Method for producing water for injection and apparatus for producing water for injection

Abstract

The present invention provides a method and an apparatus for producing water for injection, which can reduce the amount of energy used for heating and cooling water for injection in the production of water for injection. [Solution] An apparatus for producing water for injection, comprising: a water for injection producing section for producing water for injection by distilling or ultra-filtering purified water; and a circulation section for storing water for injection in a tank, enabling the stored water for injection to be transported to a place of use, and for circulating water for injection that has not been transported to the place of use within the tank; a method for producing water for injection, wherein the temperature of the water for injection is adjusted to 50°C or higher when the storage time of the water for injection in the circulation section exceeds a predetermined time, and the temperature of the water for injection is adjusted to less than 50°C when the storage time is less than the predetermined time.

Description

[Technical Field]

[0001] The present invention relates to a method for producing water for injection and an apparatus for producing water for injection that uses less energy. [Background technology]

[0002] The quality and quality control of pharmaceutical water used in pharmaceuticals is regulated by the pharmacopoeias of each country. The Japanese Pharmacopoeia classifies pharmaceutical water into four standards: tap water, purified water, sterile purified water, and water for injection. Of these, water for injection (WFI) is used to manufacture injectable solutions, so viable bacteria and endotoxins must be strictly removed. WFI is produced by distilling or ultra-filtrating (mainly ultrafiltration) either tap water that has been pretreated with ion exchange or reverse osmosis, or purified water. Furthermore, since the produced WFI is stored in the manufacturing equipment prior to use, strict water quality control is required to prevent the generation or incorporation of viable bacteria and endotoxins into the WFI.

[0003] In general, water for injection produced by distillation or ultrafiltration is circulated by a pump through a circulation system in a manufacturing system, in which a water for injection storage tank and a point of use are connected by circulation piping. The water is sampled from the point of use (POU) as needed and used. This circulation system operates continuously to prevent the establishment of microorganisms and organic matter within the system. The piping design of the circulation system requires maintaining a flow velocity (usually 1 m / sec or higher) that creates sufficient turbulence within the piping. Furthermore, when the main piping is branched into a cheese pipe (T-shaped pipe) or the like and a valve or other closure mechanism is present at the end of the branch (called a dead leg), the distance from the center of the main pipe to the closure mechanism at the end of the branch pipe must be within six times the inner diameter of the branch pipe, and preferably within three times the inner diameter. Furthermore, the circulating water for injection is constantly maintained at a high temperature, for example, above 50°C, preferably above 65°C, and more preferably above 80°C, to prevent the growth of viable bacteria and endotoxins. Since water for injection used at the point of use is usually required to be kept at room temperature, the water for injection is cooled to room temperature after being transported to the place of use or during the transport process before use (see, for example, Patent Document 1). In addition, for the purpose of managing the water quality, the production system is periodically stopped, the water is drained, and then the valves, piping, etc. of the production system are sterilized with superheated steam (see, for example, Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent Publication No. 2020-138154 [Patent Document 2] Patent Publication No. 2008-178582 Summary of the Invention [Problem to be solved by the invention]

[0005] As described above, in conventional processes for producing water for injection using distillation or ultrafiltration, water for injection is circulated in a circulation system at 80°C or higher to prevent the increase of viable bacteria and endotoxins, and the required amount of water for injection is cooled and supplied to the point of use. In contrast, ultrafiltration makes it possible to produce and supply water for injection at room temperature or near room temperature (sometimes referred to as cold WFI), which requires excessive heating simply to prevent the increase of viable bacteria and endotoxins in the circulation system. Therefore, a method for supplying cold WFI without concerns about the increase of viable bacteria and endotoxins is desired.

[0006] Furthermore, methods that constantly maintain high temperatures within the circulation system require constant steam to heat the water for injection, and additional energy is required to cool it when it is used, resulting in the issue of increased energy consumption.In recent years, as demands for reducing carbon dioxide emissions have increased internationally based on the Sustainable Development Goals (SDGs) adopted by the United Nations, efforts to reduce energy consumption by realizing cold WFI have become an urgent priority, even in water for injection manufacturing systems.

[0007] The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a method for producing water for injection and an apparatus for producing water for injection that can reduce the amount of energy used for heating and cooling water for injection in the production of water for injection. [Means for solving the problem]

[0008] An embodiment of the present invention has the following configuration. [1] A water for injection manufacturing department in which purified water is distilled or ultra-filtered to produce water for injection; a circulation section in which the water for injection is stored in a tank, the stored water for injection is transportable to a place of use, and the water for injection that has not been transported to the place of use is circulated within the tank, When the retention time of the water for injection in the circulation part exceeds a predetermined time, the temperature of the water for injection is adjusted to 50°C or higher, A method for producing water for injection, wherein the temperature of the water for injection is adjusted to less than 50°C when the retention time of the water for injection in the circulation part is equal to or shorter than a predetermined time. [2] The method for producing water for injection described in [1], wherein whether the retention time exceeds a predetermined time or is less than a predetermined time is determined based on the amount of water for injection transported to the place of use. [3] The method for producing water for injection described in [1], wherein it is determined whether the storage time exceeds a predetermined time or is less than a predetermined time based on the storage level in the tank. [4] The method for producing water for injection according to [1], wherein the purified water is ultra-filtered in the water for injection production unit. [5] The method for producing water for injection described in [4], wherein when the storage time of the water for injection in the circulation unit exceeds a predetermined time, the supply of water for injection from the water for injection production unit to the circulation unit is stopped, and the temperature of the water for injection in the circulation unit is adjusted to 50°C or higher. [6] The method for producing water for injection according to [4], wherein, when the storage time of the water for injection in the circulation section exceeds a predetermined time, part or all of the water for injection that has not been transported to the place of use is circulated to the stage preceding the ultrafiltration of the water for injection production section, thereby adjusting the storage time of the water for injection in the circulation section to be equal to or less than the predetermined time.

[0009] [7] An apparatus for producing water for injection, comprising: a water for injection producing unit for producing water for injection; and a circulation unit for circulating and storing the produced water for injection, The injection water production unit has a distillation device that distills purified water or an ultrafiltration device that ultrafilters purified water, the circulation unit includes a tank for storing the water for injection, a circulation pipe for transporting a part or all of the water for injection in the tank to a place of use and circulating the water for injection that has not been transported to the place of use, and a temperature adjustment means for adjusting the temperature of the water for injection in the circulation pipe, The temperature adjusting means adjusts the temperature of the water for injection to 50°C or higher when the storage time of the water for injection in the circulation unit exceeds a predetermined time, and adjusts the temperature of the water for injection to less than 50°C when the storage time of the water for injection in the circulation unit is less than the predetermined time. [8] Further comprising a flow rate detection device that detects a flow rate difference between the upstream side and downstream side of the location of use of the circulation pipe, The apparatus for producing water for injection according to [7], wherein whether the predetermined time is exceeded or is equal to or less than the predetermined time is determined based on the value of the flow rate detection device. [9] An injection water manufacturing device as described in [7], which has a storage level meter that detects the storage level in the tank, and whether the specified time is exceeded or is below the specified time is determined based on the value of the storage level meter.

[10] The apparatus for producing water for injection described in [7], wherein the water for injection producing unit has an ultrafiltration device.

[11] The apparatus for producing water for injection described in

[10] , further comprising a switching unit that, when the storage time of the water for injection in the circulation unit exceeds a predetermined time, circulates part or all of the water for injection that has not been transported to the place of use to the upstream stage of the ultrafiltration device, thereby adjusting the storage time of the water for injection in the circulation unit to less than a predetermined time.

[12] The injection water manufacturing apparatus described in

[11] , wherein the switching unit closes the supply pipe for injection water from the injection water manufacturing unit to the circulation unit when the storage time of the injection water in the circulation unit is 50°C or higher, and circulates the injection water within the circulation unit. The symbol "~" indicates a range of values ​​including the values ​​before and after it. [Effects of the Invention]

[0010] According to the method and apparatus for producing water for injection of the present invention, the amount of energy used for heating and cooling water for injection in the production of water for injection can be reduced, thereby contributing to a reduction in carbon dioxide emissions. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a block diagram schematically illustrating an apparatus for producing water for injection according to an embodiment. [Figure 2] FIG. 1 is a flow chart of a method for producing water for injection according to an embodiment. [Figure 3] FIG. 10 is a block diagram schematically showing an apparatus for producing water for injection according to another embodiment. [Figure 4] 1 is a graph schematically showing the change in temperature of the water for injection when adjustment to a temperature below 50°C is started a predetermined period before the start of use of the water for injection, and the change in the amount of water for injection used at the site of use. [Figure 5] FIG. 10 is a block diagram schematically showing an apparatus for producing water for injection according to another embodiment. [Figure 6] FIG. 10 is a flow chart of a method for producing water for injection according to another embodiment. [Figure 7] FIG. 10 is a block diagram schematically showing an apparatus for producing water for injection according to another embodiment. [Figure 8] FIG. 10 is a diagram showing the open / closed states of four valves in the first circulation step. [Figure 9] FIG. 10 is a diagram showing the open / closed states of four valves in the second circulation step. [Figure 10] FIG. 1 is a diagram schematically illustrating a state in which two three-way valves are used instead of four valves in an apparatus for producing water for injection according to an embodiment. [Figure 11] FIG. 10 is a diagram schematically illustrating another state in which two three-way valves are used instead of four valves in the apparatus for producing water for injection according to the embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, embodiments of the present invention will be described with reference to the drawings. Fig. 1 is a block diagram schematically showing an apparatus 1 for producing water for injection according to an embodiment of the present invention. Fig. 2 is a flow chart of a method for producing water for injection according to an embodiment of the present invention.

[0013] The apparatus 1 for producing water for injection of the embodiment shown in Fig. 1 includes a water for injection producing unit 10 that produces water for injection from purified water, and a circulation unit 20 that circulates the produced water for injection. The water for injection in the circulation unit 20 is transported to a point of use (POU) 30 for use. The circulation unit 20 is provided with a tank TK, a pump P, and a temperature adjustment means 21 along the direction in which the water for injection flows.

[0014] The method for producing water for injection of this embodiment shown in Figure 2 is performed by an apparatus 1 for producing water for injection. The method for producing water for injection of this embodiment includes a water for injection production step S10, a circulation step S20, and a transfer step S30 to a point of use (POU). The circulation step S20 includes a storage step S21 and a temperature adjustment step S22, and the water for injection that has passed through the temperature adjustment step S22 is sent to the transfer step S30 to a point of use (POU).

[0015] The injection water production unit 10 shown in FIG. 1 has a distillation apparatus for distilling purified water or an ultrafiltration apparatus for ultrafiltration of purified water, and produces injection water by removing viable bacteria, endotoxins, and other impurities from the purified water using the distillation apparatus or ultrafiltration apparatus (injection water production step S10 in FIG. 2). The produced injection water is transferred to the circulation unit 20 and stored in a tank TK (storage step S21 in FIG. 2). The injection water stored in the tank TK is sent by a pump P to a temperature adjustment means 21, where the temperature is adjusted as necessary. Note that while FIG. 1 shows an embodiment in which the temperature adjustment means 21 is provided in the circulation unit 20, the temperature adjustment means 21 may be provided immediately before the circulation unit 20, and injection water whose temperature has been adjusted by the temperature adjustment means 21 may be supplied to the circulation unit 20. A portion of the temperature-adjusted injection water is transferred to a point of use (POU) 30, and the injection water that has not been transferred to the point of use (POU) 30 is returned to the tank TK. As a result, the water for injection is circulated within the circulation unit 20 (circulation step S20 in FIG. 2). In the method for producing water for injection of the embodiment, the temperature of the water for injection in the circulation unit 20 is adjusted by the temperature adjustment means 21 to be equal to or higher than 50°C or lower than 50°C depending on the retention time of the water for injection in the circulation unit 20 (temperature adjustment step S22 in FIG. 2). The retention time is the longest time from when the water for injection flows into the circulation unit 20 to when it is discharged outside the system of the circulation unit 20, for example by being transported to the point of use (POU) 30. The retention time can be calculated based on the amount of water for injection supplied to the circulation unit 20 per unit time, the amount used per unit time at the point of use (POU) 30, and the amount of water for injection stored in the circulation unit 20.

[0016] For example, the amount of water for injection circulating within the circulation unit 20 may vary depending on the amount of water for injection used at the point of use (POU) 30, i.e., the amount transported to the point of use (POU) 30. The amount of water for injection circulating within the circulation unit 20 may further vary depending on the amount of water for injection transported from the water for injection producing unit 10 to the circulation unit 20. When such a variation occurs, the temperature of the water for injection in the circulation unit 20 can be appropriately adjusted to 50°C or higher or lower than 50°C in accordance with the variation, thereby minimizing the energy required for heating and cooling the water for injection while preventing an increase in live bacteria and endotoxins due to long-term storage.

[0017] Specifically, when the retention time of the water for injection in the circulation unit 20 exceeds a predetermined time, the temperature adjustment means 21 adjusts the temperature of the water for injection in the circulation unit 20 to 50°C or higher, preferably 65°C or higher, and more preferably 80°C or higher. When the retention time of the water for injection in the circulation unit 20 is less than a predetermined time, the temperature adjustment means 21 adjusts the temperature of the water for injection in the circulation unit 20 to less than 50°C, preferably 40°C or lower, and more preferably within the range of room temperature (25°C±3°C). When the temperature inside the circulation unit 20 is maintained at less than 50°C, cold water for injection (Cold WFI) is supplied to the place of use.

[0018] Furthermore, as described above, the storage time of the water for injection in the circulation unit 20 may vary depending on the amount of water for injection transferred to the point of use (POU) 30. Therefore, based on the amount of water for injection transferred to the point of use (POU) 30, it is possible to determine whether the storage time of the water for injection in the circulation unit 20 has exceeded a predetermined time or is equal to or shorter than a predetermined time.

[0019] In the embodiment of the apparatus 1 for producing water for injection shown in FIG. 1, the water for injection production unit 10 includes a supply pipe 10a that supplies purified water to the water for injection production unit 10, a tank (not shown) that receives and stores the purified water supplied from the supply pipe 10a, a pump (not shown), and a distillation device that distills the purified water or an ultrafiltration device that ultrafilters the purified water (hereinafter referred to as an "ultrafiltration device, etc."). The purified water is supplied from the tank by the pump to the ultrafiltration device, etc., where viable bacteria and endotoxins in the water are sterilized or removed, thereby producing water for injection. Note that the water for injection production unit 10 may include at least one of a distillation device and an ultrafiltration device as the ultrafiltration device, etc., or may include both a distillation device and an ultrafiltration device.

[0020] The purified water supplied to the water for injection producing unit 10 is produced using "tap water" as raw water, which has been subjected to necessary pretreatment, by a production system that uses, alone or in combination, an ion exchange tower filled with a cation resin and an anion resin, an ion exchange process using an electrodeionization device or the like, a distillation process, and a membrane process such as a reverse osmosis membrane (RO) or ultrafiltration (UF). Among these, it is preferable to produce purified water by a system that combines a reverse osmosis membrane and an electric continuous ion exchange (EDI).

[0021] A reverse osmosis membrane device equipped with a reverse osmosis membrane (RO) can be used as the reverse osmosis membrane (RO) in the production of purified water. The reverse osmosis membrane device is composed of one or more reverse osmosis membrane modules. The reverse osmosis membrane module is composed, for example, of a casing containing a reverse osmosis membrane and a flow path material for passing water to be treated through the reverse osmosis membrane. The reverse osmosis membrane is preferably spiral-shaped, and may be hollow fiber, flat membrane, tubular membrane, or the like. The reverse osmosis membrane provided in the reverse osmosis membrane module is made of, for example, cellulose acetate, various organic polymer membranes made of aliphatic polyamides, aromatic polyamides, or composites thereof. The reverse osmosis membrane of this embodiment is preferably spiral-shaped in order to increase pressure resistance and improve treatment efficiency. The reverse osmosis membrane may be any of ultra-low pressure, low pressure, medium pressure, or high pressure reverse osmosis membranes, but low pressure or ultra-low pressure is preferred in terms of reducing power consumption during operation.

[0022] In the case of electrochemical continuous ion exchange (EDI) for the production of purified water, for example, an apparatus is used in which an anion exchange membrane and a cation exchange membrane are sandwiched between alternating demineralization and concentration compartments. Ions in the water being treated are removed using ion exchange resin packed in the demineralization compartment, while at the same time the ion exchange resin is continuously regenerated using a direct current, thereby continuously removing ionic components from the water.

[0023] The distillation device in the water for injection production unit 10 heats and vaporizes the purified water obtained above, and then collects and cools the vaporized steam to produce distilled water (water for injection). The distillation device sterilizes and removes live bacteria and endotoxins from the purified water, allowing the production of water for injection that meets the endotoxin standard value of less than 0.25 EU / mL, which is the management standard for water for injection in the "Japanese Pharmacopoeia (JP17) Quality Conformity Test."

[0024] FIG. 3 is a schematic diagram of an injection water manufacturing apparatus 100 having an injection water manufacturing unit 10 that uses an ultra-filtration device. In the injection water manufacturing apparatus 100 shown in FIG. 3, the configuration of the circulation unit 20 is the same as that of the injection water manufacturing apparatus 1 shown in FIG. 1, so components that perform the same functions are assigned the same reference numerals and detailed description will be omitted. In the injection water manufacturing apparatus 100 shown in FIG. 3, the injection water manufacturing unit 10 includes a supply pipe 10a that supplies purified water to the injection water manufacturing unit 10, a tank TK10 that stores the supplied purified water, and a pump P10 that sends the purified water in the tank TK10 to a subsequent stage. The injection water manufacturing unit 10 includes an ultra-filtration device 11 that ultra-filters the purified water sent by the pump P10, a transfer pipe 10b that transfers the purified water in the tank TK10 to the ultra-filtration device 11, and a transfer pipe 10c that sends the permeated water of the ultra-filtration device 11 to a subsequent stage. A supply pipe 20a branches off and is connected to the transfer pipe 10c, and the permeated water from the ultrafiltration device 11 is sent to the circulation section 20 via the supply pipe 20a.

[0025] The injection water production unit 10 further includes a transfer pipe 10e that returns the concentrated water from the ultrafiltration device 11 to the tank TK10, and a discharge pipe 10f that branches off from the transfer pipe 10e and is connected to the transfer pipe 10e and discharges some or all of the concentrated water in the transfer pipe 10e to the outside of the system. A valve V1f is provided on the discharge pipe 10f. A transfer pipe 10d that transfers some of the permeated water (injection water) from the ultrafiltration device 11 into the tank TK10 is also connected to the tank TK10.

[0026] Next, a method for producing water for injection in the water for injection production unit 10 of the water for injection production apparatus 100 will be described. The pump P10 in the water for injection production unit 10 is operated to send purified water from the tank TK10 to the ultrafiltration unit 11. The purified water is cross-flow filtered in the ultrafiltration unit 11 to produce permeate. This permeate is sent as water for injection to the circulation unit 20 via the supply pipe 20a. The concentrated water from the ultrafiltration unit 11 is returned to the tank TK10 via the transfer pipe 10e. At this time, a portion of the concentrated water from the ultrafiltration unit 11 may be discharged outside the system by opening the valve V1f or adjusting the aperture of the valve V1f. Alternatively, a portion of the permeate from the ultrafiltration unit 11 (water for injection) may be returned to the tank TK10 via the transfer pipe 10d by adjusting the aperture of the valve Va.

[0027] An ultrafiltration membrane (UF) can be used as the ultrafiltration device 11, and an ultrafiltration membrane device equipped with an ultrafiltration membrane (UF) can be used. The ultrafiltration membrane device is composed of one or more ultrafiltration membrane modules. The ultrafiltration membrane module is composed, for example, of a casing that houses an ultrafiltration membrane and a flow path material for passing the water to be treated through the ultrafiltration membrane. The ultrafiltration membrane provided in the ultrafiltration membrane module is preferably a hollow fiber membrane, but may also be a spiral membrane, a tubular membrane, a flat membrane, or the like. The ultrafiltration membrane is made of a material such as polysulfone, polyvinylidene fluoride, polyethylene, or polypropylene, and the nominal molecular weight cutoff is preferably in the range of 1,000 to 20,000, more preferably in the range of 2,000 to 6,000. A nominal molecular weight cutoff in the range of 1,000 to 20,000 can reliably remove live bacteria and endotoxin aggregates. Furthermore, since the molecular weight of endotoxin itself is 10,000 to 20,000, a nominal molecular weight cutoff in the range of 2,000 to 6,000 can reliably remove endotoxin itself. Either an internal pressure or external pressure ultrafiltration membrane module may be used. Because the feed water and concentrated water are processed linearly, a high membrane surface flow rate can be maintained at a low flow rate. Therefore, an internal pressure type is more preferable, as it is effective in preventing the growth of viable bacteria due to the deposition of impurities on the filtration surface of the hollow fiber membrane. Furthermore, the water for injection manufacturing apparatus 1 of the embodiment is preferably equipped with a sterilization system that sterilizes the manufacturing system to prevent the proliferation of viable bacteria on the ultrafiltration membrane. Examples of sterilization systems include a thermal sterilization system that performs thermal sterilization by supplying hot water at 50°C or higher, preferably 65°C or higher, and more preferably 80°C or higher, into the system, and a superheated steam sterilization system that performs sterilization by supplying superheated steam into the system. Using an ultrafiltration apparatus, water for injection of equal or better quality than that produced by a distillation apparatus can be produced.

[0028] In the apparatus 1 for producing water for injection shown in FIG. 1 , water for injection produced in the distillation device or ultrafiltration device of the water for injection production unit 10 is subsequently transferred to the circulation unit 20. The circulation unit 20 includes a supply pipe 20a that supplies the water for injection produced in the water for injection production unit 10 to the circulation unit 20, a tank TK that receives and stores the supplied water for injection, a pump P that transfers the water for injection, and temperature adjustment means 21 that adjusts the temperature of the water for injection. In an embodiment in which the temperature adjustment means 21 is provided immediately before the circulation unit 20, the temperature adjustment means 21 is provided in the path of the supply pipe 20a. As described above, the temperature adjustment means 21 may be provided in the circulation unit 20 or immediately before the circulation unit 20, or may be provided in either one or both of them. When the temperature adjustment means 21 is provided in the circulation unit 20, the temperature adjustment means 21 may be provided either upstream or downstream of the point of use (POU) 30.

[0029] A transfer pipe 20b is connected to the tank TK, and a transfer pipe 20d for transferring the water for injection that has passed through the transfer pipe 20b to a point of use (POU) 30 and a transfer pipe 20c for returning the water for injection that has not been transferred to the point of use to the tank TK are connected to the transfer pipe 20b. A pump P is installed in the path of the transfer pipe 20b, and the water for injection pressurized by the pump P is transferred through the transfer pipe 20b. The transfer pipes 20b and 20c constitute a circulation pipe for circulating the water for injection by returning the water for injection in the tank TK. A discharge pipe 20e for discharging the water for injection in the transfer pipe 20b to the outside of the system is connected to the transfer pipe 20b. A discharge pipe 20f for discharging the water for injection in the transfer pipe 20c to the outside of the system is connected to the transfer pipe 20c. The supply pipe 20a, transfer pipe 20d, discharge pipe 20e, and discharge pipe 20f are equipped with valves Va, Vd, Ve, and Vf, respectively. Valves Va, Vd, Ve, and Vf are variable opening valves or on-off valves, and these valves may be automatically controllable by a control device, etc. The same applies to other valves described later.

[0030] In the circulation unit 20, when water for injection is transferred from the circulation unit 20 to the point of use (POU) 30, the valve Vd is open, and the valves Ve and Vf are closed. As the water for injection is transferred to the point of use (POU) 30, the amount of water held in the tank TK decreases. In response to this decrease in the amount of water in the tank TK, the valve Va is opened, and the water for injection is transferred from the water for injection preparation unit 10 to the circulation unit 20. Furthermore, when production of water for injection in the water for injection preparation unit 10 is stopped, the valve Va is closed. When transfer of water for injection to the point of use (POU) 30 is stopped, the valve Vd is closed. In addition, by adjusting the opening of the valve Va, the amount of water for injection transferred from the water for injection preparation unit 10 to the circulation unit 20 is adjusted. By adjusting the opening of the valve Vd, the amount of water for injection transferred from the circulation unit 20 to the point of use (POU) 30 is adjusted. Furthermore, when the amount of water used at the point of use (POU) 30 is small, the valve Ve of the discharge pipe 20e or the valve Vf of the discharge pipe 20f can be opened to discharge the water for injection outside the system, thereby adjusting the time the water for injection is stored in the circulation unit 20. It is preferable that a temperature regulator be provided between the valve Vd and the point of use (POU) 30 to adjust the temperature of the water for injection to room temperature (the temperature during use). This temperature regulator is, for example, a heat exchanger.

[0031] The temperature adjusting means 21 is, for example, a heat exchanger or an electric heater. The heat exchanger adjusts the temperature of the water for injection by, for example, passing steam as a temperature adjusting medium inside when heating or cold water as a temperature adjusting medium inside when cooling, and bringing the temperature adjusting medium into contact with the water for injection via a metal plate such as stainless steel or titanium.

[0032] In the method for producing water for injection of the embodiment, the temperature adjusting means 21 adjusts the temperature of the water for injection circulating in the circulation unit 20 to either 50°C or higher or lower than 50°C depending on the retention time of the water for injection in the circulation unit 20. Specifically, the temperature adjusting means 21 adjusts the temperature of the water for injection in the circulation unit 20 to 50°C or higher when the retention time exceeds a predetermined time, and adjusts the temperature of the water for injection in the circulation unit 20 to lower than 50°C when the retention time is equal to or shorter than the predetermined time.

[0033] The predetermined retention time when adjusting the temperature can be set depending on the scale of the water for injection manufacturing apparatus 1, the amount of water produced, etc. For example, the predetermined retention time is preferably set to a value of 8 hours or less, and more preferably 2 hours or less.

[0034] Whether the retention time exceeds or is equal to or shorter than a predetermined time may be determined, for example, based on the amount of water for injection present in the circulation unit 20 and the amount of water for injection transferred to the point of use (POU) 30. For example, flow rate measuring means may be installed before and after the point of use (POU) 30 (upstream and downstream of the water flow), and the amount of water for injection transferred to the point of use (POU) 30 may be measured based on the difference in flow rate between the before and after. Alternatively, the pump discharge rate may be determined in advance when no water is being transferred to the point of use (POU) 30, and the pump discharge rate may be fixed to a constant value, and the amount of water for injection transferred to the point of use (POU) 30 may be calculated based only on the measurement value of the flow rate measuring means after (downstream of) the point of use (POU) 30. In this case, it may be further confirmed that the pump discharge rate has not changed from the fixed value by means of the pump discharge pressure, the current value supplied to the pump, or the like. When the amount of water for injection transferred to the point of use (POU) 30 is equal to or less than a predetermined transfer amount, the temperature adjusting means 21 determines that the retention time exceeds a predetermined time, and adjusts the temperature of the water for injection in the circulation unit 20 to 50°C or higher. The temperature adjusting means 21 maintains the temperature of the water for injection in the circulation unit 20 at 50°C or higher. When the amount of water for injection transferred to the point of use (POU) 30 exceeds a predetermined transfer amount, the temperature adjusting means 21 determines that the retention time is equal to or less than a predetermined time, and adjusts the temperature of the water for injection in the circulation unit 20 to less than 50°C. The temperature of the water for injection in the circulation unit 20 can be adjusted by installing a temperature sensor in the piping or tank TK in the circulation unit 20, and adjusting the output of the temperature adjusting means 21 according to the value of the temperature sensor.

[0035] The temperature sensors can be installed, for example, in the transfer pipe 20d, the transfer pipe 20b, the tank TK, etc. The temperature sensors detect the temperature of the water for injection at each location. The output of the temperature adjusting means 21 can be adjusted by a control method such as feedback based on the temperature detected by the temperature sensor. In this way, the temperature of the water for injection in the circulation unit 20 can be adjusted.

[0036] The injection water manufacturing apparatus 1 is provided with a detection device that detects the amount of injection water being transferred to the point of use (POU) 30, and based on the measurement value of the detection device, it is possible to determine whether the storage time of the injection water exceeds a predetermined time or is less than a predetermined time, and then start the above-mentioned adjustment of the temperature of the injection water.

[0037] When the storage time of the water for injection in the circulation unit 20 varies depending on the amount of water for injection transferred to the point of use (POU) 30, a detection device for detecting the water storage level in the tank TK in the circulation unit 20 can be provided, and the temperature adjustment means 21 can determine whether the storage time of the water for injection in the point of use (POU) 30 has exceeded or is below a predetermined time based on fluctuations in the hourly measured value of the water storage level of the detection device. Furthermore, by setting predetermined values ​​for the water storage level at the start of supplying water for injection from the water for injection production unit 10 to the tank TK (start water storage level) and the water storage level at the stop of supply (stop water storage level), the storage time of the water for injection in the circulation unit 20 can be calculated by counting the number of times the valve Va is opened and closed per hour, without measuring fluctuations in the measured value of the water storage level. Therefore, when the number of times the water for injection is supplied is below a predetermined value, it can be automatically determined that the storage time of the water for injection in the circulation unit 20 is below a predetermined time.

[0038] The temperature adjusting means 21 can also detect the difference in flow rate between the transfer pipe 20b on the upstream side of the point of use (POU) 30 and the transfer pipe 20c on the downstream side, and determine whether the storage time of the water for injection in the circulation unit 20 has exceeded or is below a predetermined time based on the detection result of the flow rate difference. In this case, even if a detector for detecting the transfer amount is not provided in the transfer pipe 20d, a flow rate detector for detecting the difference in flow rate between the transfer pipes 20b and 20c can be provided, and when the flow rate downstream of the point of use (POU) 30 of the circulation unit 20 becomes smaller than the flow rate upstream of the point of use (POU) 30, it can be determined that water for injection is being supplied to the transfer pipe 20d based on the detected value of the flow rate detector, and the storage time of the water for injection in the circulation unit 20 can be calculated based on the difference in flow rates. This makes it possible to automatically determine whether the storage time of the water for injection in the circulation unit 20 is below a predetermined time.

[0039] Furthermore, the amount (flow rate) of water for injection transferred to the point of use (POU) 30 may fluctuate instantaneously, which may cause the above-mentioned predetermined temperature to fluctuate drastically, resulting in unstable operation of the circulation unit 20. To avoid this, it is preferable to use an average value over a certain period (for example, an average value over 10 minutes) as the predetermined transfer amount. This makes it possible to prevent the above-mentioned unstable operation of the circulation unit 20. In addition, in order to prevent a sudden increase or decrease in temperature when starting to adjust the temperature of the water for injection in the circulation section 20, it is preferable to increase or decrease the temperature gradually using ramp soak control or the like.

[0040] Furthermore, if the usage conditions at the point of use (POU) 30 are preset by day of the week or time period, a timer may be provided in the apparatus for producing water for injection 1, and the start time of temperature adjustment may be set on the timer. The temperature adjustment means 21 may start adjusting the temperature of the water for injection to 50°C or higher or lower than 50°C using a timer or the like at the preset start time of adjustment. In this case, it is more preferable to use a storage time determination means, such as a detection device that detects the water level in the tank TK or a flow rate detection device that detects the difference in flow rate between the transfer pipes 20b and 20c, in combination, because this makes it possible to respond to usage conditions outside the preset range.

[0041] Alternatively, temperature adjustment may be initiated using a predicted flow rate estimated from the operation schedule of the factory using the water for injection or the water usage status of the previous day. In this case, the set temperature of the circulation unit 20 can be set to less than 50°C when the factory starts operation, and then set to 50°C or higher after the factory operation ends. This eliminates the need for sudden temperature changes, thereby reducing the amount of steam required when changing the temperature and thereby reducing energy consumption. Furthermore, not requiring sudden temperature changes reduces the burden on the equipment, thereby preventing equipment malfunctions and ensuring a stable supply of water for injection to the point of use (POU) 30.

[0042] When the injection water manufacturing apparatus 1 is installed in or near a pharmaceutical factory and injection water is used in the pharmaceutical factory, for example, if the predetermined transfer amount is set to zero (0), when injection water is used in the pharmaceutical factory, the transfer amount of injection water to the point of use (POU) 30 exceeds zero, exceeding the predetermined transfer amount. As a result, the retention time of injection water in the circulation unit 20 is less than the predetermined time. In contrast, when the pharmaceutical factory stops operating and injection water is not used in the pharmaceutical factory, the transfer amount of injection water to the point of use (POU) 30 becomes zero, and the retention time of injection water in the circulation unit 20 exceeds the predetermined time. When the above control method is used, the temperature of injection water in the circulation unit 20 can be maintained below 50°C while the pharmaceutical factory is operating, and the temperature of injection water in the circulation unit 20 can be maintained above 50°C only during periods when the pharmaceutical factory is not operating. Therefore, compared to conventional methods in which water for injection is constantly circulated at a high temperature of 50°C or higher and then cooled to room temperature after or during transport to the point of use (POU) 30, the energy required for heating and cooling the water for injection can be reduced, contributing to a reduction in carbon dioxide emissions. Furthermore, by maintaining the temperature of the water for injection in the circulation unit 20 at 80°C or higher during nighttime, weekends, and other times when the pharmaceutical factory is not operating, the inside of the circulation unit 20 can be thermally sterilized. As a result, the increase in viable bacteria and endotoxins in the circulation unit 20 can be further prevented. Furthermore, by providing a sterilization device that supplies superheated steam to the circulation unit 20 to sterilize the valves, piping, etc. of the water for injection manufacturing apparatus 1 and periodically performing sterilization treatment within the water for injection manufacturing apparatus system, the increase in viable bacteria and endotoxins can be further suppressed. While the above description is based on the case in which the predetermined transfer rate is zero (0), the predetermined transfer rate may be slightly greater than zero.

[0043] In the injection water manufacturing apparatus 1 according to the above embodiment, the water storage level in the tank TK may fluctuate depending on the amount of injection water manufactured by the injection water manufacturing unit 10 and the amount of injection water used and transferred to the point of use (POU) 30 (used at the point of use). For example, when the amount of injection water manufactured by the injection water manufacturing unit 10 is greater than the amount of injection water transferred to the point of use (POU) 30, the water storage level in the tank TK may rise. When the amount of injection water manufactured by the injection water manufacturing unit 10 is less than the amount of injection water transferred to the point of use (POU) 30, the water storage level in the tank TK may fall. Such increases and decreases in the amount of injection water used at the point of use (POU) 30 are absorbed by increases and decreases in the water storage level in the tank TK, and the amount of water circulating in the circulation unit 20 is stably maintained within a predetermined range. Furthermore, the amount of injection water transferred to the circulation unit 20 may be adjusted by adjusting the opening of the valve Va, as necessary, to thereby adjust the water storage level in the tank TK. Specifically, the reservoir level of the tank TK can be kept constant by controlling the opening of the valve Va in accordance with fluctuations in the amount of water for injection transported to the point of use (POU) 30. In this case, a circulation system including a tank may be installed in the water for injection manufacturing unit 10, and the water for injection that has not been transported to the circulation unit 20 may be circulated to the tank in the water for injection manufacturing unit 10.

[0044] In the embodiment of the apparatus for producing water for injection 1, the amount of water for injection transferred from the circulation unit 20 to the point of use (POU) 30 may change intermittently over a short period of time. For example, if the circulation time of the water for injection in the circulation unit 20 changes intermittently around a set predetermined time, the amount of water for injection may intermittently exceed and be below the set predetermined time. If this repetition causes the temperature of the water for injection in the circulation unit 20 to repeatedly increase and decrease, the amount of energy used for increasing the temperature may actually increase. Therefore, when the circulation time of the water for injection in the circulation unit 20 changes intermittently between values ​​around the set predetermined time, it is preferable to discharge the water for injection outside the system via the discharge pipe 20e, the discharge pipe 20f, or both, to prevent the circulation time from exceeding the set predetermined time. The water for injection can be discharged outside the system by opening the valve Ve provided in the discharge pipe 20e, the valve Vf provided in the discharge pipe 20f, or both. The discharge of the water for injection out of the system by opening and closing the valves Ve and Vf can be controlled according to a preset plan for using the water for injection at the point of use (POU) 30.

[0045] Figure 4 shows a schematic diagram of the change in the temperature of the water for injection (solid line) and the change in the amount of water for injection used at the point of use (POU) 30 (POU usage, dashed line) when adjusting the temperature of the water for injection to room temperature before operation starts and to 80°C after operation stops, assuming that the pharmaceutical factory starts operating at 9:00 AM and stops at 5:00 PM. In Figure 4, the amount of water for injection used during operation of the pharmaceutical factory is set to a constant value of 100, and the change over time in the amount of water for injection used is shown as a relative value.

[0046] As shown in FIG. 4 , the temperature of the water for injection can be adjusted to room temperature after a predetermined period of time has elapsed since the amount of water for injection transferred to the point of use (POU) 30 reaches zero, i.e., a predetermined period (before the preparation period) before the amount of water for injection transferred to the point of use (POU) 30 exceeds zero (when the water for injection is started to be used). In this way, when the start and end times of use at the point of use (POU) 30 are predetermined, the temperature of the water for injection can be gradually increased to room temperature by ramp-soak control or the like before the start of use so that the temperature of the water for injection reaches the usage temperature in time for the start of use. This method does not involve a sudden change in temperature from high to low, thereby suppressing deterioration of piping and each device that would otherwise be associated with a sudden temperature change. Another advantage is that it does not increase the amount of heat transfer medium used for temperature adjustment to achieve a sudden temperature change. In FIG. 4 , the temperature of the water for injection is adjusted to room temperature when the water for injection begins to be used at the point of use (POU) 30 (9:00 AM).

[0047] As described above, when the temperature of the water for injection in the circulation unit 20 is adjusted to 50°C or higher when the amount of water for injection transferred to the point of use (POU) 30 is zero, and when the temperature of the water for injection in the circulation unit 20 is adjusted to less than 50°C when the amount of water for injection transferred exceeds zero, it is preferable that the supply of water for injection from the water for injection preparation unit 10 to the circulation unit 20 be stopped during the period when the temperature of the water for injection in the circulation unit 20 is adjusted to 50°C or higher, and that the water for injection is supplied from the water for injection preparation unit 10 to the circulation unit 20 during the period when the temperature is adjusted to less than 50°C. While the supply of water for injection from the water for injection preparation unit 10 to the circulation unit 20 is stopped, it is preferable to close the valve Va provided on the supply pipe 20a. During this period, the water for injection is circulated through the circulation piping in the water for injection preparation unit 10 shown in FIG. 3, which is composed of the tank TK10, transfer pipe 10b, ultrafiltration device 11, transfer pipe 10c, transfer pipe 10d, and transfer pipe 10e. Furthermore, depending on the state of the circulation unit 20, the valve Va may be opened to supply water for injection from the water for injection producing unit 10 to the circulation unit 20.

[0048] During the period when the temperature of the water for injection in the circulation unit 20 is adjusted to below 50°C, i.e., during the period when the water for injection is stored in the circulation unit 20 for a predetermined time or less, the water for injection flows out almost smoothly from the water for injection preparation unit 10 to the point of use (POU) 30 via the transfer pipes 20b and 20d of the circulation unit 20. Therefore, clean water for injection from which viable bacteria, endotoxins, etc. have been removed in the water for injection preparation unit 10 can be smoothly supplied to the point of use (POU) 30. Furthermore, during the period when the temperature of the water for injection in the circulation unit 20 is adjusted to 50°C or higher, i.e., during the period when the water for injection is stored in the circulation unit 20 for a predetermined time or more, the outflow of water for injection from the water for injection preparation unit 10 to the circulation unit 20 is stopped, thereby circulating a relatively small amount of water for injection, thereby minimizing the amount of energy used to heat the water for injection to a high temperature. Furthermore, by minimizing the amount of water for injection stored in the tank (TK), energy use can be reduced more effectively. Furthermore, by carrying out the above operation, it is possible to prevent an increase in live bacteria and endotoxins.

[0049] According to the method and apparatus for producing water for injection of the above embodiment, by appropriately setting the start timing of temperature adjustment to above 50° C. and below 50° C., it is possible to maintain the circulated water for injection at a high temperature only when the amount of water for injection used is small, particularly when the water for injection is not being used. Therefore, compared to the conventional method in which water for injection is constantly circulated at a high temperature and cooled during transportation to the place of use, the amount and time of water for injection to be heated and cooled can be reduced, and the energy required for heating and cooling can be significantly reduced.

[0050] In the method for producing water for injection of the embodiment described above, water for injection transferred from the water for injection production unit 10 is temporarily stored in the tank TK, and then the temperature is adjusted by the temperature adjustment means 21 before being transferred to the point of use (POU) 30. However, the water for injection transferred from the water for injection production unit 10 may also have its temperature adjusted by the temperature adjustment means 21 before being transferred to the point of use (POU) 30, and then the water for injection that was not transferred to the point of use (POU) 30 may be returned to the tank TK. This embodiment will now be described with reference to the drawings.

[0051] Fig. 5 is a block diagram schematically showing an apparatus 2 for producing water for injection according to another embodiment. Fig. 6 is a flow diagram of a method for producing water for injection according to another embodiment. The apparatus 2 for producing water for injection shown in Fig. 5 has a water for injection producing section 10 similar to that of the above-described embodiment, and a circulation section 40 that circulates the produced water for injection. The water for injection in the circulation section 40 is transferred to a point of use (POU) 30 for the water for injection and used. In the circulation section 40, a pump P, a temperature adjustment means 41, a point of use (POU) 30, and a tank TK are arranged along the flow of the water for injection transferred from the water for injection producing section 10.

[0052] A supply pipe 40a is connected to the circulation unit 40, supplying the water for injection produced in the water for injection producing unit 10 to the circulation unit 40, and a transfer pipe 40b is connected to the supply pipe 40a. A transfer pipe 40d is connected to the transfer pipe 40b, and the transfer pipe 40c is connected to the transfer pipe 40b, and the water for injection that has not been transported to the point of use (POU) 30 is supplied to the tank TK. A pump P and a temperature control means 41 are installed in the path of the transfer pipe 40b, and the water for injection pressurized by the pump P is temperature-controlled by the temperature control means 41 and transported to the transfer pipe 40d and the transfer pipe 40c. The water for injection that has not been transported to the point of use (POU) 30 is stored in the tank TK via the transfer pipe 40c. A transfer pipe 40f is connected to the tank TK, and the transfer pipe 40f sends the water for injection in the tank TK to the transfer pipe 40b, and a discharge pipe 40e is connected to the tank TK, and the water for injection in the tank TK is discharged to the outside of the system. The transfer pipe 40b, the transfer pipe 40c, the tank TK, and the transfer pipe 40f constitute a circulation pipe for circulating the water for injection. A valve V4e is provided in the discharge pipe 40e, and the amount of water for injection discharged from the tank TK to the outside of the system is adjusted by opening and closing the valve V4e or adjusting the opening degree thereof.

[0053] The injection water manufacturing apparatus 2 shown in Figure 5 differs from the injection water manufacturing apparatus 100 shown in Figure 3 in that the tank TK is located downstream of the point of use (POU) 30, rather than between the injection water manufacturing unit 10 and the point of use (POU) 30, along the flow of the injection water.Therefore, while the injection water is circulated at a temperature below 50°C, i.e., when a large amount of injection water is used at the point of use (POU) 30, an increase in live bacteria and endotoxins in the injection water is less likely to occur, and the water quality is less likely to deteriorate.

[0054] The method for producing water for injection of this embodiment shown in Figure 6 is performed by the apparatus 2 for producing water for injection shown in Figure 5. The method for producing water for injection of this embodiment includes a water for injection producing step S10, a circulating step S40, and a transfer step S30 to the point of use (POU) 30. The circulation step S40 includes a temperature adjustment step S41 and a storage step S42, in this order. A portion of the water for injection that has passed through the temperature adjustment step S41 is sent to the transfer step S30 to the point of use (POU) 30, and the remainder is sent to the storage step S42. In the method for producing water for injection of this embodiment, when the storage time of the water for injection in the circulation unit 40 exceeds a predetermined time, the temperature adjustment means 21 adjusts the temperature of the water for injection to 50°C or higher, and when the storage time of the water for injection in the circulation unit 40 is equal to or shorter than the predetermined time, the temperature of the water for injection is adjusted to less than 50°C (temperature adjustment step S41).

[0055] In terms of enhancing the sterilizing effect on live bacteria, endotoxins, and the like in the circulation step S40, the temperature of the water for injection when the storage time of the water for injection in the circulation unit 40 exceeds a predetermined time is 50° C. or higher, preferably 65° C. or higher, more preferably 70° C. or higher, and even more preferably 80° C. or higher. Furthermore, in terms of ease of use of the water for injection at the point of use (POU) 30, the temperature of the water for injection when the storage time of the water for injection in the circulation unit 40 is less than a predetermined time is less than 50° C., preferably 40° C. or lower, more preferably 36° C. or lower, and even more preferably room temperature (25° C.±3° C.).

[0056] As with the injection water manufacturing apparatus 100 of the above-described embodiment, it may be determined whether the storage time of the injection water in the circulation unit 40 exceeds or is equal to or shorter than a predetermined time based on the amount of injection water transferred to the point of use (POU) 30. When the amount of injection water transferred to the point of use (POU) 30 is equal to or shorter than the predetermined amount, it can be determined that the storage time of the injection water in the circulation unit 40 exceeds the predetermined time. When the amount of injection water transferred to the point of use (POU) 30 exceeds the predetermined amount, it can be determined that the storage time of the injection water in the circulation unit 40 is equal to or shorter than the predetermined time. For example, the predetermined amount of injection water transferred to the point of use (POU) 30 is typically approximately zero (0). That is, when the amount of injection water transferred to the point of use (POU) 30 is approximately zero (0), the temperature of the injection water is adjusted to 50°C or higher, and when the amount of transfer exceeds approximately zero (0), the temperature of the injection water is adjusted to less than 50°C.

[0057] If there is no change in the production volume of the injection water production unit 10 or if the production volume is set in advance, a detection means for detecting the amount of injection water transferred to the point of use (POU) 30 can be provided to determine whether the storage time of the injection water in the circulation unit 40 exceeds or is less than a predetermined time. In this case, the detection means is, for example, a detection means for detecting the water storage level in the tank TK in the circulation unit 20. Another detection means detects the amount of injection water transferred to the point of use (POU) 30, for example, by detecting the difference in flow rate between the transfer pipe 40b upstream of the point of use (POU) 30 and the transfer pipe 40c downstream of the circulation unit 40. Another detection means detects the amount of injection water transferred to the point of use (POU) 30, for example, by detecting the difference in flow pressure between the transfer pipe 40b upstream of the point of use (POU) 30 and the transfer pipe 40c downstream of the circulation unit 40. Furthermore, when the amount of water for injection to be used at the point of use (POU) 30 is set in advance, a timer or the like may be provided in the water for injection manufacturing apparatus 2, and the timer or the like may cause the temperature adjustment means 41 to start adjusting the temperature of the water for injection to 50° C. or higher or to less than 50° C. at the preset start time of adjustment. When adjusting the temperature of the water for injection to 50° C. or higher or to less than 50° C. is started by a timer or the like, the start time of adjustment can be set according to the amount of water for injection to be transferred to the point of use (POU) 30, which is set in advance.

[0058] The method for detecting the amount of water for injection transported to the point of use (POU) 30, the method for adjusting the temperature to above 50°C or below 50°C, and preferred embodiments are the same as those in the method for manufacturing water for injection using the above-mentioned water for injection manufacturing apparatus 1, so detailed explanations will be omitted.

[0059] Next, a method and apparatus for producing water for injection according to another embodiment will be described with reference to Figure 7. In the method for producing water for injection according to this embodiment, in a first circulation step, water for injection is circulated throughout the water for injection production unit and the circulation unit, and in a second circulation step, water for injection is circulated through both the water for injection production unit and the circulation unit, or through only the circulation unit. When water for injection is used at the point of use (POU), the temperature of the water for injection is adjusted to less than 50°C in the first circulation step regardless of the amount used. When water for injection is not used at the point of use (POU), in the second circulation step, the water for injection production unit and the circulation unit are separated and the water for injection is circulated separately, or the temperature of the water for injection in the circulation unit is adjusted to 50°C or higher and the water for injection is circulated within the circulation unit.

[0060] Fig. 7 is a block diagram schematically showing an apparatus for producing water for injection 3 according to an embodiment of the present invention. The apparatus for producing water for injection 3 shown in Fig. 7 has an apparatus for producing water for injection 50 and a circulation unit 20. In the circulation unit 20, components that perform the same functions as those in the apparatus for producing water for injection 1 shown in Fig. 1 are designated by the same reference numerals, and detailed description thereof will be omitted.

[0061] In the injection water production apparatus 3, the injection water production unit 50 includes a supply pipe 50a that supplies purified water to the injection water production unit 50, a tank TK1 that stores the supplied purified water, and a pump P1 and supply pipe 50b that send the purified water in the tank TK1 to a subsequent stage. The injection water production unit 50 includes an ultrafiltration device 51 that ultrafilters the purified water sent by the pump P1, a transfer pipe 50c that sends permeated water from the ultrafiltration device 51 to a subsequent stage, and a temperature adjustment means 52 that is provided in the transfer pipe 50c and adjusts the temperature of the permeated water. In FIG. 7, one temperature adjustment means 52 is provided upstream of a crosslinking pipe 50g (described later), but it is also possible to provide multiple temperature adjustment means within the injection water production unit 50 system. The permeated water from the ultrafiltration device 51 is used as injection water. In the apparatus for producing water for injection 3, an example is shown in which an ultrafiltration apparatus is used to produce water for injection, but a distillation apparatus may be used instead of the ultrafiltration apparatus, or an ultrafiltration apparatus and a distillation apparatus may be used together.

[0062] An ultrafiltration device is preferably used to produce water for injection because it can reduce the amount of energy used in the water for injection production apparatus 3. When a distillation device is used to produce water for injection, purified water is heated to approximately 95°C to 125°C to produce water for injection, and the water for injection can be supplied to the circulation unit 20 without significantly reducing the temperature. Therefore, the excess energy required to heat the water for injection to 80°C or higher, which is necessary to prevent the increase of viable bacteria and endotoxins in the circulation system of the water for injection production unit 50, is less than when an ultrafiltration device is used. However, when the water for injection is stored in the circulation unit 20 for a predetermined time or less, the high-temperature water for injection is cooled before being supplied to the point of use (POU) 30, and when the water for injection is stored in the circulation unit 20 for more than the predetermined time, it is heated again, requiring cooling and heating energy. In contrast, when an ultrafiltration device is used to produce water for injection, the temperature of the water for injection produced in the water for injection production unit 50 is close to room temperature, making the above-mentioned cooling and heating unnecessary, and the effects of this embodiment can be significantly achieved. The preferred embodiments of the distillation apparatus and ultrafiltration apparatus are the same as those of the apparatus 1 for producing water for injection shown in FIG.

[0063] The injection water producing unit 50 further includes a transfer pipe 50e that returns the concentrated water from the ultrafiltration device 51 to the tank TK1, and a discharge pipe 50f that branches off from the transfer pipe 50e and is connected to the transfer pipe 50e and discharges some or all of the concentrated water in the transfer pipe 50e to the outside of the system. A valve V5f is provided on the discharge pipe 50f. In addition, a transfer pipe 50d that transfers the injection water transferred from the circulation unit 20 into the tank TK1 is connected to the tank TK1.

[0064] In the apparatus for producing water for injection 3, a supply pipe 20a is connected to the transfer pipe 50c downstream of the temperature adjustment means 52 via a valve V3. The end of the supply pipe 20a opposite the valve V3 is connected to the tank TK of the circulation unit 20, so that water for injection produced in the water for injection production unit 50 is transferred to the circulation unit 20 via the supply pipe 20a. In addition, in the circulation unit 20 in the apparatus for producing water for injection 3, a transfer pipe 20g is connected to the end of the transfer pipe 20c of the apparatus for producing water for injection 1 shown in FIG. 1 opposite the point of use (POU) 30. The other end of the transfer pipe 20g is connected to the end of the transfer pipe 50d opposite the tank TK1 via a valve V2. As a result, water for injection that has not been transferred to the point of use (POU) 30 is returned to the tank TK1 of the water for injection production unit 50 via the transfer pipe 20g and the transfer pipe 50d. The apparatus 3 for producing water for injection is provided with a bridging pipe 50g that connects the transfer pipe 50d and the transfer pipe 50c on the side of the valve V2 that is closer to the water for injection production section 50. The connection position of the transfer pipe 50c and the bridging pipe 50g (the bridging position by the bridging pipe 50g) may be either upstream or downstream of the temperature adjustment means 52, as long as it is closer to the water for injection production section 50 than the valve V3. One end of a transfer pipe 20h is connected to the side of the transfer pipe 20g opposite the valve V2, and the other end of the transfer pipe 20h is connected to a tank TK in the circulation section 20. A valve V1 is provided in the bridging pipe 50g, and a valve Va is provided in the transfer pipe 20h.

[0065] Next, a method for producing water for injection using the apparatus for producing water for injection 3 will be described. In the method for producing water for injection of this embodiment, in the first circulation step, the temperature of the water for injection is adjusted to less than 50°C by the temperature adjustment means 52 and the temperature adjustment means 21. Specifically, first, valves V1 and Va are closed, and valves V2 and V3 are opened. Pump P1 of the water for injection production unit 50 and pump P of the circulation unit 20 are operated, and purified water is sent from tank TK1 to ultrafiltration device 51 by pump P1 of the water for injection production unit 50. The purified water is subjected to cross-flow filtration in the ultrafiltration device 51 to produce permeate. This permeate is sent to the subsequent stage as water for injection. A portion of the concentrated water from the ultrafiltration device 51 is returned to tank TK1 via transfer pipe 50e. The water for injection (permeate) produced in the ultrafiltration device 51 is adjusted to a temperature below 50°C by the temperature adjustment means 52 as necessary, and then supplied to and stored in the tank TK of the circulation unit 20 via the supply pipe 20a. The water for injection in the tank TK is sent by the pump P to the temperature adjustment means 21, where it is further adjusted to a temperature below 50°C as necessary. Thereafter, by opening the valve Vd as necessary, the water for injection is transferred to the point of use (POU) 30 via the transfer pipe 20b and the transfer pipe 20d. The water for injection that has not been transferred to the point of use (POU) 30 flows through the transfer pipe 20g and the transfer pipe 50d in this order and is returned to the tank TK1 of the water for injection production unit 50.

[0066] FIG. 8 shows the open and closed states of valves V1, Va, V2, and V3 in FIG. 7 during this first circulation step. In FIG. 8, solid valves indicate closed valves, and open valves indicate open valves. Valves V1, Va, V2, and V3 function as a switching unit S that switches the circulation system between a first circulation system in which the water for injection is circulated through the system of the water for injection production unit 10 and the circulation unit 20, and a second circulation system in which the water is circulated only through the system of the circulation unit 20. By adjusting the apertures of valves V1 and V3 as needed, a portion of the water for injection is transferred to the circulation unit 20 and the remainder is circulated within the water for injection production unit 50. This makes it possible to adjust the amount of water for injection transferred to the circulation unit 20 without changing the amount of water produced in the water for injection production unit 50. Furthermore, by adjusting the apertures of valves V2 and Va as needed, it is possible to adjust the balance of the water volumes between the water for injection production unit 50 and the circulation unit 20. By adjusting the opening of valves V2 and Va, the pressure inside the piping of the circulation section 20 can be made higher than the pressure inside the piping of the transfer pipe 50d that transfers water to the tank TK1 of the injection water production section 50, thereby preventing backflow from the injection water production section 10 to the circulation section 20 via valve V2.

[0067] Subsequently, in the second circulation step, the water for injection in the circulation unit 20 is adjusted to 50°C or higher. In the second circulation step, valves V2, V3, and Vd are closed, and valves V1 and Va are opened. Valves V5f and Ve are opened or their opening degrees are adjusted as needed. This separates the circulation system of the water for injection production unit 50 from that of the circulation unit 20, and the water for injection is circulated within each system or within the circulation unit 20. Specifically, when water for injection is circulated within the water for injection production unit 50, purified water stored in the tank TK1 is supplied to the ultrafiltration device 51 by the pump P1. The water for injection produced by cross-flow filtration of the purified water in the ultrafiltration device 51 has its temperature adjusted as needed by the temperature adjustment means 52, and flows sequentially through the crosslinking pipe 50g and the transfer pipe 50d before being returned to the tank TK1. The concentrated water produced by cross-flow filtration of purified water in the ultrafiltration device 51 is returned to the tank TK1 via the transfer pipe 50e. Furthermore, within the circulation unit 20, the water for injection in the tank TK is sent by the pump P to the temperature adjustment means 21, which adjusts the temperature of the water for injection to 50°C or higher, thereby preventing the growth of viable bacteria and endotoxins within the circulation unit 20. This reduces the amount of energy required to raise the temperature compared to adjusting the entire water for injection production unit 50 and circulation unit 20 to 50°C or higher. The water for injection adjusted to 50°C or higher is returned to the tank TK via the transfer pipes 20b, 20c, and 20h. At this time, by lowering the water level in the tank TK before adjusting the temperature to 50°C or higher and reducing the amount of water in the entire circulation unit, the amount of energy required to raise the temperature can be further reduced.

[0068] In the water for injection production unit 50, the second circulation step may comprise a normal operation step and a sterilization step. Because the water for injection production unit 50 includes a distillation apparatus or ultrafiltration apparatus for producing water for injection, in the normal operation step, the temperature of the water for injection is adjusted to less than 50°C by the temperature adjustment means 52 and circulated within the water for injection production unit 50. In the sterilization step, the temperature of the water for injection is raised to 50°C or higher, preferably 80°C or higher, to sterilize the system with hot water. Alternatively, in the sterilization step, superheated steam may be supplied into the water for injection production unit 50 to sterilize the valves, piping, and the like of the production apparatus 3. In this manner, the normal operation step and the circulation step can each be performed periodically. As described above, the water for injection in the circulation unit 20 is adjusted to 50°C or higher throughout the normal operation step and the sterilization step. This reduces the amount of energy required for heating compared to adjusting the entire water for injection production unit 50 and circulation unit 20 to 50°C or higher.

[0069] The open and closed states of valves V1, Va, V2, and V3 in Fig. 7 during this second circulation process are shown in Fig. 9. In Fig. 9, the black valves indicate that they are closed, and the white valves indicate that they are open.

[0070] In Figure 7, valves V1, Va, V2, and V3, as well as a portion of the transfer pipe 50d, transfer pipe 20g, bridging pipe 50g, transfer pipe 20a, and transfer pipe 20h surrounded by these (switching section S) become dead legs depending on whether they are open or closed. Therefore, it is preferable to set the distance from the center of the main pipe to the closing mechanism at the end of the branch pipe within six times, preferably three times, the inner diameter of the branch pipe. Furthermore, by replacing valves V1 and V3 with three-way valve V40 and valves V2 and Va with three-way valve V60, the dead legs of switching section S can be reduced. A three-way valve has three openings and one flow path connecting two of the openings. The flow path within the valve can be changed by switching the connection point between this flow path and the openings.

[0071] 10 shows a schematic diagram of the positional relationship between the flow paths and openings of the three-port valves V40 and V60 during the first circulation step when the three-port valves V40 and V60 are used. The three openings of the three-port valve V40 are connected to transfer pipe 50c, cross-linking pipe 50g, and supply pipe 20a, respectively. The three openings of the three-port valve V60 are connected to transfer pipe 20c, transfer pipe 20g, and transfer pipe 20h, respectively. During the first circulation step, the three-port valve V40 is switched so that its flow path connects transfer pipe 50c to supply pipe 20a. At the same time, the three-port valve V60 is switched so that its flow path connects transfer pipe 20c to transfer pipe 20g. Figure 11 shows a schematic diagram of the positional relationship between the flow paths and openings of the three-port valves V40 and V60 during the second circulation process when the three-port valves V40 and V60 are used. In the second circulation process, the three-port valve V40 is switched so that its flow path connects transfer pipe 50c and cross-linking pipe 50g. At the same time, the three-port valve V60 is switched so that its flow path connects transfer pipe 20h and transfer pipe 20c. This reduces the number of valves and piping, simplifying the device configuration.

[0072] According to the apparatus for producing water for injection 3 of this embodiment, when water for injection is being used at the point of use (POU) 30 and the retention time of the water for injection in the circulation unit 20 is equal to or shorter than a predetermined time, the water for injection is circulated throughout the entire system of the production apparatus 3 by circulating the water for injection through the water for injection production unit 50 and the circulation unit 20. This makes it extremely unlikely for the water for injection to stagnate, and high-quality water for injection can be stably supplied to the point of use (POU) 30. Furthermore, for example, when the use of water for injection at the point of use (POU) 30 stops and the transfer of water for injection to the point of use (POU) 30 accordingly stops, the retention time of the water for injection in the circulation unit 20 exceeds a predetermined time, so the water for injection is circulated within each of the systems of the water for injection production unit 50 and the circulation unit 20, or within the circulation unit 20 alone. This allows for a significant reduction in the amount of energy used to heat and cool the water for injection, contributing to a reduction in carbon dioxide emissions. [Example]

[0073] Next, examples will be described, but the present invention is not limited to the following examples.

[0074] Using a water for injection manufacturing apparatus similar to that shown in Figure 3, the retention time of the water for injection during temperature adjustment was set to 2 hours under the conditions shown in Table 1. The temperature of the water for injection was adjusted depending on whether the retention time exceeded 2 hours. The estimated energy consumption for heating the water for injection was calculated under these conditions. Table 2 shows the results. The energy consumption for Comparative Example 1 is shown as 100, and the values ​​for Examples 1 and 2 are shown as relative values. The test apparatus was operated under the conditions shown in Table 3, and the viable bacterial counts in the water for injection in the water for injection circulation section were measured at the beginning of water flow, after 300 days of water flow (300 days after water flow), and after 500 days of water flow (500 days after water flow). These results are shown in Table 4. The times in the table are in Japan time. The viable bacterial counts were measured using the microbial monitoring method specified in the quality control of pharmaceutical water in the Reference Information of the Japanese Pharmacopoeia. This measurement method involves culturing and counting viable bacteria collected using a membrane filter. In the Japanese Pharmacopoeia, the standard value is the number of viable bacteria per 100 ml, but in the examples, the number of viable bacteria per 1000 ml, which is 10 times the amount, is counted and converted to the number of viable bacteria per 100 ml.

[0075] [Table 1]

[0076] [Table 2]

[0077] [Table 3]

[0078] [Table 4]

[0079] It can be seen from Table 2 that the energy consumption under the conditions of the Examples is significantly reduced compared to the Comparative Examples. Furthermore, it was confirmed from Table 4 that under all the conditions of the Examples, water for injection with a concentration of 10 CFU / 100 ml or less, which is the management standard for water for injection, could be produced.

[0080] Using a water for injection manufacturing apparatus similar to that shown in Figure 3, the retention time of the water for injection during temperature adjustment was set to 8 hours under the conditions shown in Table 5, and the temperature of the water for injection was adjusted depending on whether the retention time exceeded 8 hours. The results of calculations of the amount of energy used for heating were shown in Table 6. The amount of energy used for Example 6 and Comparative Example 3 was shown as a relative value, with Comparative Example 1 set to 100. The test apparatus was also operated under the conditions shown in Table 5, and the viable bacterial counts in the water for injection in the water for injection circulation section were measured at the beginning of water flow, after 300 days of water flow (300 days after water flow), and after 500 days of water flow (500 days after water flow). These results are shown in Table 7.

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] From Tables 5 to 7, it was confirmed that, similar to Tables 1 to 4 above, even when the residence time of water for injection in the circulation section was set to 8 hours, the method of the example significantly reduced energy consumption and made it possible to produce water for injection with a concentration of 10 CFU / 100 ml or less, which is the management standard for water for injection. [Explanation of symbols]

[0085] 1, 2, 3: Water for Injection Manufacturing Apparatus, 10, 50: Water for Injection Manufacturing Unit, 20, 40: Circulation Unit, 21, 41, 52: Temperature Control Device, 51: Superheater, 10a, 20a, 40a, 50a: Supply Pipe, 10b, 10c, 10d, 10e, 20b, 20c, 20d, 20g, 20h: Transfer Pipe, 10f, 20e: Discharge Pipe, 40b, 40c, 40d: Transfer Pipe, 40e: Discharge Pipe, 40f: Transfer Pipe, 50b, 50c, 50d 、50e: Transfer pipe、50f: Discharge pipe、50g: Bridging pipe、P、P1、P10: Poup、TK、TK1、TK10: Tank、Va、Vd、Ve、V1、V2、V3、V4e、V5f: Ball、V40、V60: 3-square-shaped、S: Switching unit、S10: Water for injection production process、S20: Circulation process、S21: Storage process、S22: Temperature adjustment process、S30: Transfer process、S40: Circulation process、S41: Temperature adjustment process、S42: Storage process

Claims

1. an injection water production department in which purified water is distilled or ultra-filtered to produce injection water; a circulation section in which the water for injection is stored in a tank, the stored water for injection is transportable to a place of use, and the water for injection that has not been transported to the place of use is circulated within the tank, When the retention time of the water for injection in the circulation part exceeds a predetermined time, the temperature of the water for injection is adjusted to 50°C or higher, A method for producing water for injection, wherein the temperature of the water for injection is adjusted to less than 50°C when the retention time of the water for injection in the circulation part is equal to or shorter than a predetermined time.

2. 2. The method for producing water for injection according to claim 1, wherein whether the retention time exceeds a predetermined time or is equal to or shorter than a predetermined time is determined based on the amount of water for injection transported to the site of use.

3. The method for producing water for injection according to claim 1, wherein whether the retention time exceeds a predetermined time or is equal to or shorter than a predetermined time is determined based on the water level in the tank.

4. The method for producing water for injection according to claim 1, wherein the purified water is ultra-filtered in the water for injection production section.

5. 5. The method for producing water for injection according to claim 4, wherein when the storage time of the water for injection in the circulation unit exceeds a predetermined time, the supply of the water for injection from the water for injection production unit to the circulation unit is stopped, and the temperature of the water for injection in the circulation unit is adjusted to 50°C or higher.

6. A method for producing water for injection as described in claim 4, wherein when the storage time of the water for injection in the circulation section exceeds a predetermined time, part or all of the water for injection that has not been transported to the place of use is circulated upstream of the circulation section, thereby adjusting the storage time of the water for injection in the circulation section to be equal to or less than the predetermined time.

7. 5. The method for producing water for injection according to claim 4, wherein when the storage time of the water for injection in the circulation unit exceeds a predetermined time, part or all of the water for injection that has not been transported to the place of use is circulated to the water for injection production unit, thereby adjusting the storage time of the water for injection in the circulation unit to be equal to or shorter than the predetermined time.

8. The injection water manufacturing department produces injection water, and the circulation department circulates and stores the produced injection water. An apparatus for producing water for injection having a unit, the injection water producing unit has a distillation device for distilling purified water or an ultrafiltration device for ultrafiltration of purified water, the circulation unit has a tank for storing the injection water, a circulation pipe for transporting part or all of the injection water in the tank to a place of use and circulating the injection water that has not been transported to the place of use, and a temperature adjustment means for adjusting the temperature of the injection water in the circulation pipe, The temperature adjusting means adjusts the temperature of the water for injection to 50°C or higher when the storage time of the water for injection in the circulation unit exceeds a predetermined time, and adjusts the temperature of the water for injection to less than 50°C when the storage time of the water for injection in the circulation unit is less than the predetermined time.

9. 9. The apparatus for preparing water for injection according to claim 8, further comprising a flow rate detection device that detects a difference in flow rate between the upstream side and the downstream side of the place of use in the circulation pipe, and whether the difference exceeds the predetermined time or is equal to or less than the predetermined time is determined based on the value of the flow rate detection device.

10. 9. The apparatus for preparing water for injection according to claim 8, further comprising a water level meter that detects the water level in the tank, and whether the predetermined time is exceeded or is equal to or less than the predetermined time is determined based on the value of the water level meter.

11. The apparatus for preparing water for injection according to claim 8, wherein the water for injection preparing section has an ultrafiltration device.

12. An injection water manufacturing apparatus as described in claim 11, further comprising a switching unit that, when the storage time of the injection water in the circulation unit exceeds a predetermined time, circulates some or all of the injection water that has not been transported to the place of use upstream of the circulation unit, thereby adjusting the storage time of the injection water in the circulation unit to less than a predetermined time.

13. 12. The apparatus for preparing water for injection according to claim 11, further comprising a switching unit that, when the storage time of the water for injection in the circulation unit exceeds a predetermined time, circulates part or all of the water for injection that has not been transported to the place of use to the water for injection preparation unit, thereby adjusting the storage time of the water for injection in the circulation unit to be equal to or shorter than the predetermined time.

14. 14. The apparatus for preparing water for injection according to claim 12 or 13, wherein the switching unit closes a supply pipe for water for injection from the water for injection preparation unit to the circulation unit when the temperature of the water for injection in the circulation unit is 50°C or higher, and circulates the water for injection in the circulation unit.

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