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Reverse osmosis (RO) entails the use of a semi-permeable membrane (permeable to the solvent, i.e. water molecules, but impermeable to solutes, i.e. contaminants). Osmosis describes the movement of solvent molecules across such a membrane from a solution of lower solute concentration to one of higher solute concentration. The force promoting this movement is termed ‘osmotic pressure’. During reverse osmosis, a pressure greater than the natural osmotic pressure is applied to the system from the higher solute concentration side, causing solvent molecules to flow in the opposite direction.
RO membranes are manufactured from polymers such as cellulose acetate or polyamides. A single pass of water through such membranes can remove 95% of all dissolved solids and 99% of microorganisms and endotoxins. Double RO systems are often employed, increasing the efficiency of the process still further, and providing some element of protection against the consequences of puncture of one of the membranes. While RO systems are less expensive than distillation, many regard distillation as being a safer option. Pin-head punctures of RO membranes can be hard to detect. Membranes are also susceptible to microbial colonization and cannot be exposed to high temperatures, which renders effective sanitation more difficult.
Distribution system for WFI
Upon its manufacture, WFI is fed into a sealed storage vessel, often made from stainless steel. The water is circulated via a series of pipework throughout the building, and from which a number of outlet valves are available. The pipework leads back to the storage tank, allowing constant recirculation of the water throughout the facility. Because of this it is known as a ring main or loop system (Figure 3.6).
As pharmacopoeial specifications preclude the addition of sanitizing agents such as chlorine, maintenance of WFI within microbiological specifications requires special attention. While circulating, the WFI is maintained at a flow rate of the order 9 ft/s. This ensures constant turbulent flow, discouraging microbial attachment to internal surfaces of the distribution pipes. The WFI is also constantly maintained at temperatures of the order of 85°C, again to discourage microbial growth.
Water collected from the WFI hot loop is generally allowed to cool before use for biopharmaceutical processing (hot buffers would not only potentially denature the protein
108 BIOPHARMACEUTICALS (a)
Figure 3.6. (a) Generalized diagram of how WFI is distributed throughout a typical pharmaceutical
facility. One or more outlet valves from the ring main system are in place in the clean rooms in which product manufacture is undertaken. Note that no such outlet is present in the clean room where final product fill will take place (i.e. the grade B cleanroom housing the grade A laminar flow hood in the above example). (b) Illustration of an acceptable valve design at a WFI outlet point. This design prevents stagnation of water, which could occur if such an outlet point was poorly designed, as illustrated in (c). Refer to text for specific details
THE DRUG MANUFACTURING PROCESS 109
product, but their pH values could change quite dramatically when cooled from 85°C to 25°C). In some instances a separate loop system is constructed in which WFI is circulated at ambient temperature allowing its immediate use in processing operations. To maintain water quality, however, this entire circulating system must be emptied and sanitized every 24 h.
Careful design of circulating systems also helps to maintain the microbiological quality of WFI. Circulating pipework lengths are fused together by welding, as opposed to the use of threaded fittings, which could harbour bacteria. ‘Dead-legs’ (areas where water could stagnate, e.g. at water outlet points), are avoided, and bends in pipes are smooth and curving, as opposed to the use of abrupt T-junctions. UV cells are also fitted on-line in the system, subjecting circulating water to their continual bactericidal influence.
Upon initial installation, the pipework is cleaned by passage of detergent or other cleaning agents, followed by a water rinse. ‘Passivation’ (exposure of the internal pipework surfaces to chemical agents, rendering the surface less reactive subsequently) is then undertaken, usually by oxidation using nitric acid or certain organic acids.
WFI is quite corrosive, especially at 85°C, and it can promote leeching from even high-grade stainless steel piping. Addition of ozone to the WFI can alleviate this, as the ozone’s microcidal properties facilitate prolonged storage/circulation of the water at 25°C. Other innovations in this field include replacement of stainless steel pipework with chemically inert plastics. However, extensive tests need to be undertaken in order to prove that WFI cannot leach potentially dangerous substances from these plastics before their use will become routine.