Background of the invention Particularly pure water is required for certain industrial uses in, for example, the pharmaceutical and electronics industries. In this context, by pure water is meant water purified for extraordinary uses, which is essentially sterile and from which inorganic and organic impurities have been removed to such an extent that preset quality requirements are fulfilled.

The quality requirements set for water are directed to its chemical and microbiological properties. The chemical quality can be properly monitored by conductivity measurement.

From a microbiological point of view, the properties to be monitored are sterility and pyrogenicity. Bacteria, for example, shred cell membrane fragments into their environment.

These fragments are essentially lipopolysaccharides, acting as pyrogens, i. e. fever-raising agents. These are relatively thermostable compounds, and may require high temperatures and prolonged heating periods for disintegration or loss of adverse properties. Pyrogens are removed from water in high quality distillation, and may also be removed by reverse osmosis due to the very narrow pores in the membranes used therein.

In the pharmaceutical field, the greatest purity requirements are applied to water used for injectable preparations, the so-called water for injection (WFI) grade. When water for injection is produced, the aforementioned biogenic units, which are smaller than microbes, must be removed. Methods approved for the production of WFI grade water are defined in pharmacopoeias. The 23 US Pharmacopoeia, issued in 1996, stipulates that water for injection may be produced by means of distillation or reverse osmosis. The corresponding European Pharmacopoeia allows only distillation.

High grade distillation processes require substantial investments and production costs are high. Reverse osmosis is a more economical method, but often causes higher maintenance costs.

By ultrafiltration, it is possible to remove even large molecules, as pyrogens, from water.

The membranes used are, however, usually sensible to heat and harsh chemical conditions.

Microbes and pyrogens must first be removed from the apparatus itself before the filtration process commences, and in addition the feed side must be cleaned, sterilized and freed of pyrogens at regular intervals during production. Most ultrafiltration equipment is badly suited for this type of use.

US patent 5,104,546 discloses a method for the production of pyrogen-free water using a crossflow ultrafiltration element comprising a zirconium oxide membrane on a ceramic support. The material may be freed of pyrogens chemically, for example with nitric acid.

The thermal stability of the ceramic filtration elements is also significant, and they may be repeatedly steam sterilized.

International Patent Application W098/28060 discloses a method for manufacturing a flat, porous ceramic filter cassette, suitable for both dead-end and crossflow filtration. With proper choice of materials, the resulting filter element will have the physical and chemical resistance properties required for operation under sterilizing conditions.

US patent 4,664,793 discloses a device for the production of pure water, wherein the purified water is circulated in a main circuit including a storage vessel. The water in said circuit is heat treated (60-90 °C) in a batchwise manner when the bacterial concentration in the circuit has reached a preset threshold value. The circuit includes a dead-end filtration unit and a heat exchanger for cooling the purified water to its working temperature with external cooling water. By these means it is not, however, possible to produce, for example, water for injection, as the indicated temperature would call for a long residence time in order to reach the required sterility level.

Disclosure of the invention General description A method according to claim 1 for the production of pure water has now been invented, comprising no periodical sterilization cycles as the continuous process comprises an integrated stage for heat sterilization of liquid water before the filtration step, and in addition the filtration itself is carried out under heat sterilizing conditions. Preferably, the pure water produced may be WFI grade.

Another objective of the invention is to provide a device according to claim 4 for the production of purified water, which device comprises as its essential components a

continuously operating hot sterilization section and a filtration section wherein the filtration capacity, when required, is sufficient for producing pyrogen-free water.

Description of a preferred embodiment The features of the invention are set forth below, with reference to the attached drawing which shows the layout of a device for carrying out a process according to the invention.

Feed water enters through pipe (1) and first passes heat exchanger (2), where it is preheated with the heat of reject stream (3). Next, the pressure is raised with pump (4), preferably to about 15 bar. A second preheating takes place in exchanger (5), in the other side of which the product, e. g. water for injection, flows. The final temperature raise to the sterilization temperature takes place in heater (6) which may be for example a steam-heated heat exchanger as shown in the figure, or an electrical heater. By means of filtration circuit circulation pump (8), the water is fed through a crossflow-type filter unit (9), whereby part of the water, the permeate, penetrates the pores and is purified, while the remaining part, the retentate, is recycled to the filtration circuit. This type of filter unit is widely used for demanding separations, as disclosed in e. g., Cheryan M.,"Ultrafiltration and Microfiltration Handbook", Technomic Publishing Co., Inc., Lancaster, PA., 6-7.

The material of the filtration element shall be sufficiently inert and thermostable; preferably the filtration element or-elements is of a ceramic material, for example of the type disclosed in International Patent Application W098/28060, cited above and having a large surface-to- volume ratio and a functional filter membrane on a monolithic ceramic support. Ceramic materials include, for example, materials based on aluminium, titanium and zirconium oxides, carbides or nitrides. Other possible filter materials include metals, for example sintered acid resistant steel. Specialty polymers, including PTFE (polytetrafluoroethylene), FEP (fluorinated ethylene propylene) PEEK (polyether ether ketone), PES (polyether sulfone), having the required heat-resistant properties and chemical stablity may be used.

The separation capacity of the filtration element shall correspond to the purity requirements of the water product, and if necessary it shall be sufficient for the separation of pyrogens.

For separation of endotoxins or pyrogens, a pore size in the range 1 nm to 20 nm is typically used; for viruses, a corresponding typical pore size is in the range 4 nm to 100 nm; and for bacteria, a typical pore size range is 100 nm to 30 u. m.

Preferably, several filtration units (two shown in the figure) are coupled in parallel, whereby backwashing and maintenance may be carried out during operation as disclosed below.

The return flow (10) from the filtration circuit is split between the filtration circuit and the reject stream (3) by means of a control valve (11). It is characteristic for a process according to the invention, that the filtration circuit (5,6,8,9,10), together with the filtration unit, forms a high temperature zone which continuously stays sterile during production of purified water.

The pure water, the pressure of which has fallen according to the pressure loss of the filtration unit, is led through pipe (12) to heat exchanger (5), where the temperature of said water usually is lowered to below boiling temperature, as the heat is carried to the beginning of the filtration circuit. Preferably, heat exchanger (5) is a shell-and-tube exchanger wherein the ends of the tubes are joined to double end jacket plates to prevent the contamination of purified product water by water from the filtration circuit, should leakage occur at the joint between tube and end plate; instead, filtration circuit water would leak to the outside.

Through control valve (13), the purified water is carried to its point of consumption in tube (16). Reject water can be diverted through branch (17) during plant startup.

Preferably, the filtration units are provided with means for pressure measurement on both feed side and product side, and with means for comparison of these measurements. As the pressure drop over a filtration unit reaches a threshold value during operation as deposits are built up, backwashing can be carried out with pure water by means of parallel filtration units, whereby one or both of product valves (14,15) is closed, and valve (7) is opened.

The material of the device shall fulfill the technical and regulatory requirements, generally acid resistant steel and PTFE are the materials of choice in addition to the material of the filter units. The temperature of the water circulating in the fitration circuit is constantly above its atmospheric-pressure boiling point, and as the circuit pressure may be in the order of 15 bar as set forth above or even higher, the apparatus must be designed to operate under elevated pressure at the relevant temperature; consequently, the pumps, tubing and valves must be chosen accordingly and the vessels designed according to the relevant pressure vessel codes and regulations.

As a permanent high temperature zone is included in a continuous process, the separate sterilizing stages usually carried out at regular intervals in purified water production devices, have been eliminated. The minimum water dwell time in the sterilization zone is

adjusted to the temperature used in order to provide continuous sterility on the pressure side of the filtration elements. The temperature of the sterilization section is above 100 °C; preferably it is above 140 °C ; and most preferably it is in the range 140-150 °C. Because water is not evaporated at any point, and a substantial part of the energy in the streams leaving the process is transferred to the feed stream, energy economy is good. The amount of energy required for evaporating the water would be about three times that required for heating the water to 140-150 °C under pressure.

The disclosed device is designed for production of purified water, but it is obvious to a person skilled in the art, that other aqueous liquids may be sterilized and purified taking into account their physical and chemical properties.