Overview
The pharmaceutical and dialysis water markets share many similarities. Both require high purity water for their specific applications and are regulated by government agencies. In a broad sense, the quality requirements for each are relatively similar and the water treatment includes many of the same technologies such as reverse osmosis (RO), deionization (DI), and sterilizing grade filters. However, the governing regulations, process and equipment design, and operational practices are distinct for each. Let’s consider some of the requirements, practices, and design nuances from the dialysis water industry that could be considered for the pharmaceutical water industry.
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1. USP Water Quality Requirements are Minimum Standards
USP mandates minimum water quality standards for compendial waters, however additional water quality requirements beyond those prescribed by USP Monographs may be required. There is actually a little known and seldom referenced monograph in USP for Water for Dialysis which outlines general quality attributes for water used for dialysate. However, the standards that have been adopted by the industry are based on the guidance of an industry organization; the Association for the Advancement of Medical Instrumentation (AAMI). AAMI standards for impurities in dialysis water include those for bacteria, endotoxin, specific chemical contaminants with documented toxicity in hemodialysis, and other selected elements.
Should there be more testing for specific parameters for USP waters? For pharmaceutical waters standards prescribed by USP, generalized parameters such as conductivity and total organic carbon (TOC) may not accurately reflect the requirements for specific drug products or substances. As example, often times when pharmaceutical waters such as USP Purified Water and WFI fail the USP conductivity test, it is based on excess alkalinity, which may have zero effect on the final product. More important parameters may include toxic metals which may be present in final product waters but undetected by generalized parameter testing. Like waters for dialysate, undesirable impurities would be specific for each drug application and possibly the route of administration. It may be judicious to perform elemental analysis testing for pharmaceutical waters periodically.
2. Series Activated Carbon for Chlorine/Chloramine Removal
Chloramine exposure, in particular above 0.1 ppm concentration, can cause hemolytic anemia among other issues in dialysis patients. Dialysis water treatment systems must use the most robust technology to ensure that any chlorine, including chloramine, is removed from the feed water. Hence, activated carbon has become the standard in the dialysis water industry for chlorine/chloramine removal.
Dialysis water treatment systems must use the most robust technology to ensure that any chlorine, including chloramine, is removed from the feed water.
The pharmaceutical water industry often used series water softeners or service exchange mixed bed units. The design benefit is that the primary (lead) vessel can be run until it has completely exhausted its capacity. Any leakage from the primary would be detected and removed in the secondary (polishing) unit. However, this concept is not often adopted for activated carbon units.
In the dialysis industry, activated carbon units are always positioned in series operation. For inclusion in the Medicare program, the Centers for Medicare and Medicaid Services (CMS) requires that facilities producing dialysis water must employ series activated carbon units with each unit having an empty bed contact time of at least 5 minutes (10 minutes total). Testing for free and total chlorine at the outlet of the primary activated carbon unit occurs beginning of each shift of dialysis treatments. This approach to chlorine/chloramine removal all but eliminates any risk of patient exposure.
3. Plastic Piping Systems are Practical for High Purity Water
Like the microelectronics water industry, plastic piping has a proven track record in the dialysis water industry. With ever increasing stainless steel prices and new hygienic joining methods for plastic piping systems, the use of clean plastics should be more often considered for pharmaceutical waters. Dialysis water distribution lines are often constructed of polypropylene. Other plastic materials may be used provide they do not contribute impurities such as metals or bacterial contaminants to the water. For smaller systems these may be flexible tubing joined with pressed fitting connections. Both industries use continuously recirculated systems with dead-legs or stagnant areas minimized wherever possible.
With ever increasing stainless steel prices and new hygienic joining methods for plastic piping systems, the use of clean plastics should be more often considered for pharmaceutical waters.
Recently implemented changes to the AAMI guidelines have tightened the microbial standard for dialysis waters to more closely resemble USP standards for pharmaceutical waters. Even with the tightened standards of less than 100 cfu/ml for bacteria and less than 0.25 EU/ml for bacterial endotoxin, plastic distribution systems are able to deliver water that meets these requirements.
4. Final Filters Rated for 0.05 Micron are Effective
Cartridge style ultrafilters (UF) having a nominal rating of less than 0.1 micron are effectively used in the dialysis water industry for endotoxin reduction and control. These are often rated as 0.05 micron to as low as 0.001 micron filters and are considered a disposable technology. They are often the final process step in dialysis water treatment and are mandatory for use downstream of deionization units.
The pharmaceutical water industry has historically been less receptive to cartridge ultrafiltration and has employed cross flow filtration UF for validated endotoxin removal. Where additional membrane processes, such as RO, are used to purify the water, final cartridge UF used as a polishing technique, or possibly in a distribution network, should be considered. Filter operation can be monitored by differential pressure across the filter, the filters can be sanitized in place, and they would also provide the added benefit of removing viable bacteria in addition to bacterial endotoxin.
Filter operation can be monitored by differential pressure across the filter, the filters can be sanitized in place, and they would also provide the added benefit of removing viable bacteria in addition to bacterial endotoxin.
5. Have a Validated Back-up Treatment Option (Even if you Never Need It)
It is commonplace for dialysis water RO system to have a validated back-up service exchange deionization (SDI) system for use should the RO unit have to be taken out of service. This would ensure that a patient’s treatment program would not be interrupted should there be an issue with the primary RO treatment system. These systems are installed and validated in parallel to the primary treatment system ready to be employed immediately.
For pharmaceutical manufacturing applications where large volumes of water may be used, the use of SDI exclusively is usually cost prohibitive. However, the installation and validation of a back-up SDI system could be used to minimize risk at a reasonable cost for a short period. This could be for an unplanned RO system shutdown or while the primary system is offline for maintenance.
Summary
Each high purity water market has practices that are unique to their specific industry. These are driven by regulating agencies, industry groups or associations, or adopted over the years with little or no scientific basis. Every high purity water industry can learn from the best practices of their counterparts. It is often the lack of visibility to other high purity water industries, possibly coupled with resistance to deviate from historical practices, which leads to stagnant thinking.
Every high purity water industry can learn from the best practices of their counterparts.