Reduce the Water Footprint of your Industrial Water System

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. #DialysisWater #USPWater #PurifiedWater #highpurity1 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.

These Five Trends Suggest They Are. Background #Waterquality requirements for pharmaceutical processing have not changed significantly as treatment technologies have improved. Coupled with a perception that systems must be designed and operated in accordance with regulatory expectations, the #pharmaceuticalwater industry has historically been slow to adopt new practices or novel processes. Instead, the focus has been on refining existing materials and devices, and the industry has been dominated by the use of stainless steels and hot water sanitizable components and materials. In the #microelectronics industry, where higher water quality is required to prevent contamination during device processing, there is an ever increasing demand for cleaner water. To meet the more stringent requirements at points-of-use, microelectronic water systems require polishing techniques to deliver water for use to avoid quality degradation. They employ hygienic plastic piping materials of construction and rely on real-time process analytics to ensure quality. Recently, an increase in non-traditional approaches to the design and operation of pharmaceutical water systems mirror those utilized in microelectronics water processing. Trends in Pharmaceutical Water Process Design 1. Polishing techniques in storage and distribution systems Polishing is a generalized term used to describe supplemental techniques used to further purify water after a primary deionization process. Typical polishing techniques may include deionization, UV light, or submicron filtration. Pharmaceutical water systems would generally store and distribute without polishing due to the less stringent quality requirements and perception that the process would draw regulatory scrutiny. Recently, the use of polishing has become more commonplace especially in #USPPurifiedWater Systems. 2. Ozone sanitization Ozone has been successfully employed for sanitization of USP Purified Water Storage and Distribution Systems for some time. The emergence of automated continuous ozone for #WFI systems is only recent due to new regulations in the European Monograph concerning WFI production. Many companies have adopted the use of continuous ozone as an alternative to heat disinfection to save sanitization downtime, and capital and operating costs. 3. Plastic piping systems Plastic piping systems are becoming more common for pharmaceutical water applications especially for USP Purified Water Systems. Driving factors include the rise in stainless steel prices, increased availability of fittings and valves, and acceptance of automated hygienic pipe welding machines. The increase of polishing components in the distribution loop has led to more chemically sanitized plastic piping systems because of the ability to extend time intervals between sanitization. 4. On-line and inter-component monitoring There has been an increased focus in the industry to improve the monitoring throughout the entire pharmaceutical water treatment train and not just relying on end-point testing to ensure quality. Many companies have implemented inter-component monitoring programs and regularly sample or analyze after each unit operation in a system. This can be done my grab samples or on-line instrumentation for key process parameters. This practice can be critical to predicting upsets or changing conditions before the end product is affected. 5. Use of ultrafiltration The use of ultrafiltration in the pharmaceutical processing industry is not new, but more applications are now focused on pure water systems as well. Ultrafiltration (UF) can be used to treat feed water and aid in the reduction of suspended solids, organics, microbials, and endotoxin. It can also be employed as a polishing technique for bacterial and endotoxin removal. UF has recently become widely used as a terminal membrane barrier in non-distillation based systems for the production of WFI. Reasons for Trends Several factors are driving the changing paradigm for pharmaceutical water design and operation. There is less emphasis on meeting perceived regulatory expectations as companies adopt a science and risk based approach for these systems. This is helping to change or eliminate some longstanding traditions that have been in place for decades in the industry. Engineers are looking to the successful practices of other #highpuritywater industries such as microelectronics and finding that systems can generate and deliver ultrapure water quality with very low bacteria and endotoxin without excessive heat sanitizations. Current trends are also being driven by the need to reduce system operating and capital costs. Successful designs include using sanitization techniques such as continuous ozone that use less energy, and by reducing the frequency of sanitizations by incorporating additional polishing techniques for microbial control into the design. The Future of Pharmaceutical Water Systems While some of these trends may continue in the future, we predict the following items could disrupt the pharmaceutical water industry in the future: More disposable technology (less cleaning and sanitization) Less customization of unit operations. Systems conservatively designed to operate on a wide range of feed water supplies More membrane based systems including the use of low pressure RO or nanofiltration Increase use of process analytical technology including on-line monitoring to make real time adjustments to process variables. This will ultimately include on-line bacteria and endotoxin testing. Point-of-use filtration. With the current uptick in the use of submicron filtration in the distribution loop piping, the next logical step would be to allow for terminal filtration at the points-of-use. Regardless of what the next impression or development is in the industry, hopefully focusing less on meeting regulatory expectations. This will lead to new, commercially successful, cost effective technologies and solutions enjoyed by other high purity water industries.

There were many predictions on how the pharmaceutical water market may be altered when the recent European Pharmacopeia (EP) Water for Injection (#WFI) Monograph change was adopted. Previously this monograph had limited the method of manufacture for WFI exclusively to distillation. Decades in the making, the EP WFI monograph was officially modified in the spring of 2017 allowing for alternate, and most logically membrane based, WFI production methods for water used in the manufacture of parenteral products sold into the European Union. Although there were many concerns surrounding this change, eventually the European Medicines Agency was confronted with enough scientific and operating data from the industry, coupled with an international push to harmonize standards, to recommend that alternate methods to distillation for generation of WFI be included in the EP WFI monograph. In the #pharmaceuticalwater industry where not much has changed over the last couple decades and with minimal new technologies introduced to the marketplace during that period, this was a big deal. Background Distillation has long been synonymous with the production of WFI, driven primarily by the EP monograph mandate, but also in that it is a very forgiving process. Although the feed water to distillation units should be carefully monitored for impurities that may cause scale or oxidation, short term operation will successfully produce WFI when fed potable water in most cases. In addition, once commissioned and validated, the operation of these systems require few modifications or tuning adjustments and have limited maintenance requirements. Pharmaceutical distillation units, however, are constructed of high grade stainless steels and require significant plant utilities, (e.g. plant steam, chilled water, and electricity) to operate. Compared to membrane based systems such as #reverseosmosis (RO), distillation based systems generally will have higher operating costs and require a larger capital investment. Stills are expensive. Impact on WFI Market There was no shortage of prognostications on the effect of the EP WFI monograph change may have on the pharmaceutical water industry. Certain companies such as large volume parenteral manufacturers and RO system fabricators had long lobbied for the change, and some hopefully predicted that distillation would be readily phased out as a commercially viable treatment technology. Other companies that either successfully operated or manufactured distillation units forecast minimal changes to the WFI market moving forward and that distillation would continue its dominance of the industry. What has occurred in the first year was not a universal acceptance of alternate WFI production methods but more of a moderate impact on the marketplace. While there has not been any sort of mass de-commissioning of existing distillation units for WFI manufacturing, membrane based systems for new WFI generation systems has certainly gained a foothold. There have been several WFI generation systems, mostly featuring RO, Electrodeionization (EDI), and terminal ultrafiltration (UF) that have been designed, installed, and successfully validated in the U.S. over the last year. Many of these employ #ozone for sanitization of the WFI storage and distribution systems eliminating the need for plant steam entirely. Yet, over that same time period there have been many distillation units validated for WFI generation as well. The Look Ahead There has undoubtedly been modest interest in membrane based WFI generation since the EP WFI monograph change was promulgated. Our experience is that most forward thinking companies that are willing to challenge traditional pharmaceutical industry standards have been the most receptive, in addition to those on a tight budget. We predict this interest will only increase as more non-traditional WFI systems successfully undergo regulatory scrutiny and inspections. The ultimate impact on the industry remains uncertain. There will inevitably be some highly publicized, ill-designed and operated systems that will cause some to be reluctant to consider alternatives to distillation. Other case studies will flaunt the capital and operating cost savings for membrane based WFI systems as paragons for future projects. For the foreseeable future, the WFI industry will continue to adopt change cautiously as the regulatory expectations, especially among EU inspectors) are revealed. Nevertheless, in the stagnant pharmaceutical water industry any type of change is welcome.