Water for Injection (WFI) international pharmacopoeial standards have been brought closer through harmonization efforts, but significant differences still exist. The USP WFI monograph allows production by “distillation or a purification process proven to be equal to or superior to distillation.” USP language is the least restrictive in terms of acceptable processes among the major pharmacopoeial groups. The Japanese Pharmacopeia (JP) allows distillation, or reverse osmosis (RO) followed by ultrafiltration (UF). Distillation is the only WFI method of production that is approved by the European Pharmacopoeia (EP).
Historically, distillation has been the preferred method for producing WFI in the biopharmaceutical industry, and today, most pharmaceutical WFI is produced by distillation. Regulatory requirements have helped significantly in the domination of WFI production by distillation, but distillation has also been successful in attainment of the water quality specifications. Yet, most other high-purity industries use reverse osmosis, deionization and ultrafiltration, not distillation, to produce WFI equivalent or higher quality water. Type A laboratory water limits for total bacterial count and endotoxin are respectively ten and eight times lower than WFI. ASTM Type 1.2 water for microelectronics has similar microbial restrictions with total organic carbon and conductivity limits well below WFI. Those applications are routinely satisfied with membrane-based systems producing water at ambient temperature. Those industries, however, do not have regulated process limitations.
Distillation Based WFI Systems
To meet USP requirements, WFI must be produced by “distillation or a purification process proven to be equal to or superior to distillation.” Additionally, the water must pass conductivity and total organic carbon (TOC) tests, and the bacteria endotoxin level must be below 0.25 endotoxin units per milliliter (EU/mL). The microbial level must not be above 10 colony-forming units (CFU) per 100 mL. Distillation is effective at quantitative reduction of most water contaminants and can produce water with low conductivity, low TOC, low microbial levels and low endotoxin levels.
Almost all pharmaceutical distillation based systems implement either multiple effect or vapor compression stills. Both still types employ various techniques for recovery of latent and sensible heat to minimize energy consumption. Both technologies produce WFI quality water when properly implemented and operated. Each still type has advantages and disadvantages and each has significant successful operational history.
While stills are reliable, they are not perfect, and can produce pyrogenic product water when operated incorrectly, when they fail mechanically or when the feed water contains contaminant levels beyond the still reduction capability. If fed with high endotoxin feed water from the raw supply or pretreatment equipment, in cases where there is no membranebased system pre-treating the still, the product water from the still may fail the endotoxin test. Many successful distillation systems exist with no membrane pretreatment, but several other systems have required retrofit of reverse osmosis (RO) or ultrafiltration (UF) pretreatment after periodic product water endotoxin failures due to high still feed endotoxin levels.
The FDA Guide for Inspections of High-Purity Water Systems recognizes the still pretreatment design question regarding potential use of a membrane process. Section V of the Guide states, “Many of the still fabricators will only guarantee a 2.5-log to 3-log reduction in the endotoxin content. Therefore, it is not surprising that in systems where the feed water occasionally spikes to 250 EU/mL, unacceptable levels of endotoxins may occasionally appear in the distillate (WFI). For example, three new stills, including two multi-effect, were recently found to be periodically yielding WFI with levels greater than 0.25 EU/mL.”
The FDA Guide further states, “Pre-treatment systems for the stills included only deionization systems with no RO, ultrafiltration or distillation. Unless a firm has a satisfactory pre-treatment system, it would be extremely difficult for them to demonstrate that the system is validated.” The decision to implement or not implement reverse osmosis in still pretreatment is generally more relevant to vapor compression stills than multiple effect stills. Vapor compression stills operate at a necessary for scale and corrosion prevention. Multiple effect stills generally require feed water with low levels of chloride, silica and total solids and are almost always pretreated with reverse osmosis and/or an ion exchange process. Since reverse osmosis is present in almost all ME still feed systems, the feed endotoxin levels are quite low.
Vapor Compression Distillation
Vapor compression distillation systems generally implement scale control, dechlorination and in some cases reduction of ionized solids and/or endotoxin. A vapor compression distillation system often consists of softening, heat exchanger, hot-water-sanitizable activated carbon, prefilter, optional hot-water sanitizable RO and finally, a vapor compression still. The key design consideration is inclusion or exclusion of RO. RO is excluded when ionized solids and endotoxin reduction is not deemed necessary for reliable, consistent attainment of WFI quality parameters. RO is implemented when the user believes that reduction of endotoxin and ionized solids in the still feed assures that WFI quality is consistently attained, maintenance is minimized and hot blowdown is minimized. Many systems of both types are in operation. If only endotoxin reduction is desired in the still pretreatment system, UF may be substituted for RO.
Besides meeting all pharmacopoeial requirements, vapor compression distillation offers other advantages:
- Generally reliable operation
- Typically more energy efficient than multiple effect distillation
- Can be operated on softened/dechlorinated feed
- May not require a complex system design
- Relatively low maintenance
Potential disadvantages of vapor compression stills include:
May be more labor intensive than multiple effect distillation with compressor and associated drive gear
May have higher life cycle cost than membrane based systems
Multiple Effect Distillation
A multiple-effect distillation (MED) system often consists of a multi-media filter, softening, break tank, heat exchanger, hot-water-sanitizable activated carbon, prefilter, optional pH adjustment, 254-nanometer ultraviolet (UV) light, hot-water-sanitizable RO, continuous electrodeionization (CEDI), followed by the multiple-effect distillation unit. The pretreatment system is generally comprehensive because the high operating temperature makes MED stills susceptible to chloride stress corrosion and scale. The pretreatment system typically minimizes chloride, silica and total dissolved solids levels. Membrane based pretreatment typically reduces endotoxin to very low levels such that the still
endotoxin challenge is negligible.
Besides meeting all pharmacopoeial requirements, multi-effect distillation has the advantage of few moving parts and this can minimize maintenance requirements.
Potential disadvantages include:
- Generally requires high-quality feed water: less than 0.5 ppm chloride; less than 1.0 ppm silica; less than 5.0 μS/cm conductivity
- Typically higher energy costs than vapor compression distillation
- Typically higher cooling water requirements than vapor compression
- May have higher life cycle costs than membrane-based system
What Other Treatment Methods Work?
A number of separation methods, such as RO and UF, can remove endotoxin. Oxidation with ozone also removes endotoxin. Heat, distillation, UF, RO, filtration, ozone, UV and chemical methods can all achieve low microbial levels in the product water. Other market applications such as microelectronics and select laboratory water types have water quality specifications far tighter than WFI including extremely low endotoxin limits. Almost all of these systems utilize membrane technologies for primary treatment. Membrane systems may offer lower operating economics as no water evaporation occurs. Systems either operate at ambient temperature normally or are heated to high temperature without evaporation and condensation. The content of stainless steel is often less with membrane systems compared to distillation.
Membrane-Based WFI Systems
Most alternative designs to distillation have used one or two passes of RO, often with an ion exchange process and in virtually all cases, final polishing with UF or RO. The system designs over decades have been driven by practicality and regulation. The first alternative to distillation allowed by USP decades ago was RO. RO technology was generally not up to the task of consistent WFI performance and the technology did not flourish. Hot water sanitizable membranes did not exist and chemical sanitization was often inconsistent, allowing periodic microbial excursions beyond WFI specification. Some validated systems existed, but placements were few.
The presence of membrane systems was enhanced when the Japanese Pharmacopoeia allowed RO followed by UF as an alternative to distillation. Hot water sanitizable and continuous hot ultrafiltration elements were available and contributed to successful operation. Ultrafiltration had a lengthy, successful history in pharmaceutical manufacturing and was accepted. This technology change led to implementation of more systems that produced “WFI quality” water where pharmacopoeial WFI compliance was not required.
The change by USP to open WFI production to “distillation or a purification process proven to be equal to or superior to distillation” has helped to increase interest in membrane based WFI systems.
EP has created a monograph for Highly Purified Water with no process limitations and water quality specifications identical to WFI. This has helped to increase membrane system placement for production of “WFI quality” water.
Two-pass RO (TPRO), also known as product staged RO, was one of the earliest WFI membrane configurations. TPRO systems were more popular prior to the presence of conductivity and TOC tests. At that time the USP WFI monograph only allowed distillation or RO for process and it was accepted that the still or RO would be the terminal process. FDA had noted in The FDA Guide for Inspections of High-Purity Water Systems that if RO was used for WFI that two stages should be used to assure attainment of the quality specifications. TPRO can typically meet all of the required water quality parameters, but consistent attainment of Stage 1 conductivity can be an issue with some feed waters. TPRO systems often consist of a multi-media filter, softening, break tank, heat exchanger, hot-water-sanitizable activated carbon, prefilter, optional pH adjustment, 254-nm UV and two stages of hot-water-sanitizable reverse osmosis.
The implementation of a WFI conductivity test requirement and the liberalization of the USP WFI allowable processes increased use of systems implementing reverse osmosis, ion exchange processes and ultrafiltration or a final stage of RO. The logic of this type of system configuration is that the combination of reverse osmosis and ion exchange easily meet the conductivity and TOC specifications while the final ultrafilter or RO stage assures compliance with the endotoxin and microbial requirements. Systems of this type have had a lengthy history in production of “WFI quality water” prior to acceptance as a method to produce WFI to pharmacopoeial standards. The basic system capability for production of water with low contaminant levels has been long proven in other markets such as microelectronics for decades.
Most membrane based systems have several components that are either intermittently hot water sanitized or maintained continuously at a self sanitizing high temperature. Some systems have a final membrane stage that operates at the same elevated temperature as the storage and distribution system. Several systems of this type have been in operation for over ten years with water quality performance equivalent to distillation based systems.
A typical membrane based WFI system includes dechlorination, softening, a hot-water-sanitizable RO device followed by a hot water sanitized CEDI device. A continuous hot-water UF device polishes the water prior to storage and use as WFI if the water will be stored hot. A hot water sanitized UF or RO serves as the final stage if the product water will be stored at ambient temperature.
Advantages of using RO/RO or RO/UF to produce WFI are as follows:
- May be the lowest life cycle cost alternative
- Typically low energy requirements
- Typically very low conductivity, TOC, endotoxin and microbial levels
- Generally reliable operation
- Can be intermittently or continuously hot sanitized
- There is some history in the U.S. Pharmacopeia and Japanese Pharmacopoeia of using RO and UF for WFI \
The most significant disadvantage is that EP does not allow a WFI production method other than distillation and therefore WFI membrane use is limited to non-EP applications. The history of membrane based WFI system usage is significantly less than with distillation, and this has negatively affected confidence in membrane systems among
some pharmaceutical companies. Additionally, the RO system requires periodic cleaning, the membranes must be replaced at some point, and membranes can fail just as any technology has failure mechanisms.
Capital and operating cost comparison for distillation and membrane based systems is a key element of system choice when regulatory requirements do not dictate distillation only. This paper does not provide costs for several key reasons. Equipment specifications for materials of construction, instrumentation, control and other major cost factors impact capital costs significantly and capital costs are meaningless without detailed specifications. Operating costs are directly impacted by utility costs for water, wastewater, power, steam, chilled water and others and vary tremendously site to site. These costs are best based upon actual conditions case to case for accurate analysis. The significant possibility of lower life cycle economics for membrane based systems is based upon the relative absence of distillation based systems in non-regulated high purity applications.
Why Has Membrane-Based WFI Production Failed to Flourish?
With all the potential advantages of using membrane based technologies for producing WFI, why has it not caught on in the industry? For one reason, when RO was first approved for use in WFI production, the technology was not completely “ready” for this application. Hot-water-sanitizable RO did not exist, and chemical sanitization is not as effective as heat. Full-fit RO membrane elements were not available and neither was continuous hot operation. Early failures discouraged use, and, while endotoxin control was not a problem, microbial control was. Ultrafiltration technology, while “ready,” did not have USP or EP approval.
Membrane technology has a significant successful history in production of WFI in Japan and in the U.S., but membrane system implementation is limited to facilities or applications where the EP requirements are not a factor. Since a significant percentage of pharmaceutical manufacturers produce for the European market, the EP distillation requirement stifles membrane implementation.
Most WFI systems are distillation based. Distillation has a lengthy successful history in WFI production. Most other high purity systems in other markets use membrane processes rather than distillation, but no regulatory requirements exist. Water quality specifications for use such as microelectronics manufacturing often greatly exceed WFI quality requirements.
USP and JP allow membrane based designs as well as distillation. The EP requirement for distillation eliminates any choice of alternate technologies for companies wanting to comply with EP. Membrane based systems are therefore only employed where EP compliance is not required or where “WFI quality” water is desired such as for meeting the requirements of EP Highly Purified Water, preparation of intermediates or other uses.
Although some successful membrane based systems have been in operation for several years, the historical database is not nearly as large as for distillation. Membrane-based systems are beginning to be placed and are considered more frequently because membrane based systems may offer lifecycle cost advantages in reduced capital or operating costs. The choice is one of many riskbased decisions in the pharmaceutical industry. Users need to consider product, market, capital cost, utility costs, commissioning/qualification, maintenance and risk to make an informed decision.
Case Study for WFI Production: Alkermes, Inc.
Alkermes pulmonary drug delivery platform technology enables delivery of both small molecules and complex macromolecules to the lungs. This system can provide efficient dry-powder delivery of small molecule, peptide, and protein containing drug particles to either the deep lung or the upper respiratory tract, based on the product needs. Alkermes designed and built a manufacturing facility to support production of late stage clinical supplies as well as commercial production of its pulmonary drug delivery products. The manufacturing operations at the site include spray drying to produce the bulk dry powder, capsule filling, packaging, CIP systems for cleaning, and a clean steam system. The purified water system was designed to support the formulation activities associated with production of the bulk powder in the spray drying operation, the CIP system for cleaning process equipment, and as feed water to the clean steam system.
Dry powder inhalation products are typically not produced under aseptic manufacturing conditions. Based on this, the initial project requirements specified USP Purified Water as the appropriate grade of water for the manufacturing site. This decision was revisited after detailed engineering had been completed on the project. The review team identified a potential for tightening of microbial specifications in the final drug product, particularly for products that might be used in patients with compromised immunosytems. Based on this assessment, it was decided that the microbial specifications of the water should be tightened as well to support the current as well as any future drug product microbial and endotoxin requirements.
The water system had already been ordered and was in fabrication when the system requirements were changed. The Alkermes engineering team met with the system supplier to identify solutions that could meet the revised water system requirements while minimizing the impact on the cost and schedule of the project. Several options were discussed, including the option of the reverse osmosis and continuous electrodeionization (CEDI) systems that were already specified as being able to meet the new requirements, and installation of a still to produce WFI grade water. The team identified the addition of an ultrafiltration step as the best way to meet the tightened water specifications while minimizing the cost and schedule impact to the project. The system supplier was willing to guarantee that, with the addition of an ultrafiltration step, the water generation system would be able to meet USP Water for Injection specifications with regard to microbial and endotoxin requirements.
The ultrafilter unit operation is relatively small physically and had a minimal impact on the layout of the generation and distribution system. This minimized any costs associated with piping layout changes. It also minimized the schedule impact because it did not require significant re-piping to accommodate the ultrafilter unit into the layout. The ultrafilter unit and hardware also had short lead times, which further minimized the impact to the overall project schedule. In addition, the capital cost of the ultrafilter system was relatively small. This minimized the impact to the project cost.
System Description and Discussion
The Alkermes water system is designated as an EP Highly Purified Water (HPW) System. The system consists of a generation system that is supplied with city water and produces up to 8 gpm of highly purified product water that meets USP, WFI test specifications. The product water is supplied from the HPW generation system to the top of a 3,000 gallon hot storage tank that is maintained at 80°C. The hot water storage loop is continuously circulated by pumping water from the bottom of the storage tank, through a heat exchanger and back into the top of the storage tank. If the storage tank is full, the product water is circulated back to the HPW generation system as feed water.
The HPW distribution loop is self contained and normally maintained at room temperature or 24°C. The HPW distribution loop and hot storage loop are connected so that when water is drawn from the distribution loop, hot water is supplied from the storage loop to the distribution loop. A heat exchanger in the HPW distribution loop cools the water prior to feeding the water out into the plant and to the use points. Every 24 hours the cooling heat exchanger is turned off and the HPW loop is heated to 80ºC and held at temperature for 60 minutes. The system design is based on the “Hot Storage – Self Contained Distribution” design that is described in the ISPE Baseline Guide, Water and Steam Systems.
The overall water system includes several unit operations to meet the required product specifications. City water from the Massachusetts Water Resource Authority system is filtered using a multi-media filtering system to remove coarse particulates. The first unit operation in the HPW generation system is the particulate filter system. The particulate filters are nominal 5.0 μm cartridge filters designed to remove large particulates from the incoming feed water. The particulate filter system includes two banks of five cartridge filters, each of which can be operated in parallel with either one or two units in operation.
The next stage in the HPW generation system is a duplex water softening system. The water softening system is an ion exchange process that is designed to remove divalent and trivalent ions from the incoming city water and replace them with a monovalent sodium ion. The softening process prevents scale in the reverse osmosis unit downstream.
Two activated carbon filter skids in parallel are located downstream of the water softeners. The carbon filters are designed to remove chlorine from the feed water. Chlorine is added by municipal authorities to the city water as a microbial control agent. Chlorine can oxidize the reverse osmosis membranes and negatively impact system performance. In addition, it is recognized that the carbon beds can serve as an environment for microbiological growth once the chlorine is removed. The heat sanitization cycles for the carbon filters are designed to control the bioburden levels in the carbon filters.
Ultraviolet (UV) lamp units are installed downstream of the carbon filters for inhibiting microbial growth after the chlorine has been removed by the carbon beds and prior to feeding the RO membranes with the in process water. The intensity of the UV lamps is monitored and documented in rounds sheets during routine operations of the system.
The next stage in the HPW generation system is the reverse osmosis process, which is part of the final treatment system. The system includes single pass RO membranes. The RO process is a pressure driven process with a semi-permeable membrane designed to remove minerals, organics, particulates, microbiological material, and endotoxin. The RO membranes reject a significant portion of the feed stream while allowing a portion of the purified water stream to pass through the membrane. The daily performance of the RO membrane is monitored by measuring the percent rejection of conductive elements in the feed water to the reverse osmosis unit.
The CEDI unit is located downstream of the RO membranes and removes ionized species from water using electrically active media and electrical potential to effect ion transfer. The CEDI system is a continuous process in that the ions are continuously removed and the ion exchange resins are regenerated continuously. In addition, there is a UV unit as part of the CEDI skid. As discussed above, the UV unit is designed to limit microbial growth. The last unit operation in the final treatment portion of the HPW generation system is the ultrafiltration system. The ultrafilter (UF) includes a 0.02 μm single pass filter and is designed to provide the final step in meeting the WFI specifications. Figure 1 includes a process flow diagram indicating the different unit operation steps in the HPW generation system.
Heat is used to sanitize both the HPW generation system and the HPW distribution system. The carbon filter, reverse osmosis skid and associated piping are sanitized weekly using 80ºC water. The entire generation system including the carbon filter, RO skid, CEDI system, ultrafilter and associated piping is heat sanitized monthly. The distribution
system is sanitized nightly by heating the entire distribution loop to 80ºC.
The HPW generation and storage and distribution system was routinely monitored with a combination of in-line and off-line testing to confirm that the system was performing as expected. Critical performance attributes were identified for the unit operations within the generation system, along with appropriate test methods and acceptance criteria. The
performance attributes were routinely monitored to confirm that the system was performing as expected. This includes, for example, routinely monitoring the free chlorine and bioburden levels after the carbon filter. In addition, the storage and distribution system was monitored at various points throughout the system. This included a rotating schedule of sampling various use points and testing for bioburden, endotoxin, conductivity, TOC, heavy metals and nitrates. Appropriate specifications were established for the use point monitoring that included alert and action levels for the various attributes. Data and acceptance criteria are presented below.
As discussed above, the HPW was used for cleaning operations, clean steam feed water, and for formulation activities in producing dry powders used for inhalation therapies. Alkermes identified test attributes and specifications along with acceptance criteria that were appropriate for the intended use of the water. The specifications met the standards outlined for WFI compendial grade water.
The HPW storage and distribution system was sampled and tested on a routine basis to monitor the quality of the water. The schedule included sampling and testing of water from various points in the HPW storage and distribution system. Data is presented below from the January through December 2007 period that demonstrates the overall performance of the system. The data includes test points from the outlet of the generation system before the product water enters the storage and distribution system as well as at use points within the storage and distribution system.
Endotoxin test data is presented below from two different sample points in the HPW system. Figure 2 includes data from the generation system outlet. Figure 3 illustrates data from a charge port on the distribution system which is used to fill a formulation tank. In both cases, all samples were found to be below the detection limit of 0.05 EU/mL, which satisfies the alert limit of Not More Than (NMT) 0.13 EU/mL.
Total aerobic bioburden test data is presented below from two different locations in the HPW system for the period January through December of 2007. Figure 4 includes data from the outlet of the HPW generation system. Figure 5 includes data from a charge port on the distribution system, which is used to supply a formulation tank. In both cases, all test data from the ports were non-detectable for bioburden, or below the alert limit of NMT 1 CFU/100.
Total organic carbon (TOC) data is presented for the formulation tank charge port, which is located on the HPW distribution system. The data is plotted in figure 6. The acceptance criteria include an alert limit of NMT 250 ppb. All values tested during the January to December 2007 period were below the alert limit of 250 ppb.
This case study presents data demonstrating that WFI can be produced using a membrane based water purification system. Monitoring data from a calendar year are presented for several critical performance attributes of the HPW generation and distribution system. All of the critical performance attributes met the standards outlined for WFI compendial grade water.
A membrane based water purification system was chosen to minimize cost and schedule impact when the design basis was changed during the construction phase of Alkermes’ manufacturing site. The addition of an ultrafiltration unit operation, which is compact in size, minimized the impact on the design and layout of the overall water system. The ultrafilter had a relatively short lead time and the capital cost was low. In addition, the operating cost of the ultrafiltration unit is significantly lower than the operating cost of a still, minimizing the impact on operating costs.