4.1 Validation (See Procedure C-CP-10-01 Rev.00)

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Quality of Water for
Haemodialysis and Dialysis Fluids
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FMC GUIDELINE
TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS
DOC. NO.: C-CG-10-01
REV.:
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EFFECTIVE DATE: 01.01.2001
SCOPE OF GUIDELINE:
This Guideline is valid for all European FMC Dialysis Centres.
APPROVALS
DOCUMENT OWNER: DR. JUDITH KIRCHGESSNER
TITLE: SCIENTIFIC PROJECT MANAGER
SIGNATURE:
DATE: 08/01/01
VICE PRESIDENT CLINICAL MANAGEMENT EUROPE
NAME: DR. GIANCARLO ORLANDINI
SIGNATURE:
DATE:
CORPORATE MANAGEMENT SYSTEM REPRESENTATIVE
NAME: DR. WOLFGANG KÜMMERLE
SIGNATURE:
DATE:
DOCUMENT INFORMATION:
THIS GUIDELINE IS NEW

THIS GUIDELINE SUPERCEDES DOCUMENT NO:
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MEMBERS of WORKING GROUP
1
2
3
4
5
6
7
NAME
DR. JUDITH KIRCHGESSNER
TITLE
SCIENTIFIC PROJECT MANAGER; CLINICAL MANAGEMENT EUROPE
NAME
HELEN W IESEN
TITLE
MANAGER QMS-DIALYSIS CLINICS; QUALITY, REGULATORY AND ENVIRONMENTAL MANAGEMENT
NAME
KLAUS KNAUER
TITLE
ENVIRONMENTAL MANAGEMENT SYSTEM REPRESENTATIVE; QUALITY, REGULATORY AND
ENVIRONMENTAL MANAGEMENT
NAME
DAVID EVANS
TITLE
PRODUCT MANAGER W ATER TREATMENT, AREA4/W ESTERN EUROPE
NAME
DR. RALF LENZ
TITLE
QUALITY SYSTEM REPRESENTATIVE, PRODUCT AND PROVIDER BUSINESS CENTRAL EUROPE
NAME
FRANK IMBESCHEID
TITLE
PRODUCT MANAGER W ATER TREATMENT, PRODUCT AND PROVIDER BUSINESS CENTRAL EUROPE
NAME
RALF POHL
TITLE
PRODUCT MANAGER HYGIENE, PRODUCT AND PROVIDER BUSINESS CENTRAL EUROPE
8
9
10
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FMC GUIDELINE
TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS
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CONTENTS
1
2
3
4
5
6
7
8
9
Page
SCOPE ....................................................................................................................................................... 5
AIM ..............................................................................................................................................................5
INTRODUCTION .........................................................................................................................................6
3.1
Chemical Contaminants of Water ....................................................................................................... 7
3.2
Microbiological Contaminants of Water ...............................................................................................8
CONCEPT OF WATER QUALITY CONTROL .........................................................................................10
4.1
Validation (See Procedure C-CP-10-01 Rev.00) ...............................................................................10
4.2
Re-validation ......................................................................................................................................10
4.3
Routine Analysis (See Instruction C-CI-10-01 Rev.00) ......................................................................10
QUALITY STANDARDS ...........................................................................................................................10
5.1
Quality of Feed Water ........................................................................................................................11
5.2
Chemical Quality of Dialysis Water (RO-Permeate) ..........................................................................11
Tab. 1: FMC Standard for Chemical Quality of Dialysis Water (RO-Permeate) .......................12
Tab. 2: Standard for Process (physical) Parameters ...............................................................12
5.3
Microbiological Quality of Dialysis Water, Concentrates and Dialysis fluids ......................................13
Tab. 3: FMC Standard for Microbiological Quality ....................................................................13
STANDARDS FOR QUALITY CONTROL ................................................................................................14
6.1
Relationship with water supplier .........................................................................................................14
6.2
Validation (parameters, number of samples, sampling frequency, sample points) ............................14
6.2.1
Chemical Parameters .................................................................................................................15
6.2.2
Process Parameters ...................................................................................................................15
6.2.3
Microbiological Parameters.........................................................................................................15
6.3
Re-validation (parameters, number of samples, sampling frequency, sample points).......................16
6.3.1
Chemical Parameters .................................................................................................................16
6.3.2
Process Parameters ...................................................................................................................16
6.3.3
Microbiological Parameters.........................................................................................................16
6.4
Routine Analysis (parameters, number of samples, sampling frequency, sample points) .................17
6.4.1
Chemical Parameters .................................................................................................................17
6.4.2
Process (physical) Parameters ...................................................................................................17
6.4.3
Microbiological Parameters.........................................................................................................18
6.5
Sample Collection and Sample Points ...............................................................................................19
Tab. 4: Sampling Points ...........................................................................................................19
Tab. 5: Samples to be Analysed in Validation and Routine ......................................................19
Tab. 6: Standard of Sampling Frequency .................................................................................20
6.6
Methods of Analysis ...........................................................................................................................20
6.6.1
Analysis of Chemical and Process Parameters ..........................................................................21
6.6.2
Microbiological Analysis ..............................................................................................................21
Viable micro-organisms (microbial growth): ..............................................................................22
Endotoxins .................................................................................................................................23
6.7
External Laboratory ............................................................................................................................24
6.8
Cleaning and Disinfection...................................................................................................................24
CORRECTIVE AND PREVENTIVE ACTION............................................................................................24
DOCUMENTATION ..................................................................................................................................24
REFERENCES ..........................................................................................................................................26
APPENDIX: Overview of Water Quality Control in Tabular Form
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Scope
This Guideline is valid for all European Dialysis Centres managed by FMC.
2
Aim
The aim of this guideline is to ensure, through FMC standard and preventive measures, that the
patient treated with haemodialysis is not exposed to any unjustifiable risks and that neither acute
reactions nor chronic damage are triggered off by the preparation of fluids and the treatment itself.
Therefore, this guideline defines the chemical and microbiological quality of :
 water for the preparation of haemodialysis fluids and substitution fluids for haemo-(dia-)
filtration,
 dialysis fluids prepared from concentrates and water, and
 substitution fluids for HF and HDF (on-line).
According to the different treatment modes, graded limits are defined for the individual preparation
steps.
Furthermore, in order to control and continuously prove the quality of the respective fluids a
concept is outlined consisting of validation and routine analysis of the whole water treatment
system, starting from the quality control of the incoming feed water.
The concept of quality control of water treatment systems is a recommendation and should be
carried out and kept to according to the local situation and the techniques/equipment installed (see
Corporate Guideline C-CG-10-02 Rev.00: “Water Treatment Equipment”).
Please note: recommendations are highlighted in italics
Furthermore, a summary of this guideline (overview of water quality control) in tabular form can be
found in the appendix of this guideline. In addition, the appendix of the guideline on water
treatment equipment (C-CG-10-02 Rev.00) provides an overview on the positioning of sampling
points and the minimum recommended sampling frequency.
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Introduction
The chemical and microbiological contamination of dialysis fluids is a serious problem in
haemodialysis therapy and one cause, might be the water used for the preparation of dialysis
fluid1,2. Obviously, the incoming feed (raw) water from municipal water supplies
generally is of insufficient quality for dialysis and therefore has to be purified with specifically
designed water treatment devices to achieve the required quality3,4. However, the composition and
quality of incoming water varies widely depending on its source (ground water, surface water), its
geographical origin and seasonal variations. Hence, the water treatment systems have to be
adapted to the individual local situation in order to achieve a consistent quality of water. Water
treatment systems may also invoke additional hazards if malfunction or user errors occur.
Moreover, different treatment steps as well as the sequence of those steps may lead to severe
chemical and microbiological contamination. Based on this knowledge, routine monitoring of water
quality has to be implemented.
During haemodialysis each patient is exposed to approximately 250 – 600 litres of water per week
and hence, each patient is exposed to the potential risk of chemical or microbiological
contamination. If water purity is inadequate, toxins may diffuse non-selectively across the dialysis
membrane directly into the blood stream of the dialysis patient. Moreover, end stage renal disease
patients are no longer able to excrete distinct toxins via their kidneys. The extent of exposure
together with the non-selective absorption and incapability of urinary excretion places the dialysis
patient at a much higher risk to water-borne contamination than the healthy population. Therefore,
the chemical and microbiological quality of the water used for dialysis is essential if an additional
health risk to those patients is to be avoided.
Strict quality standards for dialysis water are demanded, especially when today’s dialysis practices
are considered, e.g. the use of bicarbonate dialysis, high-flux dialysis with highly permeable
membranes, on-line methods5,6,7,8,9,10. Despite this the use of poor chemical and microbiological
quality water and dialysis fluids is widespread and has been demonstrated in multicentre studies
conducted in the US11, Sweden12, Germany13, Canada14, Japan15, Greece16,17 and Austria18.
Moreover, patient reactions such as headache, nausea, vomiting, cramps or haemolysis related to
chemical impurity of water19,20 as well as outbreaks of infections related to microbial
contamination21 are regularly described.
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3.1
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Chemical Contaminants of Water22
The level of chemical contaminants is subject to local and seasonal variations. The main
contaminants are inorganic salts but also organic substances which may be of (I) natural (tannin,
lignine), (ii) agricultural origin (pesticides, nitrogen-compounds) or (iii) industrial pollution (aromatic
hydrocarbons). The main sources of these chemicals are :
 supplementation of drinking water with chemicals by the municipal authorities (e.g.
aluminium sulphate, chlorine, chloramine or fluoride),
 migration from the water piping system (e.g. copper, zinc, lead),
 cleaning chemicals from routine disinfection of water treatment system (chlorine,
hypochlorite, peracetic acid).
The most important chemical contaminants are:
1. ions also found in standard dialysis fluids (Ca, K, Na, Mg)
2. trace elements (aluminium, copper, silver, zinc, cadmium, arsenic, mercury, lead, silver, iron,
selenium, chromium, silicon, barium),
3. organic substances (pesticides and aromatic hydrocompounds such as benzene),
4. disinfectants and preservatives (formaldehyde, sodium hypochlorite, hydrogen peroxide,
chloramines, free chlorine, peracetic acid),
5. group of N-compounds (nitrate, nitrite, nitrosamines), sulphates and fluorides.
In general, chemical contaminants may cause acute and chronic complications during dialysis.
Some may interfere with the maintenance of body homeostasis, cell membrane potential or
multiple enzyme activities. Others are toxic when present in the human body in relatively low
concentrations. Even extremes of high or low concentrations of some chemicals, especially the
electrolytes present in the dialysis fluid, can be physiologically unsafe. High magnesium and
calcium content, for instance, lead to “hard water syndrome” and nausea, hypertension, headache,
confusion, seizure or progressive lethargy. Other contaminants like heavy metals may accumulate
in the body and produce various toxic side effects such as haemolysis or nervous system
disorders. Aluminium overload for instance may cause anaemia, encephalopathy and osteopathy.
However, the relatively wide range of side effects of inadequate purity of water will not be
discussed in this guideline (for an overview, please see22).
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3.2
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Microbiological Contaminants of Water
Naturally occurring water-borne filamentous fungi, yeasts, bacteria and their fragments may
pollute water used for haemodialysis. Commonly found micro-organisms are gram-negative
bacteria or non-tuberculous mycobacteria. In addition, biologically active substances released by
living bacteria or products of bacterial lysis can be found in water. Due to their ability to induce
fever in humans, these derivatives are termed pyrogens. The most important pyrogen in dialysis is
the cell-wall component of gram-negative bacteria called endotoxin or lipopolysaccharide (LPS),
which is released during bacterial lysis22.
In general, the microbiological quality of dialysis fluids is highly influenced by the hygienic status of
preparation and delivery systems. However, micro-organisms are able to colonize solid surfaces
and give rise to sessile communities called biofilms. These biofilms, - potentially being formed in
the whole water system and tubing of dialysis machines -, are the main source of recontamination. They result in high levels of living germs and their products in dialysis water, liquid
bicarbonate concentrates and the final dialysis fluids22.
Originally this appears to be of minor clinical relevance as the likelihood of whole bacteria to
penetrate the dialysis membrane is very small. However, their products (e.g. pyrogens) such as
endotoxins are able to penetrate the dialysis membrane by diffusion and stimulate blood
monocytes to produce cytokines 23,24. Due to their heterogeneous nature it is impossible to
completely abolish dialysis penetration by these so-called cytokine-inducing substances.
Several in vitro studies have shown that the adsorption capacity of a membrane to cytokineinducing substances is much more important for the prevention of cytokine induction than solely
the pore size of the membrane25,26,27. Therefore, microbiological safety levels of low-flux dialysis
are not necessarily higher than high-flux dialysis or on-line treatment modalities.
Similarly to chemical pollution the microbiological contaminants may also cause acute and chronic
complications during dialysis. A typical acute consequence is a pyrogenic reaction accompanied
by fever, chills, nausea, vomiting, hypotension, myalgias and headache. If cytokine- inducing
substances, e.g. endotoxins, invade human subjects, high plasma levels of cytokines, fever and
hypotension are induced within a couple of hours28. Use of ultrapure dialysis fluid (as defined in
chapter 5.3) can significantly decrease the incidence of pyrogenic reactions in the hemodialysis
population29,30.
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Ultrafiltration of dialysis fluid is an effective technique for the production of ultrapure dialysis
fluids25,31,32,33. Most of the retention capacity of dialysis fluid filters is based on adsorptive
mechanisms which may exhaust during operation if highly contaminated dialysis fluid is filtered.
Therefore, ultrafiltration of dialysis fluid cannot compensate for inadequate hygienic conditions
upstream of the filter. Instead, dialysis fluid filtration should be considered as a polishing
procedure and part of a comprehensive hygiene concept. With such an approach, dialysis fluid
(before filtration) can be obtained with appropriate microbiological qualities.
More important than the generation of acute reactions is the impact of cytokine-inducing
substances on the long-term well-being of haemodialysis patients. Known long-term effects such
as impaired immunodeficiency state or altered erythropoietin response are believed to be related
to a chronic cytokine induction, which may be linked, at least partly, to microbiological
contamination of dialysis fluid. Clinical studies revealed that even minute amounts of cytokineinducing substances are perceived by the patients' immune system without causing any acute
clinical symptoms34. Several lines of evidence suggest that permanent stimulation leads to various
chronic complications such as dialysis-related amyloidosis, muscle wasting, progressive loss of
bone mass, immunodysfunction and cardiovascular disease35,36,37,38,39. Since infections and
cardiovascular disease are major causes of mortality, it is tempting to speculate whether systemic
cytokine induction due to poor microbiological dialysis fluid quality increases mortality in the
haemodialysis population as well40,41.
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Concept of Water Quality Control
In order to assure the quality of water, certain standards have to be defined. The results of the
main processes as well as the results of the water quality evaluation must be documented.
Routine risk analyses have to be performed and potential adaptations of the purification process
have to be considered. The process of water quality control consists of validation, re-validation and
routine analysis.
4.1
Validation (See Procedure C-CP-10-01 Rev.00)
The Validation is the confirmation by examination and provision of objective evidence that the
particular requirement for a specific intended use can be consistently fulfilled.
It records the status and the characteristics of the whole water treatment system including the
technical details (see Corporate Guideline C-CG-10-02 Rev00: “Water Treatment Equipment”) and
the quality of incoming feed water as well as the quality of water during the purification process.
4.2
Re-validation
Within the Re-validation process, the evidence base gained during validation is confirmed.
It records the current status and the characteristics of the whole water treatment system and
compares it to the information recorded at the initial validation (see Corporate Guideline C-CG-1002Rev00: “Water Treatment Equipment”).
4.3
Routine Analysis (See Instruction C-CI-10-01 Rev.00)
Quality control is carried out through routine analysis in order to guarantee that the requirements
are fulfilled consistently. It comprises of regular monitoring of critical areas which are
representative for the whole treatment system. The routine analysis has to be performed based on
the protocol established during validation and adapted during re-validation.
5
Quality Standards
The FMC standard for chemical and microbiological quality of dialysis water, concentrates, dialysis
fluids and substitution fluids for haemo- (dia-) filtration (substitution fluid) complies with the
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European Pharmacopoeia (PhEu – Suppl. 2001: Monographs 012842, 116743 and 086144), or if not
regulated here, with the Association for the Advancement of Medical Instrumentation (AAMI,
USA)45 and the European Norm (Draft: EN 13867)46 or, if more stringent, the quality should comply
with regional or local standards.
Standards on process (physical) parameters (Tab. 2) should comply with the instructions of the
manufacturer for the individual treatment steps of the water purification plant and the dialysis
machines as well as with medical requirements.
Furthermore, the quality of water achieved after each purification step has to correspond with
performance characteristics given by the manufacturer. If no standardised limits are available, the
performance characteristics must be defined by the manufacturer and/or the maintenance
provider, at least after validation.
5.1
Quality of Feed Water
The water treatment system has to be designed, taking into consideration the local situation, in
order to produce water for dialysis of the recommended quality, as follows below.
The type and level of contaminants of feed water must be identified based on the
contaminants listed in the FMC standard (Table 1 and 3 and see also Corporate Guideline C-CG10-02 Rev00: “Water Treatment Equipment”: chapter 4.1).
5.2
Chemical Quality of Dialysis Water (RO-Permeate)
Table 1 summarises standards for the chemical quality of dialysis water. It refers to water treated
by reverse osmosis (dialysis water or RO-permeate) to be used in the preparation of dialysis fluids
from concentrates. The final composition of dialysis fluids and substitution fluids is not a subject of
this guideline. However, it is regulated in the European Pharmacopoeia (see above) which should
be complied with.
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Tab. 1: FMC Standard for Chemical Quality of Dialysis Water (RO-Permeate)
Max. Conc. Level (mg/l)
Max. Conc. Level (mg/l)
CONTAMINANTS
AAMI
PhEu
FMC
CONTAMINANTS
AAMI
PhEu
FMC
Calcium
Magnesium
Potassium
Sodium
Fluoride
Chloride
Free Chlorine
Chloramines
Nitrates
Sulphates
Aluminium
Copper
2
4
8
70
0.2
-----0.5
0.1
2
100
0.01
0.1
2
2
2
50
0.2
50
0.1
-----2
50
0.01
------
2
2
2
50
0.2
50
0.1
0.1
2
50
0.01
0.1
Chromium
Lead
Zinc
Mercury
Barium
Arsenic
Silver
Cadmium
Selenium
Silica
Ammonium
Heavy metals
0.014
0.005
0.1
0.0002
0.1
0.005
0.005
0.001
0.09
-----------
----------0.1
0.001
------------------------------0.2
0.1
0.014
0.005
0.1
0.0002
0.1
0.005
0.005
0.001
0.09
-----0.2
0.1
Tab. 2: Standard for Process (physical) Parameters
PARAMETER
pH
Temperature
Hardness
Conductivity
Resistance
Pressures
Flows
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Standard according to
1. Manufacturer’s instructions
for the individual process steps
of the water purification plant
and for the dialysis machines.
2. Medical requirements
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Microbiological Quality of Dialysis Water, Concentrates and Dialysis Fluids
Table 3 summarises the microbiological standards to be met. It refers to microbial counts and
endotoxin concentration of dialysis water (permeate), dialysis fluid and all other reprocessing
fluids.
Based on the growing wealth of data on the subject of clinical consequences of inadequate
microbiological dialysis fluid quality, the use of ultrapure dialysis fluid is advised, regardless of
the treatment modality.
The prerequisite to perform on-line techniques, such as on-line HF and on-line HDF, is a
double filtration of dialysis fluid or an additional filtration of ultrapure fluids.
Tab. 3: FMC Standard for Microbiological Quality4748
SAMPLES
Dialysis water (RO-Permeate)
Bicarbonate concentrate
Acid concentrate
Dialysis fluid (unfiltered)
Ultrapure (1 x filtered) dialysis fluid
Substitution fluid (2 x filtered dialysis
fluid)
SAMPLES
Dialysis water (RO-Permeate)
Bicarbonate concentrate
Acid concentrate
Dialysis fluid (unfiltered)
Ultrapure (1 x filtered) dialysis fluid
Substitution fluid (2 x filtered dialysis
fluid)
SAMPLES
Dialysis water (RO-Permeate)
Bicarbonate concentrate
Acid concentrate
Dialysis fluid (unfiltered)
Ultrapure (1 x filtered) dialysis fluid
Substitution fluid (2 x filtered dialysis
fluid)
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Microbial Counts (CFU/ml)
AAMI SPh
RKI PhEu EN
≤ 200 ≤ 100 ≤ 100 ≤ 100
≤ 100
≤ 100
≤ 2000 ≤ 100 ≤ 100
FMC
≤ 100
≤ 100
≤ 100
≤ 100
≤1
0
AAMI: Association for the
Advancement of Medical
Instruments, USA45
SPh: Swedish
Pharmacopoeia 199747
RKI: Robert Koch Institute,
Germany48
PhEu: European
Pharmacopoeia 199742,43,44
Yeast and Moulds (CFU/ml)
AAMI SPh
RKI PhEu EN
FMC
≤ 10
≤ 10
≤ 10
≤ 10
≤ 10
≤ 10
≤1
EN = European Norm (prEN
13867)46
0
AAMI
≤5
Endotoxin (IU/ml)
SPh
PhEu
EN
≤ 0.25 ≤ 0.25
≤ 0.5# ≤ 0.5#
≤ 0.5# ≤ 0.5#
≤ 0.25
FMC
≤ 0.25
≤ 0.5#
≤ 0.5#
≤ 0.5
≤ 0.03
≤ 0.03
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# when concentrates are
appropriately diluted
with dialysis water
(ready-to-use dilution)
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Standards for Quality Control
Standards for samples, sampling frequency and sample points are summarised in Tables 4 to 6.
6.1
Relationship with water supplier
The attention of the water supplier should be drawn to the fact that the feed water delivered to a
dialysis centre requires a distinctly defined water quality.
The water supplier is asked to provide the information on the source and the quality (level of
contaminants/additives) as well as the quality stability of feed water (trend analysis of the previous
year). This information can be gathered through the use of a questionnaire (see “Questionnaire for
Water Supplier”).
Any changes of water source or contaminants/additives affecting water quality must be reported
immediately to the dialysis centres by the water supplier. This will then enable a detailed risk
analysis to be carried out, followed by any necessary action to maintain an adequate water quality.
The first evaluation of feed water is performed during the validation.
A re-evaluation is recommended once, preferably twice per year.
Please note, that no matter how the relationship with the water supplier is, it is the responsibility of
the centre to regularly evaluate the quality of feed water.
6.2
Validation (parameters, number of samples, sampling frequency, sample points)
A validation (first evaluation) has to be performed once for all newly installed water purification
systems. Operating water treatment systems are inspected retrospectively in order to meet the
requirements of validation. Data mandatory for validation which are not available are completed
supplementarily.
All chemical, process (physical) and microbial parameters (generally completed before the start of
operation of the whole system and/or significant system changes) have to be evaluated.

Sample points are defined based on the design of the entire system.

Samples are taken and analysed in order to identify malfunctions and areas with a potentially
high risk of contamination.

Finally, a protocol for routine analysis is defined according to the results of the validation. The
minimum requirements for the protocol must include: the position of sampling points,
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frequency of sampling, type of analysis and potential actions in case of quality deviations.
Based on this protocol the routine analysis is designed and established.
6.2.1
Chemical Parameters
During validation a full chemical analysis (parameters as summarised in Table 1) of the following
minimum number of samples is recommended:
 the feed water
 the RO-permeate or UF-permeate (dialysis water).
In general, the individual parameters to be analysed depend on the quality of feed water (source of
water, type of routine additives, kind of pipe line materials) and on the type/components of the
whole water treatment system. Additional and different parameters may have to be evaluated in
order to assess the whole system and the adequate quality of water (see appendices to Corporate
Guideline C-CG-10-02 Rev00: “Water Treatment Equipment”).
6.2.2
Process Parameters
Process parameters (Table 2) such as hardness, conductivity, temperature, pressures and flows
have to be evaluated during validation in order to check the equipment performance against the
design specification (see Corporate Guideline C-CG-10-02Rev00: “Water Treatment Equipment”).
6.2.3
Microbiological Parameters
During validation the following minimum number of samples has to be analysed on microbial
counts (viable cells) including yeast/moulds and endotoxins (Table 3) in order to identify areas
of higher risk of contamination:





feed water (optional)
pre-reverse osmosis (softened) water,
RO-permeate and/or UF-permeate (dialysis water),
concentrates (central delivery system only) and
dialysis fluids (all machines)
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Re-validation (parameters, number of samples, sampling frequency, sample points)
A re-validation has to be performed once or preferably twice per year.
All chemical, process (physical) and microbial parameters have to be evaluated based on trend
analysis of routine measurements of the previous year.
Beyond this retrospective analysis of routine results (trend analysis), additional samples which
are not routinely controlled might be required in order to evaluate potential risks.
The results of the re-validation will dictate whether the routine test plan has to be modified.
6.3.1
Chemical Parameters
A full chemical analysis is recommended for:
 the feed water (information from water supplier)
 the RO-permeate (dialysis water).
6.3.2
Process Parameters
All process parameters are analysed retrospectively based on daily and/or monthly records (see
Appendices to Corporate Guideline C-CG-10-02 Rev00: “Water Treatment Equipment”).
6.3.3
Microbiological Parameters
The microbial analysis comprises the following minimum evaluation:
 feed water
→ optional
 the pre-reverse osmosis
(softened) water
→ additional
 RO-permeate and/or
UF-permeate (dialysis water)
→ trend analysis based on all individual sampling points
 concentrates
(central delivery system only)
→ trend analysis based on all individual sampling points
 dialysis fluids
→ trend analysis considering all machines
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ROUTINE ANALYSIS (parameters, number of samples, sampling frequency, sample points)
The plan of routine sampling is developed according to the results of the validation (sampling plan)
and/or adapted according to the results of the re-validation. The analysis parameters, number of
samples, sampling points and frequency of measurements have to be selected depending on the
expected water quality at the respective area/component within the system.

Samples are taken and analysed at defined intervals.

A re-analysis must be performed, where appropriate,




if the results of analysis (chemical or microbiological) exceed the defined quality limits,
in case of any system changes,
after opening any areas of the water treatment system,
after disinfection of the distribution loop.

Necessary actions, have to be initiated accordingly in order to improve the water quality.

Finally, the routine-protocol has to be adapted accordingly.
6.4.1
Chemical Parameters
Similarly to validation the individual chemical parameters to be analysed routinely depend on the
quality of feed water (source of water, type of routine additives, pipe line materials) and on the
type/components of the whole water treatment system. However, common local contaminants
such as free chlorine, chloramines and trace elements must also be considered and included in
the routine analysis more frequently.
For example, it is recommended to measure:
- free chlorine, chloramines
• daily in the post-carbon water
- other local contaminants (e.g. Al, SO4, NO3, F)
• monthly in pre-RO (softened) water
• 3-monthly (quarterly) in RO-permeate or UF-permeate
A comprehensive chemical analysis should be conducted at least once per year, preferably twice
per year as defined for re-validation (see chapters 4.2 and 6.3).
6.4.2
Process (physical) Parameters
Routine analysis must at least cover the conductivity, hardness, pH, temperature, pressures and
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flows. If available, on-line tests offered as part of single treatment devices can be used to test
some of these parameters. Most of these parameters have to be checked daily. An overview of
routine process control is given in the Appendix of Corporate Guideline C-CG-10-02 Rev00:
“Water Treatment Equipment”.
6.4.3
Microbiological Parameters
During routine operation the following minimum number of samples must be analysed for
microbial growth and endotoxin levels in intervals of 1 – 3 months:
 the RO-permeate or UF-permeate,
 the concentrates in case of central delivery systems and
 the dialysis fluids
Dialysis fluids, which are filtered more than once, only need to be checked after their final filtration.
Each sampling of dialysis fluid must cover at least 10% of all machines so that in the course
of one year each machine will be checked at least once. However, in case of contamination or if
the frequency of usage is low, more samples have to be taken.
In general, the frequency of sampling is chosen according to the results of the validation and/or
the re-validation but not below the minimum recommendation of 3-month intervals. More frequent
sampling is recommended for the first months after validation. The frequency can be lowered if
stable and adequate results are achieved for 4 consecutive measurements. In case of quality
deterioration, the frequency of sampling has to be increased and appropriate actions have to be
initiated. However, more critical sampling points (e.g. bicarbonate concentrates) have to be
evaluated more frequently than less critical ones (acidic concentrates).
In case of special events such as




patient reactions,
any system changes,
opening of the water treatment and distribution system (e.g. repairs, maintenance),
after disinfection,
additional samples have to be analysed beside the routine evaluation (see chapter 7).
A disinfection must be carried out and microbial samples must be taken after each opening of
the water treatment and distribution system.. The timing of sampling must be chosen in order to
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detect any contamination. Therefore, it should not be performed directly after disinfection but at
least 15 minutes after the start of operation.
6.5
Sample Collection and Sample Points
Samples must only be taken under standardised conditions by trained personnel. Instructions for
handling, storage and transport of samples have to be taken into consideration depending on the
individual parameters to be analysed and on the analytical method to be applied. If applicable,
international standards such as ISO 5667-349 can be taken into consideration.
The individual samples should be taken at distinct sample points (Table 4). However, the individual
sample points depend on the design of the water treatment and distribution system. Therefore,
more sampling points might be necessary if treated water storage tanks or post RO-treatment are
used. All potential sampling points are outlined in the appendices of the Corporate Guideline CCG-10-02 Rev00: “Water Treatment Equipment”.
Tab. 4: Sampling Points
Samples
Sampling point
Feed water
directly at water inflow
Pre-reverse osmosis (softened) water
before reverse osmosis
RO-Permeate (dialysis water)
before first dialysis machine and return-flow, after last dialysis machine
and in the middle of the water distribution loop at the permeate inflow
tube (rotate around different machine points)
Concentrates (centrally delivered)
at the transition of the utility line to the dialysis machines or at special
sampling points at supply and return lines
 Bicarbonate
- at least at two points of the delivery system (supply, return)
 Acid concentrate
- one sampling point (return) due to lower risk of contamination
Dialysis fluid (unfiltered & ultrapure)
directly before the dialyser
Substitution fluid (2 x filtered dialysis
fluid)
directly after second filtration at the outflow tube.
Tab. 5: Samples to be Analysed in Validation and Routine
VALIDATION & RE-VALIDATION
CHEMICAL PROCESS
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ROUTINE
CHEMICAL PROCESS
MICROBIAL
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SAMPLES
(Tab. 1)
(Tab. 2)
CFU
LAL
Feed water
Xa
X
(X+)
(X)
X
X+
X
Softened water
Permeate
X
EFFECTIVE DATE: 01.01.2001
X
X+
X
 Bicarbonate
X
X+
 Acid concentrate
X
Dialysis fluid (unfiltered)
(Tab. 1)
(Tab. 2)
CFU
LAL
X
X mandatory
(X) optional
X
Xc
X
X
X
X
X
X
X
X+
X
X
X
X
X
Xb
Xb
X
Xd
Xd
Ultrapure dialysis fluid
X
Xb
Xb
X
Xd
Xd
Substitution fluid (2 x
filtered)
X
Xb
Xb
X
Xd
Xd
Concentrates
a
water supplier
or dialysis centre
b
all machines
c
selected
parameters
d 10%
of machines
rotating
+ including
yeast & mould
CFU: Colony forming units of micro-organisms
LAL: Limulus-Amoebocyte-Lysate assay for endotoxins
Tab. 6: Standard of Sampling Frequency
Quality Control
FREQUENCY
Parameters and Recommendations
Validation
all chemical, process and microbial parameters - in
Once for the
general before the start of operation of the whole system
whole water
treatment system and/or significant system changes
Re-validation
Once or twice
per year
Routine

(Routine plan according to
validation/re-validation)
1 - 3 months  viable micro-organisms and endotoxins
intervals

Monthly
 local chemical contaminants, others on local demands

Daily
 process parameters such as conductivity, hardness etc
all chemical, process and microbial parameters based on
trend analysis of routine measurements
Adaptation during routine with respect to microbial control
1. results out of limit
Increase
Introduce corrective actions (see chapter 7)
2. results meet standard
< 4 times consecutively
Constant
maintain current frequency for the respective parameter
3. results meet standard
> 3 times consecutively
Constant or
decrease
maintain or lower frequency for the respective parameter,
but not below minimum recommendation
6.6
Methods of Analysis
The results of any chemical or microbial analysis depend heavily on the method used. Therefore,
standardised methods are required in order to achieve reproducible results and to allow a reliable
assessment of water and dialysis fluid quality. In general the analytical methods recommended by
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the European Pharmacopoeia42,43,44 should be applied. If more stringent, other methods
complying with other Pharmacopoeias or with local standards or if applicable, with
international standards (e.g. ISO 622250) should be used. All methods and devices used have to
be validated and revalidated regularly. Each new method has to be validated before initiation.
6.6.1
Analysis of Chemical and Process Parameters
In daily routine, process or chemical parameters can be evaluated by on-line methods integrated
as functioning tests for certain devices. Such devices have to be validated regularly. Other
methods such as the peroxide test for disinfectants are recommended for “quick checks” in the
daily routine only. However, they do not replace above-mentioned validated analytical methods.
The following table summarises common methods suitable for the analysis of chemical
contaminants:
Methods of Analysis
Contaminants
Flame Atomic Absorption Spectroscopy
Barium, Cadmium, Calcium, Magnesium, Zinc
Cold Vapour Atomic Absorption Spectroscopy
Mercury
Furnace Atomic Absorption Emissions
Spectroscopy (Electrothermal Atomisation)
Aluminium, Cadmium, Chromium, Copper, Lead,
Selenium, Silver
Flame Photometry
Potassium, Sodium
Molecular Photoluminescence
Fluoride, Nitrogen
Ion Chromatography
Chloride, Sulphate
Colorimetry
Free Chlorine, Chloramines
Hydride Generation Atomic Absorption
Spectroscopy
Arsenic
Molecular Photoluminescence
Ammonium, Silica
6.6.2
Microbiological Analysis
The microbiological tests comprise the culture of viable microorganisms (bacteria, yeast and
mould) and endotoxin measurement by LAL-assays. The samples must be collected under sterile
and pyrogen-free conditions in order to avoid falsely positive results.
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Viable micro-organisms (microbial growth):
Bacteria should be monitored using a culturing technique that is proven to give good recovery of
bacteria from the respective sample.
 It is recommended to assay the bacterial growth by the pour-plate technique with
subsequent culture in plates.
 Based on current publications 51,52,53,54,55 and as recommended by the Swedish
Pharmacopoeia47, a low nutrient agar such as Tryptone Glucose Extract Agar or Reasoners
2A should be used.
 The samples should be incubated for 7 days at a temperature of 22 ± 2°C. Longer incubation
times and higher temperatures may give better recovery for some bacteria. However, the
culture conditions have to be chosen in order to detect any contamination and to assure that
Pseudomonas aeruginosa, the most common germ in water, is recovered if present.
 At the end of incubation, the number of colony forming units should be counted in a consistent
way.
 The number of colonies per plate should be less than 100 per ml sample; of those less than 10
CFU/ml yeast or mould (see below)
 If higher numbers are expected, the sample volume should be reduced and/or the sample
should be diluted accordingly and a disinfection immediately carried out. Do not wait a further 7
days for the results.
 Each sample should be cultured in duplicate and the result expressed as mean.
The culturing method for bacteria with a long incubation time usually recovers total viable counts
since it will allow yeast and moulds to grow if there are sufficient numbers. However, they adhere
well to surfaces and appear at low levels in flowing water so the samples should be filtered.
 Hence, the growth of yeast and moulds should be assayed by membrane filter method with
subsequent culture in plates containing the suitable medium such as Sabouroud or malt
extract agar.
 The samples (membranes) should be incubated for 7 days at a temperature of 22 ± 2°C.
 At the end of incubation, the colonies growing on the surface of the membrane are counted in a
consistent way.
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 The number of colonies per plate should be less than 10 per ml sample.
 Each sample should be cultured in duplicate and the result expressed as mean.
Endotoxin
The European Pharmacopoeia (Suppl 2001, chapter 2.6.14) describes three techniques of
Limulus-Amoebocyte-Lysate (LAL)-assay to detect or quantify bacterial endotoxins:
 Gel-clot technique, based on gel formation (limit test or semi-quantitative),
 Turbidimetric technique, based on the development of turbidity after cleavage of an
endogenous substrate (kinetic or end point),
 Chromogenic technique, based on the development of colour after cleavage of a synthetic
peptide-chromogen complex (kinetic or end point).
All three techniques are suitable as long as the recommended tests for validation are followed and
fulfilled. Hence, a batch specific validation of the LAL-test has to be performed before initiation of
the test.The samples are evaluated on substances which might catalyse or inhibit the LALreaction. Furthermore, a representative and linear standard curve must be guaranteed.
 In general, it is recommended to measure the concentration of endotoxins quantitatively with
the turbidimetric or preferably the chromogenic LAL-assay having a sensitivity of at least
0.005 lU/ml.
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External Laboratory
External laboratories can be engaged to perform the chemical or microbiological analysis. They
must certify that the methods as well as the devices used comply with the present requirements
and that those methods and devices are validated and revalidated regularly.
6.8
Cleaning and Disinfection
Cleaning and disinfection of the water treatment and water distribution system must be scheduled
according to the microbial quality of water assessed during validation and routine analysis. For
further details please see Corporate Guideline C-CG-10-02 Rev00: “Water Treatment Equipment”.
7
Corrective and Preventive Action
The results of each routine analysis must be evaluated in order to detect any deviations from the
defined quality standards. In case of any deviations, the source of that deviation be identified
immediately and a risk analysis has to be performed by a qualified and authorised person in order
to judge potential hazards for the patients. Depending on the kind (e.g. bacterial, chemical)
amount (concentration level) and source of contamination, immediate actions such as disinfection
and/or installation of additional filters in case of microbial contamination as well as additional and
more frequent sampling must be initiated.
In general, during validation potential weak points of the local water treatment system should be
identified, e.g. with respect to contamination or operation. As a worst case situation, these weak
points as well as other generally known risks have to be considered in the plan for routine analysis
in the form of corrective (immediate) and preventive actions.
The corrective actions describe operations/procedures to be initiated if any incident occurs.
Preventive actions are measures implemented to avoid the occurrence or re-occurrence of any
incident.
8
Documentation
As part of the quality concept of FMC, a detailed documentation of every single manipulation of
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water purification is mandatory. Sampling points, the sampling itself, results of analysis, cleaning
and disinfection as well as every system change must be documented in the appropriate forms.
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References
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23
Laude-Sharp M, Caroff M, Simard L, Pusineri C, Kazatchkine MD:´, Haeffner-Cavaillon N: Induction of IL-1
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24 Pereira BJ, Snodgrass BR, Hogan PJ, King AJ: Diffusive and convective transfer of cytokine-inducing
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27 Schindler R, Krautzig S, Lufft V, Lonnemann G, Mahiout A, Marra MN, Shaldon S, Koch KM: Induction of
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29 Erley CM, von Herrath D, Amir-Moazami B, Schaefer K: Beneficial effect of a bacteria and pyrogen
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30 Pegues DA, Oettinger CW, Bland LA, Oliver JC, Arduino MJ, Aguero SM, McAllister SK, Gordon SM,
Favero MS, Jarvis WR: A prospective study of pyrogenic reactions in hemodialysis patients using
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31 Oliver JC, Bland LA, Oettinger CW, Arduino MJ, Garrard M, Pegues DA, McAllister S, Moone T, Aguero S,
Favero MS: Bacteria and endotoxin removal from bicarbonate dialysis fluids for use in conventional, highefficiency, and high-flux hemodialysis. Artif Organs 1992; 16(2):141-145.
32 Bambauer R, Walther J, Meyer S, Ost S, Schauer M, Jung WK, Gohl H, Vienken J: Bacteria- and
endotoxin-free dialysis fluid for use in chronic hemodialysis. Artif Organs 1994; 18(3):188-192.
33 Pertosa G, Gesualdo L, Bottalico D, Schena FP: Endotoxins modulate chronically tumour necrosis factor α
and interleukin 6 release by uremic monocytes. Nephrol Dial Transplant 1995; 10:328-333.
34 Schindler R, Lonnemann G, Schaffer J, Shaldon S, Koch KM, Krautzig S: The effect of ultrafiltered
dialysate on the cellular content of interleukin-1 receptor antagonist in patients on chronic hemodialysis.
Nephron 1994; 68(2):229-233.
35 Dinarello CA: Cytokines: Agents provocateurs in hemodialysis? Kidney Int 1992; 41(3):683-694.
36 Baz M, Durand C, Ragon A, Jaber K, Andrieu D, Merzouk T, Purgus R, Olmer M, Reynier JP, Berland Y.:
Using ultrapure water in hemodialysis delays carpal tunnel syndrome. Int J Artif Organs 1991; 14(11):681685.
37 Descamps-Latscha B, Herbelin: Long-term dialysis and culture immunity: A critical survey. Kidney Int 1993;
43 Suppl.41:S135-S142.
38 Girndt M, Köhler H, Schiedhelm-Weick E, Schlaak JF, Meyer zum Büchenfelde KH, Fleischer B:
Production of interleukin-6, tumor necrosis factor α and interleukin-10 in vitro correlates with the clinical
immune defect in chronic hemodialysis patients. Kidney Int 1995; 47:559-565
39 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH: Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336(14):973-999.
40 Bergström J, Heimbürger 0, Lindholm B, Qureshi AR: Elevated serum c-reactive protein is a strong
predictor of increased mortality and low serum albumin in hemodialysis patients. J Am Soc Nephrol 1995;
6:573.
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FMC GUIDELINE
TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS
DOC. NO.: C-CG-10-01
REV.:
00
EFFECTIVE DATE: 01.01.2001
41
Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH:
Immunologic function and survival in hemodialysis patients. Kidney Int 1998; 54:236-244.
42 European Pharmacopoeia 3rd Edition - Supplement 2001: Monograph 2000:0128, Solutions for
haemodialysis.
43 European Pharmacopoeia 3rd Edition - Supplement 2001: Monograph 1997:1167 corrected 2000,
Haemodialysis solutions, concentrated, water for diluting.
44 European Pharmacopoeia 3rd Edition - Supplement 2001: Monograph 2000:0861. Haemofiltration,
solutions for.
45 AAMI Standards and Recommended Practices, Arlington, Virginia, published by the Association for the
Advancement of Medical Instruments, Vol. 3: Dialysis, 1998.
46 Draft of the European Norm: Concentrates for haemodialysis and related therapies 2000 (prEN 13867).
47 Swedish Pharmacopoeia: Läkemedelsstandard for Finnland och Sverige 1997: Preparation and handling of
solutions for haemodialysis.
48 Robert Koch-Institut – Bundesinstitut für Infektionskrankheiten und nicht übertragbare Krankheiten:
Richtlinie für Krankenhaushygiene und Infektionsprävention. Gustav Fischer Verlag Stuttgart, Dezember
1996. Anlage zu Ziffer 5.1.: Anforderungen der Krankenhaushygiene bei der Dialyse. Bundesgesundhbl.
12/94
49 International Standard: ISO 5667-3:1994: Water quality – sampling – Part 3: guidance on the preservation
and handling of samples.
50 International standard: ISO 6222:1999(E): Water quality – Enumeration of culturable micro-organisms –
colony count in a nutrient agar culture medium.
51 Korsholm E, Sogaard H. Colony counts in drinking water bacteriology- importance of media and methods.
Zentralbl Bakteriol Mikrobiol Hyg [B] 1987 Oct; 185(1-2):112-120
52 Harding GB, Pass T, Wright R. Bacteriology of hemodialysis fluids: Are current methodologies meaningful?
Artif Organs 1992; 16(5):448-456
53 Williams HN, Quinby H, Romberg E. Evaluation and use of a low nutrient medium and reduced incubation
temperature to study bacterial contamination in the water supply of dental units. Can J Microbiol 1994;
40(2):127-131
54 Pass T, Wright R, Sharp B, Harding GB: Culture of dialysis fluids on nutrient rich media for short periods at
elevated temperatures underestimates microbial contamination. Blood Purif 1996; 14:136-145.
55 Zacheus OM, Martikainen PJ: Efficiency of medium containing a low concentration of organic nutrients in
the enumeration of thermophilic bacteria from hot water. Cytobios 1997; 92:149-157.
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