A reliable method for producing highly purified water.

On 1 June 2002, the European Agency for the Evaluation of Medicinal Products (EMEA) released the water quality standard highly purified water (HPW).¹ The composition of HPW is identical to the quality of water for injection (WFI), as defined in the European Pharmacopoeia (EP).² Although HPW meets the same quality standards as WFI, it is not accepted for applications requiring WFI quality (Table I).

Figure 1: Construction of the hollow fibre module.

This new water quality was issued as a result of increased pressure on European pharmaceutical manufacturers to produce WFI equivalent water by processes other than distillation. Various companies were already using this water quality for final rinsing. However, the procedure lacked valid EP backing and was only internally endorsed as "purified water low endotoxin" or "purified water with endotoxin monitoring."

Large amounts of water are needed for the cleaning and final rinsing of equipment. Because of the high cost of producing WFI by distillation, HPW allows the use of more economical methods of producing equivalent grade water. The main cost advantage of these alternative processes is that physical methods, such as a combination of reverse osmosis (RO) and ultrafiltration (UF), have a 10-15 times lower operational cost compared with a thermal process such as distillation. In addition, the investment costs for RO and UF are comparable, if not also favourable, for the physical processes.

Figure 2: Ultrafiltration membrane structure.

Overall, HPW allows a more cost-effective operation without a decrease in quality. This requirement from the industry is a new challenge for the water treatment industry to build reliable HPW generation systems.

Where is water of this quality used?

The EP defines HPW as: "... intended for use in the preparation of products where water of high biological quality is needed, except where WFI is required."

¹

The use of HPW is not defined to the same degree of detail as purified water (PW) and WFI, and there is no application in the EP for which the use of HPW is explicitly required.

Table I: Definition of HPW.

The decision as to which water quality should be used depends on the relationship of the water with the product; that is, is the water directly or indirectly related to the product? A direct relationship is when the water is a component of the finished product or is needed during manufacture, even if it is not contained in the finished product. An indirect relationship is when the water is used for cleaning and rinsing the equipment and containers. As a rule of thumb, the use of water can be divided into three general categories.

Final formulation. This category covers the area of sterile medicinal products such as parenteralia and solutions for haemofiltration. Only WFI quality is accepted for the production of these. PW is accepted for ophthalmic and sterile preparations for use in the nose, ears and on the skin. However, WFI is frequently used for safety reasons. In this case, HPW is a useful and cheaper alternative to WFI.

Figure 3: Schematic of a UF system that can be sanitized with hot water.

For non-sterile products, PW is accepted for all applications. Nevertheless, there are some applications where WFI or sterilized HPW should be used instead, such as in sterile, apyrogenic solutions for nebulizers.

During the manufacture of APIs and medicinal products. This is when the water is not used as a vehicle in the final product. In this category, the required water quality depends on the following factors:

• the production step in which the water is used

• the processes that follow this step

• the type of final product.

Depending on the application, EMEA specifies the use of drinking water; PW; PW with special endotoxin requirements; or WFI. PW with an endotoxin content of not more than 0.25 IU/mL is specified for the final production stage of active pharmaceutical ingredients (APIs) that are used in sterile or parenteral products. This is an application where HPW can be more advantageous.

Figure 4: A UF unit that can produce HPW.

Cleaning and rinsing. The possible applications listed above for the use of HPW in galenic manufacture are very limited and large amounts of HPW will not be required for them. A demand for large amounts of water will probably be found when the water is indirectly related to the product.

It is expected that the water quality used for the final rinse complies with the quality laid down in the EP for the actual production process. In other words, the rinsing is done with water of the same quality as that used for the product.

Only water of WFI quality is accepted for the manufacture of sterile parenteral products, which means that WFI is also demanded for the final rinse and for clean-in-place (CIP). However, this requirement in the EP is modified to permit the use of HPW for the final rinse and CIP applications if the possible pyrogens are removed from the product in a subsequent stage. A prerequisite for this alternative to WFI is that the system is validated accordingly.

Figure 5: The pinhole test.

Permitted processing steps

The EP does not specifically define a method, but mentions that double-stage RO, combined with other methods such as UF and deionization for the production of HPW are commonly used. The raw water used for the production must comply with the official drinking water regulations.

UF suitability

Not only living bacteria, but also their decomposition products, can have toxic effects on human beings. The best known toxins of this type are probably endotoxins. These are parts of the outer envelope of Gram-negative bacteria and are released when these bacteria break down. If they enter the blood, even in very small quantities, they can, for example, cause recurring fever cycles after an infusion (pyrogens).

Endotoxins consist mainly of polysaccharides and their individual particles have a molecular weight of 10000-20000 kDa. In water, however, they normally form a conglomerate, which means that the cut-off is higher. The UF modules used in the pharmaceutical industry have a cut-off of 6000 kDa; therefore, subsequent UF of PW will have no effect on its conductivity, but will ensure the safe removal of pyrogens and micro-organisms.

RO modules have a far lower cut-off (<100 Da) than UF modules and an RO/RO or RO/electrodeionization (EDI) process produces excellent results with respect to micro-organisms and pyrogens. However, the RO membrane has mechanical shortcomings and so a precisely defined cut-off cannot be guaranteed. This makes system validation more difficult as there is no method available for testing the integrity of the RO membrane.

Here, the UF module has several important advantages:

• A reliable cut-off value can be specified because of its design.

• There is no risk of a short-circuit between the filtrate and the raw water because no o-rings are used as the seal between the incoming water and the filtrate; instead, the ends of the fibres are cast into epoxy resin blocks (Figure 1).

• The membrane has a double-asymmetrical construction and any leaks cannot result in contaminated product water (Figure 2).

• The module can be sanitized at 90 °C; some types can even be sterilized with pure steam at 121 °C.

• Sterilization of the UF modules is done in situ; that is, without removing the module from the system.

• The integrity of the module can be tested at any time.

UF permits endotoxin values in the product water of <0.25 EU/mL to be guaranteed and the process can be tested for integrity.

Because of its properties, UF is approved in the 11th Japanese Pharmacopoeia for the production of WFI. A large number of these systems have already been installed in Japan and, as a result of their positive results, UF systems have also been installed in Europe for sterile and pyrogen filtration.

UF system construction

UF modules are not capable ofaccumulating the contamination removed from the water and must, therefore, be operated as cross-flow filters— there must always be a flow of water along the surface of the membranes to remove the contamination. For this reason, a UF system always produces a concentrate in addition to the desired filtrate.

Most older UF units were installed downstream of an ion exchange system and, therefore, these systems can be sterilized with pure steam at 121 °C. This process is executed automatically. The modules are first heated to a temperature of approximately 85 °C in circulation mode. The system is then drained automatically with the aid of automatic valves before it is filled with pure steam. The resulting condensate is removed via a condensate drain. The cost of developing such systems is correspondingly high.

Sterilization of the modules at 121 °C is not done to ensure the microbiological quality of the product water, but to remove all deposits from the UF modules. Because the UF modules are normally preceded by a membrane process and, in most cases, by an EDI unit, the incoming water only contains very few particles that could block the UF membranes. Therefore, the system described below does not use steam sterilization and the modules are cleaned by backwashing. However, the entire system can still be sanitized at 85 °C. The construction of such a system is thus cheaper, as expensive components such as automatic drain valves, the condensate drain and the complex design are no longer necessary. Figure 3 is an example of an executed HPW system.

The incoming water first passes through the water purification system with the process steps water softener, RO and EDI. This unit reliably generates water whose quality complies with United States Pharmacopeia 27. The following stage, for the removal of pyrogens, is the UF unit. The resulting HPW is stored in a tank from which it is distributed to the consumers.

During the design of the system, great care was taken to avoid dead spaces within the units and, in particular, at the transition from the water purification system to the UF unit. Water circulates continuously through all parts of the system, regardless of the operating mode. This is also true when no water is being produced; that is, when the storage tank is full. Both parts of the system circulate their water continuously to minimize the risk of microbial growth. However, this results in the continuous consumption of energy and production of waste water, particularly in the RO unit. To reduce the water and energy costs, the water purification system is equipped with an output regulation system so that it operates at a reduced output during the circulation phase. This is achieved with the aid of a frequency-controlled high-pressure pump. In addition, the concentrate discharge valve is motor-actuated so that the waste water output of the system can be reduced even further.

Both the UF unit and the water purification system can be sanitized with hot water at 85 °C. The sanitization cycle is started at regular intervals and is executed automatically. To prove that sanitization has been done, the temperature is recorded on a data recorder. This temperature is measured in the pipe close to the tank as this is the coldest point in the entire system and the point from which the water is returned to the inlet of the heater in the UF unit (Figure 4).

Testing the modules' integrity

The membranes are tested by the manufacturer and each delivered module is accompanied by an inspection and test certificate. In addition to the flow rate, the cut-off value of the membrane is tested and a bubble test is executed. A description of the testing procedures and a test certificate is available from the manufacturer.

An integrity test is done at regular intervals to ensure the integrity of the modules after longer periods of operation and/or after sanitization. The test recommended for this purpose is the "pinhole test" (Figure 5).

For this test, the water on the inside of the hollow fibre is blown out with sterile compressed air; therefore, only the outside of the module is in contact with the water. All inlets and outlets of the module are then sealed and a hose is laid from the permeate outlet to a vessel containing water. Sterile air or nitrogen is then applied to the module at a pressure of 2 bar and the pressure is kept constant for 2 min. If air bubbles appear in the water after this settling period, there is a leak in the membrane. If no bubbles are visible, the integrity of the module is proven.

Summary

UF has proved to be a genuine alternative for the production of pyrogen-free water. It offers considerable cost advantages compared with distillation and guarantees more safety than other membrane methods such as RO.

UF has now been used for more than 15 years for the production of pyrogen-free water and the number of validated systems is correspondingly high. Most of the water generated by these systems is not used directly for production, but for the final rinsing of sterile products that are administered parenterally.

The reliability of this method is also reflected in the validation results. In systems that have already been running for several years, typical values for the endotoxin content are <0.05 IU/mL and the limit value of 0.25 IU/mL has never been reached or exceeded.

References

1. Note for Guidance on Quality of Water for Pharmaceutical Use, EMEA/CVMP/115/01 REVISION (EMEA, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, 2002).

2. European Pharmacopoeia 4th Edition (EDQM, 226, avenue de Colmar BP 907, F-67029 Strasbourg, France, 2002). ?