Water for haemodialysis and related therapies

ISO 13959:2009 specifies minimum requirements for water to be used in the preparation of concentrates, dialysis fluids for haemodialysis, haemodiafiltration and haemofiltration and for the reprocessing of haemodialysers. ISO 13959:2009 does not address the operation of water treatment equipment nor the final mixing of treated water with concentrates to produce the dialysis fluids used in such therapies. That operation is the sole responsibility of dialysis professionals. ISO 13959:2009 does not apply to dialysis fluid regenerating systems.

Eau pour hémodialyse et thérapies apparentées

General Information

Status
Withdrawn
Publication Date
14-Apr-2009
Withdrawal Date
14-Apr-2009
Current Stage
9599 - Withdrawal of International Standard
Start Date
17-Mar-2014
Completion Date
17-Mar-2014
Ref Project

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INTERNATIONAL ISO
STANDARD 13959
Second edition
2009-04-15
Water for haemodialysis and related
therapies
Eau pour hémodialyse et thérapies apparentées
Reference number
ISO 13959:2009(E)
ISO 2009
---------------------- Page: 1 ----------------------
ISO 13959:2009(E)
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ii © ISO 2009 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 13959:2009(E)
Contents Page

Foreword ............................................................................................................................................................iv

Introduction.........................................................................................................................................................v

1 Scope......................................................................................................................................................1

2 Terms and definitions ...........................................................................................................................1

3 Dialysis water requirements.................................................................................................................3

3.1 Dialysis water verification and monitoring.........................................................................................3

3.2 Microbiological requirements ..............................................................................................................3

3.3 Chemical contaminants ........................................................................................................................3

4 Tests for compliance with microbiological and chemical requirements.........................................4

4.1 Microbiology of dialysis water.............................................................................................................4

4.2 Chemical contaminants test methods.................................................................................................4

Annex A (informative) Rationale for the development and provisions of this International

Standard .................................................................................................................................................7

Bibliography......................................................................................................................................................11

© ISO 2009 – All rights reserved iii
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ISO 13959:2009(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 13959 was prepared by Technical Committee ISO/TC 150, Implants for surgery, Subcommittee SC 2,

Cardiovascular implants and extracorporeal systems.

This second edition cancels and replaces the first edition (ISO 13959:2002), which has been technically

revised.
iv © ISO 2009 – All rights reserved
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ISO 13959:2009(E)
Introduction

Assurance of adequate water quality is one of the most important aspects of ensuring a safe and effective

delivery of haemodialysis, haemodiafiltration or haemofiltration.

This International Standard contains minimum requirements, chemical and microbiological, for the water to be

used for preparation of dialysis fluids, concentrates and for the re-use of haemodialysers and the necessary

steps to assure compliance with those requirements. Haemodialysis and haemodiafiltration can expose the

patient to more than 500 l of water per week across the semi-permeable membrane of the haemodialyser or

haemodiafilter. Healthy individuals seldom have a weekly oral intake above 12 l. This over 40-fold increase in

exposure requires control and monitoring of water quality to avoid excesses of known or suspected harmful

substances. Since knowledge of potential injury from trace elements and contaminants of microbiological

origin over long periods is still growing and techniques for treating drinking water are continuously developed,

this International Standard will evolve and be refined accordingly. The physiological effects attributable to the

presence of organic contaminants in dialysis water are important areas for research. At the time this

International Standard was published it was premature to specify threshold values for organic contaminants

below those published by various regulatory authorities.

The final dialysis fluid is produced from concentrates or salts manufactured, packaged and labelled according

to ISO 13958 mixed with water meeting the requirements of this International Standard. Operation of water

treatment equipment and haemodialysis systems, including ongoing monitoring of the quality of water used to

prepare dialysis fluids, and handling of concentrates and salts are the responsibility of the haemodialysis

facility and are addressed in ISO 23500. Haemodialysis professionals make choices about the various

applications (haemodialysis, haemodiafiltration, haemofiltration) and should understand the risks of each and

the requirements for safety for fluids used for each.

The verbal forms used in this International Standard conform to usage described in Annex H of the

ISO/IEC Directives, Part 2. 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; and

⎯ “may” is used to describe a permissible way to achieve compliance with a requirement or test.

This International Standard is directed towards manufacturers and providers of water treatment systems and

also to haemodialysis facilities.
© ISO 2009 – All rights reserved v
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INTERNATIONAL STANDARD ISO 13959:2009(E)
Water for haemodialysis and related therapies
1 Scope

This International Standard specifies minimum requirements for water to be used in the preparation of

concentrates, dialysis fluids for haemodialysis, haemodiafiltration and haemofiltration and for the reprocessing

of haemodialysers.

This International Standard does not address the operation of water treatment equipment nor the final mixing

of treated water with concentrates to produce the dialysis fluids used in such therapies. That operation is the

sole responsibility of dialysis professionals.

This International Standard does not apply to dialysis fluid regenerating systems.

2 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
2.1
action level

concentration of a contaminant at which steps should be taken to interrupt the trend toward higher,

unacceptable levels
2.2
chlorine, total
sum of free and combined chlorine

NOTE chlorine can exist in water as dissolved molecular chlorine (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.
2.3
colony-forming unit
CFU

measure of bacterial or fungal cell numbers that theoretically arise from a single cell or group of cells when

grown on solid media
NOTE Colonies can form from groups of organisms when they occur in aggregates.
2.4
dialysis fluid

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 document to mean the fluid made from dialysis water and

concentrates which is delivered to the dialyser by the dialysis fluid delivery system. Such phrases as “dialysate,” “dialysis

solution,” or “dialysing fluid” can 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.”
© ISO 2009 – All rights reserved 1
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ISO 13959:2009(E)

NOTE 3 Dialysis fluid does not include prepackaged parenteral fluids used in some renal replacement therapies, such

as haemodiafiltration and hemofiltration.
2.5
dialysis water

water that has been treated to meet the requirements of this International Standard 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

2.6
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 (2.12)].
2.7
endotoxin units

units assayed by the Limulus amoebocyte lysate (LAL) test when testing for endotoxins

NOTE 1 Because the 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 1983

harmonization of endotoxin assays, EU and IU are equivalent.
2.8
feed water

water supplied to a water treatment system or an individual component of a water treatment system

2.9
Limulus amoebocyte lysate test
LAL
assay used to detect endotoxin

NOTE The detection method uses the chemical response of the horseshoe crab (Limulus polyphemus) to endotoxin.

2.10
microbial
referring to microscopic organisms, bacteria, fungi and so forth
2.11
microbial 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)
2.12
pyrogen
fever-producing substance

NOTE Pyrogens are most often lipopolysaccharides of gram-negative bacterial origin [see also endotoxin (2.6)].

2 © ISO 2009 – All rights reserved
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ISO 13959:2009(E)
3 Dialysis water requirements
3.1 Dialysis water verification and monitoring

The quality of the dialysis water, as specified in 3.2 and 3.3, shall be verified upon installation of a water

treatment system. Monitoring of the dialysis water quality shall be carried out thereafter.

3.2 Microbiological requirements

Total viable microbial counts in dialysis water shall be less than 100 CFU/ml, or lower if required by national

legislation or regulations. An action level shall be set based on knowledge of the microbial dynamics of the

system. Typically, the action level will be 50 % of the maximum allowable level.

Endotoxin content in dialysis water shall be less than 0,25 EU/ml, or lower if required by national legislation or

regulations. An action level shall be set, typically at 50 % of the maximum allowable level.

NOTE See Clause A.1 for a history of these requirements.
3.3 Chemical contaminants

Dialysis water shall not contain chemicals at concentrations in excess of those listed in Tables 1 and 2, or as

required by national legislation or regulations.
NOTE See Clause A.2 for explanation of values supplied.

Where the dialysis water is used for the reprocessing of haemodialysers, (cleaning, testing and mixing of

disinfectants) the user is cautioned that the dialysis water shall meet the requirements of this International

Standard. The dialysis water should be measured at the input to the dialyser reprocessing equipment.

Table 1 — Maximum allowable levels of toxic chemicals and
dialysis fluid electrolytes in dialysis water
Maximum concentration
Contaminant
mg/l
Contaminants with documented toxicity in haemodialysis
Aluminium 0,01
Total chlorine 0,1
Copper 0,1
Fluoride 0,2
Lead 0,005
Nitrate (as N) 2
Sulfate 100
Zinc 0,1
Electrolytes normally included in dialysis fluid
Calcium 2 (0,05 mmol/l)
Magnesium 4 (0,15 mmol/l)
Potassium 8 (0,2 mmol/l)
Sodium 70 (3,0 mmol/l)

The physician has the ultimate responsibility for ensuring the quality of water used for dialysis.

Unless otherwise noted.
© ISO 2009 – All rights reserved 3
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ISO 13959:2009(E)
Table 2 — Maximum allowable levels of trace elements in dialysis water
Maximum concentration
Contaminant
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
4 Tests for compliance with microbiological and chemical requirements
4.1 Microbiology of dialysis water

Samples shall be collected where a dialysis machine connects to the water distribution loop, from a sample

point in the distal segment of the loop or where water enters a mixing tank.

Samples shall be assayed within 4 h of collection, or be immediately refrigerated and assayed within 24 h of

collection on a regular schedule. Total viable counts (standard plate counts) shall be obtained using

conventional microbiological assay procedures (pour plate, spread plate, membrane filter techniques).

Membrane filtration is the preferred method for this test. The calibrated loop technique is not accepted.

Culture media should be tryptone glucose extract agar (TGEA), Reasoners 2A (R2A), or other media that can

be demonstrated to provide equivalent results. Blood agar and chocolate agar shall not be used. Incubation

temperatures of 17 °C to 23 °C and incubation time of 168 h (7 d) are recommended. Other incubation times

and temperatures may be used if it can be demonstrated that they provide equivalent results. No method will

give a total microbial count.

The presence of endotoxins shall be determined by the Limulus amoebocyte lysate (LAL) test. Other test

methods may be used if it can be demonstrated that they provide equivalent results.

4.2 Chemical contaminants test methods

Compliance with the requirements listed in Table 1 can be shown by using chemical analysis methods

[3]

referenced by the American Public Health Association , methods referenced by the U.S. Environmental

[46]

Protection Agency , methods referenced in applicable pharmacopoeia, and/or other equivalent validated

analytical methods.

Compliance with the requirements listed in Table 2 can be shown in one of three ways.

⎯ Where such testing is available, the individual contaminants in Table 2 can be determined using chemical

[3]

analysis methods referenced by the American Public Health Association , methods referenced by the

[46]

U.S. Environmental Protection Agency , and/or other equivalent analytical methods.

⎯ Where testing for the individual trace elements listed in Table 2 is not available, and the source water can

be demonstrated to meet the standards for potable water as defined by the WHO or local regulations, an

analysis for total heavy metals can be used with a maximum allowable level of 0,1 mg/l.

4 © ISO 2009 – All rights reserved
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ISO 13959:2009(E)

⎯ If neither of these options is available, compliance with the requirements of Table 2 can be met by using

water that can be demonstrated to meet the potable water requirements of the WHO (see Reference [51])

or local regulations and a reverse osmosis system with a rejection of > 90 % based on conductivity,

resistivity or TDS. Samples shall be collected at the end of the water purification cascade or at the most

distal point in each water distribution loop.
Table 3 lists tests for each contaminant, along with an appropriate reference.
Table 3 — Analytical tests for chemical contaminants
Contaminant Test name Reference, test number
Aluminium Atomic absorption (electrothermal) American Public Health Assn, #3113
Antimony Atomic absorption (platform) US EPA, #200.9
Arsenic Atomic absorption (gaseous hydride) American Public Health Assn, #3114
Barium Atomic absorption (electrothermal) American Public Health Assn, #3113
Beryllium Atomic absorption (platform) US EPA, #200.9
Cadmium Atomic absorption (electrothermal) American Public Health Assn, #3113
EDTA titrimetric method or
atomic absorption (direct aspiration) or
American Public Health Assn, #3500-Ca D
Calcium ion specific electrode or
American Public Health Assn, #3111B
inductively-coupled plasma spectrometry
(direct aspiration)
DPD ferrous titrimetric method or American Public Health Assn, #4500-Cl F
Total chlorine
DPD colorimetric method American Public Health Assn, #4500-Cl G
Chromium Atomic absorption (electrothermal) American Public Health Assn, #3113
Atomic absorption (direct aspiration) or American Public Health Assn, #3111
Copper
neocuproine method American Public Health Assn, #3500-Cu D
Ion selective electrode method or

sodium 2-(parasulfophenylazo)-1,8-dihydroxy- American Public Health Assn, #4500-F C

Fluoride
3,6-naphthalenedisulfonate American Public Health Assn, #4500-F D
(SPADNS) method
Lead Atomic absorption (electrothermal) American Public Health Assn, #3113
Atomic absorption (direct aspiration) or

Magnesium inductively-coupled plasma spectrometry American Public Health Assn, #3111

(direct aspiration)
Flameless cold vapour technique
Mercury American Public Health Assn, #3112
(atomic absorption)
Nitrate Cadmium reduction method American Public Health Assn, #4500-NO E
Atomic absorption (direct aspiration) or
flame photometric method or American Public Health Assn, #3111
American Public Health Assn, #3500-K D
Potassium ion specific electrode or
inductively-coupled plasma spectrometry American Public Health Assn, #3500-K E
(direct aspiration)
© ISO 2009 – All rights reserved 5
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ISO 13959:2009(E)
Table 3 (continued)
Contaminant Test name Reference, test number
Atomic absorption (gaseous hydride) or American Public Health Assn, #3114
Selenium
atomic absorption (electrothermal) American Public Health Assn, #3113
Silver Atomic absorption (electrothermal) American Public Health Assn, #3113
Atomic absorption (direct aspiration) or
flame photometric method or
American Public Health Assn, #3111
Sodium ion specific electrode or
American Public Health Assn, #3500-Na D
inductively-coupled plasma spectrometry
(direct aspiration)
Sulfate Turbidimetric method American Public Health Assn, #4500-SO E
Thallium Atomic absorption (platform) US EPA, 200.9
European Pharmacopoeia, 2.4.8
Total heavy metals Colorimetric
US Pharmacopoeia, <231>
Atomic absorption (direct aspiration) or American Public Health Assn, #3111
Zinc
dithizone method American Public Health Assn, #3500-Zn D
6 © ISO 2009 – All rights reserved
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ISO 13959:2009(E)
Annex A
(informative)
Rationale for the development and provisions of
this International Standard
A.1 Microbiology of dialysis water

NOTE The information in this clause is intended to give the reader a historical prospective of how the microbial limits

were developed for this document.

Originally, it was considered that the water used to prepare dialysis fluid need not be sterile. However, several

studies had demonstrated that the attack rates of pyrogenic reactions were related directly to the number of

[13] [17] [18]

bacteria in dialysis fluid (Dawids and Vejlsgaard ; Favero et al. ; Favero et al. ). These studies

provided the rationale for setting the maximum level of bacteria in dialysis water at 200 CFU/ml in the original

AAMI standard for water quality published in 1982. Later, the European community chose to use a slightly

lower level of 100 CFU/ml as their bacterial limit for dialysis water and that value has been adopted in this

International Standard. Because 7 d can elapse between sampling water for the determination of microbial

contamination and receiving results, and because bacterial proliferation can be rapid, action levels for

microbial counts were introduced into this International Standard. These action levels allow the user to initiate

corrective action before levels exceed the maximum levels established by this International Standard.

Several groups of investigators have shown convincingly that pyrogenic reactions are caused by

lipopolysaccharides or endotoxins that are associated with gram-negative bacteria. Furthermore, gram-

negative water bacteria have been shown to be capable of multiplying rapidly in dialysis water prepared by

distillation, deionization, reverse osmosis and softening. Dialysis fluid made with this water likewise provides a

very good growth medium for these types of bacteria. Even at low levels of bacterial contamination, pyrogenic

reactions have been reported when the source of endotoxin was exogenous to the dialysis system (i.e.

[20]

present in the community water supply) (Hindman et al. ). Consequently, it was thought prudent to impose

an upper limit on the endotoxin content of dialysis water. A level of 2 EU/ml was chosen by AAMI as the upper

limit for endotoxin, since compliance with that level could be easily achieved with contemporary water

treatment systems using reverse osmosis, ultrafiltration or both. At the same time the European community

chose to use an upper limit of 0,25 EU/ml for endotoxin. During revision of this International Standard in 2008,

the 0,25 EU/ml limit was included as the upper limit for endotoxin in dialysis water.

A.2 Chemical contaminants test methods

NOTE This historical review is provided to help the reader understand the considerations given to the chemical

contamination of water used for dialysis treatments.

Contaminants identified as needing restrictions on the allowable level that can be present in water for dialysis,

are divided into three groups for the purposes of this International Standard. The first group includes

chemicals shown to cause toxicity in dialysis patients. These chemicals include fluoride, aluminium,

chloramines, sulfate, nitrate, copper, zinc and lead. Chlorine is included here because of its potential toxicity.

Toxicity of fluoride in dialysis patients at the levels usually associated with fluoridated water, 1 mg/l, is

questionable. In the absence of a consensus on fluoride's role in uraemic bone disease, it was initially thought

[39]

prudent to restrict the fluoride level of dialysis fluid (Rao and Friedman ). Subsequently, illness in all of

eight dialysis patients, with the death of one patient, was reported as a result of accidental overfluoridation of

[11]

a municipal water supply (CDC ). Fluoride levels of up to 50 mg/l were found in water used for dialysis that

was treated only with a water softener. Probably these illnesses would have been less severe, if not prevented,

if the dialysis water had been treated with deionization or reverse osmosis. In one case, where deionizers

[5]

were allowed to exhaust, 12 of 15 patients became acutely ill from fluoride intoxication (Arnow et al. ). Three

© ISO 2009 – All rights reserved 7
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ISO 13959:2009(E)

of the patients died from ventricular fibrillation. Fluoride concentrations in the water used to prepare the

dialysis fluid were as high as 22,5 mg/l.

The suggested maximum aluminium level has been specified to prevent accumulation of this toxic metal in the

[29] [32]

patient (Kovalchik et al. ; Masuyama and Tachibana ). Aluminium is particularly likely to increase

suddenly to high levels caused by changes in the method of water treatment to include aluminium-containing

compounds. As with fluoride, water treatment would provide a measure of safety even if the aluminium levels

should increase dramatically between chemical tests of the dialysis water.
[14]

The toxicity of chloramines is undisputed (Eaton et al. ). Although the role of free chlorine in oxidative blood

damage is unclear, its high oxidation potential and ability to form chloramines suggests the avoidance of

highly chlorinated water in preparation of dialysis fluid. Chlorine can be present in water as both free chlorine

and chlorine in chemically combined forms. Chloramines are a form of chemically combined chlorine.

Determining the level of chloramines typically involves measuring both total chlorine and free chlorine and

assigning the difference in concentrations to chloramines. During revision of this International Standard in

2008, the working group chose to simplify this situation by setting a maximum allowable level for total chlorine

at the same value used previously for chloramine (0,1 mg/l), thus permitting a single test to be used.

Sulfate at levels above 200 mg/l has been related to nausea, vomiting and metabolic acidosis. The symptoms

[12]

disappear when the level remains below 100 mg/l (Comty et al. ). Nitrates are a marker for bacterial

[10]

contamination and fertilizer runoff, and have caused methaemoglobinaemia (Carlson and Shapiro ). They

should, therefore, be permitted only at very low levels. Both copper and zinc toxicity have been demonstrated

when these substances are present in dialysis fluid at levels below those permitted by the U.S. Environmental

[21] [35]

Protection Agency (EPA) standard (Ivanovich et al. ; Petrie and Row ). Hence, a lower level has been

chosen.

Dialysis fluid lead levels of 52 µg/l to 65 µg/l have been associated with abdominal pain and muscle weakness

[24]

(Kathuria et al. ). There is no evidence of lead toxicity when lead levels in water or dialysis fluid are below

5 µg/l.

The second group of substances addressed in 3.3 and Table 1 consists of physiological substances that can

adversely affect the patient if present in the dialysis fluid in excessive amounts. Calcium, magnesium,

potassium and sodium are examples of these substances.

Of the physiological substances that can be harmful when present in excessive amounts, calcium has been

reduced from the 10 mg/l originally selected to 2 mg/l on the basis of the critical role of calcium in bone

disorders associated with renal disease. A level of 10 mg/l would have allowed a potential 20 % error in

dialysis fluid calcium, whereas a level of 2 mg/l reduces that error risk to less than 5 %.

[47]

The third group of chemical contaminants addressed in 3.3 is based on a U.S. EPA . When the AAMI

[53] [47]

standard ANSI/AAMI RD5 was initially developed, the U.S. EPAs included barium, selenium, chromium,

silver, cadmium, mercury and arsenic. Selenium and chromium levels were set at the “no-transfer” level (Klein

[27]

et al. ). The “no-transfer” level was chosen even though it is above the U.S. EPA limit for selenium and

28 % of the U.S. EPA limit for chromium, because a restriction is not needed below the level at which there is

no passage from the dialysis fluid to the blood. The standard specifie
...

DRAFT INTERNATIONAL STANDARD ISO/DIS 13959
ISO/TC 150/SC 2 Secretariat: ANSI
Voting begins on: Voting terminates on:
2008-02-11 2008-07-11

INTERNATIONAL ORGANIZATION FOR STANDARDIZATION • МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ • ORGANISATION INTERNATIONALE DE NORMALISATION

Water for haemodialysis and related therapies
Eau pour hémodialyse et thérapies apparentées
[Revision of first edition (ISO 13959:2002)]
ICS 11.040.40

In accordance with the provisions of Council Resolution 15/1993 this document is circulated in

the English language only.

Conformément aux dispositions de la Résolution du Conseil 15/1993, ce document est distribué

en version anglaise seulement.

To expedite distribution, this document is circulated as received from the committee secretariat.

ISO Central Secretariat work of editing and text composition will be undertaken at publication

stage.

Pour accélérer la distribution, le présent document est distribué tel qu'il est parvenu du

secrétariat du comité. Le travail de rédaction et de composition de texte sera effectué au

Secrétariat central de l'ISO au stade de publication.

THIS DOCUMENT IS A DRAFT CIRCULATED FOR COMMENT AND APPROVAL. IT IS 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, 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 NATIONAL REGULATIONS.

RECIPIENTS OF THIS DRAFT ARE INVITED TO SUBMIT, WITH THEIR COMMENTS, NOTIFICATION OF ANY RELEVANT PATENT RIGHTS OF WHICH

THEY ARE AWARE AND TO PROVIDE SUPPORTING DOCUMENTATION.
International Organization for Standardization, 2008
---------------------- Page: 1 ----------------------
ISO/DIS 13959
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ii ISO 2008 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/DIS 13959
30 Contents Page

31 Foreword......................................................................................................................................................... iv

32 Introduction .................................................................................................................................................... iv

33 1 Scope................................................................................................................................................... 1

34 2 Definitions........................................................................................................................................... 1

35 3 Dialysis water requirements .............................................................................................................. 3

36 3.1 Dialysis water verification and monitoring....................................................................................... 3

37 3.2 Microbiological requirements............................................................................................................ 3

38 3.3 Chemical contaminants ..................................................................................................................... 3

39 4 Tests for compliance with chemical and microbiological requirements........................................ 4

40 4.1 Microbiology of dialysis water........................................................................................................... 4

41 4.2 Chemical contaminants test methods .............................................................................................. 4

42 Annex A (informative) Rationale for the development and provisions of this standard .......................... 8

43 A.1 Water microbiology ............................................................................................................................ 8

44 A.2 Maximum level of chemical contaminants .......................................................................................9

47 Tables

48 1 Maximum allowable levels of toxic chemicals and dialysis fluid electrolytes in

49 dialysis water ..................................................................................................................................... 3

51 2 Maximum allowable levels of trace elements in dialysis water....................................................... 6

53 3 Analytical tests for chemical contaminants ..................................................................................... 6

55 Bibliography .................................................................................................................................................. 13

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56 Foreword

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

58 standards bodies (ISO member bodies). The work of preparing International Standards is normally

59 carried out through ISO technical committees. Each member body interested in a subject for which a

60 technical committee has been established has the right to be represented on that committee.

61 International organizations, governmental and non-governmental, in liaison with ISO, also take part in

62 the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all

63 matters of electrotechnical standardization.

64 International Standards are drafted in accordance with the rules given in the ISO/IEC Directives,

65 Part 2.

66 The main task of technical committees is to prepare International Standards. Draft International

67 Standards adopted by the technical committees are circulated to the member bodies for voting.

68 Publication as an International Standard requires approval by at least 75 % of the member bodies

69 casting a vote.

70 Attention is drawn to the possibility that some of the elements of this document may be the subject of

71 patent rights. ISO shall not be held responsible for identifying any or all such patent rights.

72 ISO 13959 was prepared by Technical Committee ISO/TC 150, Subcommittee SC 2, Cardiovascular

73 implants and extracorporeal systems.

74 This second edition cancels and replaces the first edition, which has been technically revised.

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75 Introduction

76 Assurance of adequate water quality is one of the most important aspects of ensuring a safe and

77 effective delivery of haemodialysis, haemodiafiltration or haemofiltration.

78 This International Standard contains minimum requirements, chemical and microbiological, for the

79 water to be used for preparation of dialysis fluids, concentrates, and for the reuse of haemodialyzers

80 and the necessary steps to assure compliance with those requirements. Haemodialysis and

81 haemodiafiltration can expose the patient to more than 500 litres of water per week across the semi-

82 permeable membrane of the haemodialyser or haemodiafilter. Healthy individuals seldom have a

83 weekly oral intake above 12 litres. This near 40-fold increase in exposure requires control and

84 monitoring of water quality to avoid excesses of known or suspected harmful substances. Since

85 knowledge of potential injury from trace elements and contaminants of microbiological origin over long

86 periods is still growing and techniques for treating drinking water are continuously developed, this

87 International Standard will evolve and be refined accordingly. The physiological effects attributable to

88 the presence of organic contaminants in dialysis water are important areas for research. At the time

89 this International Standard was published it was premature to specify threshold values for organic

90 contaminants below those published by various regulatory authorities.

91 The final dialysis fluid is produced from concentrates or salts manufactured, packaged, and labelled

92 according to ISO 13958, Concentrates for haemodialysis and related therapies, mixed with water

93 meeting the requirements of this standard. Operation of water treatment equipment and

94 haemodialysis systems, including ongoing monitoring of the quality of water used to prepare dialysis

95 fluids, and handling of concentrates and salts are the responsibility of the haemodialysis facility or

96 addressed in other ISO standards. Haemodialysis professionals make choices about the various

97 applications (haemodialysis, haemodiafiltration, haemofiltration) and should understand the risks of

98 each and the requirements for safety for fluids used for each.

99 This International Standard is directed towards manufacturers and providers of water treatment

100 systems and also to haemodialysis facilities.
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101
Water for haemodialysis and related therapies
102 1 Scope

103 This International Standard specifies minimum requirements for water to be used in the preparation of

104 concentrates, dialysis fluids for haemodialysis, haemodiafiltration and haemofiltration and for the

105 reprocessing of haemodialysers.

106 This standard does not address the operation of water treatment equipment nor the final mixing of

107 treated water with concentrates to produce the dialysis fluids used in such therapies. That operation is

108 the sole responsibility of dialysis professionals.

109 This International Standard does not apply to dialysis fluid regenerating systems.

110 2 Terms and definitions

111 For the purposes of this document, the following terms and definitions apply.

112 2.1
113 action level

114 concentration of a contaminant at which steps should be taken to interrupt the trend toward higher,

115 unacceptable levels
116 2.2
117 chlorine, total
118 sum of free and combined chlorine

119 NOTE chlorine can exist in water as dissolved molecular chlorine (free chlorine) or in chemically combined forms

120 (combined chlorine). Where chloramine is used to disinfect water supplies, chloramine is usually the principal

121 component of combined chlorine.
122 2.3
123 CFU
124 colony-forming unit

125 organism capable of replicating to form a distinct, visible colony on a culture plate

126 NOTE In practice, a colony can be formed by a group of organisms.
127 2.4
128 dialysis fluid

129 aqueous fluid containing electrolytes, buffer, and, usually, glucose, which is intended to exchange

130 solutes with blood during haemodialysis

131 NOTE 1 The words “dialysis fluid” are used throughout this document to mean the fluid made from dialysis water

132 and concentrates that is delivered to the dialyser by the dialysis fluid supply system. Such phrases as “dialysate”

133 or “dialysis solution” can be used in place of dialysis fluid.
134 NOTE 2 In some cases, glucose is also known as dextrose.

135 NOTE 3 Dialysis fluid does not include prepackaged parental fluids used in haemodiafiltration.

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136 2.5
137 dialysis water

138 water that has been treated to meet the requirements of this standard and which is suitable for use in

139 haemodialysis applications, including the preparation of dialysis fluid, reprocessing of dialysers,

140 preparation of concentrates and preparation of substitution fluid for online convective therapies

141 2.6
142 endotoxin
143 major component of the outer cell wall of gram-negative bacteria

144 NOTE Endotoxins are lipopolysaccharides, which consist of a polysaccharide chain covalently bound to lipid A.

145 Endotoxins can acutely activate both humoral and cellular host defences, leading to a syndrome characterized by

146 fever, shaking, chills, hypotension, multiple organ failure, and even death if allowed to enter the circulation in a

147 sufficient dose (see also pyrogen).
148 2.7
149 EU
150 endotoxin units

151 units assayed by the Limulus amoebocyte lysate (LAL) method when testing for endotoxins

152 NOTE 1 Because the activity of endotoxins depends on the bacteria from which they are derived, their activity is

153 referred to a standard endotoxin.

154 NOTE 2 In some countries, endotoxin concentrations are expressed in international units (IU). Since the 1983

155 harmonization of endotoxin assays, EU and IU are equivalent.
156 2.8
157 feed water

158 water supplied to a water treatment system or an individual component of the system

159 2.9
160 LAL
161 Limulus amoebocyte lysate test
162 assay used to detect endotoxin

163 NOTE The detection method uses the chemical specific response of the horseshoe crab (Limulus polyphemus)

164 to endotoxin.
165 2.10
166 microbial
167 referring to microscopic organisms, bacteria, fungi, and so forth
168 2.11
169 microbial contamination

170 contamination with any form of microorganism (e.g. bacteria, yeast, fungi, and algae) or with the by-

171 products of living or dead organisms such as endotoxins, exotoxins, and microcystin (derived from

172 blue-green algae)
173 2.12
174 pyrogen
175 fever-producing substance.

176 NOTE Pyrogens are most often lipopolysaccharides of gram-negative bacterial origin (see also endotoxin).

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177 3 Dialysis water requirements
178 3.1 Dialysis water verification and monitoring

179 The quality of the dialysis water, as specified below, shall be verified upon installation of a water

180 treatment system. Monitoring of the dialysis water quality shall be carried out thereafter.

181 3.2 Microbiological requirements

182 Total viable microbial counts in dialysis water shall be less than 100 CFU/ml, or as required by national

183 legislation or similar. An action level shall be set based on knowledge of the microbial dynamics of the

184 system. Typically, the action level will be 50 % of the maximum allowable level.

185 Endotoxin content in dialysis water shall be less than 0,25 EU/mL, or as required by national legislation or

186 similar.
187 NOTE See A.1 for a history of these requirements.
188 3.3 Chemical contaminants

189 Dialysis water shall not contain chemicals at concentrations in excess of those in Tables 1 and 2, or

190 as required by national legislation or similar.
191 NOTE See A.2 for explanation of values supplied.

192 Where the dialysis water is used for the reprocessing of haemodialysers, (cleaning, testing and mixing

193 of disinfectants) the user is cautioned that the dialysis water shall meet this standard. The dialysis

194 water should be measured at the input to the dialyser reprocessing equipment.

195 Table 1 — Maximum allowable levels of toxic chemicals and dialysis fluid electrolytes in

196 dialysis water
Contaminant Maximum Concentration (mg/L)
Contaminants with documented toxicity in haemodialysis
Aluminium 0,01
Total chlorine 0,1
Copper 0,1
Fluoride 0,2
Lead 0,005
Nitrate (as N) 2
Sulphate 100
Zinc 0,1
Electrolytes normally included in dialysis fluid
Calcium 2 (0,05 mmol/L)
Magnesium 4 (0,15mmol/L)
Potassium 8 (0,2 mmol/L)
Sodium 70 (3,0 mmol/L)

The physician has the ultimate responsibility for ensuring the quality of water used for dialysis.

Unless otherwise noted.
197
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198 Table 2 — Maximum allowable levels of trace elements in dialysis water
Contaminant Maximum Concentration
(mg/L)
Antimony 0,006
Arsenic 0,005
Barium 0,1
Beryllium 0,0004
Cadmium 0,001
Chromium 0,014
Mercury 0,0002
Selenium 0,09
Silver 0,005
Thallium 0,002
199
200 4 Tests for compliance with chemical and microbiological requirements
201 4.1 Microbiology of dialysis water

202 Samples shall be collected where a dialysis machine connects to the water distribution loop, from a

203 sample point in the distal segment of the loop, or where water enters into a mixing tank.

204 Samples shall be assayed within 4 h of collection, or be immediately refrigerated and assayed within

205 24 h of collection on a regular schedule. Total viable counts (standard plate counts) shall be obtained

206 using conventional microbiological assay procedures (pour plate, spread plate, membrane filter

207 techniques). Membrane filtration is the preferred method for this test. The calibrated loop technique is

208 not accepted.

209 Culture media should be tryptone glucose extract agar (TGEA), Reasoners 2A (R2A), or other media

210 that can be demonstrated to provide equivalent results. Blood agar and chocolate agar shall not be

211 used. Incubation temperatures of 17° C – 23° C and incubation time of 168 h (7 days) are

212 recommended. Other incubation times and temperatures may be used if it can be demonstrated that

213 they provide equivalent results. No method will give a total microbial count.

214 The presence of pyrogens shall be determined by the Limulus amoebocyte lysate (LAL) assay for

215 endotoxins. Other test methods may be used if it can be demonstrated that they provide equivalent

216 results.
217 4.2 Chemical contaminants test methods

218 Compliance with the requirements listed in Table 1 can be shown by using chemical analysis methods

219 referenced in the American Public Health Association’s Standard methods for the examination of

220 water and wastewater, methods referenced in the U.S. Environmental Protection Agency’s Methods

221 for the Determination of metals in environmental samples, and/or other equivalent analytical methods.

222 Compliance with the requirements listed in Table 2 can be shown in one of three ways:

223 ⎯ Where such testing is available, the individual contaminants in Table 2 can be determined using

224 chemical analysis methods referenced in the American Public Health Association’s Standard

225 methods for the examination of water and wastewater, methods referenced in the U.S.

226 Environmental Protection Agency’s Methods for the Determination of metals in environmental

227 samples, and/or other equivalent analytical methods.
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228 ⎯ Where testing for the individual trace elements listed in Table 2 is not available, and the source

229 water can be demonstrated to meet the standards for potable water as defined by WHO or local

230 regulation, an analysis for total heavy metals can be used with a maximum allowable level of at

231 0,1 mg/L.

232 ⎯ If neither of these options is available, compliance with the requirements of Table 2 can be met

233 by using water that can be demonstrated to meet the potable water requirements of WHO or local

234 regulation and a reverse osmosis system with a rejection of > 90 % based on conductivity,

235 resistivity or TDS. Samples shall be collected at the end of the water purification cascade or at

236 the most distal point in each water distribution loop.

237 Table 3 lists tests for each contaminant, along with an appropriate reference.

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238 Table 3 — Analytical tests for chemical contaminants
Contaminant Test Name Reference, Test Number
Aluminium Atomic Absorption (electrothermal) American Public Health Assn, #3113
Antimony Atomic Absorption (platform) US EPA, #200.9
Arsenic Atomic Absorption (gaseous hydride) American Public Health Assn, #3114
Barium Atomic Absorption (electrothermal) American Public Health Assn, #3113
Beryllium Atomic Absorption (platform) US EPA, #200.9
Cadmium Atomic Absorption (electrothermal) American Public Health Assn, #3113
Calcium EDTA Titrimetric Method, or American Public Health Assn, #3500-
Atomic Absorption (direct aspiration), or Ca D
Ion Specific Electrode, or American Public Health Assn, #3111B
Inductively-coupled plasma spectrometry (direct
aspiration)

Total chlorine DPD Ferrous Titrimetric Method, or American Public Health Assn, #4500-

DPD Colorimetric Method Cl F
American Public Health Assn, #4500-
Cl G
Chromium Atomic Absorption (electrothermal) American Public Health Assn, #3113

Copper Atomic Absorption (direct aspiration), or American Public Health Assn, #3111

Neocuproine Method American Public Health Assn, #3500-
Cu D
Ion Selective Electrode Method, or
Fluoride American Public Health Assn, #4500-
sodium 2-(parasulfophenylazo)-1,8-
F C
dihydroxy- American Public Health Assn, #4500-
F D
3,6-naphthalenedisulfonate
(SPADNS) Method
Lead Atomic Absorption (electrothermal) American Public Health Assn, #3113

Magnesium Atomic Absorption (direct aspiration), or American Public Health Assn, #3111

Inductively-coupled plasma spectrometry (direct
aspiration)

Mercury Flameless Cold Vapor Technique (Atomic American Public Health Assn, #3112

Absorption)
Nitrate Cadmium Reduction Method American Public Health Assn, #4500-
NO E

Potassium Atomic Absorption (direct aspiration), or American Public Health Assn, #3111

Flame Photometric Method, or American Public Health Assn, #3500-K
Ion Specific Electrode, or D
American Public Health Assn, #3500-K
Inductively-coupled plasma spectrometry (direct
aspiration)

Selenium Atomic Absorption (gaseous hydride), or American Public Health Assn, #3114

Atomic Absorption (electrothermal) American Public Health Assn, #3113
Silver Atomic Absorption (electrothermal) American Public Health Assn, #3113

Sodium Atomic Absorption (direct aspiration), or American Public Health Assn, #3111

Flame Photometric Method, or American Public Health Assn, #3500-
Ion Specific Electrode, or Na D
Inductively-coupled plasma spectrometry (direct
aspiration)
Sulphate Turbidimetric Method American Public Health Assn, #4500-
SO E
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Contaminant Test Name Reference, Test Number
Thallium Atomic Absorption (platform) US EPA, 200.9
Total heavy metals Colorimetric European Pharmacopoeia, 2.4.8
US Pharmacopoeia, <231>

Zinc Atomic Absorption (direct aspiration), or American Public Health Assn, #3111

Dithizone Method American Public Health Assn, #3500-
Zn D
239
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240 Annex A
241 (informative)
242
243 Rationale for the development and provisions of this standard
244 A.4.1 Microbiology of dialysis water

245 NOTE The information in this clause is to give the reader a historical prospective of how the microbial limits were

246 developed for this document.

247 Originally, it was considered that neither the water used to prepare dialysis fluid nor the dialysis fluid

248 itself needed to be sterile. However, several studies had demonstrated that the attack rates of

249 pyrogenic reactions were related directly to the number of bacteria in dialysis fluid (Dawids and

250 Vejlsgaard 1976; Favero et al. 1974; Favero et al. 1975). These studies provided the rationale for

251 setting the bacterial level specified in the original AAMI standard for water quality published in 1982.

252 Even at low levels of bacterial contamination, pyrogenic reactions have been reported when the

253 source of endotoxin was exogenous to the dialysis system (i.e. present in the community water

254 supply) (Hindman et al. 1975). In addition, it had been shown that problems relating to microbial

255 contamination in dialysis systems did not usually have a single cause, but rather were the result of a

256 number of causes and factors involving the water treatment system and the water distribution systems,

257 and, in some cases, the type of haemodialyser. Understanding the various factors and their influence

258 on contamination levels is the key to preventing high levels of microbial contamination.

259 Several groups of investigators have shown convincingly that pyrogenic reactions are caused by

260 lipopolysaccharides or endotoxins that are associated with gram-negative bacteria. Furthermore,

261 gram-negative water bacteria have been shown to have the capability of multiplying rapidly in a

262 variety of hospital-associated fluids, including distilled, deionized, reverse osmosis, and softened

263 water, all of which have been used in the past as supply water for haemodialysis systems. The

264 dialysis fluid, which is a balanced salt solution made with this water, likewise provides a very good

265 growth medium for these types of bacteria.

266 Several investigators (Jones et al. 1970; Kidd 1964) have shown that bacteria growing in dialysis fluid

267 produced products that could cross the dialysis membrane. It has also been shown (Gazenfeldt-Gazit

268 and Eliahou 1969; Raij et al. 1973) that gram-negative bacteria growing in dialysis fluid produced

269 endotoxins that in turn stimulated the production of anti-endotoxin antibodies in haemodialysis

270 patients. These data suggest that bacterial endotoxins, although relatively large molecules, do indeed

271 cross dialysis membranes, either intact or as fragments. The use of the very permeable membranes

272 known as high-flux membranes has raised the possibility of a greater likelihood of passage of

273 endotoxins into the blood path. Several studies support this contention. Vanholder et al. (1992)

274 observed an increase in plasma endotoxin concentrations during dialysis against dialysis fluid

3 4

275 containing 10 to 10 CFU/mL Pseudomonas species. In vitro studies using both radiolabelled

276 lipopolysaccharide and biological assays have demonstrated that biologically active substances

277 derived from bacteria found in dialysis fluid can cross a variety of dialysis membranes (Laude-Sharp

278 et al. 1990; Evans and Holmes 1991; Lonnemann et al. 1992; Ureña et al. 1992; Bommer et al. 1996).

279 Also, patients treated with high-flux membranes are reported to have higher levels of anti-endotoxin

280 antibodies than normal subjects or patients treated with conventional low-flux membranes (Yamagami

281 et al. 1990). Finally, it was reported that the use of high-flux dialysers is a significant risk factor for

282 pyrogenic reactions (Tokars et al. 1996). Although other investigators have not been able to

283 demonstrate endotoxin transfer across dialysis membranes (Bernick et al. 1979; Bommer et al. 1987),

284 the preponderance of reports now supports the ability of endotoxin to transfer across at least some

285 high-flux membranes under some operating conditions.

286 In addition to the acute risk of pyrogenic reactions, there is increasing indirect evidence that chronic

287 exposure to low amounts of endotoxin might play a role in some of the long-term complications of

288 haemodialysis therapy. Patients treated with ultrafiltered dialysis fluid have demonstrated a decrease

289 in serum β -microglobulin concentrations (Quellhorst 1998), a decrease in markers of an inflammatory

290 response (Schindler et al. 1994; Sitter et al. 2000; Schiffl et al. 2001; Rahmati et al. 2004), and an

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291 increased responsiveness to erythropoietin (Sitter et al. 2000; Matsuhashi and Yoshioka 2002;

292 Rahmati et al. 2004). In longer-term studies, use of microbiologically ultrapure dialysis fluid has been

293 associated with a decreased incidence of β -microglobulin-associated amyloidosis (Baz et al. 1991;

294 Kleophas et al. 1998; Schiffl et al. 2000), better preservation of residual renal function (McKane et al.

295 2002; Schiffl et al. 2002), and improved nutritional sta
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