The objective of the International Organization for Standardization (ISO) 23500 series is to provide users with guidance for handling water and concentrates and for the production and quality oversight of dialysis fluid used for hemodialysis and related therapies. The need for such guidance is based on the critical role of dialysis fluid quality in providing safe and effective hemodialysis and the recognition that day-to-day dialysis fluid quality is under the control of the health professionals who deliver dialysis and related therapies.
This new series combines five previous standards (see below) into one series. The series uses ISO 23500-1 as the base standard, replacing ISO 23500:2014, and is intended primarily for use by health professionals who deliver dialysis therapy. ISO 23500-2 (previously 26722), 23500-3 (previously 13959), 23500-4 (previously 13958), and 23500-5 (previously 11663) are intended for use primarily by designers and manufacturers of systems, equipment, disposables, and ancillary supplies. As is the case with earlier versions of the standards, the annexes provide further information on the rationale for the development and provisions of these documents.
In addition to the renumbering scheme, technical revisions of each standard have been incorporated. The overall focus is on risk management for design and process controls to identify deviations early and correct them before they pose a risk to the patient. The equipment used in the various stages of dialysis fluid preparation generally is obtained from specialized vendors, and dialysis practitioners typically are responsible for maintaining that equipment following installation. Therefore, the series of standards provides guidance on quality oversight and maintenance of the equipment to ensure that dialysis fluid quality is acceptable at all times. At various places throughout these standards, the user is advised to follow the manufacturer's instructions regarding the operation and maintenance of equipment. In those instances in which the equipment is not obtained from a specialized vendor, the user is responsible for validating the performance of the equipment in the hemodialysis setting and ensuring that appropriate operating and maintenance manuals are available.
Key Content and Changes
The ISO committee strived to consolidate topics across the standards and to reference back to a single location to provide consistency across the series. The largest changes in this consolidation were related primarily to microbiology testing methods, carbon design and testing, and testing residuals following bleach disinfection.
Self-contained, integrated systems designed and validated to produce dialysis water and dialysis fluid are increasingly becoming available and used clinically. These standards apply to systems assembled from individual components. Consequently, some of the requirements in 23500-1 and 23500-2 might not apply to integrated systems; however, such systems are required to comply with the requirements of 23500-3, 23500-4, and 23500-5. To ensure conformity when using such systems, adherence to the manufacturer's instructions regarding the operation, testing, and maintenance of such systems is required to ensure that the system is being operated under validated conditions.
Microbiological Testing Methods and Their Application
Whenever possible, the Association for the Advancement of Medical Instrumentation (AAMI) attempts to harmonize with international standards, adopting them as U.S. standards. In 2014, AAMI published the ANSI/AAMI versions of the 2011–14 ISO versions of the hemodialysis and related therapies standards (i.e., 23500, 11663, 13958, 13959, 26722) with the addition of a U.S. deviation.
The U.S. deviation added back the Tryptic Soy Agar (TSA) method for bacterial analysis of dialysis water and dialysis fluid (standard dialysis fluid and ultrapure dialysis fluid). The ISO versions of these standards only allowed for the use of Tryptone Glucose Yeast Extract Agar (TGEA) and Reasoner's 2A Agar (R2A) media with a lower incubation temperature (17–23°C) and longer incubation time (seven days). The ISO committee had previously removed the TSA method in favor of the TGEA and R2A methods, as they were viewed as more precise and saw more use internationally as the standard test methods.
Although the TSA method may not be as precise, it still is indicative of action needed five days sooner than the other methods, as described above.1,2 The TSA method, which allows for an incubation temperature of 35° to 37°C and an incubation time of 48 hours, is used extensively by dialysis facilities in the United States.
In 2015, the process began of revising the ISO standards into five documents for the 23500 series. At that time, the U.S. delegation requested that the TSA method be reinstated in these standards, supported by the findings from Maltais et al.1 and the U.S. Pharmacopeia (USP) 38 <1231> (Water for Pharmaceutical Purposes).2 USP 38 <1231> provides guidance on adopting alternative culture methods and balancing time to results against maximizing recovery of more fastidious or slower-growing bacteria. This guidance is included in the 23500 standards and/or annexes.
No specific recommendations are made in the 23500 series of standards related to action limits or routine measurements for yeast and filamentous fungi in dialysis water or dialysis fluid. However, 23500-1 does provide suggested methodologies (Sabouraud or Malt Extract Agar with a seven-day incubation period at temperatures of 20–22°C) should testing for these microbes be wanted or needed.
Other methods for bacterial, endotoxin, chemical contaminants, yeast, and fungi analysis also can be used if they have been appropriately validated and are comparable with the recommended methods. This caveat is repeated throughout the standard series.
In keeping with risk-based process control, sampling frequency should be based on validation and ongoing trend analysis for surveillance, testing, cleaning, and/or disinfection.
Testing for bacteria and endotoxin is not required for standard dialysis fluid or ultrapure dialysis fluid if the dialysis machine fluid path is fitted with an appropriate capacity bacteria and endotoxin retentive filter, validated by the manufacturer, and operated and surveilled according to the manufacturer's instructions, unless the manufacturer requires such tests in the IFU.
Figure D.1 in 23500-1 provides a suggested approach to action when bacterial and/or endotoxin levels are greater than the maximum allowable levels.
The topic of cyanotoxins is introduced. Cyanotoxin types vary by region of the world, and several countries have issued some form of guidance, recommendation, or standard to establish limits on these toxins in drinking water. However, the 23500 series of standards does not require or recommend testing for these toxins at the dialysis facility level.
Sampling Methods and Their Application
New information in 23500-1 allows for three approaches to sample collection from the dialysis water distribution system: (1) according to system manufacturer's instructions, (2) following guidance in the standard if no instructions are provided, or (3) using a facility-validated method. The sections on sampling dialysis fluid (23500-5) and dialysis water (23500-1) have been rewritten.
Storage and Handling of Testing Samples
The new 23500 series expands on previous instructions, recommending storage of samples for bacteria and endotoxin testing at less than 10°C if analysis cannot occur within four hours of collection and that the samples should be maintained at that temperature without freezing through transport to the laboratory for analysis. Storage for more than 24 hours should be avoided. These recommendations apply to both dialysis water and dialysis fluid samples.
Strategies for Microbiological Control
Although flow velocity previously was used to reduce bacterial contamination and biofilm, this method, by itself, is not adequate, particularly if flow is not continuous. Thus, regular disinfection becomes much more critical. System design can help, as well as education and training of clinic personnel to understand the importance of consistent disinfection and preventive maintenance given the design and use of the clinic's water distribution system.
Monitoring of Carbon Media
Even if no chlorine is used for feed water disinfection, at least one carbon bed or filter should be installed and changed on a routine schedule. System design should incorporate protective measures (e.g., redundant carbon beds, redundant chloramine removal devices, online chlorine monitors) to prevent patient exposure to unsafe product water in the event of a single point of failure. In cases of high water pH or high levels of organics or additives, other means are described to assist chlorine and chloramine removal.
Disinfection with Sodium Hypochlorite
When sodium hypochlorite is used for disinfection of the reverse osmosis system, the downstream distribution loop, dialysis machines, concentrate containers, or pick-up tubes and mixers, the post–rinse water residual level should be that recommended by the manufacturer/installer of these systems. This is not to be confused with the product water limit, namely 0.1 mg/L total chlorine.
Information on organic contaminants, pesticides, and other chemicals in incoming water and their effects on the performance of water pretreatment systems is discussed. Removal methods for some of these contaminants are provided in several standards and annexes.
New information has been added on backflow prevention, electrical safety, and personnel.
Although flow velocity previously was used to reduce bacterial contamination and biofilm, this method, by itself, is not adequate, particularly if flow is not continuous. Thus, regular disinfection becomes much more critical.
Application of Standards Series
At the time of this writing, publication of the 23500 series of standards was imminent (i.e., expected in early spring). Following release of the standards, it is anticipated that they will be considered for adoption by regulatory bodies in each individual country.
Denny Treu is senior vice president of research and development at NxStage Medical, Inc., in Lawrence, MA; co-chair of the AAMI Renal Disease & Detoxification Standards Committee; expert member of ISO/TC 150/SC 2/WG 5, Renal Replacement, Detoxification, and Apheresis; and expert member of IEC 62D MT20 Haemodialysis equipment. Email: email@example.com
Jo-Ann B. Maltais, PhD, is principal at Maltais Consulting in Arvada, CO; co-chair of the AAMI Renal Disease & Detoxification Standards Committee; and expert member of ISO/TC 150/SC 2/WG 5, Renal Replacement, Detoxification, and Apheresis Email: firstname.lastname@example.org