JP2020131093A - Device for producing injection water and method for producing the same - Google Patents

Abstract

To provide a device for producing injection water using ultrafiltration including no a distillation device.SOLUTION: The device for producing injection water includes a refined water production part for subjecting raw water to reverse osmosis filtration and ion exchange to obtain refined water, an ultrafiltration module for subjecting the refined water to ultrafiltration with a hollow fiber membrane to obtain permeated water, a bubble mixing part disposed at a refined water side or a permeated water side of the ultrafiltration module to mix passing water with bubbles, a particle counter disposed at a side opposite to the bubble mixing part interposing the ultrafiltration module to measure a bubble amount of the refined water or the permeated water, and a tank for sterilization injection water for storing the permeated water of the ultrafiltration module.SELECTED DRAWING: Figure 2

Description

The present invention relates to an apparatus and a method for producing water for injection, and more specifically, it is possible to produce by ultrafiltration of reverse osmosis membrane filtration and ion-exchanged purified water, and to inspect the film deterioration of the ultrafiltration. The present invention relates to an apparatus and a method for producing water for injection.

Sterilized injectable water (sometimes abbreviated as WFI) used to dissolve and prepare injectables must remove all types of microorganisms and febrile substances (endotoxins). For this reason, since ancient times, distilled water obtained by distilling purified water that has undergone microfiltration or ion exchange has been used as the diluent or solution for injection.
Conventional equipment for producing purified water for injections is a microfilter for removing solid and colloidal substances, an ion exchanger for removing impurities and electrolytes, and for removing microorganisms and endotoxins. A reverse osmosis membrane filter or an ultrafiltration filter, a heating tank for storing purified water that has passed through these facilities, and heating and evaporating the tank, and the steam evaporated by heating this tank are separated from droplets. It has a structure including a demister and a condenser that condenses the vapor separated by the demister (for example, Patent Document 1).

However, the conventional device for producing sterile water for an injection solution accompanied by such distillation has to be a large-scale device because distillation is an essential requirement, and the purified water is heated and evaporated. There is a problem that there is a lot of waste of energy, such as cooling this again to condense steam.
On the other hand, in recent years, the technology for producing ultrapure water used for semiconductors and the like has made remarkable progress. For example, membrane permeation technology such as ultrafiltration has been used to supply pure water having a higher purity than distilled water. It has become. Currently available ultrapure water has reached a level where the concentration of impurities can be reduced to 1 ppt (1 ng / L). However, when ultrafiltration (sometimes abbreviated as UF) is used to produce a sterile solution for injections that does not rely on distillation, for example, it may be used under high temperature conditions, after the UF. When water for injection is produced by a device that does not have a membrane treatment or distillation device, if the UF is damaged, endotoxin or the like may reach the place of use (POU), so endotoxin or the like may be removed from the UF. It is required that it can be done without trouble for a long period of time, and it is necessary to guarantee the performance, and it was unclear whether it can be applied.

A point to be noted in water treatment equipment such as water purification equipment using membrane permeation technology is the probability that the membrane will deteriorate in the micro part during use and the raw water under pressure will infiltrate the treated water side from the filtration membrane. Is to increase over time. Therefore, in the field of water treatment, it is necessary to regularly check the deterioration state of the membrane. Several methods have been developed as methods for checking the deterioration state of the membrane, but as a method for easily and in real time monitoring the membrane life, air is mixed with raw water to generate microbubbled water. However, a method for measuring the turbidity state of purified water permeated through a membrane is disclosed (for example, Patent Document 2).

Japanese Unexamined Patent Publication No. 03-000187 Japanese Unexamined Patent Publication No. 2008-296087

In Patent Document 1, since distillation is an essential requirement, there is a problem that the apparatus becomes large-scale and there is a lot of waste of energy such as heating and evaporating purified water and cooling it again to condense steam. There is. Further, even if the air bubble inspection described in Patent Document 2 is combined with the manufacturing apparatus for performing distillation, the air bubbles disappear by distillation, so that there is a problem that the inspection by air bubbles cannot be performed.

The present invention has been made to solve the above-mentioned problems, and is an apparatus for producing water for injection, which can produce water for injection without requiring distillation and can inspect membrane deterioration by air bubbles. And to provide a manufacturing method.

The device for producing water for injection of the present invention, which has been made to solve the above problems, is limited to a purified water production unit in which raw water is reverse osmosis filtered and / or ion-exchanged to obtain purified water, and the purified water is limited by a hollow thread film. An ultrafiltration module that is externally filtered to obtain permeated water, a bubble mixing section that is provided on the purified water side or the permeated water side of the ultrafiltration module and mixes air bubbles with the passing water, and the ultrafiltration module. It is provided on the opposite side of the sandwiched bubble mixing portion, and is provided with a bubble measuring means for measuring the amount of bubbles in purified water or permeated water, and a sterile injection water tank for storing the permeated water of the ultrafiltration module. It is characterized by.

In this case, the ultrafiltration module is preferably a module that performs ultrafiltration by an external pressure type in which the purified water is supplied to the outer surface of the hollow fiber membrane and the permeated water is taken out from the inner surface of the hollow fiber membrane. ..
Further, it is preferable that the heat exchanger is arranged on the upstream side or the downstream side of the UF module and on the upstream side of the sterile injection water tank.

The method for producing injectable water of the present invention, which has been made to solve the above problems, has a purified water production stage in which raw water is back-permeated and / or ion-exchanged to obtain purified water, and the purified water has a hollow filament membrane. Bubble-containing water is supplied to the ultrafiltration module by the permeated water manufacturing stage in which the ultrafiltration module is ultrafiltered to obtain permeated water, and the bubble water supply unit provided on the purified water side or the permeated water side of the ultrafiltration module. A bubble-containing water supply step to measure the amount of bubbles in the bubble-containing water that has passed through the ultrafiltration module by a bubble measuring means provided on the opposite side of the bubble water supply section sandwiching the ultrafiltration module. It is characterized by comprising a permeated water storage stage in which the permeated water of the ultrafiltration module is stored in a sterilized water tank for injection.

It is preferable to periodically supply bubble-containing water to the ultrafiltration module in the permeated water production stage while the ultrafiltration module is arranged, and perform a deterioration confirmation test by the bubble measuring means.

According to the injectable water production apparatus of the present invention, the injectable water can be obtained only by the purified water production unit and the ultrafiltration without including the distillation apparatus, so that the operation is simple and the apparatus is simplified. Can be done. This reduces the chance of contamination. Further, unlike distillation, the amount of heat required to evaporate the purified water once and then cool it again becomes unnecessary, so that energy can be reduced and the manufacturing cost can be reduced. Further, since it is possible to inspect the membrane deterioration of the UF module by mixing air bubbles, it is possible to achieve both the production of water for injection and the membrane inspection. For membrane inspection, it is possible to easily carry out regular tests without changing the placement state, for example, by removing the UF module from the placement state, and producing water for injection for the test. Since it is not necessary to open the device, the chance of contamination can be suppressed. Then, the membrane test can notice the membrane abnormality earlier than the increase in endotoxin concentration is actually detected, and at that time, maintenance such as membrane replacement can be performed, so that the provision of high-quality injection water is guaranteed. it can.
Further, when the external pressure type UF module is used, long-term operation can be performed as compared with the case where the internal pressure type UF module is used.

It is a production flow chart of the water for injection of this invention. It is a block diagram of the water for injection production apparatus of this invention.

Hereinafter, embodiments of the present invention will be described in detail based on the attached drawings. The configuration of the present invention is not limited to the present embodiment.
FIG. 1 is a flow chart for producing water for injection according to an embodiment of the present invention, and FIG. 2 is a block diagram of the apparatus for producing water for injection according to the present invention.

As shown in FIGS. 1 and 2, the apparatus for producing water for injection using ultrafiltration (hereinafter, may be abbreviated as UF) of the present embodiment first uses raw water as a reverse osmosis membrane (Reverse Osmosis Membrane). : Purified water production unit 10 that is filtered by RO membrane (hereinafter, may be abbreviated as RO membrane) and then subjected to continuous ion exchange (hereinafter, may be abbreviated as EDI) to obtain purified water, and hollow yarn. The ultrafiltration module 20 that performs ultrafiltration (UF) by an external pressure type in which purified water is supplied to the outer surface of the membrane and permeated water is taken out from the inner surface of the hollow osmosis membrane, and the permeated water of the ultrafiltration module 20 are stored. A water tank for sterile injection (WFITK) 30 is provided.

The reverse osmosis membrane filtration device 12 is a filter provided with a reverse osmosis membrane (RO membrane), and while passing water through a reverse osmosis membrane (RO membrane) having a pore size of 2 nanometers or less, ions. It is a membrane that does not allow impurities other than water, such as salts and salts, to permeate, and is used to obtain fresh water from seawater and to remove water from dairy products and fruit juices for concentration. When purifying water or concentrating beverages using a reverse osmosis membrane, it is necessary to apply pressure to the liquid to be filtered (raw water), but the pressure depends on the salt concentration of the liquid to be filtered and is at least About 5 atm is required. When seawater is used as raw water, 55 atm or more is required to obtain fresh water from seawater. Therefore, the reverse osmosis membrane filtration device 12 is provided with a pump 14 for pumping a liquid (raw water). As the RO, any of ultra-low pressure, low pressure, medium pressure, and high pressure can be used, but ultra-low pressure, low pressure, and medium pressure are preferable from the viewpoint of running cost. As the material of the membrane, a membrane made of polyamide (PA), cellulose acetate or the like can be used, but a membrane made of polyamide is preferable in terms of treated water quality. As the shape of the film, a hollow fiber, a spiral, a plate and frame type or the like can be considered, but the spiral type is preferable because it is resistant to clogging due to turbidity or the like.
In the case of a nanofilter (NF membrane) composed of a filtration membrane having a pore size of 1 to 2 nanometers, it can be used in place of the RO membrane.

The electrolyte of the purified water that has passed through the reverse osmosis membrane filtration device 12 is removed by ion exchange. A continuous ion exchange device (EDI) 16 is used for this ion exchange. This device has developed a technology in which ion exchange resins are installed one by one to allow water to permeate, and by combining an ion exchange membrane and an ion exchange resin, water is continuously supplied like electrodialysis. It is to be purified.
The continuous ion exchange device (EDI) 16 has an anion exchange membrane that allows only anions to pass to the anode side when energized and a cation exchange membrane that allows only cations to pass to the cathode side when energized in an electrolytic tank provided with an anode and a cathode. When a direct current is passed through the electrodes, the anions in the water move to the anode side and the cations move to the cathode side, and the cation exchange membrane and anion exchange are exchanged. By the action of the membrane, a region where ions are diluted and a region where ions are concentrated appear. The water that passes through the region where the ions are diluted becomes pure water, and the concentrated water that passes through the region where the ions are concentrated is drained. The ion exchange resin plays a role of temporarily retaining ions.
As an EDI module for such a continuous ion exchange device 16, for example, GE models such as MK-3 Mini HT and MK-2 Mini HT are commercially available, and these can be preferably used. Instead of the continuous ion exchange device 16, it is also possible to use a filling tower filled with a cation exchange resin and / or an anion exchange resin.

The deionized water generated by the continuous ion exchange device 16 is stored in the purified water tank 18, then pumped by the pump 21 and ultrafiltered (UF) by the ultrafiltration module 20. Ultrafiltration (UF) is used for removing bacteria and viruses in drinking water, separating or concentrating heat-sensitive substances such as proteins and enzymes in the food processing field, and artificial dialysis in the medical field. This ultrafiltration (UF) removes fine solids, virus-containing microorganisms and endotoxins contained in deionized water.
Ultrafiltration (UF) is a filtration technique used in the field of ultrapure water production to remove fine particles in the finishing stage. In this embodiment, cross-flow filtration is performed using a hollow fiber membrane having a diameter of about 0.5 to 30 mm and molded into a hollow fiber. By using cross-flow filtration, deterioration and damage due to membrane blockage can be suppressed as compared with full-volume filtration, and long-term operation becomes easier.

As the UF module 20, a method is used in which the hollow fiber membrane is permeated from the outer surface and filtered from the outside to the inside of the hollow fiber membrane so that the permeated water is taken out from the inner surface (external pressure type). Filtering to (internal pressure type) can also be used. However, it is preferable to use the external pressure type in the following points.
-Since the possibility of deterioration or breakage of the hollow yarn is low when the hollow yarn is operated for a long period of time, the water quality of WFI can be maintained for a long period of time. This is because the filtration area per hollow fiber is larger in the external pressure type than in the internal pressure type, so it is considered that the resistance to the burden of long-term water flow, particularly long-term heating water flow, is high.
-Since the flow path on the secondary side (permeated water side) is simple, there is little possibility of bacterial growth and endotoxin and pyrogen retention, and it is easy to maintain the treated water quality.

In this embodiment, the bubble generator 22 for sending bubbles into the purified water from the purified water tank 18 is installed on the upstream side of the ultrafiltration module 20. This is used when inspecting the deterioration state of the ultrafiltration membrane (UF membrane), and is not operated during the production of water for injection.
Further, the particle counter 24 is installed on the downstream side of the ultrafiltration module 20. The first purpose of this is to measure the bubbles mixed in the purified water by using it in combination with the bubble generator 22, but it may be used for the purpose of detecting foreign substances mixed in during the production of water for injection. .. However, in that case, in order to suppress deterioration of the particle counter, it is preferable that hot water having a heat sterilization temperature described later does not enter the particle counter. Therefore, it is preferable to place a heat exchanger for heat sterilization, which will be described later, downstream of the particle counter, or if it is placed upstream of the particle counter, cool it by providing a second heat exchanger between it and the particle counter. ..

As the bubble generator, for example, a mixer for generating fine bubbles such as Ramond Nanomixer (registered trademark) manufactured by Nanox Co., Ltd. can be used as a bubble generator that mixes a gas in water and then turns it into fine bubbles. .. Further, an air diffuser or a diffuser that mixes gas while forming fine bubbles can be used. Furthermore, it is also possible to use a pump capable of pumping with a mixture of gas and water. In this case, the bubble-containing water may be supplied from the branch line by this pump, but the upstream pump 21 may be substituted by this pump. As such a pump, a whirlpool turbo mixer KTM (trade name) manufactured by Nikuni Co., Ltd. can also be used.

The gas supplied by the bubble generator 22 is preferably an inert gas such as nitrogen or carbonic acid. In the case of air, impurities in the air may be mixed into the system as it is, so it is preferable to use one that has been deendotoxin or depyrogen treated by air filter filtration, heat sterilization, or the like. Oxygen, ozone, hydrogen, etc. are not preferable because they may explode or promote the growth of bacteria.
In the present embodiment, the bubble-containing water is supplied from the primary side (supply water side), but it can also be supplied from the permeated water side. In this case, a particle counter is installed on the primary side. For example, in the case of external pressure type ultrafiltration (UF), if bubble-containing water is supplied from the primary side, bubbles may accumulate inside the primary side ultrafiltration (UF) module. It is possible to avoid this problem.

Further, the bubble generating device 22 is not installed on the piping from the purified water TK to UF or on the piping from UF to WFITK, and the bubble-containing water produced by using the bubble generating device is directly introduced immediately before or after the UF. It is also possible to.
As the ultrafiltration (UF), it is usually installed vertically, but it can also be installed horizontally. In this case, it is possible to avoid the generation of gas accumulation. Further, although the ultrafiltration (UF) is installed vertically during the production of water for injection, a mechanism for changing the direction of the ultrafiltration module 20 is provided only when the ultrafiltration (UF) is inspected, that is, when water containing bubbles is supplied. You may assemble. This method can be realized, for example, by reconnecting pipes or using flexible pipes. When this method is used, ultrafiltration (UF) is placed vertically for water flow, so deterioration due to membrane vibration due to water flow during water flow is minimized, and air bubbles accumulate in the UF during ultrafiltration (UF). It is possible to prevent this from occurring and increase the sensitivity for detecting abnormalities.

As a method of confirming the amount of bubbles, it is possible to sample and visually observe the bubbles in water, but it is preferable to use a particle counter for quantification in terms of practical sensitivity. As the particle counter, a commercially available particle counter can be used, and for example, a light scattering method or a light shielding method can be used. In particular, those capable of measuring particles of 0.1 μm or more are preferable. For example, a product number made by Rion: KS-42A (trade name), Ultrapore UP-100 manufactured by ANATEL (trade name), and the like can be used.

The material of the hollow yarn film is not particularly limited, and is not particularly limited. Polyacrylonitrile, polyphenylene sulfone, polyphenylene sulfide sulfone, polyvinylidene fluoride, ethylene-tetrafluoroethylene copolymer, polytetrafluoroethylene polypropylene, polyethylene, polysulfone, poly. Inorganic materials such as ether sulfone, polyimide, polyetherimide, polyamide, polyetherketone, polyetheretherketone, poly (4-methylpentene), polyvinyl alcohol copolymer, cellulose, cellulose acetate and ceramic can be selected. Of these, polyvinylidene fluoride and polysulfone are preferable from the viewpoint of film strength.
The pore diameter of the hollow fiber membrane is not particularly limited, and can be conveniently selected within the range of 0.001 μm to 1 μm. The molecular weight cut-off is preferably 1000 to 20000, more preferably 3000 to 10000. In that case, since the pore size of the ultrafiltration (UF) membrane is considered to be less than 10 nm, it is possible to remove picornavirus and barbovirus, which are currently the smallest viruses, and at the same time, endotoxin can also be removed. ..

As the UF membrane module 20, a hollow fiber membrane bundle composed of a large number of the above hollow fiber membranes is loaded into a pressure-resistant tubular case, both ends of the membrane bundle are adhesively fixed to the tubular case, and one end or both ends are adhered to. A structure in which the adhesive fixing portion is cut to open the inside of the hollow fiber membrane can be used. Further, a pressurized membrane module of a type in which pressurized raw water is introduced into the module and filtered by the hollow fiber membrane surface can be used.

The UF membrane module 20 may be placed vertically, that is, the adhesive fixing portions at both ends may be arranged in a substantially vertical direction, or horizontally, that is, the adhesive fixing portions at both ends may be arranged in a substantially horizontal direction. In this case, if there is no risk of air bubbles accumulating inside the ultrafiltration (UF) module on the primary side described above, the amount of air required for the air scrubbing test for inspecting the deterioration of the hollow fiber membrane will be reduced. It is preferably placed vertically.
As the UF membrane module 20 provided with the external pressure type hollow fiber membrane, for example, the trade name “Microza UF (OLT6036H)” manufactured by Asahi Kasei Corporation can be preferably used. Further, as the UF membrane module including the internal pressure type hollow fiber, for example, the trade name "Microza UF (SIP-3023)" manufactured by Asahi Kasei Corporation can be used.

In the case of the external pressure type, since the inner diameter of the UF membrane module is larger than the inner diameter of the inlet nozzle on the supply water side in the UF module, the flow velocity in the UF membrane module becomes slower. When the flow velocity becomes slow, the effect of suppressing foreign matter adhesion to the film surface, which is a feature of cross-flow filtration, weakens. Therefore, endotoxin may adhere to the membrane surface of UF, and the quality of treated water may gradually deteriorate.

レイノルズ数が過剰に大きくなると、供給水がＵＦ膜に与える衝撃が大きくなり、膜が折れる可能性があるため好ましくない。
なお、濃縮水流量を上記範囲にするために、濃縮水の一部をポンプのサクション側に戻すことにより循環運転することも有効である。 In order to prevent this, the flow rate of the supplied water may be increased to increase the flow velocity, and for that purpose, the flow rate of the concentrated water may be increased. That is, it is preferable to operate so that the following Reynolds number calculated from the inner diameter of the UF membrane module, the flow rate of concentrated water, and the flow velocity in the UF membrane module determined from the inner diameter of the UF membrane module is 1000 to 10000. 2500-5000 is more preferable.

If the Reynolds number is excessively large, the impact of the supplied water on the UF membrane is large, and the membrane may be broken, which is not preferable.
In addition, in order to keep the flow rate of concentrated water within the above range, it is also effective to carry out circulation operation by returning a part of concentrated water to the suction side of the pump.

The water that has passed through the ultrafiltration module 20 is first stored in a sterile injection water tank (WFITK). The shape of the sterile injection water tank (WFITK) is not limited as long as it is a storage container isolated so that impurities and microorganisms do not enter from the outside. The material of the tank is not particularly limited, but it is preferable to select a tank material in which no component elutes or rust is generated from the container. For example, an electropolished product of SUS316L is preferably used.
The water stored in the sterile injection water tank (WFITK) is sent to the place of use (point of use: POU) through the liquid feeding line at the time of use. The liquid feeding line preferably has a structure capable of providing sterile injection water to the next step or subdivision filling step of the production line in a sterile and clean state. For example, if the liquid feeding line is equipped with a circulation line for returning to the injection water tank (WFITK) and the structure is such that the sterile injection water not used in the POU is constantly circulated to the sterile injection water tank (WFITK), contamination due to retention is suppressed. Is preferable.
The capacity of the tank is not particularly limited and can be appropriately set according to the required amount.

The heat exchanger 40 may be arranged on the upstream side or the downstream side of the ultrafiltration (UF) module 20 and on the upstream side of the sterile injection water tank (WFITK). The heat exchanger 40 is a facility for sterilizing purified water for injection by heating to produce sterilized water for injection (WFI), and heats purified water to 50 to 90 ° C (preferably 70 to 80 ° C). Sterilize. The water for injection produced by this heat sterilization is sterilized and can be used as sterilized water for injection (WFI).

The heating method in the heat exchanger 40 is not particularly limited, and for example, it can be carried out in a heating tank with steam piping, or it can be sterilized by heating using a convection type heat exchanger using a double pipe. The position where the heat exchanger 40 is installed may be either upstream or downstream of the ultrafiltration (UF) module 20 and upstream of the sterile injection water tank (WFITK). When the ultrafiltration (UF) module 20 is installed on the upstream side, the water sent to the ultrafiltration (UF) module 20 is hot water, but its temperature is 50 to 90 ° C. or lower, and this temperature range. You need to select an ultrafiltration (UF) module that you can use. For example, the product name "C-02-HR" manufactured by Kuraray Aqua Co., Ltd., the product name "Microza UF (OLT6036H)" and "Microza UF (SIP-3023)" manufactured by Asahi Kasei Corporation can be preferably used. On the other hand, when the heat exchanger is installed on the downstream side of the ultrafiltration (UF) module 20, the water sent to the ultrafiltration (UF) module 20 is at room temperature and is ultrafiltered (UF) without any problem. be able to.
Further, a heat exchanger 40 can be installed in the ultrafiltration module 20 to sterilize while performing ultrafiltration.

The usage of the injectable water production apparatus using ultrafiltration will be described below.
As shown in FIG. 1, the raw water is sent to the reverse osmosis membrane (RO membrane) filtration device 12 by the pump 14, and the filtered purified water is removed from the electrolyte by the continuous ion exchange device 16. The deionized water that has passed through the continuous ion exchange device 16 is stored in the purified water tank 18. After that, the stored purified water is pumped by the pump 21 and heated to 50 to 90 ° C. (preferably 70 to 80 ° C.) by the heat exchanger (HEX) 40 arranged on the upstream side of the ultrafiltration module 20. After that, it is sent to the ultrafiltration module 20 for ultrafiltration.
The purified water finished by the ultrafiltration module 20 is stored in the sterilized injection water tank 30 as sterilized injection water.
The concentrated water separated from the sterile injection water by ultrafiltration is discarded from the concentrated water line and / or returned to any location on the purified water production line. In order to optimize the Reynolds number in the UF module, it is advisable to return a part of the concentrated water to the suction side of the pump if necessary.

[Example 1]
Water was passed under the following conditions using the manufacturing apparatus shown in FIG.
The ultrafiltration module 20 used the trade name "Microza UF (model: OLT6036H)" manufactured by Asahi Kasei Corporation. This ultrafiltration module 20 was cross-flow filtration, had an effective membrane area of 34 m ² , a molecular weight cut-off of 6000, and the hollow fiber material was polysulfone, and one module 20 was used. It was operated at a permeated water flow rate of 8.0 m ³ / h and a temperature of 80 ° C. In addition, a part of the concentrated water was returned to the suction side of the pump so that the Reynolds number in the UF module became 3000.
The particle counter used the product number KS-42A (trade name) manufactured by Rion, and the bubble generator used the whirlpool turbo mixer KTM (trade name) manufactured by Nikuni. Gas using nitrogen was fed at a feed rate of about 1L / min from N ₂ gas cylinder.

[Example 2]
The ultrafiltration module 20 of Example 1 was changed to an internal pressure type, and the number of modules used was set to 3 according to the membrane area of the UF membrane. As the internal pressure type ultrafiltration module, the product name was "Model SIP-3023" (effective film area 7.2 m ² , fractional molecular weight 6000) manufactured by Asahi Kasei Corporation, and five modules were used to match the effective film area. Other conditions were the same as in Example 1.

[Measuring method of air bubbles]
The deterioration confirmation test was carried out by returning the ultrafiltration module 20 to room temperature without operating the heat exchanger. The UF membrane permeated water used in the deterioration confirmation test was discarded as it was.
Purified water is pumped from the purified water tank 18 that stores the purified water that has passed through the reverse osmosis membrane filtration device (RO) 12 and the continuous ion exchange device (EDI) 16 to the ultrafiltration module 20 by a vortex turbo mixer, and at the same time, a nitrogen bomb. The nitrogen (N ₂ ) gas injected from the above was used as microbubbles in a vortex turbo mixer to send bubbles. The number of bubbles in pure water that passed through the ultrafiltration device 20 was measured with a particle counter.

[Water quality inspection method]
In order to inspect the quality of the water for injection produced in Examples 1 and 2, the water for injection that passed through the ultrafiltration module 20 was sampled and the endotoxin concentration was measured.
The endotoxin concentration was measured by using the turbidimetric method (optical measurement method) among the endotoxin test methods in the Japanese Pharmacopoeia. This measurement is a method of optically measuring the change in turbidity associated with the gelation of the lysate test solution by endotoxin.
As a comparative example, the operation was performed by replacing the UFs of Examples 1 and 2 with a distiller manufactured in-house. The treatment flow rate was 2.0 m ³ / h, which is less than in Examples 1 and 2. Water for injection that passed through the distiller was sampled in the same manner as in Examples 1 and 2, and endotoxin was measured by the colorimetric method.

[Bubble measurement test results]
Durability test of the UF membrane in Example 1 using the external pressure type UF membrane and Example 2 using the internal pressure type UF membrane was carried out by placing fine bubbles of nitrogen (N ₂ ) on the upstream side of the ultrafiltration module 20. While adding, the number of bubbles contained in the permeated water was measured on the downstream side of the ultrafiltration module 20. The deterioration confirmation test of the ultrafiltration (UF) membrane was continued for up to 1600 days at a frequency of about once a week. The test results are shown in Table 1.

From the results in Table 1, when the external pressure type UF membrane of Example 1 was used, no bubbles were observed on the particle counter until 1100 days after the start of use. When the internal pressure type UF membrane of Example 2 was used, no bubbles were observed on the particle counter until 500 days after the start of use.

[Result of water quality inspection]
In order to inspect the quality of the water for injection produced in Examples 1 and 2, the water for injection that passed through the ultrafiltration module 20 was sampled and the endotoxin concentration was measured. The water quality test was carried out about once a week for up to 1600 days. The test results are shown in Table 2.

Looking at the results of the water quality test at the initial stage of water flow, the concentration of endotoxin contained in the water for injection obtained in Examples 1 and 2 was 0.005 EU / mL or less, which is the detection limit, which is more than two orders of magnitude better than the comparative example. It was the result.
From this, the device for producing water for injection of the present invention is preferable as the device for producing water for injection regardless of whether the ultrafiltration module using either the external pressure type UF membrane or the internal pressure type UF membrane is used. It became clear that it could be used.

From the results in Table 1, when the external pressure type UF membrane of Example 1 was used, the endotoxin concentration was below the detection limit until 1400 days after the start of use, and no endotoxin contamination was observed. When the internal pressure type UF membrane of Example 2 was used, the endotoxin concentration was below the detection limit until 900 days after the start of use, and no endotoxin contamination was observed. Negative control sterile water for injection was below the detection limit of 0.005 EU / L throughout the test period.
From the above, the ultrafiltration module using the external pressure type UF membrane of Example 1 is used continuously for at least 1100 days, and the ultrafiltration module using the internal pressure type UF membrane of Example 2 is used continuously for at least 500 days. It became clear that it could be done.

[Comparison of Examples 1 and 2]
In the case of the ultrafiltration module 20 using the internal pressure type UF membrane of Example 2, an increase in the number of fine bubbles was observed on the downstream side of the ultrafiltration module 20 900 days after the start of water flow. Is the detection of N ₂ bubbles flowing out of the UF membrane. At this point, the endotoxin concentration of the UF membrane permeated water was measured, but it was below the detection limit of 0.005 EU / L. The increase in endotoxin concentration began 1100 days after the start of water flow.
In the case of the ultrafiltration module using the external pressure type UF membrane of Example 1, the number of fine bubbles started to increase 1400 days after the start of water flow. However, there was no increase in endotoxin concentration at this point. The increase in endotoxin concentration started about 1600 days after the start of water flow.

When the number of fine bubbles is increased on the downstream side of the ultrafiltration module, the endotoxin concentration does not increase. Therefore, by checking the deterioration state of the UF membrane by measuring the number of bubbles, the quality of the water for injection is high. It was shown that the guarantee is possible.
In addition, both the increase in the number of bubbles and the increase in endotoxin concentration in the ultrafiltration module start earlier in the internal pressure type UF membrane than in the external pressure type UF membrane, so the external pressure type UF membrane should withstand long-term operation. It has been shown.

10: Purified water production unit 12: Reverse osmosis membrane filtration device 14, 21: Pump 16: Continuous ion exchange device (EDI)
18: Purified water tank 20: Ultrafiltration (UF) module 22: Bubble generator 24: Particle counter 26: UF membrane module 30: Sterilized water tank for injection (WFITK)
40: Heat exchanger EDI: Continuous ion exchange HEX: Piping equipment POU: At the time of use RO: Reverse osmosis TK: Tank UF: Ultrafiltration WFI: Sterilized injection water

ここで、Ｄは代表径、Ｖは代表流速を表しており、

レイノルズ数が過剰に大きくなると、供給水がＵＦ膜に与える衝撃が大きくなり、膜が折れる可能性があるため好ましくない。
なお、濃縮水流量を上記範囲にするために、濃縮水の一部をポンプのサクション側に戻すことにより循環運転することも有効である。 In order to prevent this, the flow rate of the supplied water may be increased to increase the flow velocity, and for that purpose, the flow rate of the concentrated water may be increased. That is, when the UF membrane module diameter is L1, the hollow fiber membrane outer diameter is L2, the number of hollow fiber membranes is n, and the kinematic viscosity coefficient [determined by temperature] of the treated water is ν, the flow rate of the supply water is S. Yo suitably adjusted to the following Reynolds number is preferably to be operated such that 1000 to 10000, 2500 to 5000 is more preferable.

Here, D represents a representative diameter and V represents a representative flow velocity.

If the Reynolds number is excessively large, the impact of the supplied water on the UF membrane is large, and the membrane may be broken, which is not preferable.
In addition, in order to keep the flow rate of concentrated water within the above range, it is also effective to carry out circulation operation by returning a part of concentrated water to the suction side of the pump.

[Water quality inspection method]
In order to inspect the quality of the water for injection produced in Examples 1 and 2, the water for injection that passed through the ultrafiltration module 20 was sampled and the endotoxin concentration was measured.
The endotoxin concentration was measured by using the turbidimetric method (optical measurement method) among the endotoxin test methods in the Japanese Pharmacopoeia. This measurement is a method of optically measuring the change in turbidity associated with the gelation of the lysate test solution by endotoxin.
As a comparative example, the operation was performed by replacing the UFs of Examples 1 and 2 with a distiller manufactured in-house. The treatment flow rate was 2.0 m ³ / h, which is less than in Examples 1 and 2. Water for injection that passed through the distiller was sampled in the same manner as in Examples 1 and 2, and endotoxin was measured by the turbidimetric method .

Claims (8)

Purified water production department that reverse osmosis filtration and / or ion exchanges raw water into purified water
An ultrafiltration module that ultrafilters the purified water with a hollow fiber membrane to obtain permeated water.
A bubble water supply unit provided on the purified water side or the permeated water side of the ultrafiltration module and supplying bubble-containing water to the ultrafiltration module,
A bubble measuring means provided on the opposite side of the bubble water supply section sandwiching the ultrafiltration module and measuring the amount of bubbles in the bubble-containing water that has passed through the ultrafiltration module.
An apparatus for producing water for injection, which comprises a sterilized water tank for injection for storing the permeated water of the ultrafiltration module. The apparatus for producing water for injection according to claim 1, wherein the bubble measuring means is a particle counter. The ultrafiltration module is a module that performs ultrafiltration by an external pressure type in which the purified water is supplied to the outer surface of the hollow fiber membrane and the permeated water is taken out from the inner surface of the hollow fiber membrane. Item 1. The apparatus for producing water for injection according to Item 1. The device for producing water for injection according to claim 1, wherein the heat exchanger is arranged on the upstream side or the downstream side of the ultrafiltration module and on the upstream side of the water tank for sterile injection. The device for producing water for injection according to claim 1, wherein neither a membrane treatment device nor a distillation device is installed on the downstream side of the ultrafiltration module. The apparatus for producing injectable water according to claim 1, wherein the sterile injectable water tank is provided with an injectable water at 50 to 90 ° C. and a circulation line to a place of use (POU). Purified water production stage in which raw water is reverse osmosis filtered and / or ion exchanged to obtain purified water.
The permeated water production stage in which the purified water is ultrafiltered by an ultrafiltration module having a hollow fiber membrane to obtain permeated water.
A bubble-containing water supply step of supplying bubble-containing water to the ultrafiltration module by a bubble-containing water supply unit provided on the purified water side or the permeated water side of the ultrafiltration module.
A bubble measurement step in which the amount of bubbles in the bubble-containing water that has passed through the ultrafiltration module is measured by a bubble measuring means provided on the opposite side of the bubble water supply unit that sandwiches the ultrafiltration module.
A method for producing water for injection, which comprises a permeated water storage stage for storing the permeated water of the ultrafiltration module in a sterilized water tank for injection. 7. The seventh aspect of the invention, wherein the bubble-containing water is periodically supplied to the ultrafiltration module in the arranged state of the permeated water production stage, and a deterioration confirmation test is performed by the bubble measuring means. How to make water for injection.

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