Pure steam and water for injection in the pharmaceutical industry

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The most common procedures for the production of water for injection and pure steam and their application in the pharmaceutical industry

Both pure steam and water for injection (WFI) are used in many areas of the pharmaceutical industry. Pure steam is mainly used for sterilizing tanks, filters and piping systems, as well as products in sterilizers. Moreover, it is used for air-moistening in cleanroom systems. WFI is used for the production of medicaments and intermediates, as well as for the final cleaning of equipment.

Quality has first priority with both the production of pure steam and WFI. Therefore, limit values are defined and, with the respective measuring technique, controlled and guaranteed. Production procedures are at least judged by their quality, but that alone is no longer enough. Because increasing energy costs lead to higher operation costs, GMP aspects have to be applied in reference to the pharmaceutical security and qualified and validated procedures with reference to process and control guarantee stability. Complete documentation and simple visualization systems that are matched to the user’s requirements are becoming increasingly important, since water-treatment systems are, in general, “energy provision systems.” They are not subject to daily variations, but must produce water of a constant quality over long periods of time. Service activities such as preventative maintenance and regular calibration work must be simple and practical, and must remain so in the future. This is supported by complete documentation and clear visualization concepts. The main emphasis is on quality-relevant data, but fault and alarm signals must be self-explanatory and easy to understand.

Since the specified water quality has to be achieved not only at the output of the water-treatment plant, but also at the points of use, due attention must be paid to the storage and distribution of the WFI produced by the water-treatment system. Integrated systems delivered in the form of turnkey projects guarantee comprehensive safety and compliance with the customer’s requirements and with applicable pharmaceutical regulations.

If we take a look at the defined manufacturing processes with respect to the requirements of the applicable pharmaceutical regulations, we see that both the United States Pharmacopeia (USP) and the Japanese Pharmacopeia (JP) permit, in addition to the classical distillation process, a membrane process with at least two stages. In reality, therefore, processes such as reverse osmosis (RO)/electrodeionization (EDI) with a following RO or ultrafiltration stage are already in use, but the membrane technology does not yet offer the high safety assurances provided by the phase transition from liquid water to water vapor in the distillation process. This is particularly true in cases where the WFI is not used as final rinse water, but is actually used in the production process. This means that distillation systems, as required by the European Pharmacopeia (EP), are still widely used in the U.S. and Japan.

Two physically similar systems with completely different principles are used for distillation, namely vapor compression (VC) and multiple effect distillation (ME) systems. Both methods are based on the physical law that any particles, endotoxins, pyrogens or other contaminants remain in the water during the phase transition from water to steam. Unfortunately, large amounts of energy must be transferred to the water in order to achieve this phase transition and this input of energy causes the water to move rapidly. This is, in fact, necessary in order to transfer the heat from the secondary medium (normally hot steam) to the water to be evaporated. However, this movement of the water can cause droplets of fluid to be formed and carried away with the water vapor. These droplets may contain undesirable contaminants and must be removed from the water vapor. An optimally designed system ensures removal of the droplets, is as small as possible, consumes as little energy as possible, and incurs as little investment cost as possible. Lastly, water-treatment systems must ensure that they themselves are not a source of particles or dust caused by mechanical wear in fast-running components such as pumps, compressors and similar devices. Both processes must comply with these requirements.

VC systems are based on the principle of the heat pump with four cycles: evaporation, compression, condensation and expansion. In these systems, the water is evaporated at a low pressure (in some cases, in a vacuum) and at a correspondingly low temperature. It is then condensed again. One advantage of these systems is the small amount of heat required. From the pharmaceutical viewpoint, however, this can also be regarded as a drawback sinc higher temperatures would provide better protection against the growth of germs in the water. In addition, mechanically rotating compressors are critical components of such systems because they are generally installed on the “clean” side of the process and are thus in direct contact with the water being produced. Still, the amount of energy that can be saved, particularly in systems which produce large amounts of WFI (> 5000 l/h), is considerable. Another benefit of these systems is that they need no cooling water. They are used primarily for the production of “cold” WFI, i.e., in cases where the water for injection has to be delivered at low temperatures to the points of use. VC systems are not widely used in Europe at present, and this is probably due to the widespread use of warm production and storage and also to the customers’ reservations with respect to the safety, maintenance and availability of these systems. Most of the VC systems in use today can be found in the United States.


Figure 1. Multiple effect distillation unit. Source: Christ Water Technology Group
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Without a doubt, most plants use the ME process for the production of WFI, where the evaporation capacity is split between several columns (see Figure 1). Depending on the yearly production and energy cost, as many as eight columns can be used. It is yet to be determined whether the energy savings from minor heating and cooling needs justify the capital expenditure that accompanies an increased number of columns.

As in VC systems, ME systems vaporize the feedwater only once. Due to the fact that there is a pressure gradient between the individual evaporator stages (columns), and the fact that only the first stage of such a system is heated with externally provided energy (steam or electricity), the maximum pressure must be achieved in this stage. Heating steam at a pressure of 8 bar is common, resulting in a pressure of up to 7 bar and a temperature of more than 150°C on the pure-steam side of the first column. Sufficient heating steam pressure is still the precondition for using seven or more columns, as there needs to be enough pressure to reach the necessary temperature gradient for the whole system. The water vapor produced by the first column is condensed in the second column, and the heat it releases vaporizes some of the feedwater. This process is repeated in the following columns, where the pressure gradually drops and the temperature falls to about 100°C. The pure steam leaving the last column enters a condenser cooled by the incoming feedwater, which flows in the opposite direction. At the end of the process chain, the WFI produced by the second and subsequent columns and the condensate produced by the condenser are cooled again to the necessary WFI outlet temperature of about 85° to 100°C.

This principle means that less heating and cooling energy is needed as the number of columns increases. If there are seven or more columns, and if cold feedwater is used, cooling water is unnecessary because the feedwater is sufficient for condensing the water vapor and cooling the final product.

When planning a facility for the production of WFI, investment and operating cost estimates and comparisons must consider the expenses for heating and cooling< necessary for production of the planned quantities of WFI.

A special form of the ME distillation system is the so-called “single effect” system. In this system, all of the WFI is generated in a single column. This system is generally used for lesser amounts of WFI (< 150 l/h) and short production cycles, as one liter of WFI represents high operating and small capital costs.

What is the difference between today?s ME systems and what benefits do they offer the customer?


Figure 2. Heat Exchanger for energy recovery. Source:Christ Water Technology Group.
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When comparing such systems, the first thing to consider is the number of stages or columns. Only by comparing like systems (i.e., with the same number of columns and preheaters) can one compare expected operating values. Some manufacturers only offer preheaters as an option, but a comparison of the operating and investment costs makes their use almost indispensable. Further reductions in the operating costs can also be achieved by using the hot condensate for preheating the feedwater, instead of using external energy (see Figure 2). With respect to minimizing the investment costs, consider the option offered by some systems for parallel extraction of pure steam from the first column. Increasing the size of the first column may make it unnecessary to invest in a separate pure-steam generator. The importance of manufacturing in accordance with GMP means that the manufacturer should pay close attention to the details. Wherever possible, for example, the pure medium (WFI or pure steam) should be transported through the pipes of the cooler and the condenser, and not through the outer shell. Proven principles, such as the FDA-compliant design of double-tubes or the possibility of integrating the WFI outlet valves directly above the tank, allow complete sterilization of all plant components. These aspects can be regarded as improvements in pharmaceutical safety.


Figure 3. Pure steam generator. Source: Christ Water Technology Group
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As can be seen from the process steps described above, the generation of pure steam consists of vaporizing the water and removing any droplets, but not the subsequent condensation and cooling. In other words, it consists of the steps executed in the first column of an ME system (see Figure 3). VC systems are not suitable for this because the objective is to create stable high pressures and temperatures.

At this point, we should take a look at the various evaporator principles used in ME distillation systems and thus in pure-steam generators. There are two different kinds of evaporators: falling-film evaporators and circulation evaporators. Both types use completely water-filled heat transmitter pipes.

In addition to steam quality, the stability of pure-steam pressure and a fast reaction rate in the system are extremely important to the extraction and production of changing amounts of pure steam. The circulation evaporator can meet these requirements better because it contains a large quantity of hot water that automatically evaporates when the pressure drops, and thus maintains the production even before the heating system can react. This large amount of hot water has an additional advantage over the input of cold feedwater: it does not cause a large drop in the steam pressure. The system can compensate for variations without the need for preheated feedwater.

In the case of the falling-film evaporator, additional preheaters or pumps must be installed in the hot circulation area in order to achieve the same effect. This will increase the costs of operation and maintenance.


Figure 4. Floating heat exchanger design. Source: Christ Water Technology Group
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Another factor common to all pure-steam systems must be considered: the continual cycle of heating and cooling and the resulting thermal stresses. Subject to much less thermal stress, designs with floating internal heat exchangers are clearly superior (see Figure 4).

The quality requirements for pure steam are generally the same as for WFI. However, with respect to dissolved gases, the requirements of EN 285 must also be observed. This standard specifies that the dissolved gases may not exceed 3.5 percent by volume. This particularly applies to processes where the pure steam is used either directly or indirectly for the sterilization of pharmaceutical products in sterilization chambers. It is not applicable to pure steam generators that are used for air-moistening in cleanrooms. There, it is important that the pure steam is sterile in order to avoid the possibility of contamination in pharmaceutical production.


Figure 5. Conductivity of CO2. Source: Christ Water Technology Group
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With respect to the requirements of EN 285, two physical principles must be taken into account: the solubility of gases in water and the specific conductivity of carbon dioxide in ultrapure water. The only gases which can be present in ultrapure water are oxygen, nitrogen, carbon dioxide and the various noble gases, all of which may be present in the ratios in which they exist in the surrounding air. It should also be remembered that all volatile components are transported into the steam generator with the feedwater and will be present in the pure steam or its condensate (WFI). Because the quality of the feedwater is affected by the generation, storage and distribution of dissolved gases, all measures for reducing the amount must be implemented before the water reaches the steam generator. The method of membrane degassing during production of the ultrapure water is a relatively new process through which the conductivity of the product is decreased by removing carbon dioxide (see Figure 5). CO2 absorbers on the storage tank have a similar effect. As water is removed, they absorb the CO2 from the air entering the tank. However, this measure accounts for only a small amount of the dissolved gases which can be expected in the water.


Figure 6. Skid-mounted membrane degasser. Source: Christ Water Technology Group
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There are only two possible solutions for reducing the solubility of gases in ultrapure water: hot storage of the feedwater or membrane degassing with vacuum support immediately before the water enters the pure-steam generator. In principle, both of these methods are suitable for continuous operation in order to reduce the amount of gases which cannot be condensed from >3.5 percent to <1 percent. However, because the water has to remain in the hot system for some time in order to remove the gases, hot storage of the feedwater is relatively expensive, and the storage systems are large and costly. Membrane degassing systems need less space and can be operated with a continuous flow of water. From the pharmaceutical viewpoint, such systems should be sanitized with hot water from time to time, but this is easily possible with the modules currently available on the market. Some manufacturers are already installing the membrane degassing systems directly on the rack of the pure-steam generator and are offering this combination as an FAT-tested “black box” (see Figure 6).

The technical details and theoretical principles presented show that optimal production of WFI and/or pure steam is subject to many different considerations and requirements. These factors must be considered as part of all interacting systems for the production and use of pharmaceutical water. The manufacturing of WFI cannot be considered in isolation, and the comprehensive expertise provided as part of a turnkey project is essential for the successful operation of the overall system. III

Rene Bratz studied process engineering at the University of Technology in Dresden, Germany. Currently, he is a product manager for pharmaceutical plants at Christ Pharma & Life Science AG in Aesch, Switzerland, where he is responsible for the development of Multitron distillation units and Vapotron pure-steam generators. Prior to that, he was a project manager with Pharmatec Deutschland GmbH in Dresden, Germany, where he was involved with planning and development of water plants, WFI distillation units, pure-steam generators, and sterilizers.

 

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