to the
manufacturer's instructions. The dialysis machine should be disinfected following each treatment
according to the manufacturer's instructions. Because the line supplying dialysis water to the dialysis
machine is not disinfected when the machine is disinfected, this line should be disinfected when the
reverse osmosis system is disinfected and consideration should be given to replacing this line on a
regular basis, such as yearly. Opaque tubing is preferred for this line to reduce the likelihood of algae
growth; however, the tubing is to be approved by the manufacturer of the dialysis machine.
Consideration should also be given to installing an endotoxin-retentive filter in the dialysis machine, if
the machine allows that option. If installed, this filter should be maintained and replaced according to
the manufacturer's instructions.
F.5.7 Backflow prevention
Unlike central water systems in hospitals, water systems used in the patients home in most cases
connect directly to potable water systems. Though it is very unlikely that a portable (acute) water
treatment system would back up and contaminate the potable water system, backflow prevention is
considered a necessary and safe precaution for these systems. A backflow prevention device, such as a
pressure principle backflow assembly (PPBA) or a vacuum breaker, should be installed at the point of
connection to the potable water system. In some instances, a local code could require a “break tank”
device in place of a PPBA as the preferred method to prevent backflow. Portable water treatment
system designers should consider possible pressure drops and their effects on downstream
components when sizing such devices. Backflow prevention devices should be tested and maintained
per local plumbing codes.

ISO/DIS 23500-1
Spent dialysis fluid and reject water from a reverse osmosis system unit should be discharged to drain
in a manner that minimizes the potential for contamination of the patient-care area and the dialysis
machine. An appropriate floor drain or standpipe connected to a sink drain should be utilized for this
purpose. If such a drain is not available, spent dialysis fluid and reverse osmosis reject water may be
discharged into a sink. If such a discharge is used, the sink should not be used for other purposes during
dialysis and care should be taken to properly clean the sink after the treatment. In all cases, there
should be an air gap at the point of discharge to prevent backflow into the dialysis machine.
F.5.8 Electrical safety
Consideration should be given to the requirements of IEC/TR 62653 with respect to wiring. The power
source used for the water treatment equipment should comply with the requirements of IEC 60601-1.
Portable water treatment systems should comply with applicable electrical safety standards regarding
electrostatic discharge (ESD), electromagnetic compatibility (EMC), and any other electrical safety
standards as outlined in IEC 60601-1. It is critically important that electrical noise and current leakage
be minimized in both the critical care and general bedside settings. These environments are likely to
have life-sustaining equipment, such as ventilators, for which loss of function because of electrical
interference could evoke a medical emergency. An electrical safety check should be performed at least
once per year. An electrical safety check should also be performed following repairs that involve the
power supply system, including repairs to power cords and cord caps. Portable water treatment system
component enclosures should possess a level of water resistance equal to IEC 60529 IPX 1. Continued
monitoring of the water system is necessary to maintain treatment methods consistent with safety
F.6 Concentrate
F.6.1 Bicarbonate concentrate
Excess bicarbonate concentrate should be discarded after each treatment.
Bicarbonate concentrate containers ( if reused ) and concentrate pick up tubes should be disinfected at
least weekly, or at a frequency required by local regulatory requirements. Following disinfection they
should be rinsed with treated water allowed to air dry and stored inverted at the end of each treatment
day. If concentrate containers are not reused they should be discarded in accordance with local
requirements.
If the bicarbonate solution is prepared from a powder, the patient/helpers should be appropriately
trained to ensure that the solution preparation is in accordance with documented procedures.
F.6.2 Acid concentrate
The patient/helpers should be trained to know that different haemodialysis machines use different
proportioning ratios for concentrate and water and that they should ensure use of the correct acid
concentrate for their haemodialysis machine. The acid concentrate used should be documented as part
of the treatment record.
F.7 Monitoring
F.7.1 Dialysis Water and dialysis fluid quality
The chemical quality of the dialysis water should be analysed at least once a year to ensure that it meets
the requirements of ISO 23500-3. More frequent analysis could be needed if there are seasonal
variations in source water quality or if the source water is supplied from a well. When any repairs are
made to water treatment equipment, the impact on dialysis water quality should be evaluated and a
chemical analysis performed if indicated. Chemical testing might not be required when replacing
consumable components, such as filters 2017-02-09
Downloaded: or other components defined by the manufacturer as requiring

ISO/DIS 23500-1
regular replacement under normal use. Chemical testing might not be required when an entire water
purification device is replaced with an equivalent device which has been validated by the manufacturer
according to an equivalent performance specification as the device being replaced.
The microbiological quality of the dialysis fluid should be analysed using cultures and endotoxin
measurements. If the dialysis fluid meets the recommendations of ISO 23500-5, then the dialysis water
feeding the dialysis machine, and the bicarbonate concentrate, can be assumed to meet the appropriate
requirements. Sampling for microbiological testing should be performed before disinfecting the water
treatment system and dialysis machine. To avoid disconnecting hoses, and opening the system to
possible contamination, the system should be designed with the necessary sampling ports. To obtain
meaningful results, a system should be established to ensure proper collection of the samples and their
timely submission to the testing laboratory.
As part of their training for home haemodialysis, patients/helpers should be instructed in any sample
collection or water and dialysis fluid quality tests that they will be expected to perform in their homes.
If the sample is collected by someone other than the patient/helper, that person should also be trained
in the correct procedures for sample collection and testing.
F.7.2 Equipment
F.7.2.1 General
A log sheet should be provided by the dialysis facility and used to record all measures of water
treatment system performance required by the equipment manufacturer or the dialysis facility.
Measurements should be made at least 15 min after the water treatment system has been set in
operation and before dialysis is initiated.
If any measure of water treatment system performance is found to be outside its acceptable range, the
dialysis centre should be notified.
F.7.2.2 Cartridge filter
Monitoring the pressure drop (∆P) across a sediment filter may be used in the home environment to
determine when the sediment filter has increased resistance of flow. Systems for use in the home
environment which are capable of detecting reduced flow conditions through a sediment filter by
alternative methods (such as with flow monitoring or insufficient feed-water detection) should also be
considered acceptable for determination of sediment filter replacement.
F.7.2.3 Softener
The water hardness should be monitored prior to each treatment, using a sample obtained through a
labelled sample port located between the softener and the reverse osmosis membranes or from the
reject line from the reverse osmosis system. For hardness tests requiring colour differentiation, the
person performing the analysis should be able to distinguish between the colour outputs of the test
criteria. If the person cannot differentiate these colours, an automated meter should be used.
F.7.2.4 Carbon media
When the source water contains chloramine at a concentration of 1 mg/l, or more, the total chlorine
concentration should be checked prior to each treatment. The patient/helper should be trained how to
perform the total chlorine analysis, and should be trained regarding what action to take if total chlorine
is detected above the specified limit. Depending on the test used, the patient/helper should be capable
of distinguishing between different shades of pink or a digital meter should be used to indicate the total
chlorine concentration.
F.7.2.5 Reverse osmosis


ISO/DIS 23500-1
Prior to each treatment, the performance of the reverse osmosis system should be monitored by
checking the product-water conductivity and per cent rejection.
F.8 Personnel
Policies and procedures that are understandable by the patient and/or carer are mandatory, along with
a training programme that includes quality testing, the risks and hazards of improperly prepared
concentrate, and bacterial issues.
Persons operating equipment in the home should be appropriately trained. The training should be
specific to the functions performed. A record of training should be held centrally, and a periodic audit of
the operator’s compliance with procedures should be undertaken.


ISO/DIS 23500-1
Annex G
(informative)
Special considerations for acute haemodialysis
G.1 General
The items included within this annex are equipment used to treat water for the preparation of
concentrates and dialysis fluid in the acute (hospital) setting. This annex deals with portable water
treatment systems intended for use with a dialysis delivery system to deliver dialytic therapies at the
bedside. This annex excludes equipment used in central systems that supply three or more points of use
in an “acute dialysis” room. These systems are considered “central” water systems and thus are covered
by the general guidance of this International Standard. Equipment used for a single patient in a home or
nursing home setting is excluded from this annex because it falls within the scope of Annex F.
The recommendations outlined in this International Standard are generally applicable in the acute
setting, with the addition of the guidance provided in this annex. If less rigorous approaches are used
the onus is on the user to ensure appropriate dialysis water quality through increased monitoring and
maintenance of the water treatment system.
G.2 Fluid quality

Water and concentrate used to prepare dialysis fluid for acute haemodialysis should meet the quality
requirements set forth in Clause 3 of ISO 23500-3and Clause 4 of ISO 23500-4, respectively.
Dialysis fluid prepared from dialysis water and concentrate for use in acute haemodialysis should meet
the quality requirements set forth in Clause 4 of ISO 23500-5.
Monitoring to demonstrate on going compliance with the chemical quality requirements of Clause 3 of
ISO 23500-3should be performed as described in Clause 7 and G.3, with the exception that, in general,
monitoring is not necessary on days when the equipment is not in operation.
Compliance with the microbiological quality requirements of Clause 3 of ISO 23500-3and Clause 4 of
ISO 23500-5 requires regular and frequent disinfection of the equipment coupled with testing to
demonstrate compliance with those requirements. If test results fail to show compliance with the
requirements, steps should be taken to change the frequency and/or procedure of disinfection and
testing until compliance can be demonstrated.
Because patients in the acute setting are likely to be more susceptible to microbiological contaminants
in the dialysate, there could be benefit in using ultrapure dialysis fluid.
G.3 Equipment
G.3.1 General
This subclause contains recommendations for water treatment equipment specific to the acute
haemodialysis setting. The general requirements and recommendations for equipment used to treat
water for haemodialysis applications contained in ISO 23500-3 and ISO 23500-2 apply, unless
otherwise noted in this annex.
The installer and userLicensed

of acuteto:haemodialysis
Team ANSI ISOwater treatment systems are responsible for assuring that
the water produced Downloaded:
by the system can meet the maximum allowable chemical and microbiological
2017-02-09

ISO/DIS 23500-1
contaminant levels specified in Clause 3 of ISO 23500-3:20xx, or the prescription of the physician at
installation. Beyond this qualification, it becomes the responsibility of the physician in charge of acute
dialysis or his/her representative to monitor the system to ensure that the treatment device or devices
maintain a level of water quality that meets the requirements of Clause 3 of ISO 23500-3.
When patients receive treatment in an acute setting, dialysis equipment is taken to the patient's bedside
and connected to a nearby water supply. Such supply may contain chemicals added to the water within
hospitals to ensure that the distribution network is free of pathogens (e.g, Legionella, pseudomonas,
and mycobacteria) and underlines the need for personnel responsible for dialysis in a renal or intensive
care setting to be aware of any potential effects that the disinfection of the hospital water treatment
system may have on the product water used in the preparation of dialysis fluid.
Consideration should also be given to seasonal or worst-case water quality when selecting portable
water treatment systems. The use of pretreatment to remove contaminants that might impair the
performance of the portable reverse osmosis (RO) or deionization (DI) system is recommended.
Any maintenance procedure related to the water treatment equipment, such as exchange of exhausted
components, should be performed when no patient is connected to the dialysis delivery system.
G.3.2 Backflow prevention
Unlike central water systems in free-standing dialysis clinics, acute water systems in most cases
connect directly to potable water systems. Though it is very unlikely that a portable (acute) water
treatment system would back up and contaminate the potable water system, backflow prevention is
considered a necessary and safe precaution for these systems. A backflow prevention device, such as a
pressure principle backflow assembly (PPBA) or a vacuum breaker, should be installed at the point of
connection to the potable water system. In some instances, a local code could require a “break tank”
device in place of a PPBA as the preferred method to prevent backflow. Portable water treatment
system designers should consider possible pressure drops and their effects on downstream
components when sizing such devices. Backflow prevention devices should be tested and maintained
per local plumbing codes.
Spent dialysis fluid and reject water from a reverse osmosis system unit should be discharged to drain
in a manner that minimizes the potential for contamination of the patient-care area and the dialysis
machine. An appropriate floor drain or standpipe connected to a sink drain should be utilized for this
purpose. If such a drain is not available, spent dialysis fluid and reverse osmosis reject water may be
discharged into a sink. In that circumstance, the sink should not be used for other purposes during
dialysis and care should be taken to properly clean the sink after the treatment. In all cases, there
should be an air gap at the point of discharge to prevent backflow into the dialysis machine.
G.3.3 Electrical safety
Consideration should be given to the requirements of IEC/TR 62653 with respect to wiring. The power
source used for the haemodialysis equipment should comply with the requirements of
IEC 60601-2-16.The power source used for the water treatment equipment should comply with the
requirements of IEC 60601-1.
Portable water treatment systems should comply with applicable electrical safety standards regarding
electrostatic discharge (ESD), electromagnetic compatibility (EMC), and any other electrical safety
standards as outlined in IEC 60601-1. It is critically important that electrical noise and current leakage
be minimized in both the critical care and general bedside settings. These environments are likely to
have life-sustaining equipment, such as ventilators, for which loss of function because of electrical
interference could evoke a medical emergency. An electrical safety check should be performed at least
once per year. An electrical safety check should also be performed following repairs that involve the
power supply system, including repairs to power cords and cord caps. Portable water treatment system

ISO/DIS 23500-1
component enclosures should possess a level of water resistance equal to IEC 60529 IPX 1. Continued
monitoring of the water system is necessary to maintain treatment methods consistent with safety.
G.3.4 Carbon media
Patients in the acute setting might be less capable of coping with premature chlorine/chloramine
breakthrough than stable patients being treated in an outpatient facility because of their co-morbid
conditions. Where practical, when the municipal water contains chloramine at a concentration of
1 mg/L or more, portable water treatment systems should include two carbon beds in series, which
together provide a minimum of 10 min empty bed contact time (EBCT). Historically, the requirement
for two carbon beds in series was waived for portable dialysis systems because of the impracticality of
providing these features while retaining the portability of the system. However, alternative
technologies are now available that allow portability while retaining the redundancy associated with
two carbon beds in series. Some portable reverse osmosis systems employ one granular activated
carbon (GAC) tank followed by a dense carbon block as a polisher. Alternatively, experience suggests
that two carbon block filters in series rated according to the NSF for a minimum chlorine reduction
capacity of 150 m3 (approximately 40 000 gal) at a flow rate of 7,7 l/min (2 gal/min) and an incoming
free chlorine concentration of 2 mg/L can be used. When used, carbon block filters should be intended
for chloramine removal. Block carbon filters used in this application should not compromise the feed-
water requirements specified by the manufacturer of the reverse osmosis system. Testing to
demonstrate that the level of total chlorine is less than 0,1 mg/l should be performed before each
treatment using a sample obtained from a port located between the two beds or filters. The equipment
should be allowed to operate for at least 15 min before the test sample is drawn. For prolonged
treatments, such as sustained low-efficiency dialysis (SLED), testing may be performed approximately
every 8 h providing the EBCT of the carbon media is based on a dialysate flow rate of at least
500 ml/min and the actual dialysate flow rate is not more than 300 ml/min. Where it is not possible to
provide the equivalent of a 10 min EBCT with carbon, practical alternatives include the addition of
ascorbic acid to the acid concentrate or more frequent monitoring of the product water during the
dialysis treatment.
Acute dialysis programmes should determine if the potable water supplied by the hospital or other
water supplier contains secondary disinfectants and request that they be notified in advance of the use
of secondary disinfectants, to ensure that their impact on water quality and patient safety can be
evaluated. An example of a secondary disinfection would be the installation of a chlorine-dioxide-
generating system. In the event that chlorine dioxide is present in the potable water, and in the absence
of data regarding the haemolytic potential of chlorine dioxide, it is suggested that, in the interim,
chlorine dioxide levels be measured using a commercially available test kit and that the maximum
acceptable chlorine dioxide level be set at 0,1 mg/L.
G.3.5 Ion exchange
G.3.5.1 Deionization
When deionization is the primary method of water treatment, two portable mixed-bed DI tanks in a
worker-polisher configuration are recommended. Alternatively, a cation tank and an anion tank,
followed by a mixed-bed tank, can be installed. A DI polishing cartridge may also be used following a
portable RO when the source water chemistry is such that the portable RO, on its own, will not produce
water meeting the quality requirements of Clause 3 of ISO 23500-3. Deionization systems for acute
haemodialysis should have a mechanism to prevent product water from reaching the point of use if the
specific resistivity of the water is 1 MΩ·cm or less. DI should be followed by an ultrafilter or other
bacteria- and endotoxin-reducing device to remove microbiological contaminants that originate in the
deionizer resin bed.


ISO/DIS 23500-1
G.3.5.2 Softeners
Unless otherwise specified by the manufacturer of the reverse osmosis system, water treatment
systems presented with incoming water with a hardness of >10 GPG (equivalent to 170 ppm of calcium
carbonate or 10 °dH) should have a softener or other means of preventing scale formation. At lower
levels of hardness (<10 GPG), the user may forgo the use of a softener by increasing the frequency of
membrane descaling (acid cleaning) or by periodically replacing the reverse osmosis membranes in
accordance with the instructions of the manufacturer of the reverse osmosis system. The amount of
hardness in the source water and the volume of water used will determine the frequency of membrane
cleaning and/or membrane replacement. To minimize space and weight requirements, softeners used
in portable systems should not be equipped with a brine tank. Instead, a separate regeneration station
with a brine tank and water source should be used for regenerating softeners.
Unlike central water treatment systems, regeneration devices, such as softeners, used in portable
(acute) water treatment systems do not include a means to prevent product water from reaching the
reverse osmosis system during regeneration. A portable water treatment system should not be
operated without all its pretreatment devices online. In hospital settings where there is central
softening of the potable water supply, hospital maintenance/plant staff should be made aware of the
potential impact of hard water on reverse osmosis performance and the potential hazard to
haemodialysis patients of untimely regeneration.
G.3.6 Reverse osmosis
A reverse osmosis system should demonstrate delivery of water meeting the quality requirements of
Clause 3 of ISO 23500-3; otherwise, additional treatment devices should be employed. The user may
define monitoring in terms of per cent rejection and product-water conductivity (RO). Compliance with
both monitored parameters is required since an increase in feed-water contaminants might result in
product water unsuitable for haemodialysis applications, even though the per cent rejection of the
membrane modules remains high. In this scenario, an additional water purification device should be
installed after the reverse osmosis system to meet the standard. An example of such a device would be a
deionizer polishing cartridge. The user should establish alarm limits for rejection and product-water
conductivity or total dissolved solids (TDS) specific to the acute site.
Because reverse osmosis membranes tend to fail gradually, the risk is different from exhaustion of a
deionizer where very high levels of contaminants, such as fluoride, might occur abruptly in the product
water. It is recommended that reverse osmosis systems used in an acute dialysis setting incorporate a
means of preventing the product water from reaching the patient in the event of a product-water
conductivity or rejection rate alarm. Means of preventing product water from reaching the patient could
include an automated divert to drain valve, reverse osmosis shutdown, or an immediate response by
the operator to an alarm.
G.3.7 Endotoxin-retentive filters
It has been argued that the use of endotoxin-retentive filters in a water treatment system for acute
dialysis using reverse osmosis is redundant, given that such systems are operated in a direct-feed
configuration. Endotoxin-retentive filters should be installed after the deionizer tanks in systems using
deionization. Even with reverse osmosis, it can be difficult to maintain portable water treatment
equipment and the associated dialysis machine free of microbiological contamination because the
equipment is often used intermittently and is subject to frequent connection and disconnection. For
these reasons, in-line dialysis fluid filters are recommended as a final barrier against contamination of
the dialysis fluid.
G.4 Microbial control strategies

Control of microbial contamination
Licensedisto:the single
Team ANSImost
ISO difficult aspect of maintaining portable equipment
in compliance with the requirements of ISO 23500-5. Because of the non-routine nature of acute

ISO/DIS 23500-1
dialysis, systems used for acute haemodialysis operate intermittently and may be frequently connected
and disconnected, furthermore, they may be reserved specifically for use in an acute patient care
setting. Thus, they should be designed and maintained to minimize bacterial proliferation. There should
be a continuous quality assessment performance improvement programme for monitoring the
performance and maintenance of systems used for acute dialysis. The reverse osmosis system should be
disinfected according to the manufacturer's instructions, and more frequently if the equipment is not
operated for several days or if test results demonstrate that the disinfection schedule is inadequate to
ensure compliance with the microbiological quality requirements of 4.1 of ISO 23500-5. The potential
for bacterial proliferation can be diminished by operating the equipment for at least 15 min each day,
regardless of whether or not a treatment is being performed. Another approach would be to add a
bacteriostatic agent (e.g. sodium bisulfite) to reverse osmosis systems that are to be stored. If a
bacteriostatic agent is used, the machine should be clearly labelled to indicate the presence of that
agent. Because of the potential for bacterial growth in carbon media, the manufacturer's instructions for
scheduled replacement of carbon media should be followed, even though the product water might still
meet the requirements for total chlorine. In the absence of a manufacturer's recommendation, carbon
media should be replaced at least every six months. Provided that there is a continuous flow of dialysis
fluid through the machine, dialysis machines that are used to perform multiple treatments during the
day should be cleaned following each treatment and disinfected at the end of the day according to the
manufacturer's instructions. If there is no dialysis fluid flow for more than 4 h between treatments, the
machine should be disinfected before a second treatment is performed. If the machine is not disinfected
daily, it should be disinfected before it is used. Because the line supplying water to the dialysis machine
is not disinfected when the machine is disinfected, this line should be disinfected when the reverse
osmosis system is disinfected and consideration should be given to replacing this line on a regular basis,
such as yearly. Opaque tubing is preferred for this line to reduce the likelihood of algae growth;
however, the tubing is to be approved by the manufacturer of the dialysis machine.
If individual containers of bicarbonate concentrate and pick up tubes are used, they shall be disinfected
as described in 8.2.2.4. If reusable containers are used for bicarbonate concentrate, they shall also be
disinfected as described in 8.2.2.4.
Consideration should be given to installing an in-line dialysis fluid filter in the dialysis machine, if the
machine manufacturer allows that option. If installed, the dialysis fluid filter should be maintained and
replaced according to the manufacturer's instructions.


ISO/DIS 23500-1
Bibliography
Chemical contaminants with known toxicity to dialysis patients
Aluminium
[1] ALFREY A.C. Aluminum toxicity in patients with chronic renal failure. Ther. Drug Monit. 1993; 15:
593–597.
[2] ALFREY A.C., LEGENDRE G.R., KAEHNY W.D. The dialysis encephalopathy syndrome. Possible
aluminum intoxication. N. Engl. J. Med. 1976;294: 184–188.
[3] BEREND K., VAN DER VOET G., BOER W.H. Acute aluminum encephalopathy in a dialysis center
caused by a cement mortar water distribution pipe. Kidney Int. 2001; 59: 746–753.
[4] BEREND K., KNOOPS G.J., DE WOLFF F.A. Prosecution after an outbreak of subacute aluminum
intoxication in a hemodialysis center. Leg Med (Tokyo). 2004; 6: 1–10
[5] BOHRER D., BERTAGNOLLI D.C., DE OLIVEIRA S.M., DO NASCIMENTO P.C., DE CARVALHO L.M., GARCIA S.C.
et al. Role of medication in the level of aluminium in the blood of chronic haemodialysis patients.
Nephrol. Dial. Transplant. 2009; 24: 1277–1281
[6] BUREN D.R., OLSEN S.M., BLAND L.A., ARDUINO M.J., REID M.H., JARVIS W.R. Epidemic aluminum
intoxication in hemodialysis patients traced to use of an aluminum pump. Kidney Int. 1995; 48:
469–474.
[7] CANNATA-ANDÍA J.B. Reconsidering the importance of long-term low-level aluminum exposure in
renal failure patients. Semin. Dial. 2001; 14: 5–7.
[8] CANNATA-ANDÍA J.B., FERNÁNDEZ-MARTÍN J.L. The clinical impact of aluminium overload in renal
failure. Nephrol. Dial. Transplant. 2002; 17 (Suppl 2): 9–12.
[9] CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC). Elevated serum aluminum levels in
hemodialysis patients associated with use of electric pumps. Wyoming, 2007. MMWR Morb.
Mortal. Wkly. Rep. 2008; 57: 689–691.
[10] DAVISON A.M., WALKER G.S., OLI H., LEWINS A.M. Water supply aluminium concentration, dialysis
dementia, and effect of reverse-osmosis water treatment. Lancet. 1982; 2: 785–787.
[11] FERNÁNDEZ-MARTÍN J.L., CANTEROS A., ALLES A., MASSARI P., CANNATA-ANDÍA J. Aluminum exposure
in chronic renal failure in Iberoamerica at the end of the 1990s: overview and perspectives. Am.
J. Med. Sci. 2000; 320: 96–99.
[12] HANNA-ATTISHA M, LACHANCE J, SADLER RC, CHAMPNEY SCHNEPP A.Elevated Blood Lead
Levels in Children Associated With the Flint Drinking Water Crisis: A Spatial Analysis of Risk and
Public Health Response. Am J Public Health. 2016;106:283-90
[13] HODGE K.C., DAY J.P., O'HARA M., ACKRILL P., RALSTON A.J. Critical concentrations of aluminium in
water used for dialysis. Lancet. 1981; 2: 802–803.
[14] JAFFE J.A., LIFTMAN C., GLICKMAN J.D. Frequency of elevated serum aluminum levels in adult
dialysis patients. Am. J. Kidney Dis. 2005; 46: 316–319
[15] KAISER L., SCHWARTZ K.A. Aluminum-induced anemia. Am. J. Kidney Dis. 1985; 6: 348–352.

ISO/DIS 23500-1
[16] KOVALCHIK M.T., KAEHNY W.D., HEGG A.P., JACKSON J.T., ALFREY A.C. Aluminum kinetics during
haemodialysis. J. Lab. Clin. Med. 1978; 92: 712–720.
[17] MASUYAMA J., TACHIBANA Y. Effects of water purification on renal osteodystrophy in the patients
with regular hemodialysis therapy. J Japan Soc Kidney Dis. 1984; 26: 407–416.
[18] PARKINSON I.S., WARD M.K., KERR D.N.S. Dialysis encephalopathy, bone disease and anaemia:
The aluminium intoxication syndrome during regular haemodialysis. J. Clin. Pathol. 1981; 34
:1285–1294.
[19] RAHMAN H., CHANNON S.M., PARKINSON I.S., SKILLEN A.W., WARD M.K., KERR D.N.S. Aluminum in the
dialysis fluid. Clin. Nephrol. 1985; 24 (Suppl 1): S78–S83.
[20] STUMM W., MORGAN J.J. Aquatic Chemistry: Chemical Equilibria and Rates in Natural Waters. Third
Edition, New York; John Wiley & Sons:1996,.
[21] WARD M.K., FEEST T.G., ELLIS H.A., PARKINSON I.S., KERR D.N.S. Osteomalacic dialysis
osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminium. Lancet.
1978; 1: 841–845.
Fluoride
[22] AL-WAKEEL J.S., MITWALLI A.H., HURAIB S., AL-MOHAYA S., ABU-AISHA H., CHAUDHARY A.R. et al. Serum
ionic fluoride levels in haemodialysis and continuous peritoneal dialysis patients. Nephrol. Dial.
Transplant. 1997; 12: 1420–1424
[23] ARNOW P.M., BLAND L.A., GARCIA-HOUCHINS S., FRIDKIN S., FELLNER S.K. An outbreak of fatal fluoride
intoxication in a long-term hemodialysis unit. Ann. Intern. Med. 1994; 121: 339–344
[24] BELLO V.A., GITELMAN H.J. High fluoride exposure in hemodialysis patients. Am. J. Kidney Dis.
1990; 15: 320–324
[25] BLAND L.A., ARNOW P.M., ARDUINO M.J., BOVA J., MCALLISTER S.K. Potential hazards of deionization
systems used for water purification in hemodialysis. Artif. Organs. 1996; 20: 2–7
[26] CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC). Fluoride intoxication in a dialysis unit —
Maryland. Morbidity and Mortality Weekly. 1980; 29: 134
[27] JOHNSON W.J., TAVES D.R. Exposure to excessive fluoride during haemodialysis. Kidney Int. 1974;
5: 451–454
[28] MOHAPATRA M., ANAND S., MISHRA B.K., GILES D.E., SINGH P. Review of fluoride removal from
drinking water. J. Environ. Manage. 2009; 91: 67–77
[29] NICOLAY A., BERTOCCHIO P., BARGAS E., COUDORÉ F., AL CHAHIN G., REYNIER J.P. Investigation of
fluoride elimination during a dialysis session. Clin. Chim. Acta. 1998; 275: 19–26
[30] PENMAN A.D., BRACKIN B.T., EMBREY R. Outbreak of acute fluoride poisoning caused by a fluoride
overfeed, Mississippi, 1993. Public Health Rep. 1997;112: 403–409
[31] RAO R.K.S., FRIEDMAN E.A. Fluoride and bone disease in uremia. Kidney Int. 1975; 7:125–129
[32] USUDA K., KONO K., YOSHIDA Y. The effect of hemodialysis upon serum levels of fluoride. Nephron.
1997; 75: 175–178


ISO/DIS 23500-1
Nitrates
[33] BADEN M. Methemoglobinemia as a complication of hemodialysis. Nippon Rinsho. 2004, 62 (Suppl

6): 319–323
[34] CARLSON D.J., SHAPIRO F.L. Methaemoglobin from well water nitrates. A complication of
haemodialysis. Ann. Intern. Med. 1970;73: 757–759
[35] FEWTRELL L. Drinking-water nitrate, methemoglobinemia, and global burden of disease: a

discussion. Environ. Health Perspect. 2004; 112: 1371–1374
Chlorine and chloramine
[36] CAILLEUX A., SUBRA J.F., RIBERI P., ALLAIN P. Uptake of trihalomethanes by patients during
hemodialysis. Clin. Chim. Acta. 1989; 181: 75–80
[37] CALDERARO R.V., HELLER L. Outbreak of hemolytic reactions associated with chlorine and
chloramine residuals in hemodialysis water. Rev. Saude Publica. 2001; 35: 481–486
[38] CENTERS FOR DISEASE CONTROL AND PREVENTION. Multistate outbreak of hemolysis in hemodialysis
patients — Nebraska and Maryland, 1998. JAMA. 1998; 280: 1299–1300
[39] COHN P., NAVITSKI M., MONACO A. Permanganate as a cause of apparent chloramine breakthrough
in dialysis water. Semin. Dial. 2005; 18: 351–352
[40] DE OLIVEIRA R.M., DE LOS SANTOS C.A., ANTONELLO I., D'AVILA D. Warning: an anemia outbreak due to
chloramine exposure in a clean hemodialysis unit — an issue to be revisited. Ren. Fail. 2009;
31: 81–83
[41] DE TORRES J.P., STROM J.A., JABER B.L., HENDRA K.P. Hemodialysis-associated methemoglobinemia
in acute renal failure. Am. J. Kidney Dis. 2002; 39: 1307–1309
[42] EATON J.W., KOLPIN C.F., SWOFFORD H.S. et al. Chlorinated urban water: A cause of dialysis-induced
haemolytic anemia. Science. 1973; 181: 463–464
[43] FAIREY J.L., SPEITEL G.E., KATZ L.E. Impact of natural organic matter on monochloramine reduction
by granular activated carbon: The role of porosity and electrostatic surface properties. Environ.
Sci. Technol. 2006;, 40: 4268–4273
[44] FLUCK S., MCKANE W., CAIRNS T., FAIRCHILD V., LAWRENCE A., LEE J. et al. Chloramine-induced
haemolysis presenting as erythropoietin resistance. Nephrol. Dial. Transplant. 1999; 14: 1687–
1691
[45] HUA G., RECKHOW D.A. Comparison of disinfection byproduct formation from chlorine and
alternative disinfectants. Water Res. 2007; 41: 1667–1678
[46] LOCKHART A.C. A hemodialysis patient with chloramine-induced hemolysis. A discussion of the
mechanism. N. C. Med. J. 1998; 59: 248–250
[47] PÉREZ-GARCÍA R., RODRÍGUEZ-BENÍTEZ P. Chloramine, a sneaky contaminant of dialysate. Nephrol.

Dial. Transplant. 1999; 14: 2579–2582
[48] PÉREZ-GARCÍA R., VERDE E., SANZ A., VALDERRÁBANO F. r-HuEPO resistance and dialysate chloramine
contamination in patients on hemodialysis. Nephron. 2000; 86: 222–223
[49] PYO H.-J., KWON Y.J., WLicensed

EE K.S., K WON
to: S.Y.,
Team ANSILEEISO
C.H., KIM S. et al. An outbreak of Heinz body positive
hemolytic anemia in chronic 2017-02-09patients. Korean J. Intern. Med. 1993; 8: 93–98
hemodialysis
Downloaded:

ISO/DIS 23500-1
[50] RICHARDSON D., BARTLETT C., GOUTCHER E., JONES C.H., DAVISON A.M., WILL E.J. Erythropoietin
resistance due to dialysate chloramine: the two-way traffic of solutes in haemodialysis. Nephrol.
Dial. Transplant. 1999; 14: 2625–2627
[51] WARD D.M. Chloramine removal from water used in haemodialysis. Adv. Ren. Replace. Ther. 1996;
3: 337–347
[52] WHITAKER H., NIEUWENHUIJSEN M.J., BEST N., FAWELL J., GOWERS A., ELLIOT P. Description of
trihalomethane levels in three UK water suppliers. J. Expo. Anal. Environ. Epidemiol. 2003; 13:
17–23
Lead
[53] DAVENPORT A., MURCUTT G., WHITING S. Cross-sectional audit of blood lead levels in regular
outpatient haemodialysis patients dialysing in north London. Nephrology (Carlton). 2009;
14: 476–481
[54] KATHURIA P., NAIR B., SCHRAM D., MEDLOCK R. Outbreak of lead poisoning in a hemodialysis unit. J.
Am. Soc. Nephrol. 2004, 15: 617A
[55] LIN J.L., LIN-TAN D.T., YEN T.H., HSU C.W., JENG C.C., CHEN K.H. et al. Blood lead levels, malnutrition,
inflammation and mortality in patients with diabetes treated by long-term hemodialysis. Am. J.
Kidney Dis. 2007; 51: 107–115
[56] SAMPSON B., CURTIS J.R., DAVIES S. Survey of blood lead and plasma aluminium concentrations in
patients of a renal unit. Nephrol. Dial. Transplant. 1989, 4 :. 375–381
Other trace metals
[57] D'HAESE P.C., SHAHEEN F.A., HURAIB S.O., DJUKANOVIC L., POLENAKOVIC M.H., SPASOVSKI G. et al.
Increased silicon levels in dialysis patients due to high silicon content in the drinking water,
inadequate water treatment procedures, and concentrate contamination: a multicentre study.
Nephrol. Dial. Transplant. 1995; 10: 1838–1844 [56] PETRIE J.J.B., ROW P.G. Dialysis anemia
caused by subacute zinc toxicity. Lancet. 1977, 1: 1178–1180
[58] GEORGE C.M., SMITH A.H., KALMAN D.A., STEINMAUS C.M. Reverse osmosis filter use and high arsenic
levels in private well water. Arch. Environ. Occup. Health. 2006; 61: 171–175
[59] MAYER D.R., KOSMUS W., POGGLITSCH H., MAYER D., BEYER W. Essential trace elements in humans.
Serum arsenic concentrations in hemodialysis patients in comparison to healthy controls. Biol.
Trace Elem. Res. 1993; 37: 27–38
[60] PIETRZAK I., BLADEK K., BULIKOWSKI W. Comparison of magnesium and zinc levels in blood in end
stage renal disease patients treated by hemodialysis or peritoneal dialysis. Magnes. Res. 2002;
15: 229–236
[61] TONELLI M., WIEBE N., HEMMELGARN B., KLARENBACH S., FIELD C., MANNS B. et al. Trace elements in
hemodialysis patients: a systematic review and meta-analysis. BMC Med. 2009; 7: 25
[62] ZHANG X., CORNELIS R., DE KIMPE J., MEES L., VANDERBIESEN V., DE CUBBER A. et al. Accumulation of
arsenic species in serum of patients with chronic renal disease. Clin. Chem. 1996; 42: 1231–1237
Chemicals and disinfectants


ISO/DIS 23500-1
[63] AMES R.G., STRATTON J.W. Effect of chlorine dioxide water disinfection on hematologic and serum
parameters of renal dialysis patients. Arch. Environ. Health. 1987;42: 280–285
[64] BEK M.J., LAULE S., REICHERT-JÜNGER C., HOLTKAMP R., WIESNER M., KEYL C. Methemoglobinemia in
critically ill patients during extended hemodialysis and simultaneous disinfection of the hospital
water supply. Crit. Care. 2009; 13: 162
[65] CHANG C.Y., HSIEH Y.H., HSU S.S., HU P.Y., WANG K.H. The formation of disinfection by-products in
water treated with chlorine dioxide. J. Hazard. Mater. 2000; 79: 89–102
[66] DAVIDOVITS M., BARAK A., CLEPER R., KRAUSE I., GAMZO Z., EISENSTEIN B. Methaemoglobinaemia and
haemolysis associated with hydrogen peroxide in a paediatric haemodialysis centre: a warning
note. Nephrol. Dial. Transplant. 2003; 18: 2354–2358
[67] GOPAL K., TRIPATHY S.S., BERSILLON J.L., DUBEY S.P. Chlorination byproducts, their toxicodynamics
and removal from drinking water. J. Hazard. Mater. 2007;140: 1–6
[68] GORDON S.M., BLAND L.A., ALEXANDER S.R., NEWMAN H.F., ARDUINO M.J., JARVIS W.R. Hemolysis
associated with hydrogen peroxide at a pediatric dialysis center. Am. J. Nephrol. 1990; 10: 123–
127
[69] NEWBIGGING N., PEEL W., BELL E., ISLES C. Unexpected cyanosis in a hemodialysis patient – did
someone add hydrogen peroxide to the dialysis water? NDT Plus. 2009; 2: 158–160
[70] RICHARDSON S.D., THRUSTON A.D. JR., RAV-ACHA C., GROISMAN L., POPILEVSKY I., JURAEV O. et al.
Tribromopyrrole, brominated acids, and other disinfection byproducts produced by disinfection
of drinking water rich in bromide. Environ. Sci. Technol. 2003; 37: 3782–3789
[71] SMITH R.P., WILLHITE C.C. Chlorine dioxide and hemodialysis. Regul. Toxicol. Pharmacol. 1990;
11: 42–62
Organic contaminants in the water
[72] DA P., GOLDONI M., TAGLIAVINI D., DAVID S. et al. Organic contamination in dialysis water:
trichloroethylene as a model compound. Nephrol. Dial. Transplant. 2006; 21: 1618–1625
Microbiological contaminants
[73] ARVANITIDOU M., SPAIA S., KATSINAS C., PANGIDIS P., CONSTANTINIDIS T., KATSOUYANNOPOULOS V. et al.
Microbiological quality of water and dialysate in all haemodialysis centres of Greece. Nephrol.
Dial. Transplant. 1998; 13: 949–954
[74] BERNICK J.J., PORT F.K., FAVERO M.S., BROWN D.G. Bacterial and endotoxin permeability of
haemodialysis membranes. Kidney Int. 1979; 16: 491–496
[75] BLAND L.A., RIDGEWAY M.R., AGUERO S.M., CARSON L.A., FAVERO M.S. Potential bacteriologic and
endotoxin hazards associated with liquid bicarbonate concentrate. Trans. Am. Soc. Artif. Intern.
Organs. 1987;33: 542–545
[76] BOLAN G., REINGOLD A.L., CARSON L.A., SILCOX V.A., WOODLEY C.L., HAYES P.S. et al. Infections with
Mycobacterium chelonei in patients receiving dialysis and using reprocessed dialyzers. J. Infect.
Dis. 1985;152: 1013–1019
[77] BOMMER J., BECKER K.P., URBASCHEK R., RITZ E., URBASCHEK B. No evidence for endotoxin transfer
across high-flux polysulfone membranes. Clin. Nephrol. 1987;27: 278–282

ISO/DIS 23500-1
[78] BOMMER J., BECKER K.P., URBASCHEK R. Potential transfer of endotoxin across high-flux polysulfone
membranes. J. Am. Soc. Nephrol. 1996; 7: 883–888
[79] CAPPELLI G., BALLESTRI M., PERRONE S., CIUFFREDA A., INGUAGGIATO P., ALBERTAZZI A. Biofilms invade
nephrology: effects in hemodialysis. Blood Purif. 2000; 18: 224–230
[80] CLARK T., HUHN G.D., CONOVER C., CALI S., ARDUINO M.J., HAJJEH R. et al. Outbreak of bloodstream
infection with the mold Phialemonium among patients receiving dialysis at a hemodialysis unit.
Infect. Control Hosp. Epidemiol. 2006; 27: 1164–1170
[81] DASGUPTA M.K. Biofilms and infection in dialysis patients. Semin. Dial. 2002; 15: 338–346
[82] DAWIDS S.G., VEJLSGAARD R. Bacteriological and clinical evaluation of different dialysis fluid
delivery systems. Acta Med. Scand. 1976; 199: 151–155
[83] EBBEN J.P., HIRSCH D.N., LUEHMANN D.A., COLLINS A.J., KESHAVIAH P.R. Microbiologic contamination
of liquid bicarbonate concentrate for haemodialysis. Trans. Am. Soc. Artif. Intern. Organs.
1987;33: 269–273
[84] EVANS R.C., HOLMES C.J. In vitro study of the transfer of cytokine-inducing substances across
selected high-flux haemodialysis membranes. Blood Purif. 1991; 9: 92–101
[85] FAVERO M.S., PETERSON N.J., BOYER K.M., CARSON L.A., BOND W.W. Microbial contamination of renal
dialysis systems and associated risks. Trans. Am. Soc. Artif. Intern. Organs. 1974; 20: 175–183
[86] GAZENFELDT-GAZIT E., ELIAHOU H.E. Endotoxin antibodies in patients on maintenance

haemodialysis. Isr. J. Med. Sci. 1969;5: 1032–1036
[87] HANDELMAN G.J., MEGDAL P.A., HANDELMAN S.K. Bacterial, DNA in water and dialysate: detection
and significance for patient outcomes. Blood Purif. 2009; 27: 81–85
[88] HENRIE M., FORD C., ANDERSEN M., STROUP E., DIAZ-BUXO J., MADSEN B. et al. In vitro assessment of
dialysis membrane as an endotoxin transfer barrier: geometry, morphology, and permeability.
Artif. Organs. 2008; 32: 701–710
[89] KIDD E.E. Bacterial contamination of dialyzing fluid of artificial kidney. BMJ. 1964; 1: 880–882
[90] KLEIN E., PASS T., HARDING G.B., WRIGHT R., MILLION C. Microbial and endotoxin contamination in
water and dialysis fluid in the central United States. Artif. Organs. 1990; 14: 85–94
[91] LAUDE-SHARP M., CAROFF M., SIMARD L., PUSINERI C., KAZATCHKINE M.D., HAEFFNER-CAVAILLON N.
Induction of IL-1 during hemodialysis: Transmembrane passage of intact endotoxin (LPS).
Kidney Int. 1990; 38: 1089–1094
[92] LONNEMANN G., BEHME T.C., LENZER B., FLOEGE J., SCHULZE M., COLTON C.K. et al. Permeability of
dialyzer membranes to TNFα-inducing substances derived from water bacteria. Kidney Int.
1992;42: 61–68
[93] LONNEMANN G., SERENI L., LEMKE H.D., TETTA C. Pyrogen retention by highly permeable synthetic
membranes during in vitro dialysis. Artif. Organs. 2001;25: 951–960
[95] LOWRY P.W., BECK-SAGUE C.M., BLAND L.A., AGUERO S.M., ARDUINO M.J., MINUTH A.N. et al.
Mycobacterium chelonae infection among patients receiving high-flux dialysis in a haemodialysis
clinic in California. J. Infect. Dis. 1990; 161: 85–90
[96] MASAKANE I., Licensed

TSUBAKIHARA Y., A
to: Team ANSI T., WATANABE Y., ISEKI K. Bacteriological qualities of dialysis
KIBAISO
fluid in Japan as of 31 December 2006. Ther. Apher. Dial. 2008; 12: 457–463

ISO/DIS 23500-1
[97] MASAKANE I., TAKEMOTO Y., NAKAI S., TSUBAKIHARA Y., AKIBA T., WATANABE Y. et al. Bacteriological
water quality in the central dialysis fluid delivery system from the survey of the Japanese Society
for Dialysis Therapy. Blood Purif. 2009;27 (Suppl 1): 11–16
[98] MOORE I., BHAT R., HOENICH N.A., KILNER A.J., PRABHU M., ORR K.E. et al. A microbiological survey of
bicarbonate-based replacement circuits in continuous veno-venous hemofiltration. Crit. Care
Med. 2009; 37: 496–500
[99] OIE S., KAMIYA A., YONEDA I., UCHIYAMA K., TSUCHIDA M., TAKAI K. et al. Microbial contamination of
dialysate amd its prevention in haemodialysis units. J. Hosp. Infect. 2003; 54: 115–119
[100] PIRES-GONÇALVES R.H., SARTORI F.G., MONTANARI L.B., ZAIA J.E., MELHEM M.S., MENDES-GIANNINI M.J.
et al. Occurrence of fungi in water used at a haemodialysis centre. Lett. Appl. Microbiol.
2008;46: 542–547
[101] RAO P.V., GUPTA N., BHASKAR A.S., JAYARAJ R. Toxins and bioactive compounds from cyanobacteria
and their implications on human health. J. Environ. Biol. 2002; 23: 215–222
[102] RAO C.Y., PACHUCKI C., CALI S., SANTHIRAJ M., KRANKOSKI K.L., NOBLE-WANG J.A. et al. Contaminated
product water as the source of Phialemonium curvatum bloodstream infection among patients
undergoing hemodialysis. Infect. Control Hosp. Epidemiol. 2009; 30: 840–847
[103] SCHINDLER R., BECK W., DEPPISCH R., AUSSIEKER M., WILDE A., GÖHL H. et al. Short bacterial DNA
fragments: Detection in dialysate and induction of cytokines. J. Am. Soc. Nephrol. 2004; 15: 3207–
3214
[104] SELENIC D., ALVARDO-RAMY F., ARDUINO M.J., HOLT S., CARDINALI F., BLOUNT B. et al. Epidemic
parenteral exposure to volatile sulfur-containing compounds at a hemodialysis center. Infect.
Control Hosp. Epidemiol. 2004;25: 256–261
[105] SOARES R.M., YUAN M., SERVAITES J.C., DELGADO A., MAGALHÃES V.F., HILBORN E.D. et al. Sublethal
exposure from microcystins to renal insufficiency patients in Rio de Janeiro, Brazil. Environ.
Toxicol. 2006;21: 95–103
[106] TEEHAN G.S., GUO D., PERIANAYAGAM M.C., BALAKRISHNAN V.S., PEREIRAV B.J., JABER B.L. Reprocessed
(high-flux) Polyflux dialyzers resist trans-membrane endotoxin passage and attenuate
inflammatory markers. Blood Purif. 2004; 22: 329–337
[107] UREÑA P., HERBELIN A., ZINGRAFF J., LAIR M., MAN N.K., DESCAMPS-LATSCHA B. et al. Permeability of
cellulosic and non-cellulosic membranes to endotoxin subunits and cytokine production during
in-vitro haemodialysis. Nephrol. Dial. Transplant. 1992; 7: 16–28
[108] VANHOLDER R., VAN HAECKE E., VEYS N., RINGOIR S. Endotoxin transfer through dialysis membranes:
Small- versus large-pore membranes. Nephrol. Dial. Transplant. 1992;7: 333–339
[109] WANG S.A., LEVINE R.B., CARSON L.A., ARDUINO M.J., KILLAR T., GRILLO F.G. et al. An outbreak of gram-
negative bacteremia in hemodialysis patients traced to hemodialysis machine waste drain ports.
Infect. Control Hosp. Epidemiol. 1999; 20: 746–751
[110] YAMAGAMI S., ADACHI T., SUGIMURA T., WADA S., KISHIMOTO T., MAEKAWA M. et al. Detection of
endotoxin antibody in long-term dialysis patients. Int. J. Artif. Organs. 1990; 13: 205–210
Microbiological methods and quality control
[111] ARDUINO M.J., BLAND L.A., AGUERO S.M., CARSON L., RIDGEWAY M., FAVERO M.S. Comparison of
microbiologic assay methods forTeam
Licensed to: ANSI ISO fluids. J. Clin. Microbiol. 1991; 29: 592–594
hemodialysis

ISO/DIS 23500-1
[112] BLAND L.A. Microbiological and endotoxin assays of haemodialysis fluids. Adv. Ren. Replace. Ther.
1995; 2: 70–79
[113] BOSSOLA M, SANGUINETTI M, SCRIBANO D, ZUPPI C, et.al. Circulating bacterial-derived DNA

fragments and markers of inflammation in chronic hemodialysis patients. Clin J Am Soc Nephrol.
2009; 4:379-85
[114] CAPELLI G., SERENI L., SCIALOJA G., MORSELLI M., PERRONE S., CIUFFREDA A. et al. Effects of biofilm
formation on hemodialysis monitor disinfection. Nephrol. Dial. Transplant. 2003; 18: 2105–2111
[115] COSTERTON J.W., CHENG K.J., GEESEY G.G., LADD T.I., NICKEL J.C., DASGUPTA M. et al. Bacterial
biofilms in nature and disease. Annu. Rev. Microbiol. 1987; 41: 435–464
[116] DONLAN R.M., COSTERTON J.W. Biofilms: Survival mechanisms of clinically relevant
microorganisms. Clin. Microbiol. Rev. 2002; 15: 167–193
[117] FLEMMING H.C. Biofouling in water systems – cases, causes and countermeasures. Appl. Microbiol.
Biotechnol. 2002; 59: 629–640
[118] FLEMMING H.-C., WINGENDER J. The biofilm matrix. Nat. Rev. Microbiol. 2010; 8: 623–633
[119] GROMILA M., GASĆO J., BUSQUELS A., GIL J., BERNABEU R., BUADES J.M. et al. Identification of culturable
bacteria present in hemodialysis water and fluid. FEMS Microbiol. Ecol. 2005; 52: 101–114
[120] GROMILA M., GASĆO J., GIL J., BERNABEU R., IÑIGO V., LALUCAT J. A molecular microbial ecology
approach to studying hemodialysis water and fluid. Kidney Int. 2006; 70: 1567–1576
[121] HAMMES F., MEYLAN S., SALHI E., KÖSTER O., EGLI T., VON GUNTEN U. Formation of assimilable
organic carbon (AOC) and specific natural organic matter (NOM) fractions during ozonation of
phytoplankton. Water Res. 2007; 41: 1447–1454
[123] JACOBS L., DEBRUYN E.E., CLOETE T.E. Spectrophotometric monitoring of biofouling. Water Sci.
Technol. 1996; 34: 533–540
[124] KAWANISHI H., AKIBA T., MASAKANE I., TOMO T., MINESHIMA M., KAWASAKI T. et al. Standard on
microbiological management of fluids for hemodialysis and related therapies by the Japanese
Society for Dialysis Therapy 2008. Ther. Apher. Dial. 2009; 13: 161–166
[125] KHARAZMI A., GIWERCMAN B., HØIBY N. Robbins device in biofilm research. Methods Enzymol. 1999;
310: 207–215
[126] LEDEBO I., NYSTRAND R. Defining the microbiological quality of dialysis fluid. Artif. Organs. 1999;
23: 37–43
[127] LIBMAN V. Use of Reynolds number as a criteria for design of high-purity water systems.
Ultrapure Water. 2006; 23: 26–34
[128] MALTAIS JB, MEYER KB, FOSTER MC. Comparison of techniques for culture of dialysis water and
fluid. Hemodial Int. 2016 Sep 5. doi: 10.1111/hdi.12477. [Epub ahead of print]
[129] MARION-FEREY K., LEID J.G., BOUVIER G., PASMORE M., HUSSON G., VILAGINES R. Endotoxin level
measurement in hemodialysis biofilm using “the whole blood assay”. Artif. Organs. 2005;
29: 475–481
[130] NYSTRAND R. Official recommendations for quality of fluids in dialysis – the need for
standardisation. J. Ren.to:
Licensed Care. 2009;
Team ANSI 35:
ISO74–81

ISO/DIS 23500-1
[131] NYSTRAND R. Microbiology of water and fluids for hemodialysis. J. Chin. Med. Assoc. 2008;
71: 223–229
[132] PASS T., WRIGHT R., SHARP B., HARDING G.B. Culture of dialysis fluids on nutrient-rich media for
short periods at elevated temperatures underestimates microbial contamination. Blood Purif.
1996; 14: 136–145
[133] PENNE E.L., VISSER L., VAN DEN DORPEL M.A., VAN DER WEERD N.C., MAZAIRAC A.H., VAN JAARSVELD
B.C. et al. Microbiological quality and quality control of purified water and ultrapure dialysis
fluids for online hemodiafiltration in routine clinical practice. Kidney Int. 2009; 76: 665–672
[134] PUNAKABUTRA N., NUNTHAPISUD P., PISITKUN T., TIRANATHANAGUL K., TUNGSANGA K., EIAM-ONG S.
Comparison of different culture methods on bacterial recovery in hemodialysis fluids. J. Med.
Assoc. Thai. 2004; 87: 1361–1367
[135] REASONER D.J., GELDREICH E.E. A new medium for the enumeration and subculture of bacteria
from potable water. Appl. Environ. Microbiol. 1985; 49: 1–7
[136] SMEETS E., KOOMAN J., VAN DER SANDE F., STOBBERINGH E., FREDERIK P., CLAESSENS P. et al.
Prevention of biofilm formation in dialysis water treatment systems. Kidney Int. 2003; 63: 1574–
1576
[137] SOINI S.M., KOSKINEN K.T., VILENIUS M.J., PUHAKKA J.A. Effects of fluid-flow velocity and water
quality on planktonic and sessile microbial growth in water hydraulic system. Water Res.
2002;36: 3812–3820
[138] VAN DER LINDE K., LIM B.T., RONDEEL J.M.M., ANTONISSEN L.P., DE JONG G.M. Improved bacteriological
surveillance of haemodialysis fluids: A comparison between tryptic soy agar and Reasoner's 2A
media. Nephrol. Dial. Transplant. 1999;14: 2433–2437
Ultrapure fluids
[139] ARIZONO K., NOMURA K., MOTOYAMA T., MATSUSHITA Y., MATSUOKA K., MIYAZU R. et al. Use of
ultrapure dialysate in reduction of inflammation during hemodialysis. Blood Purif. 2004;
22 (Suppl 2): 26–29
[140] BAZ M., DURAND C., RAGON A., JABER K., ANDRIEU D., MERZOUK T. et al. Using ultrapure water in
haemodialysis delays carpal tunnel syndrome. Int. J. Artif. Organs. 1991; 14: 681–685
[141] BOMMER J., JABER B.L. Ultrapure dialysate: facts and myths. Semin. Dial. 2006; 19: 115–119
[142] CANAU B., BOSC J.Y., LERAY H., STEC F. Microbiological purity of dialysate for on-line substitution
fluid preparation. Nephrol. Dial. Transplant. 2000; 15 (Suppl 2): 21–30
[143] GO I., TAKEMOTO Y., TSUCHIDA K., SUGIMURA K., NAKATANI T. The effect of ultrapure dialysate on
improving renal anemia. Osaka City Med. J. 2007; 53: 17–23
[144] GLORIEUX G, NEIRYNCK N, VEYS N, VANHOLDER R Dialysis water and fluid purity: more than
endotoxin. Nephrol Dial Transplant. 2012;27:4010-21
[145 ] HASEGAWA T, NAKAI S, MASAKANE I, WATANABE Y, ISEKI K, TSUBAKIHARA Y, AKIZAWA T.

Dialysis fluid endotoxin level and mortality in maintenance hemodialysis: a nationwide cohort
study. Am J Kidney Dis. 2015;65:899-904.
[146] HONDA H., SUZUKI H., HOSAKA N., HIRAI Y., SANADA D., NAKAMURA M. et al. Ultrapure dialysate
influences serum myeloperoxidase levels
Licensed to: Team ISOlipid metabolism. Blood Purif. 2009; 28: 29–39
ANSIand

ISO/DIS 23500-1
[147] IZUHARA Y., MIYATA T., SAITO K., ISHIKAWA N., KAKUTA T., NANGAKU M. et al. Ultrapure dialysate
decreases plasma pentosidine, a marker of “carbonyl stress”. Am. J. Kidney Dis. 2004; 43: 1024–
1029
[148] KLEOPHAS W., HAASTERT B., BACKUS G., HILGERS P., WESTHOFF A., VAN ENDERT G. Long-term
experience with an ultrapure individual dialysis fluid with a batch type machine. Nephrol. Dial.
Transplant. 1998; 13: 3118–3125
[149] LAMAS J.M., ALONSO M.K., SASTRE F., GARCÍA-TRÍO G., SAAVEDRA J., PALOMARES L. Ultrapure dialysate
and inflammatory response in haemodialysis evaluated by darbepoetin requirements – a
randomized study. Nephrol. Dial. Transplant. 2006; 21: 2851–2858
[150] LEDEBO I. Online preparation of solutions for dialysis: Practical aspects versus safety and
regulations. J. Am. Soc. Nephrol. 2002; 13: S78–S83
[151] LEDEBO I. Ultrapure dialysis fluid: Improving conventional and daily dialysis. Hemodial. Int.
2004; 8: 159–166
[152] LEDEBO I. Ultrapure dialysis fluid – direct and indirect benefits in dialysis therapy. Blood Purif.
2004; 22 (Suppl 2): 20–25
[153] LEDEBO I. Purification of dialysis fluid: historical background and perspective. Blood Purif. 2009;
27 (Suppl 1): 17–19
[154] MATSUHASHI N., YOSHIOKA T. Endotoxin-free dialysis fluid improves response to erythropoietin in
haemodialysis patients. Nephron. 2002; 92: 601–604
[155] MCKANE W., CHANDNA S.M., TATTERSALL J.E., GREENWOOD R.N., FARRINGTON K. Identical decline of
residual renal function in high-flux biocompatible haemodialysis and CAPD. Kidney Int.
2002;61: 256–265
[156] OUSEPH R., JONES S., DHANANJAYA N., WARD R.A. Use of ultrafiltered dialysate is associated with
improvements in hemodialysis-associated morbidity in patients treated with reused dialyzers.
Nephrol. Dial. Transplant. 2007; 22: 2269–2275
[157] RAHMATI M.A., HOMEL P., HOENICH N.A., LEVIN R., KAYSEN G.A., LEVIN N.W. The role of improved
water quality on inflammatory markers in patients undergoing regular dialysis. Int. J. Artif.
Organs. 2004; 27: 723–727
[158] SCHIFFL H., FISCHER R., LANG S.M., MANGEL E. Clinical manifestations of AB-amyloidosis: Effects of
biocompatibility and flux. Nephrol. Dial. Transplant. 2000; 15: 840–845
[159] SCHIFFL H., LANG S.M., STRATAKIS D., FISCHER R. Effects of ultrapure dialysis fluid on nutritional
status and inflammatory parameters. Nephrol. Dial. Transplant. 2001; 16: 1863–1869
[160] SCHIFFL H., LANG S.M., FISCHER R. Ultrapure dialysis fluid slows loss of residual renal function in
new dialysis patients. Nephrol. Dial. Transplant. 2002; 17: 1814–1818
[161] SCHINDLER R., LONNEMANN G., SCHÄFFER J., SHALDON S., KOCH K.M., KRAUTZIG S. The effect of
ultrafiltered dialysis fluid on the cellular content of interleukin-1 receptor antagonist in patients
on chronic haemodialysis. Nephron. 1994; 68: 229–233
[162] SITTER T., BERGNER A., SCHIFFL H. Dialysis fluid related cytokine induction and response to
recombinant human erythropoietin in haemodialysis patients. Nephrol. Dial. Transplant. 2000;
15: 1207–1211

ISO/DIS 23500-1
[163] STENVINKEL P., HEIMBÜRGER O., PAULTRE F., DICZFALUSY U., WANG T., BERGLUND L. et al. Strong
association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.
Kidney Int. 1999; 55: 1899–1911
[164] TIELEMANS C., HUSSON C., SCHURMANS T., GASTALDELLO K., MADHOUN P., DELVILLE J.P. et al. Effects of
ultrapure and non-sterile dialysis fluid on the inflammatory response during in vitro
hemodialysis. Kidney Int. 1996; 49: 236–243
Standards, guidelines, pharmacopoeias, and other publications
[165] IEC 60529:2001, Degrees of protection provided by enclosures (IP Code)
[166] IEC 60601-1:2012, Medical electrical equipment — Part 1: General requirements for basic safety
and essential performance
[167] IEC 60601-2-16:2012, Medical electrical equipment — Part 2-16: Particular requirements for
basic safety and essential performance of haemodialysis, haemodiafiltration and haemofiltration
equipment
[168] ASTM International D4516-00:2010, Standard Practice for Standardizing Reverse Osmosis
Performance Data
[169] BOCCATO C, EVANS D, LUCENA R , VIENKEN J .Good Dialysis practice: Water and Dialysis fluids–
A quality management guide. 2015 Pabst Science Publishers – Lengerich Germany:.
[170] KAWANISHI H., MASAKANE I., TOMO T. The new standard of fluids for hemodialysis in Japan. Blood
Purif. 2009; 27 (Suppl 1): 5–11
[171] KAWANISHI H., AKIBA T., MASAKANE I., TOMO T., MINESHIMA M., KAWASAKI T. et al. Standard on
microbiological management of fluids for hemodialysis and related therapies by the Japanese
Society for Dialysis Therapy 2008. Ther. Apher. Dial. 2009; 13: 161–166
[172] KESHAVIAH, P, LUEHMANN, D, SHAPIRO, F, COMTY, CM. Investigation of the Risks and Hazards
Associated with Hemodialysis Systems. Technical report, Contract #223 78 5046. Silver Spring
(MD): US Dept. of Health and Human Services, Public Health Service/Food and Drug
Administration/Bureau of Medical Devices, June 1980 [168] US ENVIRONMENTAL PROTECTION
AGENCY. Safe Drinking Water Act, 1996 (Public law 104-182). Washington (DC): EPA, 1996. (See
also National Primary and Secondary Drinking Water Regulations. U.S. Environmental Protection
Agency, Office of Ground Water and Drinking Water
[ 173 ] PAYNE G.M Dialysis water and dialysate recommendations; A user guide. AAMI, Arlington
Va.2014
[174] US FOOD AND DRUG ADMINISTRATION. Guidance for the Content of Premarket Notifications for
Water Purification Components and Systems for Haemodialysis. U.S. Food and Drug
Administration, Rockville, MD, 1997
[175] UNITED STATES PHARMACOPOEIAL CONVENTION, INC. United States Pharmacopoeia – National
Formulary (USP-26-NF21). Rockville (MD): United States Pharmacopeial Convention Inc., 2003
[176] EUROPEAN RENAL ASSOCIATION – EUROPEAN DIALYSIS AND TRANSPLANT ASSOCIATION. European Best
Practice Guidelines for Haemodialysis (Part 1), Section IV: Dialysis Fluid Purity. Nephrol. Dial.
Transplant. 2002, 17 (Suppl. 7): 45–62
[177] European Pharmacopoeia. European Pharmacopoeia Commission, Strasbourg, Eighth Edition,

2014 Licensed to: Team ANSI ISO

ISO/DIS 23500-1
[178] WARD R.A. Worldwide guidelines for the preparation and quality management of dialysis fluid
and their implementation. Blood Purif. 2009; 27 (Suppl 1): 2–4
[179] United States Pharmacopeia, General Information [USP 38]. Rockville, MD: United States
Pharmacopeial Convention, Inc. <1231> Water for Pharmaceutical Purposes; p. 19


Aami Iso CDV-1

Uploaded by

Copyright:

Available Formats

Aami Iso CDV-1

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Aami Iso CDV-1

Uploaded by

Copyright:

Available Formats

DOCUMENT: AAMI/ISO/CDV-1 (ISO/DIS) 23500-1, Guidance for the

preparation and quality management of fluids for

Public Review Draft Designation: AAMI/ISO/CDV-1 23500-1

COMMENT DEADLINE: 1 May 2017

Acrobat (pdf) http://www.aami.org/standards/downloadables/aamirevf.pdf

Please be sure to identify the document by designation: 'AAMI/ISO/CDV-1 23500-1,

© 2017. All rights reserved.

ISO/TC 150/SC 2 Secretariat: ANSI

Guidance for the preparation and quality management of

THIS DOCUMENT IS A DRAFT CIRCULATED

COPYRIGHT PROTECTED DOCUMENT

Licensed to: Team ANSI ISO

ISO (the International Organization for Standardization) is a worldwide federation of national

Licensed to: Team ANSI ISO

© ISO 2017 – All rights reserved iii

Licensed to: Team ANSI ISO

Licensed to: Team ANSI ISO

© ISO 2017 – All rights reserved v

Guidance for the preparation and quality management of fluids

For the purposes of this International Standard, dialysis fluid includes:

The scope of this International Standard includes

© ISO 2017 – All rights reserved 2

3 Terms and definitions

Note 1 to entry: Acetate concentrate may contain glucose.

Note 3 to entry: Acetate concentrate is used as a single concentrate.

Note 2 to entry: Acid concentrate may contain glucose.

© ISO 2017 – All rights reserved 3

Note 1 to entry: Sodium bicarbonate is also known as sodium hydrogen carbonate.

Note 2 to entry: Some bicarbonate concentrates also contain sodium chloride.

© ISO 2017 – All rights reserved 4

Note 1 to entry: The three forms of free chlorine exist in equilibrium.

© ISO 2017 – All rights reserved 5

Note 1 to entry: EBCT (min) is calculated from the following formula:

V is the volume of the particle bed, in cubic metres (m3);

Note 2 to entry: Endotoxin-retentive filters

© ISO 2017 – All rights reserved 6

Note 2 to entry: There is no dialysis fluid stream in haemofiltration.

© ISO 2017 – All rights reserved 7

© ISO 2017 – All rights reserved 8

© ISO 2017 – All rights reserved 9

4 Summary of the quality requirements of ISO 23500-4 (previously ISO 13958),

4.1 Dialysis water

4.1.2 Chemical contaminants in dialysis water

NOTE The maximum allowable levels

© ISO 2017 – All rights reserved 10

Tables 1 and 2 are reproduced from ISO 23500-3

Contaminant Maximum concentration (mg/L)

Contaminants with documented toxicity in haemodialysis

Licensed to: Team ANSI ISO

© ISO 2017 – All rights reserved 11

Table 2 — Maximum allowable levels of other trace elements in dialysis watera

Contaminant Maximum concentration (mg/L)

4.1.3 Organic Carbon, pesticides and other chemicals

4.1.4 Microbiological contaminants in dialysis water

© ISO 2017 – All rights reserved 12

Table 3 is adapted from ISO 23500-3.

Contaminant Maximum allowable level Typical action levelb

4.2 Requirements for concentrate

4.2.2 Water used to prepare concentrate