ISO 23500:2011

INTERNATIONAL ISO
STANDARD 23500
First edition
2011-05-15


Guidance for the preparation and quality
management of fluids for haemodialysis
and related therapies
Directives concernant la préparation et le management de la qualité des
fluides d'hémodialyse et de thérapies annexes





Reference number
ISO 23500:2011(E)
©
ISO 2011

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ISO 23500:2011(E)

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©  ISO 2011
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ISO 23500:2011(E)
Contents Page
Foreword .v
Introduction.vi
1 Scope.1
1.1 General .1
1.2 Inclusions.1
1.3 Exclusions.1
2 Normative references.2
3 Terms and definitions .2
4 Summary of quality requirements of ISO 13958, ISO 13959 and ISO 11663 .9
4.1 Dialysis water.9
4.2 Requirements for concentrate .11
4.3 Requirements for dialysis fluid.11
4.4 Record retention.12
5 Critical aspects of system design .13
5.1 Technical aspects.13
5.2 Microbiological aspects.13
6 Validation of system performance.14
6.1 Validation Plan.14
6.2 Installation and Operational Qualification .15
6.3 Performance Qualification.16
6.4 Routine monitoring and revalidation.16
7 Quality management .17
7.1 General .17
7.2 Monitoring of fluid quality .17
7.3 Monitoring of water treatment equipment .18
7.4 Monitoring of water storage and distribution.21
7.5 Monitoring of concentrate preparation .22
7.6 Monitoring of concentrate distribution .23
7.7 Monitoring of dialysis fluid proportioning.23
8 Strategies for microbiological control .23
8.1 General .23
8.2 Disinfection .24
8.3 Microbiological monitoring methods .26
9 Environment.28
10 Personnel .29
Annex A (informative) Rationale for the development and provisions of this
International Standard .30
Annex B (informative) Equipment .34
Annex C (informative) Monitoring guidelines for water treatment equipment, distribution systems
and dialysis fluid .50
Annex D (informative) Strategies for microbiological control.55
Annex E (informative) Validation.59
Annex F (informative) Special considerations for home haemodialysis .62
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ISO 23500:2011(E)
Annex G (informative) Special considerations for acute haemodialysis .68
Bibliography .72

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ISO 23500:2011(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through
ISO technical committees. Each member body interested in a subject for which a technical committee has
been established has the right to be represented on that committee. International organizations, governmental
and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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.
ISO 23500 was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee SC 2,
Cardiovascular implants and extracorporeal systems.
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ISO 23500:2011(E)
Introduction
This International Standard was developed by Working Group 5 of ISO/TC 150/SC 2. The Working Group's
objective was 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.
Quality requirements for the water and concentrates used to prepare dialysis fluid, and for that dialysis fluid,
are provided in ISO 13959, ISO 13958 and ISO 11663, respectively. This International Standard does not
address clinical issues that might be associated with inappropriate usage of the water, concentrates or final
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 and concentrate 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 26722.
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 standard, the auxiliary verb:
⎯ “shall” means that compliance with a requirement or a test is mandatory for compliance with this
standard;
⎯ “should” means that compliance with a requirement or a test is recommended but is not mandatory for
compliance with this standard;
⎯ “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 of haemodialysis patients and healthcare
professionals involved in the routine care of haemodialysis patients. 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 should help protect 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.
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INTERNATIONAL STANDARD ISO 23500:2011(E)

Guidance for the preparation and quality management of fluids
for haemodialysis and related therapies
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 the dialysis fluid once the equipment used
in its preparation has been delivered and installed. For the purposes of this International Standard, the dialysis
fluid includes water used for the preparation of dialysis fluid and substitution fluid, water used for the
preparation of concentrates at the user's facility, as well as concentrates and the final dialysis fluid and
substitution fluid.
Included in the scope of this International Standard are
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 is commonly prepared and distributed using the same equipment
as the water used to reprocess dialysers, water used to reprocess dialysers is also covered by this International Standard.
1.3 Exclusions
Excluded from the scope of this International Standard are sorbent-based dialysis fluid regeneration systems
that regenerate and recirculate small volumes of dialysis fluid, systems for continuous renal replacement
therapy that use prepackaged solutions, and systems and solutions for peritoneal dialysis.
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ISO 23500:2011(E)
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 13958:2009, Concentrates for haemodialysis and related therapies
ISO 13959:2009, Water for haemodialysis and related therapies
ISO 11663:2009, Quality of dialysis fluid for haemodialysis and related therapies
ISO 26722:2009, 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 Acetate concentrate may contain glucose.
NOTE 2 Acetate is used to provide buffer in place of sodium bicarbonate.
NOTE 3 Acetate concentrate is used as a single concentrate.
3.2
acid concentrate
A-concentrate
acidified concentrated mixture of salts which, when diluted with dialysis water and bicarbonate concentrate,
yields dialysis fluid for use in dialysis
NOTE 1 The term “acid” refers to the small amount of acid (usually acetic acid) that is included in the concentrate.
NOTE 2 Acid concentrate may contain glucose.
NOTE 3 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
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ISO 23500:2011(E)
3.5
bicarbonate concentrate
B-concentrate
concentrated preparation of sodium bicarbonate that, when diluted with dialysis water and acid concentrate,
makes dialysis fluid used for dialysis
NOTE 1 Sodium bicarbonate is also known as sodium hydrogen carbonate.
NOTE 2 Some bicarbonate concentrates also contain sodium chloride.
NOTE 3 Bicarbonate concentrate may be in the form of a liquid or a dry powder.
NOTE 4 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 The matrix, a slimy material secreted by the cells, protects the bacteria from antibiotics and chemical
disinfectants.
NOTE 2 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.
3.7
bleach
solution of sodium hypochlorite normally used for household cleaning and disinfection
3.8
bulk delivery
delivery of large volume containers of concentrate to a dialysis facility
NOTE 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.
3.9
central concentrate system
system that prepares and/or stores concentrate at a central point for subsequent distribution to its points of
use
3.10
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
3.11
chlorine, combined
chlorine that is chemically combined, such as in chloramine compounds
NOTE 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.
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ISO 23500:2011(E)
3.12
chlorine, free
chlorine present in water as dissolved molecular chlorine (Cl ), hypochlorous acid (HOCl) and hypochlorite ion
2
−
(OCl )
NOTE The three forms of free chlorine exist in equilibrium.
3.13
chlorine, total
sum of free and combined chlorine
NOTE 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.
3.14
colony-forming unit
CFU
measure of bacterial or fungal cell numbers that theoretically arise from a single cell when grown on solid
media
NOTE Colonies can also form from groups of organisms when they occur in aggregates.
3.15
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 The solution produced by the concentrate generator is used by the dialysis machine to make the final dialysis
fluid delivered to the dialyser.
3.16
dialysis fluid
dialysate
dialysis solution
aqueous fluid containing electrolytes and, usually, buffer and glucose, which is intended to exchange solutes
with blood during haemodialysis
NOTE 1 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” may be used in place of dialysis fluid.
NOTE 2 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 Dialysis fluid does not include prepackaged parenteral fluids used in some renal replacement therapies, such
as haemodiafiltration and haemofiltration.
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ISO 23500:2011(E)
3.17
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 The term includes reservoirs, conduits, proportioning devices for the dialysis fluid, and monitors and
associated alarms and controls assembled as a system for the purposes listed above.
NOTE 2 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 Dialysis fluid delivery systems are also known as proportioning systems and dialysis fluid supply systems.
3.18
dialysis water
water that has been treated to meet the requirements of ISO 13959 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
3.19
disinfection
destruction of pathogenic and other kinds of microorganisms by thermal or chemical means
NOTE Disinfection is a less lethal process than sterilization, because it destroys most recognized pathogenic
microorganisms but does not necessarily destroy all microbial forms.
3.20
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 EBCT (min) is calculated from the following equation:
EBCT = V/Q
where
3
V is the volume of the particle bed, in cubic metres (m );
3
Q is the flow rate of water through the bed, in cubic metres per minute (m /min).
NOTE 2 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.
3.21
endotoxin
major component of the outer cell wall of gram-negative bacteria
NOTE 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 (3.37)].
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ISO 23500:2011(E)
3.22
endotoxin-retentive filter
ETRF
membrane filter used to remove endotoxins and microorganisms from dialysis water or dialysis fluid
NOTE 1 The performance of an endotoxin-retentive filter is usually expressed as the logarithmic reduction value (LRV),
defined as log (inlet concentration)/(outlet concentration).
10
NOTE 2 Endotoxin-retentive filters may be configured in a cross-flow or dead-end mode. Some endotoxin-retentive
filters also remove endotoxins by adsorption.
3.23
endotoxin units
EU
units assayed by the Limulus amoebocyte lysate (LAL) test when testing for endotoxins
NOTE 1 Because activity of endotoxins depends on the bacteria from which they are derived, their activity is referred to
a standard endotoxin.
NOTE 2 In some countries, endotoxin concentrations are expressed in international units (IU). Since the harmonization
of endotoxin assays, EU and IU are equivalent.
3.24
feed water
water supplied to a water treatment system or an individual component of a water treatment system
3.25
germicide
agent that kills microorganisms
3.26
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 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).
3.27
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 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.
3.28
haemofiltration
form of renal replacement therapy in which waste solutes are removed from blood by convection
NOTE 1 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 (post-dilution haemofiltration), or a combination of the two (mixed dilution haemofiltration).
NOTE 2 There is no dialysis fluid stream in haemofiltration.
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ISO 23500:2011(E)
3.29
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
3.30
Limulus amoebocyte lysate test
LAL test
assay used to detect endotoxin
NOTE The detection method uses the chemical response of an extract from blood cells of the horseshoe crab
(Limulus polyphemus) to endotoxins.
3.31
manufacturer
entity that designs, manufactures, fabricates, assembles or processes a finished device
NOTE Manufacturers include, but are 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. The term does not cover preparation of concentrates from prepackaged 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.
3.32
microbiological contamination
contamination with any form of microorganism (e.g. bacteria, yeast, fungi and algae) or with the by-p
...