Method for producing water for injection and device for producing water for injection

Abstract

Provided are a method for producing water for injection and a device for producing water for injection that make it possible to reduce an energy amount used for heating and cooling the water for injection during production thereof. The device for producing water for injection includes: a production unit for water for injection in which purified water is distilled or ultrafiltered to produce water for injection; and a circulation unit in which the water for injection is stored in a tank, the stored water for injection is made transferable to a place of use, and the water for injection that is not transferred to the place of use is circulated back into the tank. In a method for producing water for injection, the temperature of the water for injection is adjusted to 50°C or higher when a storage time of the water for injection in the circulating unit exceeds a prescribed time, and the temperature of the water for injection is adjusted to less than 50°C when the storage time is the prescribed time or less.

Description

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

[0001] This invention relates to a method for producing water for injection that reduces energy consumption, and to a water for injection production apparatus.

[0002] The water quality and water quality management of water used in pharmaceuticals are stipulated by the pharmacopoeias of each country. The Japanese Pharmacopoeia classifies water for pharmaceutical use into four standards: ordinary water, purified water, sterile purified water, and water for injection. Of these, water for injection (WFI) is used in the manufacture of injectable solutions, and therefore requires strict removal of live bacteria and endotoxins. Water for injection is produced by distilling or ultrafiltration (mainly ultrafiltration) of water that has been pretreated by ion exchange, reverse osmosis, etc., from "ordinary water" or "purified water." Furthermore, since the produced water for injection is stored in the manufacturing equipment in preparation for use, strict water quality management is required to prevent the generation or contamination of live bacteria and endotoxins in the water for injection.

[0003] Generally, water for injection produced by distillation or ultrafiltration is circulated by a pump within the circulation system in the manufacturing system and is sampled and used from the point of use (POU: Point of Use) as needed. This circulation system consists of a storage tank for water for injection, a use point, and circulation piping connecting the storage tank and the use point. In this circulation system, a circulation operation is constantly performed to prevent the establishment of microorganisms and organic substances within the system. And, in terms of design, it is required to maintain a flow velocity (usually 1 m / sec or more) in the piping within the circulation system such that sufficient turbulent flow is generated within the piping. Also, within the circulation system, the main pipe branches with a tee pipe (T-shaped pipe), etc., and when there is a closing mechanism such as a valve at the end of the branch, it is required that the distance from the center of the main pipe to the closing mechanism at the end of the branch pipe be within 6 times the inner diameter of the branch pipe, and if possible, within 3 times the inner diameter. Here, the closing mechanism at the end of the branch is referred to as a "dead leg". Furthermore, the circulating water for injection is constantly maintained at a high temperature, for example, 50 °C or higher, preferably 65 °C or higher, more preferably 80 °C or higher, in order to prevent the increase of viable bacteria and endotoxins. Since the water for injection used at the use point is usually required to be at room temperature, the water for injection is cooled to room temperature before use after being transferred to the place of use or during the transfer process (for example, see Patent Document 1). Also, for water quality management, the manufacturing system is periodically stopped, drained, and then the valves, piping, etc. of the manufacturing system are sterilized with superheated steam (for example, see Patent Document 2).

[0004] JP-A-2020-138154 JP-A-2008-178582

[0005] As mentioned above, in conventional water for injection production processes using distillation or ultrafiltration, water for injection is circulated in a circulation system at 80°C or higher to prevent the increase of live bacteria and endotoxins, and then the required amount of water for injection is cooled and supplied to the place of use. In contrast, the use of ultrafiltration has made it possible to produce and supply water for injection at or near room temperature (sometimes called cold WFI). This cold WFI requires excessive heating solely to prevent the increase of live bacteria and endotoxins in the circulation system. Therefore, there is a need for a method that can supply cold WFI without concerns about the increase of live bacteria and endotoxins.

[0006] Furthermore, methods that maintain a constant high temperature within the circulation system require constant steam to heat the water for injection, and additional energy is needed for cooling during use, resulting in high energy consumption. In recent years, with the increasing international demand for reducing carbon dioxide emissions based on the SDGs (Sustainable Development Goals) adopted by the United Nations, efforts to reduce energy consumption through the realization of cold WFI (Water for Injection) have become an urgent necessity in water for injection production systems.

[0007] The method for producing water for injection and the apparatus for producing water for injection of this embodiment were made to solve the above-mentioned problems, and aim to reduce the amount of energy used for heating and cooling water for injection during production.

[0008] This embodiment has the following configuration: [1] A water for injection production apparatus comprising: a water for injection production unit for producing water for injection by distilling or ultrafiltration purified water; and a circulation unit for storing the water for injection in a tank, making the stored water for injection transportable to a place of use, and circulating the water for injection that is not transported to a place of use in the tank, wherein when the storage time of the water for injection in the circulation unit exceeds a predetermined time, the temperature of the water for injection is adjusted to 50°C or higher, and when the storage time of the water for injection in the circulation unit is less than or equal to a predetermined time, the temperature of the water for injection is adjusted to less than 50°C. [2] The water for injection production method according to [1], wherein it is determined whether the storage time exceeds a predetermined time or is less than or equal to a predetermined time based on the amount of water for injection transported to the place of use. [3] The water for injection production method according to [1], wherein it is determined whether the storage time exceeds a predetermined time or is less than or equal to 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 superfiltered in the water for injection production unit. [5] The method for producing water for injection according to [4], wherein when the storage time of 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 water for injection in the circulation unit exceeds a predetermined time, part or all of the water for injection that has not been transferred to the place of use is circulated to the stage before the superfiltration in the water for injection production unit, and the storage time of water for injection in the circulation unit is adjusted to a predetermined time or less.

[0009] [7] A water for injection manufacturing apparatus comprising a water for injection manufacturing unit for manufacturing water for injection and a circulation unit for circulating and storing the manufactured water for injection, wherein the water for injection manufacturing unit comprises a distillation apparatus for distilling purified water or an ultrafiltration apparatus for ultrafiltration purified water, and the circulation unit comprises a tank for storing the water for injection, a circulation pipe for transferring 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 transferred to a place of use, and a temperature control means for adjusting the temperature of the water for injection in the circulation pipe, wherein the temperature control 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 or equal to a predetermined time. [8] The water for injection production apparatus according to [7], further comprising a flow detection device for detecting the flow rate difference between the upstream and downstream sides of the place of use of the circulation piping, wherein whether the predetermined time is exceeded or less than the predetermined time is determined based on the value of the flow detection device. [9] The water for injection production apparatus according to [7], further comprising a storage level meter for detecting the storage level in the tank, wherein whether the predetermined time is exceeded or less than the predetermined time is determined based on the value of the storage level meter.

[10] The water for injection production apparatus according to [7], wherein the water for injection production section comprises an ultrafiltration device.

[11] The water for injection production apparatus according to

[10] , further comprising a switching unit for adjusting the storage time of the water for injection in the circulation section to a predetermined time or less by circulating a portion or all of the water for injection that has not been transferred to the place of use to the upstream of the ultrafiltration device when the storage time of the water for injection in the circulation section exceeds a predetermined time.

[12] The water for injection production apparatus according to

[11] , wherein the switching unit closes the supply pipe for water for injection from the water for injection production unit to the circulation unit when the storage temperature of the water for injection in the circulation unit is 50°C or higher, thereby circulating the water for injection within the circulation unit. The symbol "~" indicates a numerical range including the numbers before and after it.

[0010] According to the embodiment of the method for producing water for injection and the apparatus for producing water for injection, the amount of energy used for heating and cooling water for injection during production can be reduced, and this can contribute to the reduction of carbon dioxide emissions.

[0011] This is a schematic block diagram showing the production apparatus for water for injection according to an embodiment. This is a flow diagram of the method for producing water for injection according to an embodiment. This is a schematic block diagram showing the production apparatus for water for injection according to another embodiment. This is a graph schematically showing the change in the temperature of water for injection and the change in the amount of water for injection used at the place of use when the temperature is adjusted to below 50°C starting a predetermined period before the start of use of water for injection. This is a schematic block diagram showing the production apparatus for water for injection according to another embodiment. This is a flow diagram of the method for producing water for injection according to another embodiment. This is a schematic block diagram showing the open and closed states of the four valves in the first circulation process. This is a diagram showing the open and closed states of the four valves in the second circulation process. This is a schematic diagram showing the state in which two three-way valves are used instead of four valves in the production apparatus for water for injection according to an embodiment. This is a schematic diagram showing another state in which two three-way valves are used instead of four valves in the production apparatus for water for injection according to an embodiment.

[0012] The embodiments will be described below with reference to the drawings. Figure 1 is a schematic block diagram showing the water for injection production apparatus 1 of this embodiment. Figure 2 is a flow diagram of the water for injection production method of this embodiment.

[0013] The apparatus for producing water for injection 1 of the embodiment shown in Figure 1 includes a water for injection production 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 transferred to a point of use (POU) 30 for use. The circulation unit 20 is equipped with a tank TK, a pump P, and a temperature control means 21 along the direction in which the water for injection flows.

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

[0015] The water for injection production unit 10 shown in Figure 1 has a distillation apparatus for distilling purified water or an ultrafiltration apparatus for ultrafiltration purified water. The distillation apparatus or ultrafiltration apparatus removes live bacteria, endotoxins, and other impurities from the purified water to produce water for injection (water for injection production process S10 in Figure 2). The produced water for injection is transferred to the circulation unit 20 and stored in the tank TK (storage process S21 in Figure 2). The water for injection stored in the tank TK is sent to the temperature control means 21 by the pump P and its temperature is adjusted as needed. In Figure 1, the temperature control means 21 is shown to be located within the circulation unit 20, but the temperature control means 21 may be located immediately before the circulation unit 20. When the temperature control means 21 is located immediately before the circulation unit 20, the water for injection whose temperature has been adjusted by the temperature control means 21 is supplied to the circulation unit 20. A portion of the temperature-controlled water for injection is transferred to the point of use (POU) 30, while the water for injection that is not transferred to the point of use (POU) 30 is returned to the tank TK. This causes the water for injection to circulate within the circulation unit 20 (circulation process S20 in Figure 2). In the water for injection manufacturing method of this embodiment, the temperature of the water for injection in the circulation unit 20 is adjusted by the temperature control means 21 to be 50°C or higher or below 50°C, depending on the storage time of the water for injection in the circulation unit 20 (temperature control process S22 in Figure 2). The storage time is the maximum time from when the water for injection flows into the circulation unit 20 until it is discharged from the circulation unit 20, such as by being transferred to the point of use (POU) 30. The storage 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 sterile water for injection circulating within the circulation unit 20 may fluctuate depending on the amount of sterile water for injection used at the point of use (POU) 30, that is, the amount transferred to the point of use (POU) 30. The amount of sterile water for injection circulating within the circulation unit 20 may also fluctuate depending on the amount of sterile water for injection transferred from the sterile water for injection production unit 10 to the circulation unit 20. When such fluctuations occur, the storage time of the sterile water for injection in the circulation unit 20 also fluctuates. Therefore, by appropriately adjusting the temperature of the sterile water for injection in the circulation unit 20 to 50°C or higher or below 50°C according to the fluctuations, it is possible to minimize the energy required for heating or cooling the sterile water for injection while preventing an increase in viable bacteria and endotoxins due to prolonged storage.

[0017] Specifically, when the storage time of the water for injection in the circulation unit 20 exceeds a predetermined time, the temperature control 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 storage time of the water for injection in the circulation unit 20 is less than or equal to the predetermined time, the temperature control 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 to be kept below 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, it is possible to determine whether the storage time of the water for injection in the circulation unit 20 exceeds a predetermined time or falls below a predetermined time based on the amount of water for injection transferred to the point of use (POU) 30.

[0019] In the water for injection production apparatus 1 of the embodiment shown in Figure 1, the water for injection production unit 10 includes a supply pipe 10a for supplying purified water to the water for injection production unit 10, a tank (not shown) for receiving and storing the purified water supplied from the supply pipe 10a, a pump (not shown), and a distillation apparatus for distilling the purified water, or an ultrafiltration apparatus for ultrafiltration the purified water (hereinafter referred to as "ultrafiltration apparatus, etc."). The purified water is supplied from the tank to the ultrafiltration apparatus, etc. by the pump. Water for injection is produced by sterilizing or removing live bacteria and endotoxins in the water in the ultrafiltration apparatus, etc. Note that the water for injection production unit 10 only needs to have at least one of a distillation apparatus and an ultrafiltration apparatus as the ultrafiltration apparatus, etc., and may have both a distillation apparatus and an ultrafiltration apparatus.

[0020] The purified water supplied to the water for injection production unit 10 is produced using "ordinary water" as raw water and undergoing necessary pretreatment. The purified water is produced by pretreating ordinary water using a production system that includes ion exchange treatment using an ion exchange column packed with cationic resin and anionic resin, electrodeionization equipment, etc., distillation treatment, membrane treatment using reverse osmosis membranes (RO) or ultrafiltration (UF), either individually or in combination. In particular, it is preferable that the purified water is produced by a system that combines a reverse osmosis membrane with electrolytic continuous ion exchange (EDI).

[0021] For the production of purified water, a reverse osmosis (RO) membrane apparatus equipped with a reverse osmosis membrane (RO) can be used. The reverse osmosis apparatus consists of one or more reverse osmosis membrane modules. A reverse osmosis membrane module is constructed, for example, by housing a reverse osmosis membrane and a flow channel material for passing the water to be treated through the reverse osmosis membrane in a casing. The shape of the reverse osmosis membrane is preferably spiral, but it may also be hollow fiber type, flat membrane, tubular membrane, etc. The material of the reverse osmosis membrane provided in the reverse osmosis membrane module is, for example, various organic polymer membranes made of cellulose acetate, aliphatic polyamide, aromatic polyamide, or composites thereof. In this embodiment, the reverse osmosis membrane is preferably spiral in shape from the viewpoint of increasing pressure resistance and improving processing efficiency. Furthermore, the reverse osmosis membrane may be an ultra-low pressure type, low pressure type, medium pressure type, or high pressure type reverse osmosis membrane, but from the viewpoint of reducing power consumption during operation, low pressure or ultra-low pressure is preferred.

[0022] In the production of purified water, electrostatic continuous ion exchange (EDI) uses, for example, a device in which an anion exchange membrane and a cation exchange membrane are sandwiched between alternately arranged desalination chambers and concentration chambers. In this electrostatic continuous ion exchange device, ions in the water to be treated are removed by ion exchange resin packed in the desalination chamber, 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 apparatus in the water for injection production unit 10 heats and vaporizes the purified water obtained above, recovers the vaporized steam, and cools it to produce distilled water (water for injection). The distillation apparatus sterilizes and removes live bacteria and endotoxins from the purified water, making it possible to produce water for injection that meets the management standards for water for injection in the "Japanese Pharmacopoeia (JP17) Quality Conformity Test," with an endotoxin standard value of less than 0.25 EU / mL.

[0024] Figure 3 schematically shows a water for injection production apparatus 100 having a water for injection production unit 10 using an ultrafiltration device. In the water for injection production apparatus 100 shown in Figure 3, the configuration of the circulation unit 20 is the same as that of the water for injection production apparatus 1 shown in Figure 1, so the same reference numerals are used for components that perform the same function and detailed explanations are omitted. In the water for injection production apparatus 100 shown in Figure 3, 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 TK 10 that stores the supplied purified water, and a pump P 10 that sends the purified water in the tank TK 10 to the next stage. The water for injection production unit 10 includes an ultrafiltration device 11 that ultrafilters the purified water sent by the pump P 10, a transfer pipe 10b that transfers the purified water in the tank TK 10 to the ultrafiltration device 11, and a transfer pipe 10c that sends the permeate from the ultrafiltration device 11 to the next stage. The supply pipe 20a is branched and connected to the transfer pipe 10c. The permeate from the ultrafiltration device 11 is sent to the circulation unit 20 via the supply pipe 20a.

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

[0026] Next, the method for producing water for injection in the water for injection production section 10 of the water for injection production apparatus 100 will be described. The pump P10 of the water for injection production section 10 operates, and purified water is sent from the tank TK10 to the superfiltration unit 11. The purified water is cross-flow filtered in the superfiltration unit 11 to produce permeate. This permeate is sent to the circulation unit 20 via the supply pipe 20a as water for injection. The concentrated water from the superfiltration unit 11 is returned to the tank TK10 via the transfer pipe 10e. At this time, a portion of the concentrated water from the superfiltration unit 11 may be discharged outside the system by opening the valve V1f or adjusting the opening of the valve V1f. Alternatively, a portion of the permeate (water for injection) from the superfiltration unit 11 may be returned to the tank TK10 via the transfer pipe 10d by adjusting the opening 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 consists of one or more ultrafiltration membrane modules. An ultrafiltration membrane module has, for example, a casing. An ultrafiltration membrane module has an ultrafiltration membrane housed in the casing and a flow channel material for passing the water to be treated through the ultrafiltration membrane. The shape of the ultrafiltration membrane provided in the ultrafiltration membrane module is preferably a hollow fiber membrane, but may also be a spiral membrane, tubular membrane, flat membrane, etc. The material of the ultrafiltration membrane is polysulfone, polyvinylidene fluoride, polyethylene, polypropylene, etc. The nominal molecular weight cutoff of the ultrafiltration membrane is preferably in the range of 1,000 to 20,000, and more preferably in the range of 2,000 to 6,000. When the nominal molecular weight cutoff is in the range of 1,000 to 20,000, viable bacteria and endotoxin aggregates can be reliably removed. Furthermore, since the molecular weight of endotoxin alone is 10,000 to 20,000, if the nominal fractionation molecular weight is in the range of 2,000 to 6,000, endotoxin alone can be reliably excluded. Either an internal pressure type or an external pressure type ultrafiltration membrane module may be used. An internal pressure type is more preferable because the feed water and concentrated water are processed linearly, allowing for a high membrane surface flow velocity at a low flow rate, thus preventing the increase of viable bacteria due to the accumulation of impurities on the filtration surface of the hollow fiber membrane. In addition, it is preferable that the water for injection production apparatus 1 of the embodiment is equipped with a sterilization system to sterilize the production apparatus system in order to prevent the proliferation of viable bacteria on the ultrafiltration membrane. As the sterilization system, 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, or a superheated steam sterilization system that performs sterilization by supplying superheated steam into the system is preferred. It should be noted that even when an ultrafiltration apparatus is used, water for injection with water quality equivalent to or better than that when a distillation apparatus is used can be produced.

[0028] In the water for injection production apparatus 1 shown in Figure 1, the water for injection produced by the distillation apparatus or ultrafiltration apparatus 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 a temperature control means 21 that adjusts the temperature of the water for injection. In the embodiment in which the temperature control means 21 is provided immediately before the circulation unit 20, the temperature control means 21 is provided in the path of the supply pipe 20a. The temperature control means 21 may be provided in the circulation unit 20 or immediately before the circulation unit 20, and may be provided in either one or both. When the temperature control means 21 is provided in the circulation unit 20, the temperature control means 21 may be provided on either the upstream or downstream side of the place of use (POU) 30.

[0029] A transfer pipe 20b is connected to the tank TK. The transfer pipe 20b is connected to a transfer pipe 20d for transferring the water for injection that has passed through the transfer pipe 20b to the place of use (POU) 30, and to a transfer pipe 20c for returning the water for injection that has not been transferred to the place of use back to the tank TK. 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 form a circulation piping system that circulates the water for injection by returning it to the water for injection in the tank TK. In addition, a discharge pipe 20e is connected to the transfer pipe 20b for discharging the water for injection in the transfer pipe 20b to the outside of the system. A discharge pipe 20f is connected to the transfer pipe 20c for discharging the water for injection in the transfer pipe 20c to the outside of the system. 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 controlled by a control device or the like. The same applies to the other valves described later.

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

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

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

[0033] The predetermined storage time when adjusting the temperature as described above can be set according to the scale of the water for injection production apparatus 1 and the amount of water produced. For example, the predetermined storage time is preferably set to a value of 8 hours or less, preferably 2 hours or less.

[0034] Whether the above storage time exceeds or falls below 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 by the difference in flow rates before and after. Alternatively, the discharge rate of the pump P may be determined in advance when there is no water for injection being transferred to the point of use (POU) 30, and the discharge rate of the pump P may be fixed to a constant value. The amount of water for injection transferred to the point of use (POU) 30 may then be calculated solely from the measurement value of the flow rate measuring means downstream of the point of use (POU) 30. In this case, it may also be confirmed that the discharge rate of the pump P has not changed from the fixed value by means of the discharge pressure of the pump P or the current value supplied to the pump P. The temperature control means 21 can adjust the temperature of the water for injection in the circulation unit 20 to 50°C or higher when the amount of water for injection transferred to the place of use (POU) 30 is less than or equal to a predetermined amount, and the storage time exceeds a predetermined time. The temperature control means 21 then maintains the temperature of the water for injection in the circulation unit 20 at 50°C or higher. Furthermore, when the amount of water for injection transferred to the place of use (POU) 30 exceeds a predetermined amount, the temperature control means 21 can adjust the temperature of the water for injection in the circulation unit 20 to less than 50°C when the storage time is less than or equal to a predetermined time. 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 within the circulation unit 20 and adjusting the output of the temperature control means 21 according to the value of the temperature sensor.

[0035] The temperature sensor can be installed, for example, in the transfer pipe 20d, transfer pipe 20b, or inside the tank TK. The temperature sensor detects the temperature of the water for injection at each location. The output of the temperature control 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 water for injection production apparatus 1 is equipped with a detection device that detects the amount of water for injection transferred to the place of use (POU) 30. Based on the measurement value of the detection device, it can determine whether the storage time of the water for injection exceeds or falls below a predetermined time, and start adjusting the temperature of the water for injection as described above.

[0037] If the storage time of water for injection in the circulation unit 20 fluctuates depending on the amount of water for injection transferred to the place of use (POU) 30, a detection device is provided to detect the water level in the tank TK within the circulation unit 20. The temperature control means 21 can then determine whether the storage time of water for injection in the place of use (POU) 30 exceeds or falls below a predetermined time based on the fluctuation in the water level measurement value per hour from the detection device. Furthermore, by pre-setting predetermined values ​​for the water level at the start of supplying water for injection from the water for injection production unit 10 to the tank TK (start water level) and the water level at the stop of supply (stop water level), the storage time of water for injection in the circulation unit 20 can be calculated by counting the number of supply cycles per hour using the number of times valve Va is opened and closed, without having to measure fluctuations in the water level measurement value. Therefore, when the number of supply cycles is below a predetermined value, it can be automatically determined that the storage time of water for injection in the circulation unit 20 is below a predetermined time.

[0038] The temperature control means 21 can also detect the flow rate difference between the upstream transfer pipe 20b and the downstream transfer pipe 20c of the place of use (POU) 30, and based on the detection result of the flow rate difference, determine whether the storage time of the water for injection in the circulation unit 20 exceeds or falls below a predetermined time. In this case, even if a detection device for detecting the amount of transfer is not provided in the transfer pipe 20d, a flow rate detection device for detecting the flow rate difference between the transfer pipes 20b and 20c can be provided, and based on the detected value of the flow rate detection device, it can be determined that water for injection is being supplied to the transfer pipe 20d when the flow rate on the downstream side becomes smaller than the flow rate on the upstream side of the place of use (POU) 30 of the circulation unit 20, and the storage time of the water for injection in the circulation unit 20 can be calculated based on that flow rate difference. This makes it possible to automatically determine whether the storage time of the water for injection in the circulation unit 20 is less than or equal to 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 predetermined temperature to fluctuate drastically, resulting in unstable operation of the circulation unit 20. To avoid this, it is preferable to use the average value over a certain period (for example, 10 minutes, or the average over 5 to 20 minutes) as the predetermined transfer amount. This prevents the circulation unit 20 from becoming unstable as described above. In addition, to prevent a rapid rise or fall in temperature when the temperature control of the water for injection in the circulation unit 20 is started, it is preferable to use lamp soak control or the like to gradually raise or lower the temperature.

[0040] Furthermore, if the usage conditions at the place of use (POU) 30 are predetermined by day of the week and time of day, a timer may be provided in the water for injection production device 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 below 50°C using a timer or the like at the predetermined adjustment start time. In this case, it is 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 flow rate difference between the transfer pipe 20b and the transfer pipe 20c in combination, as this can also accommodate usage conditions outside of the predetermined settings.

[0041] Alternatively, temperature adjustment may be initiated using a predicted flow rate estimated from the operating schedule of the factory using the water for injection and the water usage status of the previous day. In this case, the set temperature of the circulation unit 20 can be set to below 50°C to coincide with the start of factory operations, and the set temperature of the circulation unit 20 can be set to 50°C or higher after the factory operations have ended. As a result, abrupt temperature changes are unnecessary, and the amount of steam used during temperature changes can be reduced, thus reducing energy consumption. In addition, by avoiding abrupt temperature changes, the burden on the equipment is reduced, which in turn suppresses the occurrence of equipment malfunctions and leads to the stable supply of water for injection to the point of use (POU) 30.

[0042] If the water for injection production device 1 is installed inside or near a pharmaceutical factory and water for injection is used inside the pharmaceutical factory, for example, if a predetermined transfer amount is set to zero (0), then when water for injection is used inside the pharmaceutical factory, the amount of water for injection transferred to the place of use (POU) 30 will exceed zero and exceed the predetermined transfer amount. As a result, the storage time of water for injection in the circulation unit 20 will be less than or equal to the predetermined time. On the other hand, when the pharmaceutical factory is shut down and water for injection is not used inside the pharmaceutical factory, the amount of water for injection transferred to the place of use (POU) 30 will be zero, and the storage time of water for injection in the circulation unit 20 will exceed the predetermined time. When using the above control method, the temperature of water for injection in the circulation unit 20 can be maintained below 50°C when the pharmaceutical factory is in operation, and the temperature of water for injection in the circulation unit 20 can be maintained at 50°C or higher only during periods when the factory is shut down. Therefore, compared to the conventional method of circulating sterile water for injection at a high temperature of 50°C or higher at all times and then cooling it to room temperature after or during transfer to the place of use (POU) 30, the energy required for heating and cooling the sterile water for injection can be reduced, and as a result, carbon dioxide emissions can be reduced. In addition, by maintaining the temperature of the sterile water for injection in the circulation unit 20 at 80°C or higher during nights or weekends when the pharmaceutical plant is shut down, the inside of the circulation unit 20 can be thermally sterilized. As a result, the increase of viable bacteria and endotoxins in the circulation unit 20 can be further prevented. Furthermore, by providing a sterilization device that supplies superheated steam into the circulation unit 20 to sterilize the valves and piping of the sterile water for injection production device 1, and performing sterilization treatment within the sterile water for injection production device system periodically, the increase of viable bacteria and endotoxins can be further suppressed. Although the above description has focused on the case where the predetermined transfer amount is zero (0), the predetermined transfer amount may slightly exceed zero.

[0043] In the injection water production apparatus 1 of the above-described embodiment, the water level in tank TK may fluctuate depending on the amount of injection water produced by the injection water production unit 10 and the amount of injection water used (used at the point of use) 30. For example, if the amount of injection water produced by the injection water production unit 10 is greater than the amount of injection water transferred to the point of use (POU) 30, the water level in tank TK may rise. If the amount of injection water produced by the injection water production unit 10 is less than the amount of injection water transferred to the point of use (POU) 30, the water level in tank TK may fall. Such increases and decreases in the amount of water used at the point of use (POU) 30 are absorbed by increases and decreases in the water level of tank TK, and the amount of water circulated in the circulation unit 20 is stably maintained within a predetermined range. Furthermore, if necessary, the amount of injection water transferred to the circulation unit 20 may be adjusted by adjusting the opening of valve Va, thereby adjusting the water level in tank TK. Specifically, it is possible to maintain a constant water level in the tank TK by controlling the opening of valve Va in accordance with fluctuations in the amount of water used for injection transferred to the place of use (POU) 30. In this case, a circulation system including a tank may be installed within the water for injection production unit 10, and the water for injection that was not transferred to the circulation unit 20 may be circulated to the tank within the water for injection production unit 10.

[0044] In the apparatus 1 for producing water for injection according to the embodiment, the transfer amount of water for injection from the circulation unit 20 to the point of use (POU) 30 may intermittently change in a short period. For example, if the circulation time of the water for injection in the circulation unit 20 intermittently changes near the set predetermined time, it may be intermittently repeated when exceeding the predetermined time and when it is less than the predetermined time. Due to such repetition, if the temperature increase and decrease of the water for injection in the circulation unit 20 are repeated, conversely, the energy consumption for temperature increase may increase. Therefore, when the circulation time of the water for injection in the circulation unit 20 intermittently changes around the set predetermined time, it is preferable to discharge the water for injection out of the system through the discharge pipe 20e or the discharge pipe 20f, or both, so that the circulation time does not exceed the predetermined time. By opening the valve Ve provided in the discharge pipe 20e, the valve Vf provided in the discharge pipe 20f, or both, the water for injection can be discharged out of the system. Note that 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 usage plan of the water for injection at the point of use (POU) 30.

[0045] FIG. 4 schematically shows changes in the temperature (solid line) of water for injection and changes in the usage amount of water for injection (POU usage amount, broken line) at the point of use (POU) 30 when it is assumed that the pharmaceutical factory starts operating at 9:00 am and stops operating at 5:00 pm, and the temperature of the water for injection starts to be adjusted to room temperature before the start of operation and the temperature of the water for injection starts to be adjusted to 80° C after the stop of operation. In FIG. 4, the usage amount of water for injection during the operation of the pharmaceutical factory is assumed to be constant, and the value is set to 100, and the change in the usage amount of water for injection over time is shown as a relative value.

[0046] As shown in Figure 4, the temperature of the water for injection can be adjusted to room temperature from the time the amount of water for injection transferred to the point of use (POU) 30 becomes zero, after a predetermined period has elapsed, that is, from a predetermined period before the amount of water for injection transferred to the point of use (POU) 30 exceeds zero (when the water for injection is put into use) (before the preparation period). In this way, if 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 lowered to room temperature by lamp soak control or the like from before the start of use so that the temperature of the water for injection reaches the use temperature in time for the start of use. This method does not involve a rapid temperature change from high to low temperature, so deterioration of piping and various devices due to rapid temperature changes can be suppressed. It is also advantageous in that it does not increase the amount of heat transfer medium used for temperature adjustment to cause rapid temperature changes. In Figure 4, the temperature of the water for injection is adjusted so that it reaches room temperature at the start time of use (9:00 AM) at the point of use (POU) 30.

[0047] Furthermore, as described above, when the amount of water for injection transferred to the place of use (POU) 30 is zero, the temperature of the water for injection in the circulation unit 20 is adjusted to 50°C or higher, and when the amount transferred exceeds zero, the temperature of the water for injection in the circulation unit 20 is adjusted to less than 50°C. In this case, it is preferable that the supply of water for injection from the water for injection production unit 10 to the circulation unit 20 is 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 supply of water for injection from the water for injection production unit 10 to the circulation unit 20 is continued during the period when the temperature is adjusted to less than 50°C. It is preferable to close the valve Va provided on the supply pipe 20a while the supply of water for injection from the water for injection production unit 10 to the circulation unit 20 is stopped. During this time, the water for injection is circulated in the circulation piping consisting of the tank TK10, transfer pipe 10b, ultrafiltration device 11, transfer pipe 10c, transfer pipe 10d, and transfer pipe 10e within the water for injection production unit 10 shown in Figure 3. Furthermore, depending on the condition of the circulation unit 20, valve Va may be opened to supply water for injection from the water for injection production unit 10 to the circulation unit 20.

[0048] During the period when the temperature of the water for injection in the circulation section 20 is adjusted to less than 50°C, that is, during the period when the retention time of the water for injection in the circulation section 20 is less than or equal to a predetermined time, the water for injection flows out from the water for injection production section 10 to the point of use (POU) 30 through the transfer pipes 20b and 20d of the circulation section 20 substantially without delay. Therefore, it is possible to supply the clean water for injection from which live bacteria, endotoxins, etc. have been removed in the water for injection production section 10 to the point of use (POU) 30 without delay. Also, during the period when the temperature of the water for injection in the circulation section 20 is adjusted to 50°C or higher, that is, during the period when the retention time of the water for injection in the circulation section 20 exceeds the predetermined time, by stopping the outflow of the water for injection from the water for injection production section 10 to the circulation section 20, a relatively small amount of the water for injection is circulated, so it is possible to minimize the amount of energy used by heating the water for injection to a high temperature. Furthermore, by minimizing the storage amount of the water for injection in the tank (TK), the energy consumption can be reduced more effectively. Also, by performing the above operation, it is possible to prevent an increase in live bacteria and endotoxins.

[0049] According to the method and apparatus for manufacturing water for injection of the above-described embodiment, by appropriately setting the start time of temperature adjustment to 50°C or higher and less than 50°C, when the amount of water for injection used is small, especially when the water for injection is not used, the circulated water for injection can be kept at a high temperature. For this reason, compared with the conventional method of cooling the water for injection during the process of constantly circulating it at a high temperature and transferring it to the point of use, the amount and time of the water for injection to be heated and cooled can be reduced, and the energy for heating and cooling can be significantly reduced.

[0050] In the method for manufacturing water for injection of the above-described embodiment, the water for injection transferred from the water for injection production section 10 is once stored in the tank TK, and then the temperature is adjusted by the temperature adjustment means 21 and transferred to the point of use (POU) 30. The water for injection transferred from the water for injection production section 10 may be adjusted in temperature by the temperature adjustment means 21 and transferred to the point of use (POU) 30, and then the water for injection that has not been transferred to the point of use (POU) 30 may be returned to the tank TK. Hereinafter, this embodiment will be described with reference to the drawings.

[0051] Figure 5 is a schematic block diagram showing a water for injection production apparatus 2 of another embodiment. Figure 6 is a flow diagram of a water for injection production method of another embodiment. The water for injection production apparatus 2 shown in Figure 5 has a water for injection production unit 10 similar to the embodiment described above, and a circulation unit 40 for circulating the produced water for injection. The water for injection in the circulation unit 40 is transferred to a place of use (POU) 30 for use. In the circulation unit 40, a pump P, a temperature control means 41, a place of use (POU) 30, and a tank TK are arranged along the flow of water for injection transferred from the water for injection production unit 10.

[0052] A supply pipe 40a is connected to the circulation unit 40 to supply the water for injection produced in the water for injection production unit 10 to the circulation unit 40, and a transfer pipe 40b is connected to the supply pipe 40a. A transfer pipe 40d for transferring the water for injection that has passed through the transfer pipe 40b to the place of use (POU) 30, and a transfer pipe 40c for supplying the water for injection that has not been transferred to the place of use (POU) 30 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 transferred to the transfer pipes 40d and 40c. The water for injection that has not been transferred to the place of use (POU) 30 is stored in the tank TK via the transfer pipe 40c. Tank TK is connected to a transfer pipe 40f that sends the water for injection from Tank TK to a transfer pipe 40b, and a discharge pipe 40e that discharges the water for injection from Tank TK to the outside of the system. Transfer pipes 40b, 40c, Tank TK, and 40f constitute a circulation piping system 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 Tank TK to the outside of the system is adjusted by opening or closing or adjusting the opening of valve V4e.

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

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

[0055] In terms of enhancing the bactericidal effect against live bacteria and endotoxins in the circulation process S40, when the storage time of the water for injection in the circulation unit 40 exceeds a predetermined time, the temperature of the water for injection is preferably 50°C or higher, more 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 place of use (POU) 30, when the storage time of the water for injection in the circulation unit 40 is less than a predetermined time, the temperature of the water for injection is preferably less than 50°C, more preferably 40°C or lower, more preferably 36°C or lower, and even more preferably room temperature (25°C ± 3°C).

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

[0057] If there is no change in the amount of water for injection produced in the water for injection production unit 10, or if the production amount is set in advance, a detection means is provided to detect the amount of water for injection transferred to the place of use (POU) 30, and it is possible to determine whether the storage time of water for injection in the circulation unit 40 exceeds a predetermined time or is less than or equal to a predetermined time. In this case, the detection means is, for example, a detection means that detects the water level in the tank TK in the circulation unit 40. Another detection means detects the amount of water for injection transferred to the place of use (POU) 30 by detecting the flow rate difference between the transfer pipe 40b on the upstream side and the transfer pipe 40c on the downstream side of the place of use (POU) 30 of the circulation unit 40. Another detection means detects the amount of water for injection transferred to the place of use (POU) 30 by detecting the flow pressure difference between the transfer pipe 40b on the upstream side and the transfer pipe 40c on the downstream side of the place of use (POU) 30 of the circulation unit 40. Furthermore, if the amount of water for injection to be used at the point of use (POU) 30 is predetermined, the water for injection production device 2 may be equipped with a timer or the like, and the temperature control means 41 may start adjusting the temperature of the water for injection to 50°C or higher or below 50°C at a predetermined adjustment start time using the timer or the like. When the temperature adjustment of the water for injection to 50°C or higher or below 50°C is started using the timer or the like, the start time of the adjustment can be set according to the amount of water for injection transferred to the point of use (POU) 30 that is predetermined.

[0058] The method for detecting the amount of water for injection transferred to the place of use (POU) 30, the method for adjusting the temperature to 50°C or higher or below 50°C, and preferred embodiments are the same as those for the method of producing water for injection using the water for injection production apparatus 1 described above, so a detailed explanation is omitted.

[0059] Next, Figure 7 will be used to describe a method and apparatus for manufacturing water for injection of another embodiment. In this embodiment, the method for manufacturing water for injection involves circulating water for injection throughout the entire water for injection manufacturing unit and circulation unit in the first circulation step, and circulating water for injection in each of the water for injection manufacturing unit and circulation unit, or only in the circulation unit, in the second circulation step. When water for injection is used at the point of use (POU), regardless of the amount used, the temperature of the water for injection is adjusted to less than 50°C in the first circulation step. When water for injection is not used at the point of use (POU), in the second circulation step, the water for injection manufacturing unit and circulation unit are separated and circulated individually, or the temperature of the water for injection in the circulation unit is adjusted to 50°C or higher and circulated only within the circulation unit.

[0060] Figure 7 is a schematic block diagram showing another embodiment of the water for injection production apparatus 3. The water for injection production apparatus 3 shown in Figure 7 has a water for injection production unit 50 and a circulation unit 20. In the circulation unit 20, components that perform the same functions as the water for injection production apparatus 1 shown in Figure 1 are denoted by the same reference numerals, and detailed explanations are omitted.

[0061] In the water for injection production apparatus 3, the water for injection production unit 50 includes a supply pipe 50a for supplying purified water to the water for injection production unit 50, a tank TK1 for storing the supplied purified water, and a pump P1 and transfer pipe 50b for sending the purified water in the tank TK1 to a downstream stage. The water for injection production unit 50 includes an ultrafiltration device 51 for ultrafiltration of the purified water sent by the pump P1, a transfer pipe 50c for sending the permeate from the ultrafiltration device 51 to a downstream stage, and a temperature control means 52 provided in the path of the transfer pipe 50c for adjusting the temperature of the permeate. In Figure 7, one temperature control means 52 is provided upstream of the cross-linking pipe 50g, which will be described later, but it is also possible to arrange multiple temperature control means within the system of the water for injection production unit 50. The permeate from the ultrafiltration device 51 is used as water for injection. In the example of the water for injection production apparatus 3, an ultrafiltration apparatus is shown for the production of water for injection, but a distillation apparatus may be used instead of the ultrafiltration apparatus, or the ultrafiltration apparatus and distillation apparatus may be used in combination.

[0062] Since the energy consumption in the water for injection production apparatus 3 can be reduced, it is preferable to use an ultrafiltration apparatus for the production of water for injection. When a distillation apparatus is used to produce water for injection, purified water is heated to about 95°C to 125°C to produce water for injection, and it can be supplied to the circulation unit 20 without significantly lowering the temperature. Therefore, the excess energy required to raise the temperature of 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 apparatus is used. However, when the storage time of the water for injection in the circulation unit 20 is less than a predetermined time, the high-temperature water for injection is cooled before being supplied to the place of use (POU) 30, and when the storage time of the water for injection in the circulation unit 20 exceeds a predetermined time, it is heated again, thus requiring energy for cooling and heating. In contrast, when an ultrafiltration apparatus 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, so the above-mentioned cooling and heating are unnecessary, and the effects of this embodiment can be significantly obtained. The preferred configuration of the distillation apparatus and the ultrafiltration apparatus is the same as that of the water for injection production apparatus 1 shown in Figure 1.

[0063] The injection water production 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 discharges part or all of the concentrated water in the transfer pipe 50e to the outside of the system. A valve V5f is provided in the discharge pipe 50f. In addition, a transfer pipe 50d is connected to the tank TK1 to transfer the injection water transferred from the circulation unit 20 into the tank TK1.

[0064] In the water for injection production apparatus 3, a supply pipe 20a is connected to the downstream side of the temperature control means 52 of the transfer pipe 50c via a valve V3. The opposite end of the supply pipe 20a from valve V3 is connected to the tank TK of the circulation unit 20, thereby transferring the water for injection produced in the water for injection production unit 50 to the circulation unit 20 via the supply pipe 20a. In addition, in the water for injection production apparatus 3, the circulation unit 20 is connected to the opposite side of the transfer pipe 20c of the water for injection production apparatus 1 shown in Figure 1 from the place of use (POU) 30 via a transfer pipe 20g. The other end of the transfer pipe 20g is connected to the opposite end of the transfer pipe 50d from the tank TK1 via a valve V2. As a result, water for injection that was not transferred to the place of use (POU) 30 is returned to the tank TK1 of the water for injection production unit 50 via the transfer pipes 20g and 50d. Furthermore, the water for injection production apparatus 3 is equipped with a bridging pipe 50g that connects the transfer pipe 50d and the transfer pipe 50c on the water for injection production section 50 side of valve V2. The connection position between the transfer pipe 50c and the bridging pipe 50g (the bridging position by the bridging pipe 50g) can be either upstream or downstream of the temperature control means 52, as long as it is on the water for injection production section 50 side of valve V3. One end of the transfer pipe 20h is connected to the transfer pipe 20g on the side opposite valve V2, and the other end of the transfer pipe 20h is connected to the tank TK in the circulation section 20. Valve V1 is provided on the bridging pipe 50g, and valve Va is provided on the transfer pipe 20h.

[0065] Next, a method for producing water for injection using the water for injection production apparatus 3 will be described. In the water for injection production method 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 control means 52 and the temperature control 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 activated, and purified water is sent from tank TK1 to the superfiltration device 51 by pump P1 of the water for injection production unit 50. The purified water is cross-flow filtered in the superfiltration device 51 to produce permeate. This permeate is sent to the next stage as water for injection. A portion of the concentrated water from the superfiltration device 51 is returned to tank TK1 via the transfer pipe 50e. The water for injection (permeate) produced in the superfiltration device 51 is adjusted to less than 50°C by the temperature control means 52 as needed. The water for injection, adjusted to below 50°C, is then supplied to the tank TK of the circulation unit 20 via the supply pipe 20a and stored there. The water for injection in tank TK is sent to the temperature control means 21 by the pump P, where it is further adjusted to below 50°C as needed. Then, by opening the valve Vd as needed, the water for injection is transferred to the place of use (POU) 30 via the transfer pipes 20b and 20d. The water for injection that is not transferred to the place of use (POU) 30 is returned to the tank TK1 of the water for injection production unit 50 by passing through the transfer pipes 20g and 50d in sequence.

[0066] Figure 8 shows the open / closed states of valves V1, Va, V2, and V3 in Figure 7 during this first circulation process. In Figure 8, black-filled valves indicate a closed state, and white-outlined valves indicate an open state. Valves V1, Va, V2, and V3 function as switching units S that switch the circulation system between a first circulation system that circulates within the system of the water for injection production unit 50 and the circulation unit 20, and a second circulation system that circulates only within the system of the circulation unit 20. By adjusting the opening of valves V1 and V3 as needed, it is possible to transfer a portion of the water for injection to the circulation unit 20 and circulate the remainder within the water for injection production unit 50, thereby adjusting 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. It is also possible to adjust the water volume balance between the water for injection production unit 50 and the circulation unit 20 by adjusting the opening of valves V2 and Va as needed. By adjusting the opening of valves V2 and Va, the internal pressure of the piping in the circulation section 20 can be made higher than the internal pressure of the piping in the transfer pipe 50d that transfers water for injection to the tank TK1 of the water for injection production section 50, thereby preventing backflow from the water for injection production section 10 to the circulation section 20 via valve V2.

[0067] Next, in the second circulation process, the water for injection in the circulation unit 20 is adjusted to 50°C or higher. In the second circulation process, valves V2, V3, and Vd are closed, and valves V1 and Va are opened. Valves V5f and Ve are opened or their opening is adjusted as needed. This separates the circulation system of the water for injection production unit 50 from the circulation system of the circulation unit 20, and the water for injection is circulated within each system, or within the circulation unit 20. Specifically, when circulating water for injection within the water for injection production unit 50, purified water stored in tank TK1 is supplied to the ultrafiltration device 51 by pump P1. The water for injection produced by cross-flow filtration of the purified water in the ultrafiltration device 51 is temperature-controlled as needed by the temperature control means 52, and is returned to tank TK1 by sequentially passing through the bridging pipe 50g and the transfer pipe 50d. The concentrated water produced by cross-flow filtration of purified water in the ultrafiltration device 51 is returned to tank TK1 via transfer pipe 50e. In the circulation unit 20, the water for injection in tank TK is sent to the temperature control means 21 by pump P, and the temperature control means 21 adjusts the water for injection to 50°C or higher to prevent the increase of live bacteria and endotoxins in the circulation unit 20. 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. The water for injection adjusted to 50°C or higher is returned to tank TK via transfer pipes 20b, 20c, and 20h. At this time, by lowering the water level in tank TK before adjusting the temperature to 50°C or higher to reduce the total amount of water in the circulation unit, it is possible to further reduce the amount of energy required for heating.

[0068] In the water for injection production unit 50, the second circulation process may consist of a normal operation process and a sterilization process. Since the water for injection production unit 50 has a distillation apparatus or superfiltration apparatus for producing water for injection within the system, in the normal operation process, the temperature of the water for injection is adjusted to below 50°C by the temperature control means 52 and circulated within the water for injection production unit 50. In the sterilization process, 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. In addition, in the sterilization process, superheated steam may be supplied into the water for injection production unit 50 system to sterilize valves, piping, etc. of the production apparatus 3. In this way, the normal operation process and the sterilization process can be performed periodically. As described above, the water for injection in the circulation unit 20 is adjusted to 50°C or higher through the normal operation process and the sterilization process. This makes it possible to reduce 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] Figure 9 shows the open / closed states of valves V1, Va, V2, and V3 in Figure 7 during this second circulation process. In Figure 9, black-filled valves indicate that the valve is closed, and white-outlined valves indicate that the valve is open.

[0070] Furthermore, in Figure 7, a portion of the area (switching section S) of valves V1, Va, V2, V3, and the surrounding transfer pipes 50d, 20g, bridging pipe 50g, supply pipe 20a, and transfer pipe 20h becomes a dead leg depending on the opening and closing state. Therefore, it is preferable to keep 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. Also, the dead leg of the switching section S can be reduced by changing valves V1 and V3 to three-way valve V40, and valves V2 and Va to three-way valve V60. A three-way valve has three openings and one flow path connecting two of these openings. The flow path inside the valve is changed by switching the connection point between this flow path and the openings.

[0071] Figure 10 schematically shows the positional relationship between the flow paths and openings of the three-way valves V40 and V60 in the first circulation process when using the three-way valves V40 and V60. The three openings of the three-way valve V40 are connected to the transfer pipe 50c, the bridging pipe 50g, and the supply pipe 20a, respectively. The three openings of the three-way valve V60 are connected to the transfer pipes 20c, 20g, and 20h, respectively. In the first circulation process, the three-way valve V40 is switched so that its flow path connects the transfer pipe 50c and the supply pipe 20a. At the same time, the three-way valve V60 is switched so that its flow path connects the transfer pipes 20c and 20g. Figure 11 schematically shows the positional relationship between the flow paths and openings of the three-way valves V40 and V60 in the second circulation process when using the three-way valves V40 and V60. In the second circulation process, the three-way valve V40 is switched so that its flow path connects the transfer pipe 50c and the bridging pipe 50g. At the same time, the three-way valve V60 is switched so that its flow path connects the transfer pipe 20h and the transfer pipe 20c. This makes it possible to reduce the number of valves and piping and simplify the configuration of the device.

[0072] According to the injection water production apparatus 3 of this embodiment, when injection water is being used at the place of use (POU) 30 and the storage time of injection water in the circulation unit 20 is less than or equal to a predetermined time, injection water can be circulated throughout the injection water production unit 50 and the circulation unit 20, thereby ensuring that injection water flows throughout the entire production apparatus 3 system. This makes stagnation extremely unlikely, and high-quality injection water can be stably supplied to the place of use (POU) 30. Furthermore, for example, when the use of injection water at the place of use (POU) 30 stops, and consequently the transfer of injection water to the place of use (POU) 30 stops, the storage time of injection water in the circulation unit 20 exceeds the predetermined time. In such cases, injection water is circulated within each system of the injection water production unit 50 and the circulation unit 20, or only within the circulation unit 20. Also, when the storage time of injection water in the circulation unit 20 exceeds the predetermined time, some or all of the injection water that was not transferred to the place of use (POU) 30 may be circulated to the upstream side of the circulation unit 20. When the storage time of the water for injection in the circulation unit 20 exceeds a predetermined time, some or all of the water for injection that was not transferred to the point of use (POU) 30 may be circulated to the water for injection production unit 50. In this case, the water for injection that was not transferred to the point of use (POU) 30 can be circulated to the upstream stage of the ultrafiltration device in the water for injection production unit 50. Here, the upstream stage of the ultrafiltration device is one or more of the following locations: the supply pipe 50a, the tank TK1, the section between the tank TK1 and the pump P1 in the transfer pipe 50b, or the downstream side of the pump P1 in the transfer pipe 50b. This makes it possible to adjust the storage time of the water for injection in the circulation unit 20 to less than a predetermined time. Furthermore, these measures can significantly reduce the amount of energy used for heating and cooling the water for injection, contributing to a reduction in carbon dioxide emissions.

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

[0074] Using a water for injection production apparatus similar to that shown in Figure 3, and under the conditions shown in Table 1, the energy consumption for heating was estimated when the water for injection temperature control was adjusted based on whether the retention time exceeded 2 hours or not, with the water retention time set to 2 hours. The results are shown in Table 2. Energy consumption is shown as a relative value for Examples 1 and 2, with Comparative Example 1 set to 100. In addition, the test apparatus was operated under the conditions shown in Table 3, and the number of viable bacteria in the water for injection circulation section was measured at the initial stage of water flow, 300 days after water flow (300 days after water flow), and 500 days after the start of water flow (500 days after water flow). These results are shown in Table 4. The times in the table are expressed in Japan Standard Time. The number of viable bacteria was measured using the microbial monitoring method specified in the Quality Control of Pharmaceutical Water in the Reference Information of the Japanese Pharmacopoeia. In this measurement method, viable bacteria collected using a membrane filter are cultured and measured. The Japanese Pharmacopoeia specifies the number of viable bacteria per 100 mL as the standard value. However, in this example, the number of viable bacteria per 1000 mL (10 times the standard amount) was counted and then converted to the number of viable bacteria per 100 mL for presentation.

[0075]

[0076]

[0077]

[0078]

[0079] Table 2 shows that under the conditions of the examples, energy consumption is significantly reduced compared to the comparative examples. Furthermore, Table 4 confirms that under all the conditions of the examples, it is 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.

[0080] Using a water for injection production apparatus similar to that shown in Figure 3, the storage time for water for injection during temperature control was set to 8 hours under the conditions shown in Table 5, and the temperature of the water for injection was controlled depending on whether the storage time exceeded 8 hours. The estimated energy consumption for heating at this time is shown in Table 6. Note that the energy consumption is shown as a relative value for Example 6 and Comparative Example 3, with Comparative Example 1 set to 100. In addition, the test apparatus was operated under the conditions shown in Table 5, and the number of viable bacteria in the water for injection in the water for injection circulation section was measured at the initial stage of water flow, 300 days after water flow (300 days after water flow), and 500 days after the start of water flow (500 days after water flow). These results are shown in Table 7.

[0081]

[0082]

[0083]

[0084] Tables 5 to 7 show that even when the residence time of the water for injection in the circulation section is set to 8 hours, the energy consumption is significantly reduced according to the method of the example, as in Tables 1 to 4 above, and it was confirmed that water for injection can be produced at or below the management standard of 10 CFU / 100 mL.

[0085] 1, 2, 3: Water for injection production device, 10, 50: Water for injection production section, 20, 40: Circulation section, 21, 41, 52: Temperature adjustment means, 51: Ultrafiltration device, 10a, 20a, 40a, 50a: Supply pipe, 10b, 10 c, 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, 5 0e: Transfer pipe, 50f: Discharge pipe, 50g: Bridge pipe, P, P1, P10: Pump, TK, TK1, TK10: Tank, Va, Vd, Ve, Vf, V1, V2, V3, V4e, V5f: Valve, V40, V6 0: 3-way valve, 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. A method for producing water for injection, comprising: a water for injection production unit for producing water for injection by distilling or ultrafiltration purified water; and a circulation unit for storing the water for injection in a tank, making the stored water for injection transferable to a place of use, and circulating the water for injection that is not transferred to the place of use back into the tank, wherein when the storage time of the water for injection in the circulation unit exceeds a predetermined time, the temperature of the water for injection is adjusted to 50°C or higher, and when the storage time of the water for injection in the circulation unit is less than or equal to the predetermined time, the temperature of the water for injection is adjusted to less than 50°C.

2. The method for producing water for injection according to claim 1, wherein it is determined whether the storage time exceeds a predetermined time or is less than or equal to a predetermined time based on the amount of water for injection to be transported to the place of use.

3. The method for producing water for injection according to claim 1, wherein it is determined whether the storage time exceeds a predetermined time or is less than or equal to a predetermined time 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 ultrafiltered in the water for injection production unit.

5. The method for producing water for injection according to claim 4, wherein when the storage time of 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 claim 4, wherein when the storage time of water for injection in the circulation unit exceeds a predetermined time, a portion or all of the water for injection that has not been transferred to the place of use is circulated to the stage before the ultrafiltration of the water for injection production unit so that the storage time of water for injection in the circulation unit is adjusted to be less than or equal to a predetermined time.

7. A water for injection manufacturing apparatus comprising a water for injection manufacturing unit for manufacturing water for injection and a circulation unit for circulating and storing the manufactured water for injection, wherein the water for injection manufacturing unit comprises a distillation apparatus for distilling purified water or an ultrafiltration apparatus for ultrafiltration purified water, and the circulation unit comprises a tank for storing the water for injection, a circulation pipe for transferring part or all of the water for injection in the tank to a place of use and circulating the water for injection that was not transferred to a place of use, and a temperature control means for adjusting the temperature of the water for injection in the circulation pipe, wherein the temperature control 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 or equal to a predetermined time.

8. The water for injection production apparatus according to claim 7, further comprising a flow detection device for detecting the flow rate difference between the upstream and downstream sides of the place of use of the circulation piping, wherein whether the predetermined time is exceeded or less than the predetermined time is determined based on the value of the flow detection device.

9. The water for injection production apparatus according to claim 7, comprising a water level meter for detecting the water level in the tank, wherein whether the predetermined time has been exceeded or is less than or equal to the predetermined time is determined based on the value of the water level meter.

10. The apparatus for producing water for injection according to claim 7, wherein the water for injection production unit has an ultrafiltration device.

11. The apparatus for producing water for injection according to claim 10, further comprising a switching unit that, when the storage time of water for injection in the circulating unit exceeds a predetermined time, circulates a portion or all of the water for injection that has not been transferred to the place of use to the upstream of the ultrafiltration device to adjust the storage time of water for injection in the circulating unit to a predetermined time or less.

12. The apparatus for producing water for injection according to claim 11, wherein the switching unit closes the supply pipe for water for injection from the water for injection production unit to the circulation unit when the storage temperature of the water for injection in the circulation unit is 50°C or higher, thereby circulating the water for injection within the circulation unit.

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