CN113694795A - Liquid preparation system and preparation method - Google Patents
Liquid preparation system and preparation method Download PDFInfo
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- CN113694795A CN113694795A CN202111137020.XA CN202111137020A CN113694795A CN 113694795 A CN113694795 A CN 113694795A CN 202111137020 A CN202111137020 A CN 202111137020A CN 113694795 A CN113694795 A CN 113694795A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/16—Feed pretreatment
Abstract
The invention discloses a liquid preparation system and a preparation method, which relate to the technical field of liquid preparations and comprise a concentration preparation tank, a cartridge filter, an ultrafiltration membrane package and a dilution preparation tank which are sequentially connected, wherein a bypass pipeline is also connected between the inlet of the cartridge filter and the outlet of the cartridge filter. The invention can realize effective control of endotoxin without using active carbon, avoid a large amount of liquid medicine residue, and realize water conservation, energy consumption reduction and sewage discharge reduction.
Description
Technical Field
The invention relates to the technical field of liquid preparations, in particular to a liquid preparation system and a liquid preparation method.
Background
The contrast medium series products are widely applied in clinic, and the series products are mainly characterized in that the proportion of main medicines is large, for example, the specification of iodixanol injection is 320mgI/ml, the raw medicine in each ml of injection can reach 65.2% (w/v), and the strict endotoxin control on raw and auxiliary materials is not easy to realize, and the cost is greatly increased. Therefore, the control of bacterial endotoxin in high concentration injection products has been a difficult point in commercial production.
In the production process of the conventional injection, a large amount of activated carbon is adopted to adsorb bacterial endotoxin, but the defects that the clean area is polluted by fine particle powder of the activated carbon, a filter is blocked, the pH value of contrast agent liquid is reduced, other exogenous impurities are introduced, especially the content of raw and auxiliary materials is seriously adsorbed and the like can be caused. In addition, the filter element of the conventional filter does not completely filter the active carbon in the liquid medicine, and the liquid medicine may be aggregated in the long-term storage process, so that the color of the liquid medicine is deepened and the clarity of the liquid medicine is reduced. The technical requirements for evaluating the quality of the simulated drugs and the consistency of the curative effect of the chemical injection are definitely published by the drug evaluation center of the State administration of drug in 05 months of 2020, and the production of the injection does not use active carbon.
In order to overcome the above disadvantages of activated carbon, for example, patent document CN201410260510.2 entitled ultrafiltration process of injection for MRI or CT contrast discloses a series connection of ultrafiltration membranes to remove endotoxin from iodine and gadolinium contrast agents, so that endotoxin can be effectively controlled. However, the above filtration process is not ideal because the recovery rate of the main drug is low, and the maximum recovery rate can only reach about 95%, and moreover, when the concentration of the drug solution is high and the viscosity is high, the drug solution remains more.
In recent years, ultrafiltration membranes using tangential flow technology have been successful in the use of biologicals. Be equipped with return line and permeate through the pipeline in the ultrafiltration system that uses the tangential flow technique usually, in order to protect ultrafiltration membrane package and obtain great liquid medicine flux, install the great cartridge filter of volume additional before ultrafiltration membrane package, put into several filter cores in the cartridge filter, hold back the large granule and the insoluble material in the liquid medicine effectively, thereby guarantee the patency of the liquid medicine through ultrafiltration membrane package, but this can lead to the liquid medicine to remain great, and the multistage membrane package of installation also can make and remain further increase, the yield further reduces.
Disclosure of Invention
The currently used tangential flow technology ultrafiltration systems are powered by a power device, such as a rotor pump, to create a pressure differential to pass the liquid drug through the cartridge filter and the ultrafiltration membrane module. A small part of the liquid medicine penetrates through the membrane package to enter the diluting preparation tank due to transmembrane pressure difference caused by tangential flow, and the other part of the liquid medicine tangentially and parallelly flows back to the concentrating preparation tank through the membrane package, continues to be filtered, and repeats in turn. As the liquid medicine is gradually reduced, an effective tangential flow backflow flow path can not be formed or the operation of the power device is influenced, the cartridge filter can not work, the liquid medicine can not be filtered through the cartridge filter, and therefore part of the liquid medicine is remained after the liquid medicine is filtered by the cartridge filter. Meanwhile, as the viscosity of the liquid medicine is higher, the filtering pressure difference required by the liquid medicine to permeate the cartridge filter element is higher, and the liquid medicine remaining after filtering by the cartridge filter is higher.
The invention aims to provide a liquid preparation system and a preparation method, which can realize effective control of endotoxin without using active carbon, can discharge all liquid medicines remained in a concentration preparation tank, a security filter and a pipeline, then send the liquid medicines into an ultrafiltration membrane pack for filtration, and recover the liquid medicines remained in the concentration preparation tank, the security filter and the pipeline through washing and filtering, thereby greatly improving the recovery rate of main medicines in the liquid medicines and greatly reducing the cleaning difficulty after the liquid medicines are prepared; meanwhile, after the liquid medicine is prepared, the concentration of the residual liquid medicine is low, and the liquid medicine can be cleaned to the qualified standard in a short time by using less injection water, so that the injection water used for cleaning is greatly reduced, the energy consumption and the treatment cost in sewage treatment are reduced, and the sewage discharge is reduced.
In order to realize the purpose of the invention, the technical scheme is as follows: the utility model provides a liquid preparation system, including the thick jar of joining in marriage that connects gradually, the cartridge filter, ultrafiltration membrane package and the jar of joining in marriage thinly, the filtration mode of ultrafiltration membrane package is the tangential flow filtration, and still be connected with the bypass pipeline between cartridge filter import and the cartridge filter export, the import of security filter is connected in parallel to the one end of bypass pipeline, the export of security filter is connected in parallel to the other end of bypass pipeline, when the liquid medicine in the thick jar of joining in marriage can not satisfy cartridge filter normal work, remaining liquid medicine in the cartridge filter can receive external force effect to filter out the mouth end from the cartridge filter and discharge, through the backflow of bypass pipeline to the thick jar of joining in marriage, send into in the ultrafiltration membrane package through the bypass pipeline with remaining liquid medicine in the thick jar of joining in marriage at last.
Further, the security filter is also connected with an air inlet pipeline, the air inlet pipeline is used for conveying compressed air or nitrogen and the like, the air inlet end of the air inlet pipeline is connected with an air source or an air supply pipeline, and the air outlet end of the air inlet pipeline is connected with the security filter; closing the inlet of the cartridge filter and the valve in front of the ultrafiltration membrane, opening the outlet of the cartridge filter and the valve of the bypass pipeline, introducing gas into the cartridge filter through the gas inlet pipeline, and pressurizing the cartridge filter to completely discharge the residual liquid medicine in the cartridge filter.
Furthermore, the outlet permeation end of the ultrafiltration membrane package is also connected with a diluting and mixing tank which is mainly used for storing the filtered liquid medicine and the washing and filtering liquid medicine generated by washing and filtering.
A method of preparing a liquid formulation comprising the steps of:
A. dividing the injection water for preparing the liquid medicine into two parts, wherein the proportion of the two parts of the injection water can be adjusted according to the situation, one part of the injection water and the medicine raw materials are sent into a thick preparation tank to be prepared into the liquid medicine to be filtered, and the other part of the injection water is reserved;
B. sending the prepared liquid medicine to be filtered into a cartridge filter for filtering, sending the liquid medicine filtered by the cartridge filter into an ultrafiltration membrane pack for ultrafiltration, returning a part of the ultrafiltered liquid medicine to a concentration tank through a return pipeline, and sending a part of ultrafiltered permeate liquid into a dilution tank;
C. when the liquid medicine in the concentrated preparation tank is reduced to be incapable of working, the residual liquid medicine in the security filter is sent back to the concentrated preparation tank through a bypass pipeline, the liquid medicine in the concentrated preparation tank is sent into an ultrafiltration membrane pack through the bypass pipeline for ultrafiltration, the liquid medicine in the concentrated preparation tank is reduced to be incapable of working, namely the liquid medicine in the concentrated preparation tank cannot form an effective tangential flow backflow flow path or influence the operation of a power device, so that the security filter cannot work normally, the security filter has different requirements on the liquid medicine in the filtering process according to different types of the filtered liquid medicine, different sizes of the security filter and different working conditions of the security filter, and the residual liquid medicine in the concentrated preparation tank can also change relatively;
D. after the ultrafiltration is finished, the reserved water for injection is sent into the concentration tank, does not pass through a cartridge filter, sequentially passes through a bypass pipeline and an ultrafiltration membrane package, is mixed with residual liquid medicine in the concentration tank, the bypass pipeline and the ultrafiltration membrane package, and is sent into the dilution tank after the ultrafiltration.
Further, the liquid preparation is iodixanol injection, iopromide injection, ioversol injection or iopamidol injection, and herein, the liquid preparation is not limited to the above-mentioned ones.
Further, adding other materials such as pH regulator, etc., weighing, sterilizing, filtering, bottling, capping, and sterilizing.
Further, the pH value regulator is hydrochloric acid or sodium hydroxide aqueous solution.
Furthermore, the pH value in the diluting preparation tank is 6.0-8.5, and when the liquid medicine is prepared in the diluting preparation tank, the pH value in the diluting preparation tank can be correspondingly adjusted according to different types of prepared liquid medicine.
Furthermore, the injection water for preparing the medicine raw materials is 50-90% of the total water amount of the prescription, the ratio of the amount of the injection water for preparing the medicine raw materials to the reserved injection water can be adjusted according to the residual condition of the liquid medicine during preparation and the washing and filtering times of the injection water, the injection water for preparing the medicine raw materials accounts for more than 50-90% or less than 50-90% of the total water amount of the prescription according to different prepared liquid medicines, and only a better range value is given.
Furthermore, the preparation temperature of the injection water and the medicine raw materials is 40-90 ℃, so that the dissolution speed of the medicine raw materials is accelerated without destroying the performance of the medicine raw materials in the preparation process of the injection water and the medicine raw materials, the preparation efficiency of the liquid medicine is higher, the preparation temperature of the injection water and the medicine raw materials can be correspondingly adjusted according to the properties of different medicine raw materials, and the preparation of the injection water and the medicine raw materials can be carried out at normal temperature when the temperature has great influence on the medicine raw materials.
Furthermore, the filtering temperature of the cartridge filter is 20-80 ℃, and can be relatively adjusted according to different working conditions of different cartridge filters and different performances of liquid medicines.
Furthermore, the volume of the liquid medicine filtered by the cartridge filter is 100-5000L.
Furthermore, the cartridge filter is provided with 5 inches, 10 inches, 20 inches or 30 inches of filter elements 1 to more, wherein the size, the filtering precision and the number of the filter elements can be adjusted according to the type of the liquid medicine and the filtering requirement of the liquid medicine.
Further, the filter element is a polyethersulfone, polytetrafluoroethylene or polyvinylidene fluoride filter element, and the types of the filter elements can not be limited to the three types.
Furthermore, the molecular interception amount of the ultrafiltration membrane is 1KDa-300KDa, and the size of the interception aperture can be adjusted according to the type of the liquid medicine and the filtration requirement of the liquid medicine.
Furthermore, the reserved injection water is sent into the concentration tank for washing and filtering for multiple times, preferably, the frequency of sending the reserved injection water into the concentration tank for washing and filtering can be 1 time, 2 times, 3 times, 5 times, 8 times and the like or even more, and the specific washing and filtering frequency can be adjusted according to the residual situation of the liquid medicine in the security filter
Furthermore, the power for feeding the liquid medicine in the cartridge filter back to the concentration tank is to feed gas such as compressed air or nitrogen into the cartridge filter, but is not limited to compressed air or nitrogen, the pressure of the compressed air or nitrogen can be about 0.01-0.5 MPa, the compressed air or nitrogen is mainly used for feeding the liquid medicine remaining in the cartridge filter into the concentration tank through a bypass pipeline, and the specific pressure can be adjusted according to the viscosity and the remaining condition of the liquid medicine in the cartridge filter.
The beneficial effect of the invention is that,
1. the invention has less liquid medicine residue in the concentration tank, when the cartridge filter can not work, the residual liquid medicine in the cartridge filter is directly sent back to the concentration tank through the bypass pipeline, and then the liquid medicine in the concentration tank is directly sent into the ultrafiltration membrane package through the bypass pipeline, thereby greatly reducing the residue of the liquid medicine in the cartridge filter and the pipeline.
2. The injection water is divided into two parts, and the reserved injection water is sent into the concentration tank to mix, wash and filter the residual liquid medicine in the concentration tank, the ultrafiltration membrane and the pipeline, so that the recovery rate of the main medicine is further improved; after the liquid medicine is prepared, the concentration of the residual liquid medicine is low, and the liquid medicine can be cleaned to the qualified standard in a short time by using less injection water, so that the injection water used for cleaning is greatly reduced, the sewage discharge is reduced, and the energy consumption and the treatment cost in sewage treatment are reduced.
3. The invention can improve the recovery rate of main drug from 93.4% to 100% by recovering the residual drug liquid in the security filter and the pipeline, dividing the reserved water for injection into a concentration tank and sending the water to the concentration tank for multiple times to wash and filter the concentration tank, the pipeline, the ultrafiltration membrane package, etc. The yield of each batch can be increased by 39.6 ten thousand yuan according to 1000L of iodixanol injection, and the yield value of 11.88 million yuan RMB can be increased (the sales of the product is increased well and the benefit is increased continuously) according to 3000 ten thousand bottles of estimated annual sales of the product; meanwhile, 500L of injection water is predicted to be saved in each batch of liquid medicine production, 3000 ten thousand bottles of injection water can be sold according to the predicted annual quantity, 150 ten thousand liters of injection water can be saved in one year, the treatment capacity of sewage is reduced by 1500 tons, and 300 ten thousand yuan can be sold if the injection water is calculated according to the unit price of 1.5 yuan per bottle of 500 ml.
4. The method cancels the step of removing bacterial endotoxin by activated carbon adsorption, reduces the risks of activated carbon adsorption content, pH reduction, introduction of foreign impurities and the like, and effectively controls the bacterial endotoxin; and one of the quality control indexes of the ultrafiltered liquid medicine is obviously reduced in absorbance, is obviously better than that of the activated carbon adsorption and other processes and reference preparations, is obviously better than that of the reference preparation in the sample retention process of an accelerated test, and reduces the risk of clinical use patients.
Drawings
Fig. 1 is a system block diagram of a liquid preparation system provided by the present invention.
Reference numbers and corresponding part names in the drawings:
1. the system comprises a concentration tank, 2, a cartridge filter, 3, an ultrafiltration membrane package, 4, a dilution tank, 5, a bypass pipeline, 6, a reflux pipeline, 7 and a valve.
Detailed Description
The present invention will be described in further detail below with reference to specific embodiments and with reference to the attached drawings.
Example 1
As shown in fig. 1, the liquid preparation system provided by the present invention includes a concentration tank 1, a cartridge filter 2 and an ultrafiltration membrane package 3, wherein the concentration tank 1 is used for storing liquid medicine after preparation and/or preparation, an outlet of the concentration tank 1 is connected to an inlet of the cartridge filter 2, an outlet of the cartridge filter 2 is connected to an inlet of the ultrafiltration membrane package 3, and valves 7 are installed at the outlet of the concentration tank 1, the inlet of the cartridge filter 2, the outlet of the cartridge filter 2, the inlet of the ultrafiltration membrane package 3 and the outlet of the ultrafiltration membrane package 3; meanwhile, a bypass pipeline 5 is connected between the inlet of the cartridge filter 2 and the outlet of the cartridge filter 2, the bypass pipeline 5 can directly send the liquid medicine in the cartridge filter 2 into the concentration tank 1 after being discharged, the liquid medicine in the concentration tank 1 can be directly sent into the ultrafiltration membrane package 3 through the bypass pipeline 5, and valves 7 are also installed at two ends of the bypass pipeline 5 for the convenience of controlling the bypass pipeline 5.
When the preparation system is used for preparing the injection, the injection can be ultrafiltered, and the preparation system can also be washed and filtered after the ultrafiltration of the injection is finished. Before the injection is ultrafiltered, injection water for preparing the injection is divided into two parts, one part of the injection water is sent into the concentration tank 1, medicine raw materials and the like are added into the concentration tank 1, and the injection water, the medicine raw materials and the like in the concentration tank 1 are stirred. After the medicine raw materials and the like are completely dissolved, the liquid medicine in the concentration tank 1 is sent into a security filter 2 for filtering, the liquid medicine is sent into an ultrafiltration membrane package 3 for ultrafiltration after being filtered by the security filter 2, the liquid medicine after the ultrafiltration is sent out through the ultrafiltration membrane package 3, one part of the liquid medicine flows back to the concentration tank 1, and the other part of the liquid medicine permeates into a dilution tank 4. When the liquid medicine in the concentration tank 1 can not meet the working requirement of the cartridge filter, the preparation system can not run, at the moment, the liquid medicine filtered in the cartridge filter 2 is sent into the concentration tank 1 from the filtering rear end of the cartridge filter 2 through a bypass pipeline 5 by back pressure through gas such as compressed air, and the liquid medicine in the concentration tank 1 is directly sent into an ultrafiltration membrane package 3 through the bypass pipeline 5 for ultrafiltration. When the preparation system is washed and filtered, the reserved water for injection is sent into the concentration tank 1, and the water for injection is mixed with the residual liquid medicine in the concentration tank 1, the bypass pipeline 5 and the ultrafiltration membrane package 3, and then is sent to the dilution tank 4 after ultrafiltration.
In the preparation system, the filtering mode of the ultrafiltration membrane package 3 is a tangential flow filtering mode, namely a backflow pipeline 6 is also connected between the ultrafiltration membrane package 3 and the concentrated preparation tank 1, and a valve 7 is also arranged on the backflow pipeline 6, so that the ultrafiltration membrane package 3 permeates the permeation solution ultrafiltered by the ultrafiltration membrane package 3 and is sent into the diluted preparation tank 4 in the filtering or washing and filtering process, and the backflow solution flows back to the concentrated preparation tank 1 through the backflow pipeline 6.
In some embodiments, an air intake duct is further connected to the cartridge filter 2, and the air intake duct is mainly used for conveying gas such as compressed air or nitrogen, and the compressed air is conveyed into the cartridge filter 2 through the air intake duct. When the liquid in the concentration tank 1 is reduced to the state that the system can not run, the pressure in the cartridge filter 2 is increased through compressed air, so that the residual liquid medicine in the cartridge filter 2 is directly sent into the concentration tank 1 through the bypass pipeline 5, and the recovery rate of the liquid medicine reaches about 99.9 percent; here, compressed air cannot be used to directly purge the ultrafiltration membrane package 3 with a very small molecular cut-off, as this would destroy the microstructure and integrity of the ultrafiltration membrane package 3.
In some embodiments, the outlet of the ultrafiltration membrane package 3 is further connected with a diluting preparation tank 4, a valve 7 is also installed at the inlet end of the diluting preparation tank 4, and the diluting preparation tank 4 is mainly used for collecting and mixing the ultrafiltered liquid medicine and the washing-filtering liquid medicine after washing and filtering in a centralized manner, and performing subsequent treatment on the ultrafiltered liquid medicine and the washing-filtering liquid medicine after washing and filtering, so as to finally prepare the liquid medicine meeting the standard.
The liquid preparation system provided by the invention can be used for preparing iodixanol injection, iopromide injection, ioversol injection or iopamidol injection and the like, and the liquid preparation is not limited to the above.
Example 2
Adding injection water with 50-90% of the total water amount of the prescription into a concentration preparation tank, adjusting the temperature of the prepared liquid in the concentration preparation tank to 40-90 ℃, adding a batch of iodixanol and the like into the concentration preparation tank, stirring and dissolving, reducing the temperature of the liquid medicine in the concentration preparation tank to 20-80 ℃, filtering the liquid medicine in the concentration preparation tank through a security filter, wherein the aperture of a filter element is 0.45 mu m, and the filtering pressure difference of the filter element is less than 0.4 Mpa. The filtered liquid medicine enters an ultrafiltration membrane for ultrafiltration (the interception amount of the molecules of the pores of the ultrafiltration membrane is 30KD), and the pressure of the liquid medicine entering the membrane is kept to be less than 0.5Mpa in the ultrafiltration process. The ultrafiltration permeating liquid enters a diluting preparation tank, and the reflux liquid flows back to a concentrating preparation tank.
When the residual liquid medicine in the concentration tank is 1-40 kg, the security filter and the ultrafiltration membrane package cannot work, at the moment, the reserved injection water is completely added into the concentration tank and is uniformly mixed with the residual liquid medicine, the uniformly mixed liquid medicine enters the ultrafiltration membrane package after being filtered by the security filter, the liquid medicine is sent into the dilution tank after being ultrafiltered, other materials such as a pH value regulator and the like are added into the dilution tank, and then the injection water is added for weight determination, sterilization filtration, filling, capping and sterilization at 121 ℃ for 10 min.
Sampling and monitoring the concentration and the density of the liquid medicine in the diluting and preparing tank, recording the weight of the liquid medicine, calculating the volume of the liquid medicine in the diluting and preparing tank (the weight of the liquid medicine/the density of the liquid medicine), and calculating the recovery rate of the main medicine to be 1- (the material feeding amount-the volume of the liquid medicine multiplied by the concentration of the liquid medicine)/the material feeding amount multiplied by 100 percent.
Example 3
Adding injection water with 50-90% of the total water amount of the prescription into a concentration preparation tank, adjusting the temperature of the prepared liquid in the concentration preparation tank to 40-90 ℃, adding a batch of iodixanol and the like into the concentration preparation tank, stirring and dissolving, reducing the temperature of the liquid medicine in the concentration preparation tank to 20-80 ℃, filtering the liquid medicine in the concentration preparation tank through a security filter, wherein the aperture of a filter element is 0.45 mu m, and the filtering pressure difference of the filter element is less than 0.4 Mpa. The filtered liquid medicine enters an ultrafiltration membrane for ultrafiltration (the interception amount of the molecules of the pores of the ultrafiltration membrane is 30KD), and the pressure of the liquid medicine entering the membrane is kept to be less than 0.5Mpa in the ultrafiltration process. The ultrafiltration permeating liquid enters a diluting preparation tank, and the reflux liquid flows back to a concentrating preparation tank.
When the residual liquid medicine in the concentration tank is 1-40 kg, the security filter and the ultrafiltration membrane package cannot work, at the moment, valves at the inlet of the security filter and the inlet of the ultrafiltration membrane package are closed, compressed air is fed into the security filter, and the compressed air reversely presses the liquid medicine in the security filter back into the concentration tank through a bypass pipeline. The valves of the inlet and the outlet of the cartridge filter are closed, and the liquid medicine in the concentration tank is directly sent into the ultrafiltration membrane package through a bypass pipeline for ultrafiltration.
Adding the reserved water for injection into the concentration tank, mixing with the residual liquid medicine, introducing the mixed liquid medicine into an ultrafiltration membrane package through a bypass pipeline, ultrafiltering, introducing into the dilution tank, adding the rest materials such as pH regulator, adding the water for injection, weighing, sterilizing, filtering, filling, capping, and sterilizing at 121 ℃ for 10 min.
Sampling and monitoring the concentration and the density of the liquid medicine in the diluting and preparing tank, recording the weight of the liquid medicine, calculating the volume of the liquid medicine in the diluting and preparing tank (the weight of the liquid medicine/the density of the liquid medicine), and calculating the recovery rate of the main medicine to be 1- (the material feeding amount-the volume of the liquid medicine multiplied by the concentration of the liquid medicine)/the material feeding amount multiplied by 100 percent.
Example 4
Adding injection water with 50-90% of the total water amount of the prescription into a concentration preparation tank, adjusting the temperature of the prepared liquid in the concentration preparation tank to 40-90 ℃, adding a batch of iodixanol and the like into the concentration preparation tank, stirring and dissolving, reducing the temperature of the liquid medicine in the concentration preparation tank to 20-80 ℃, filtering the liquid medicine in the concentration preparation tank through a security filter, wherein the aperture of a filter element is 0.45 mu m, and the filtering pressure difference of the filter element is less than 0.4 Mpa. The filtered liquid medicine enters an ultrafiltration membrane for ultrafiltration (the interception amount of the molecules of the pores of the ultrafiltration membrane is 30KD), and the pressure of the liquid medicine entering the membrane is kept to be less than 0.5Mpa in the ultrafiltration process. The ultrafiltration permeating liquid enters a diluting preparation tank, and the reflux liquid flows back to a concentrating preparation tank.
When the residual liquid medicine in the concentration tank is 1-40 kg, the security filter and the ultrafiltration membrane package cannot work, at the moment, valves at the inlet of the security filter and the inlet of the ultrafiltration membrane package are closed, compressed air is fed into the security filter, and the compressed air reversely presses the liquid medicine in the security filter back into the concentration tank through a bypass pipeline. The valves of the inlet and the outlet of the cartridge filter are closed, and the liquid medicine in the concentration tank is directly sent into the ultrafiltration membrane package through a bypass pipeline for ultrafiltration.
Adding the reserved water for injection into the thick preparation tank for three times, uniformly mixing the water for injection added into the thick preparation tank with the residual liquid medicine each time, feeding the uniformly mixed liquid medicine into an ultrafiltration membrane package through a bypass pipeline, and feeding the liquid medicine into the thin preparation tank after ultrafiltration. Adding other materials such as pH regulator into the diluting tank, adding injectable water, weighing, sterilizing, filtering, packaging, capping, and sterilizing at 121 deg.C for 10 min.
Sampling and monitoring the concentration and the density of the liquid medicine in the diluting and preparing tank, recording the weight of the liquid medicine, calculating the volume of the liquid medicine in the diluting and preparing tank (the weight of the liquid medicine/the density of the liquid medicine), and calculating the recovery rate of the main medicine to be 1- (the material feeding amount-the volume of the liquid medicine multiplied by the concentration of the liquid medicine)/the material feeding amount multiplied by 100 percent.
Example 5
Adding injection water with 50-90% of the total water amount of the prescription into a concentration preparation tank, adjusting the temperature of the prepared liquid in the concentration preparation tank to 40-90 ℃, adding a batch of iodixanol and the like into the concentration preparation tank, stirring and dissolving, reducing the temperature of the liquid medicine in the concentration preparation tank to 20-80 ℃, filtering the liquid medicine in the concentration preparation tank through a security filter, wherein the aperture of a filter element is 0.45 mu m, and the filtering pressure difference of the filter element is less than 0.4 Mpa. The filtered liquid medicine enters an ultrafiltration membrane for ultrafiltration (the interception amount of the molecules of the pores of the ultrafiltration membrane is 30KD), and the pressure of the liquid medicine entering the membrane is kept to be less than 0.5Mpa in the ultrafiltration process. The ultrafiltration permeating liquid enters a diluting preparation tank, and the reflux liquid flows back to a concentrating preparation tank.
When the residual liquid medicine in the concentration tank is 1-40 kg, the security filter and the ultrafiltration membrane package cannot work, at the moment, valves at the inlet of the security filter and the inlet of the ultrafiltration membrane package are closed, compressed air is fed into the security filter, and the compressed air reversely presses the liquid medicine in the security filter back into the concentration tank through a bypass pipeline. The valves of the inlet and the outlet of the cartridge filter are closed, and the liquid medicine in the concentration tank is directly sent into the ultrafiltration membrane package through a bypass pipeline for ultrafiltration.
Adding the reserved water for injection into the thick preparation tank five times, uniformly mixing the water for injection added into the thick preparation tank and the residual liquid medicine each time, feeding the uniformly mixed liquid medicine into an ultrafiltration membrane package through a bypass pipeline, and feeding the liquid medicine into the thin preparation tank after ultrafiltration. Adding other materials such as pH regulator into the diluting tank, adding injectable water, weighing, sterilizing, filtering, packaging, capping, and sterilizing at 121 deg.C for 10 min.
Sampling and monitoring the concentration and the density of the liquid medicine in the diluting and preparing tank, recording the weight of the liquid medicine, calculating the volume of the liquid medicine in the diluting and preparing tank (the weight of the liquid medicine/the density of the liquid medicine), and calculating the recovery rate of the main medicine to be 1- (the material feeding amount-the volume of the liquid medicine multiplied by the concentration of the liquid medicine)/the material feeding amount multiplied by 100 percent.
Example 6
Adding injection water with 50-90% of the total water amount of the prescription into a concentration preparation tank, adjusting the temperature of the prepared liquid in the concentration preparation tank to 40-90 ℃, adding a batch of iodixanol and the like into the concentration preparation tank, stirring and dissolving, reducing the temperature of the liquid medicine in the concentration preparation tank to 20-80 ℃, filtering the liquid medicine in the concentration preparation tank through a security filter, wherein the aperture of a filter element is 0.45 mu m, and the filtering pressure difference of the filter element is less than 0.4 Mpa. The filtered liquid medicine enters an ultrafiltration membrane for ultrafiltration (the interception amount of the molecules of the pores of the ultrafiltration membrane is 30KD), and the pressure of the liquid medicine entering the membrane is kept to be less than 0.5Mpa in the ultrafiltration process. The ultrafiltration permeating liquid enters a diluting preparation tank, and the reflux liquid flows back to a concentrating preparation tank.
When the residual liquid medicine in the concentration tank is 1-40 kg, the security filter and the ultrafiltration membrane package cannot work, at the moment, valves at the inlet of the security filter and the inlet of the ultrafiltration membrane package are closed, compressed air is fed into the security filter, and the compressed air reversely presses the liquid medicine in the security filter back into the concentration tank through a bypass pipeline. The valves of the inlet and the outlet of the cartridge filter are closed, and the liquid medicine in the concentration tank is directly sent into the ultrafiltration membrane package through a bypass pipeline for ultrafiltration.
Adding the reserved water for injection into the thick preparation tank for eight times, uniformly mixing the water for injection added into the thick preparation tank and the residual liquid medicine each time, feeding the uniformly mixed liquid medicine into an ultrafiltration membrane package through a bypass pipeline, and feeding the liquid medicine into the thin preparation tank after ultrafiltration. Adding other materials such as pH regulator into the diluting tank, adding injectable water, weighing, sterilizing, filtering, packaging, capping, and sterilizing at 121 deg.C for 10 min.
Sampling and monitoring the concentration and the density of the liquid medicine in the diluting and preparing tank, recording the weight of the liquid medicine, calculating the volume of the liquid medicine in the diluting and preparing tank (the weight of the liquid medicine/the density of the liquid medicine), and calculating the recovery rate of the main medicine to be 1- (the material feeding amount-the volume of the liquid medicine multiplied by the concentration of the liquid medicine)/the material feeding amount multiplied by 100 percent.
TABLE 1 comparison of the results of the recovery rates of the main drugs in different processes
The result shows that the recovery rate of the main drug in the embodiment 3 with the bypass pipeline is remarkably improved from 93.4 percent to 98.6 percent and is improved by 5.2 percent compared with the embodiment 2 without the bypass pipeline; the times of washing and filtering the reserved injection water are searched through the embodiments 4-6, and the recovery rate of the main drug is gradually improved to 99.9 percent and approaches to 100 percent when the washing and filtering are carried out for 5-8 times.
The content of the main drug in the products is extremely high, taking the volume of 500L of iopromide injection and the concentration of 76% (w/v) as an example, the input amount of the main drug is about 380kg, and the recovery rate is improved by 1 percent, namely, the residual main drug in a pipeline is reduced by about 3.85 kg. As the injection water is required to be used for cleaning the pipeline, the security filter and the ultrafiltration membrane package on line after production until the standard of the injection water is reached (the qualified standard is that the pH value is 5.0-7.0, the conductivity is less than or equal to 1.3us/cm, the TOC is less than or equal to 0.50mg/L and 25 ℃), the more the residual main medicine is, the more the consumed injection water is, and the preliminary prediction is made, and the injection water can be saved by 500-1000 liters by using the process.
When the recovery rate of the main drug is increased from 93.4% to about 100%, the recovery rate is increased by 66L according to 1000L of iodixanol injection per batch, namely 660 bottles of finished products, and the yield is increased by 39.6 ten thousand yuan per batch according to 600 yuan per bottle of iodixanol injection. Taking iodixanol, iopromide, iopamidol and other injection as examples, the injection has good market prospect, 3000 ten thousand bottles of sales per year can be estimated at present, and in the process of continuous growth, 11.88 hundred million yuan RMB can be newly added according to the estimation. Meanwhile, 500L of injection water is predicted to be saved in each batch of liquid medicine production, 3000 ten thousand bottles of injection water are predicted to be sold in each year according to a plurality of varieties such as iodixanol, 3000 batches of injection water are required to be produced in each 1000L batch, and 150 ten thousand liters of injection water can be saved in each year. The quality index of the water for injection is far higher than that of pure water sold in the market, and the water for injection is calculated according to the unit price of 1.5 yuan per bottle of 500ml, and 300 yuan can be sold in 150 ml. Because the residual quantity after cleaning is very little, the use of water for injection is reduced, and the treatment capacity of sewage is reduced by 1500 tons.
Example 7
Adding injection water with 50-90% of total water of a formula into a concentration preparation tank, adjusting the temperature of a preparation solution to 40-90 ℃, adding iodixanol into the injection water, stirring and dissolving, continuously adding calcium disodium edetate, sodium chloride, calcium chloride and tromethamine into the liquid medicine, stirring and dissolving for 10min, adjusting the pH value of the liquid medicine to 6.8-7.6 by using hydrochloric acid, and fixing the volume. Filtering the liquid medicine with two-stage filter membranes of 0.45 μm and 0.22 μm, subpackaging, sterilizing and marking as sample 1;
adding injection water with the total water amount of 50-90% of the formula into a concentration preparation tank, adjusting the temperature of the preparation liquid to 40-90 ℃, adding iodixanol into the injection water, stirring and dissolving, continuously adding calcium disodium edetate, sodium chloride, calcium chloride and tromethamine into the liquid medicine, stirring and dissolving for 10min, adjusting the pH value of the liquid medicine to 6.8-7.6 by using hydrochloric acid, and fixing the volume; adding activated carbon with the amount of 0.2% of the prescription into the liquid medicine, stirring and adsorbing for 20min, filtering with a 2-micron titanium rod and a 0.45-micron and 0.22-micron two-stage filter to remove the activated carbon, subpackaging, sterilizing and marking as a sample 2;
adding injection water with the total water amount of 50-90% of the formula into a concentration preparation tank, adjusting the temperature of the preparation liquid to 40-90 ℃, adding iodixanol into the injection water, stirring and dissolving, continuously adding calcium disodium edentate, sodium chloride, calcium chloride and tromethamine into the liquid medicine, stirring and dissolving for 10min, adjusting the pH value of the liquid medicine to 6.8-7.6 by using hydrochloric acid, and fixing the volume; adding activated carbon with the amount of 0.4% of the prescription amount into the liquid medicine, stirring and adsorbing for 20min, filtering by a 2-micron titanium rod and a 0.45-micron and 0.22-micron two-stage filter to remove the activated carbon, subpackaging, sterilizing and marking as a sample 3;
the samples 1, 2, 3 and the sample prepared by the ultrafiltration process in example 4 were taken AS sample 4, subjected to accelerated investigation at 40 ℃, and compared with the quality of a domestic reference preparation of iodixanol injection (underwriter: GE Healthcare AS, product: GE Healthcare Ireland Limited), and the results are shown in tables 2 and 3.
TABLE 2 comparison of sample 1-4 with reference preparation quality results for 0 day
TABLE 3 comparison of the color results of sample 4 finished product and reference preparation in accelerated 40 deg.C solution examination
From the above table results, it can be seen that: compared with the preparation process using the activated carbon, the sample subjected to ultrafiltration by using the preparation method provided by the invention can effectively control bacterial endotoxin, and the problems of reduction of the content of the raw material adsorbed by the activated carbon and pH are avoided. In addition to the above quality indicators of pH, content, bacterial endotoxin, etc. being comparable to the reference, it was surprisingly found that the solution color of sample 4 was significantly better than the reference and consistently better than the reference during the accelerated sample retention process.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The liquid preparation system is characterized by comprising a concentration preparation tank (1), a cartridge filter (2), an ultrafiltration membrane package (3) and a dilution preparation tank (4) which are sequentially connected, wherein a bypass pipeline (5) is also connected between an inlet of the cartridge filter (2) and an outlet of the cartridge filter (2).
2. The liquid preparation system according to claim 1, wherein a return line (6) is further connected between the ultrafiltration membrane module (3) and the concentration tank (1).
3. The liquid formulation preparation system according to claim 1, wherein an air inlet duct is further connected to the cartridge filter (2).
4. A method for preparing a liquid formulation, comprising the steps of:
A. dividing the injection water for preparing the liquid medicine into two parts, wherein one part of the injection water, the medicine raw materials and the like are sent into a concentration tank (1) to be prepared into the liquid medicine to be filtered, and the other part of the injection water is reserved;
B. the prepared liquid medicine to be filtered is sent into a cartridge filter (2) for filtering, the liquid medicine filtered by the cartridge filter (2) is sent into an ultrafiltration membrane package (3) for ultrafiltration, a part of the liquid medicine returns to a concentration preparation tank (10) through a reflux pipeline (6), and a part of ultrafiltration permeate liquid is sent into a dilution preparation tank (4);
C. when the liquor in the concentration tank is reduced to be incapable of working, the liquor in the cartridge filter (2) is returned to the concentration tank (1) through a bypass pipeline (5), and the liquor in the concentration tank (1) is sent into an ultrafiltration membrane package (3) through the bypass pipeline (5) for ultrafiltration;
D. after the ultrafiltration is finished, the reserved water for injection is sent into a concentration tank (1), the residual liquid medicine is mixed and sequentially passes through a bypass pipeline (5) and an ultrafiltration membrane package (3), the residual liquid medicine is mixed, and the mixture is sent into a dilution tank (4) after the ultrafiltration.
5. The method for preparing a liquid preparation according to claim 4, wherein the amount of water for injection to be used for preparing the pharmaceutical raw material in the step A is 50 to 90 percent of the total amount of the prescription.
6. The method for preparing a liquid preparation according to claim 4, wherein the water for injection reserved in step D is fed into the thickening tank (1) for washing and filtering a plurality of times.
7. The method for preparing a liquid preparation according to claim 4, wherein the motive force for returning the liquid medicine in the cartridge filter (2) to the canister (1) is to feed a gas including but not limited to compressed air or nitrogen into the cartridge filter.
8. The method for preparing a liquid preparation according to claim 4, wherein the liquid preparation includes, but is not limited to, iodixanol injection, iopromide injection, ioversol injection or iopamidol injection.
9. The method for producing a liquid preparation according to claim 4, wherein the ultrafiltrate solution and the wash-filtered solution sent out after the ultrafiltration by the ultrafiltration membrane module (3) are directly sent into the dilution tank (4).
10. The method for preparing a liquid preparation according to claim 9, wherein the rest materials such as a pH regulator and the like are added to the dilution tank (4), and the weight is determined, the sterilization filtration, the filling, the capping and the sterilization are performed.
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