Quality of Water for Haemodialysis and Dialysis Fluids DOC. NO.: C-CG-10-01 Filename: 106741805 00/10.12.99 REV.: 00 EFFECTIVE DATE 01.01.2001 Page 1 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 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: CC-QG-10-01 REV.: 00 Filename: 106741805 00/10.12.99 Page 2 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 3 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 4 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 1 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 5 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 3 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 6 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 3.1 REV.: 00 EFFECTIVE DATE: 01.01.2001 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). Filename: 106741805 00/10.12.99 Page 7 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 3.2 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 8 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 9 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 4 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 10 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 11 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 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 Page 12 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 5.3 REV.: 00 EFFECTIVE DATE: 01.01.2001 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) Filename: 106741805 00/10.12.99 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 Page 13 of 28 # when concentrates are appropriately diluted with dialysis water (ready-to-use dilution) Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 6 REV.: 00 EFFECTIVE DATE: 01.01.2001 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, Filename: 106741805 00/10.12.99 Page 14 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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) Filename: 106741805 00/10.12.99 Page 15 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 6.3 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 16 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 6.4 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 17 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 18 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 MICROBIAL Page 19 of 28 ROUTINE CHEMICAL PROCESS MICROBIAL Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 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 Filename: 106741805 00/10.12.99 Page 20 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 21 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 22 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 23 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 6.7 REV.: 00 EFFECTIVE DATE: 01.01.2001 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 Filename: 106741805 00/10.12.99 Page 24 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 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. Filename: 106741805 00/10.12.99 Page 25 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 9 REV.: 00 EFFECTIVE DATE: 01.01.2001 References 1 Favero MS, Petersen NJ, Boyer KM, Carson LA, bond WW: Microbial contamination of renal dialysis systems and associated health risks. Trans ASAIO 1974; 20:175-183. 2 Bommer J, Ritz E: Water quality – A neglected problem in hemodialysis. Nephron 1987; 46:1-6. 3 Ismail N, Becker BN, Hakim RM: Water treatment for hemodialysis. Am J Nephrol 1996; 16:60-72. 4 Cross J: The development of water treatment technology for hemodialysis. Dialysis & Transplant 1997; 26 (9):596-620. 5 Oettinger CW, Arduino MJ, Oliver JC, Bland LA: The clinical relevance of dialysate sterility. Sem Dial 1994; 7(4):263-267. 6 Berland Y, Brunet P, Ragon A, Reynier JP. Dialysis fluid and water: Their roles in biocompatibility. Nephrol Dial Transplant 1995; 10:45-47. 7 Cappelli G, Perrone S, Ciuffreda A: Water quality for on-line haemodiafiltration. Nephrol Dial Transplant 1998; 13 Suppl 5:12-16. 8 Krautzig S, Linnenweber S, Schindler R, Shaldon S, Koch KM, Lonnemann G: New indicators to evaluate bacteriological quality of the dialysis fluid and the associated inflammatory response in ESRD patients. Nephrol Dial Transplant 1996; 11 Suppl 2:87-91. 9 Perez-Garcia R, Rodriguez-Benitez POC: Why and how to monitor bacterial contamination of dialysate? Nephrol Dial Transplant 2000; 15:760-764 10 Lonnemann G: Should ultra-pure dialysate be mandatory? Nephrol Dial Transplant 2000; 15 Suppl 1:55-59. 11 Klein E, Pass T, Harding GB, Wright R, Million C: Microbial and endotoxin contamination in water and dialysate in the central United States. Artif Organs 1990; 14(2):85-94. 12 Kulander L, Nisbeth U, Danielsson BG, Eriksson O: Occurrence of endotoxin in dialysis fluid from 39 dialysis units. J Hosp Infect 1993; 24(1):29-37. 13 Bambauer R, Schauer M, Jung WK, Daum V, Vienken J: Contamination of dialysis water and dialysate. A survey of 30 centers. ASAIO J 1994; 40(4):1012-1016. 14 Laurence RA, Lapierre ST: Quality of hemodialysis water: A 7-year multicenter study. Am J Kidney Dis 1995; 25(5):738-750. 15 Tsuchida K, Takemoto Y, Yamagami S, Edney H, Niwa M, Tsuchiya M, Kishimoto T, Shaldon S: Detection of peptidoglycan and endotoxin in dialysate, using silkworm larvae plasma and limulus amebocyte lysate methods. Nephron 1997; 75:438-443. 16 Arvanitidou M, Spaia S, Katsinas C, Pangidis P, Constantinidis T, Katsouyannopoulos V, Vayonas G: Microbiological quality of water and dialysate in all haemodialysis centres of Greece. Nephrol Dial Transplant 1998; 13(4):949-954. 17 Arvanitidou M, Spaia S, Askepidis N, Kanetidis D, Pazarloglou M, Katsouyannopoulos V, Vayonas G: Endotoxin concentration in treated water of all hemodialysis units in Greece and inquisition of influencing factors. J Nephrol 1999; 12(1):32-37. 18 Vorbeck-Meister I, Sommer R, Vorbeck F, Hörl WH: Quality of water used for haemodialysis and chemical parameters. Nephrol Dial Transplant 1999; 14:666-675. 19 Ward DM: Water disasters: Pitfalls and precautions. Contemp Dial Nephrol December 1999; 22-26 20 Fluck S, McKane W, Cairns T, Fairchild V, Lawrence A, Lee J, Murray D, Polpitiye M, Palmer A, Taube D: Chloramine-induced haemolysis presenting as erythropoietin resistance. Nephrol Dial Transplant 1999; 14(7):1687-1691. 21 Roth VR, Jarvis WR: Outbreaks of infections and/or pyrogenic reactions in dialysis patients. Sem Dial 2000; 13(2): 92-96 22 Bonnie-Schorn E, Grassmann A, Uhlenbusch-Körwer I, Weber C, Vienken J: Water quality in hemodialysis. Fresenius Medical Care Textbook 1998. Filename: 106741805 00/10.12.99 Page 26 of 28 Record no C-CR-05-01 Rev. FMC GUIDELINE TITLE: QUALITY OF WATER FOR HAEMODIALYSIS AND DIALYSIS FLUIDS DOC. NO.: C-CG-10-01 REV.: 00 EFFECTIVE DATE: 01.01.2001 23 Laude-Sharp M, Caroff M, Simard L, Pusineri C, Kazatchkine MD:´, Haeffner-Cavaillon N: Induction of IL-1 during hemodialysis: Transmembrane passage of intact endotoxins (LPS). Kidney Int 1990; 38:10891094. 24 Pereira BJ, Snodgrass BR, Hogan PJ, King AJ: Diffusive and convective transfer of cytokine-inducing bacterial products across hemodialysis membranes. Kidney Int 1995; 47(2):603-610. 25 Schindler R, Dinarello CA: A method for removing interleukin-1- and tumor necrosis factor-inducing substances from bacterial cultures by ultrafiltration with polysulfon. J Imunol Methods 1989; 116:159-165. 26 Lonnemann G, Behme TC, Lenzner B, Floege J, Schulze M, Colton CK, Koch KM, Shaldon S: Permeability of dialyzer membranes to TNF alpha-inducing substances derived from water bacteria. Kidney Int 1992; 42(1):61-68. 27 Schindler R, Krautzig S, Lufft V, Lonnemann G, Mahiout A, Marra MN, Shaldon S, Koch KM: Induction of interleukin-1 and interleukin-1 receptor antagonist during contaminated in-vitro dialysis with whole blood. Nephrol Dial Transplant 1996; 11(1):101-108. 28 Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW: Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318(23):1481-1486. 29 Erley CM, von Herrath D, Amir-Moazami B, Schaefer K: Beneficial effect of a bacteria and pyrogen reduced dialysate on the occurence of fever during hemodialysis. A prospective study. J Nephrol 1989; 4:257-260 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 bicarbonate dialysis fluids filtered to remove bacteria and endotoxin. J Am Soc Nephrol 1992; 3(4):10021007. 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. Filename: 106741805 00/10.12.99 Page 27 of 28 Record no C-CR-05-01 Rev. 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. Filename: 106741805 00/10.12.99 Page 28 of 28 Record no C-CR-05-01 Rev.