December 1, 2006 (Vol. 26, No. 21)
Exploring Alternative Technologies and More Judicious Consumption of Water-for-Injection
The pharmaceutical industry is facing strong and growing pressure to reduce the cost of producing drugs. One universal way to do that is to cut operating expenses, lowering the day-to-day costs of doing business. Minimizing energy and utility usage can have a significant impact on the bottom line.
Water and the energy needed to heat, purify, store, and distribute it throughout a facility is one of the biggest expenses. “Water can cost, in some plants, more than the active ingredients,” says Gary Zoccolante, pharmaceutical technical manager at Siemens Water Technologies (www.siemens.com). Siemens acquired U.S. Filter in 2004, and that acquisition became the cornerstone for the development of Siemens Water Technologies, with U.S. Filter’s water purification products and solutions transitioning to the Siemens name throughout 2006.
Although pharma has talked about improving efficiency and saving power and water for years, Zoccolante sees signs that they are now more serious about doing so and are willing to invest capital.
Most bioprocessing and formulation operations use water-for-injection (WFI), the highest purity water and the most costly to produce. For cleaning applications, at a minimum, the final rinse water will be WFI. Prerinse and chemical cleaning cycles typically use USP purified water. USP defines purified water as containing <100 colony forming units (CFU)/mL and WFI as <0.1 CFU/mL.
Publication of the ISPE Baseline Guide for Water and Steam helped drive a change in thinking, opening people’s minds to new ideas, says Pete Matson, a senior process engineer at Alfa Laval Biokinetics (www.alfalaval.com), and giving more discretion to the engineers for decisions involving design and operational parameters.
Before the ISPE guidelines, for example, conventional wisdom held that WFI must be circulated at 80°C. The guidelines, however, stated that bacterial growth could be controlled by maintaining water temperature above 65°C, giving facilities more flexibility in the design and operation of water systems. By circulating water at a lower temperature, it takes less energy to cool down the water required for use at ambient temperature. Additionally, a lower circulating temperature would have implications for the materials used in water systems, making it possible in some settings to replace 316-L stainless steel components with thermostable plastics rated for use at 65°C.
Keeping Pace with Demand
“Demand (for WFI) is definitely growing,” says David Junkhan, lead process engineer at A and B Process Systems (www.abprocess.com), with more plants being built and WFI being used for more applications. The company specializes in the design and installation of engineered-to-order water storage, distribution, and delivery systems.
About four or five years ago, some CIP applications did not require WFI. Now that they do, these regulatory drivers are causing some existing systems “to be taxed to their capacity,” says Junkhan. As volume requirements increase, stressing the distribution and storage systems, higher degrees of maintenance are required. Furthermore, with the need for expanded capacity for WFI at ambient temperature at point-of-use sites throughout a facility, installation of additional cooling units adds to both capital and operating costs.
In Junkhan’s view, companies are being challenged to be more creative in designing water systems that can limit the use of WFI and purified water, use smaller amounts of water to do the same job (especially for cleaning), and, in general, find ways to economize across multiple points of operation.
A key cost-cutting trend is more targeted utilization of WFI. USP-purified water may be adequate for many processes used to manufacture biopharmaceuticals, for example, due to the extensive downstream processing, purification, and microbial elimination processes these types of products typically undergo. “Making the active ingredients uses the most water,” says Zoccolante of Siemens. Clean-in-place (CIP) processes in particular consume tremendous volumes of water. For CIP, purified or noncompendial water is typically sufficient for all but the final rinse, and companies can drive down costs by minimizing WFI use in these areas of operation.
Whereas it may be easier to install a single water system in a facility, and by necessity that would generate WFI to meet the highest level requirements, companies are now more willing to operate dual systems, using WFI only where required and generating USP purified or noncompendial water whenever possible. Over time, the reduced energy costs can offset the cost of installing and operating more than one water system.
In addition to WFI and USP purified water, in Europe there is a third class of water called “highly purified water, like a super grade of USP,” points out Chris Fournier, vp of marketing at Mar Cor Purification (www.marcorpurification.com). It can be used for preliminary rinsing and cleaning steps, for example, thereby reducing the size of the WFI system needed.
Unlike WFI, which is traditionally produced with a still, highly purified water is not boiled. Instead, it goes through various pretreatment steps, one or two RO passes, a deionization step, and sometimes ultraviolet radiation and a final filtration step. The end result is highly purified water that is equivalent to WFI but produced at a lower cost.
The RODI-HPW (RO/electrodeionization systems are Mar Cor’s highest quality water treatment systems for producing a highly purified grade of water. The company also offers single- and two-pass RO systems, hot water sanitizable RO and EDI systems, service deionization systems, and electrodeionization systems.
In sync with efforts to use USP-purified water more selectively, particularly in earlier phases of CIP, some companies are using softened water for the prerinse and chemical cleaning cycles, according to Steve Orichowskyj, engineering team leader at Alfa Laval Biokinetics. The advantages of this approach are savings in production costs, less water waste, and lower maintenance, validation, and testing costs.
“Every site has its own needs, experience, and bias,” says Greg Hoyt, senior bioprocess specialist at Alfa Laval. Customers also have different comfort levels with change. “A lot of customers are hesitant to use softened water,” he adds, especially if they are producing a high-value product. The use of softened water may be a more attractive option for companies with large-scale manufacturing operations, in which cost factors are more closely linked to commercial success.
“In the pharmaceutical market, I see an increasing use of ozone for sanitization of distribution loops,” says Fournier. He describes the use of low levels of ozone as a viable replacement for heat sanitization, which carries high energy costs, or for chemical sanitization methods, which require disposal of chemical waste down the drain and the need for copious amounts of high purity rinse water as key concerns. Ozone naturally breaks down in a short period of time and is destroyed when exposed to ultraviolet light, facilitating its removal from the distribution system.
Pure Water on Demand
Tenergy Christ Water (www.tenergychrist.com) installed an ozone-based Duplex 33-gpm USP water system in a new manufacturing facility for Winnepeg-Canada-based Cangene (www.cangene.com). The custom-designed system includes a loop distribution skid that utilizes a steritron electrolytic ozone generator for water sanitization.
Siemens developed its patent-pending S3 system to reduce energy costs associated with generating purified water. Whereas in most pharma plants both water generation and distribution systems recirculate sanitized water continuously to maintain microbial control, the S3 (sanitize/start/stop) process does not run all the time. It starts and stops on demand to generate USP-purified water as needed using brief hot sanitization cycles. The system is also applicable for pretreatment in a WFI system, which has historically relied on continuous recirculation as well.
For small-scale WFI cooling needs, Alfa Laval’s Pharma-X unit provides point-of-use ambient water on demand. The manual system accommodates low flow-rate usage. WFI flows at high temperature and then passes through a tube-in-tube heat exchange system that delivers WFI at ambient temperature on demand.
Millipore’s (www.millipore.com) water purification systems are designed primarily for research labs, QA/QC labs, and other support activities for pilot and production plants. They generate purified water that meets general laboratory norms, including several standards set by the U.S. and European pharmacopeias.
Earlier this year, Millipore introduced the Milli-Q® Advantage water purification systems, which can accommodate up to three ultrapure water delivery points. Each has a final purifier that removes specific contaminants. The BioPak™ filter connected to the outlet of a Milli-Q system reduces pyrogen levels in ultrapure water below 0.001 EU/mL and provides nuclease-free water.
Zoccolante describes a trend toward more standardization in the design of water systems to reduce engineering and equipment costs, minimize variability in system design and operational parameters, and accelerate procurement cycles to shorten construction and renovation times.
Engineering and design firms are working with the manufacturers of water purification equipment to increase the flexibility of their systems and ease their integration into existing facilities. Instead of having to break-up or rearrange a traditional water purification skid to accommodate the footprint or configuration of an existing space, engineering and design firms are encouraging manufacturers to take a more modular, standardized approach to system design.
Additionally, as more large-scale manufacturing facilities are being built, companies are looking more seriously at the amount of “wastewater generated by water pretreatment systems and point-of-use coolers,” says Orichowskyj.
The large volumes of wastewater generated in facilities with 100,000– 200,000 L of capacity are forcing companies to look at new usage strategies and innovative water generation and distribution technologies.
Matson points to the FDA’s PAT initiative as another factor driving change in the area of water usage and helping to minimize waste from cleaning processes. “Instead of validating the cleaning process based on an arbitrary time period, with PAT you would validate to a set parameter,” he says, enabling a more data-driven approach that can shorten cleaning and rinse cycles.
As part of PAT, companies are trying to gain a better overall understanding of manufacturing processes. This would include evaluating their water usage and doing risk assessment for replacing WFI with USP-purified water in high-volume applications.
Maintenance is another important issue, with a heightened emphasis on using performance data and analysis of trends to ensure that a particular system or process is maintained in a validated state, observes Sean Murphy, worldwide validation project manager for bioscience division at Millipore. Evidence of variability during routine assessments would allow for preventive actions that “minimize deviations in water quality, downtime, and questionable data,” says Murphy.
Orichowskyj notes a trend toward greater reliance on simulation tools for cycle development and optimization and for estimating water use when designing and constructing a large facility.
The goal would be to minimize water use wherever possible, minimize waste and energy needs, maximize efficiency in water generation, optimize water distribution systems, and enable the production of water with the necessary storage/surge capacity to meet fluctuating demands.
Finally, the increasing use of disposable systems and components in bioprocessing applications, such as single-use bag systems, will affect water usage and production costs simply because the use of disposables means there will be fewer vessels to clean.