Nimodipine injection production equipment and process

Abstract

The nimodipine injection production equipment comprises a liquid preparation device, a cleaning device and a filling and capping device, the liquid preparation device comprises a liquid preparation tank, the bottom of the lower end of the liquid preparation tank is connected with the upper end of a filter box through an electromagnetic valve, and a pressure detector is arranged on one side of the top of the upper end of the filter box; meanwhile, the front face of the filter box is detachably connected with the filter assembly through a plurality of electromagnetic columns, the lower end of the filter box is connected with a first circulating pipe and a liquid conveying pipe through a three-way valve, the other end of the first circulating pipe is connected with the upper end of one side of the filter box, and the cleaning device comprises a bottle washing device and a plug washing device. According to the nimodipine injection production equipment, a sectional liquid preparation procedure is adopted, injection water is added firstly, then auxiliary materials are added, and finally raw materials are added, the materials are completely transferred into a liquid preparation tank through rinsing operation in each step, meanwhile, a filter element in the nimodipine injection production equipment is detached and replaced after being used for a single time, so that the filter element is prevented from being perforated, and the production efficiency of the nimodipine injection is improved. The production risk of the nimodipine injection is further reduced.

Description

Technical Field

[0001] The present invention relates to the technical field related to the production of nimodipine injection, and in particular to a nimodipine injection production device and process. Background Art

[0002] Nimodipine injection is indicated for the prevention and treatment of ischemic nerve damage caused by cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Certain equipment is required in the production process of nimodipine injection, such as liquid preparation equipment, bottle washing equipment, filling equipment and capping equipment, which are collectively referred to as production equipment.

[0003] When the liquid preparation equipment in the existing production equipment is in use, the injection water, excipients and raw materials are simultaneously transported to the liquid preparation tank for stirring and mixing, which makes the raw materials dissolve poorly, affecting the quality of the finished product. In addition, the filter element is used for a long time during filtration, which makes the filter element prone to perforation, increasing the production risk. In view of the above problems, the existing equipment needs to be improved. Summary of the invention

[0004] The object of the present invention is to provide a nimodipine injection production equipment and process, so as to solve the problem that the liquid preparation equipment in the existing production equipment proposed in the above background technology, when in use, centrally transports the injection water, excipients and raw materials to the inside of the liquid preparation tank for stirring and mixing, resulting in poor dissolution of the raw materials, affecting the quality of the finished product, and the filter element is used for a long time during filtration, which makes the filter element prone to perforation, increasing the production risk.

[0005] To achieve the above-mentioned purpose, the present invention provides the following technical solutions: a nimodipine injection production equipment and process, including a liquid preparation device, a cleaning device and a filling and capping device,

[0006] The liquid dispensing device includes a liquid dispensing tank, and the outer side of the lower end of the liquid dispensing tank is connected to the inner side of the upper end of the frame, and the middle of the rear side of the frame is connected to the filter box through a mounting seat, a stirring assembly is arranged in the middle of the upper end of the liquid dispensing tank, and a feed head and a liquid inlet head are arranged on both sides of the upper end of the liquid dispensing tank, and a sampling head is arranged in the middle of the front of the liquid dispensing tank, the bottom of the lower end of the liquid dispensing tank is connected to the upper end of the filter box through an electromagnetic valve, and a pressure detector is arranged on one side of the top of the upper end of the filter box, and the front of the filter box is detachably connected to the filter assembly through a plurality of electromagnetic columns, the lower end of the filter box is connected to the first circulation pipe and the infusion pipe through a three-way valve, and the first circulation pipe is provided with a first circulation pump, and the other end of the first circulation pipe is connected to the upper end of one side of the filter box, the other end of the infusion pipe is connected to the bottom of the lower end of the liquid storage tank through a liquid suction pump, and the middle of the upper end of the liquid storage tank is connected to the first connecting pipe through a delivery pump;

[0007] The cleaning device includes a bottle washing device and a plug washing device, and the bottle washing device includes a large infusion ultrasonic rough washing machine and an auger-type bottle washing machine, which is convenient for cleaning the bottle body, and the plug washing device is used to continue cleaning the butyl rubber plug;

[0008] The filling and capping device includes a filling and stoppering machine, a large infusion bottle capping machine, a water bath sterilizer and a detection device, and the detection device includes a DJS100 / 500 light inspection line and an MFY-01 sealing tester, which are used for filling, sealing and sterilizing the liquid medicine and for finished product detection.

[0009] Preferably, the liquid preparation device adopts a segmented liquid preparation process, first adding water for injection, then adding auxiliary materials and finally adding raw materials, and each step is rinsed to allow the materials to be completely transferred to the liquid preparation tank.

[0010] Preferably, the filter assembly includes a vertical plate, a placement frame, a first filter element, a second filter element and a third filter element. The vertical plate is provided with a plurality of equally spaced plug-in holes, and the positions of the plug-in holes are arranged in a one-to-one correspondence with the positions of the electromagnetic columns. A handle is provided in the middle of the front side of the vertical plate, and a plurality of placement frames are provided equally spaced on the back side of the vertical plate, and the first filter element, the second filter element and the third filter element are respectively arranged on the placement frames. The first filter element, the second filter element and the third filter element are detachably connected to the corresponding placement frames.

[0011] Preferably, the first filter element, the second filter element and the third filter element are all 10-inch polyethersulfone microporous filter elements, and the pore size of the first filter element is 0.45 μm, while the pore size of the second filter element and the third filter element are both 0.22 μm.

[0012] Preferably, the first filter element, the second filter element and the third filter element are all single-use, so that the filter element is discarded after a single use to prevent filter element perforation, further reducing the production risk of nimodipine injection.

[0013] Preferably, the plug cleaning device includes a rinsing tank, and a liquid level meter is installed on the front side of the rinsing tank, and a second connecting pipe and a feeding port are respectively arranged on both sides of the upper end of the rinsing tank, a switch valve and a first filter are installed on the second connecting pipe, a second circulation pipe is arranged on one side of the rinsing tank, and a second filter and a second circulation pump are arranged on the second circulation pipe, and a drain valve and a discharge port are respectively arranged on both sides of the lower end of the rinsing tank, and a sealing plate is slidably connected in the middle of the discharge port.

[0014] Preferably, the first filter and the second filter are both polypropylene cartridge filters, and the pore sizes of the first filter and the second filter are both 0.22 μm.

[0015] A nimodipine injection production process comprises the following steps:

[0016] (I) Liquid preparation and filtration

[0017] Liquid preparation: Add the prescribed amount of polyethylene glycol 400 (for injection) and ethanol into the liquid preparation tank, turn on the preparation stirring (stirring speed is not less than 60 rpm, the same below) and turn it off after 5 minutes, add nimodipine (API) into the liquid preparation tank, stir for 25 minutes, add water for injection (below 40°C, the same below) to about 90% of the total preparation amount, stir in a cycle for 5 minutes, add anhydrous citric acid and sodium citrate, stir in a cycle for 5 minutes, add water for injection to the full amount, stir in a cycle for 10 minutes, and take samples to test the properties, pH and content of the intermediate product;

[0018] Filtration: After the intermediate product properties, pH and content are qualified, turn on the liquid medicine pump to circulate the liquid medicine back, so that the liquid medicine circulates through the liquid medicine system for more than 10 minutes. The liquid medicine adopts three-stage filtration: the first stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.45μm; the second stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm; the third stage filtration (terminal filtration) uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm;

[0019] The filter elements used in this product are all single-use, and the filtration pressure difference shall not exceed 0.2MPa. The filter element integrity check (bubble point method) shall be carried out before and after use. The critical value of the bubble point before and after filtration shall be ≥0.32MPa;

[0020] (ii) Bottle washing

[0021] Rough cleaning: put the bottles on the conveyor belt of the bottle storage platform, remove the unqualified products with obvious damage or cracks, the ultrasonic current value should be ≥2A, and the cleaning time should be ≥30s; turn on the conveyor belt of the bottle storage platform to keep the movement speed of the bottles within 80 bottles / minute;

[0022] Fine washing: After rough washing, the bottle body is sent to the clean area by the conveyor belt for fine washing by the auger-type bottle washing machine. Fine washing is divided into three levels of flushing: the first level is circulating water immersion, the second level is circulating water internal and external flushing, and the third level is injection water flushing. The pressure of the washing water shall not be less than 0.1MPa, the immersion time shall be ≥14s, the flushing times shall be 12 times, and the flushing time shall be 0.5s / time; visible foreign matter after cleaning shall meet the requirements;

[0023] (III) Washing the plug

[0024] Use a φ600 rinse tank for the plug washing process.

[0025] Pour the butyl rubber plugs to be cleaned into the rinsing tank, ≤ 15,000 per pot, and inject the injection water into the rinsing tank after the temperature drops to 40-60°C; when the water level in the rinsing tank is appropriate, close the injection water inlet valve, turn on the circulation pump, and keep the pressure of the filter after the pump not less than 0.1MPa, so that the butyl rubber plugs roll gently in the rinsing tank, rinse for 10 minutes, and drain. Repeat the above operation, continue rinsing for 2 times, take the washing water to check whether the visible foreign matter meets the regulations, and the visible foreign matter of the butyl rubber plugs after cleaning should meet the regulations;

[0026] (IV) Filling

[0027] Use KGSG01 / 01 filling and plugging machine to fill and plug the liquid, and drain the whole machine 3 times before filling (about 1200ml of liquid is discarded);

[0028] Adjust the filling machine to keep the filling volume stably at 51.0-55.0ml, with the target filling volume at 51.5ml; the filling machine speed should be within 80 bottles / minute, and the filling volume and visible foreign matter should be checked once every hour, which should meet the requirements;

[0029] (V) Capping

[0030] The SYZ(X)8 large infusion bottle capping machine is used for the capping process. The operating speed of the capping machine is within 80 bottles / minute, which matches the filling speed. The capping quality is checked every hour during the capping process. The seal should be firm and not loose after capping, and the appearance of the aluminum cap should meet the requirements;

[0031] Microbial limit test: 4 bottles of each batch of products are sampled at the end of capping for microbial limit test before sterilization; the acceptable standard is ≤100cfu / 100ml;

[0032] (VI) Sterilization

[0033] Use PSMSB-DC-4 water bath sterilizer for sterilization process, with common steam pressure of 0.3~0.5MPa and compressed air pressure of 0.4~0.8MPa;

[0034] Loading method: Full load, each sterilizer can be loaded with 4 vehicles, each vehicle is loaded with 6 layers, each layer is loaded with 495 bottles, each vehicle is loaded with 2970 bottles, and the maximum full load of each cabinet is 11880 bottles; when the actual batch exceeds the full load of the sterilizer, the excess samples will be destroyed and the destruction records will be kept; if it is not fully loaded, the same specification of nimodipine injection with distinguishing marks (aluminum caps of different colors) will be used as filling bottles;

[0035] Sterilization conditions: sterilization temperature 121℃, sterilization time 15 minutes, F0 value ≥15, out-of-cabinet temperature ≤65℃;

[0036] (VII) Light inspection and sealing test

[0037] Use DJS100 / 500 light inspection line for light inspection process, the illumination should be 2000~3000Lx, and remove white spots, white blocks, color spots, color blocks, glass scraps, fibers, turbidity, loose capping, all or part of the aluminum cap falling off, loose capping, insufficient filling, inferior bottles and other unqualified products during inspection;

[0038] Use MFY-01 sealing tester to check the sealing performance: randomly select products before, during and after the light inspection from each cabinet, and use the bubble release method (vacuum degree 67kPa, holding time 5 minutes) to check the sealing performance. Take 20 bottles each time, and take 60 bottles in total for each batch. No bottle shall be loosely sealed. If continuous bubbles are observed in the sample during the vacuum holding time (except for a small amount of interfering bubbles), it is judged as leakage.

[0039] (VIII) Packaging

[0040] Labeled, packed in carton, 1 piece per box.

[0041] Compared with the prior art, the invention has the following beneficial effects: the nimodipine injection production equipment and process,

[0042] (1) In order to solve the problems that the liquid preparation equipment in the existing production equipment, when in use, centrally transports the injection water, auxiliary materials and raw materials to the liquid preparation tank for stirring and mixing, resulting in poor dissolution of the raw materials, affecting the quality of the finished product, and the filter element is used for a long time during filtration, which makes the filter element prone to perforation, increasing the production risk, the present application adopts a segmented liquid preparation process, first adding injection water, then auxiliary materials and finally raw materials, and each step is rinsed to completely transfer the materials to the liquid preparation tank. At the same time, the filter element in the present application is disassembled and replaced after a single use, thereby avoiding filter element perforation and further reducing the production risk of nimodipine injection;

[0043] (2) In order to solve the problem that the existing production equipment has poor cleanliness during use, which affects the quality and safety of the product, the present application ensures the cleanliness of the bottle body and the butyl rubber stopper by rough washing and fine washing of the bottle body and rinsing of the butyl rubber stopper, controls the generation of visible foreign matter, insoluble particles, etc., and thus ensures the high quality of the preparation. At the same time, the method of controlling the microbial contamination level of the product after the capping process is completed is adopted to ensure that the product quality can be monitored under the worst conditions, thereby further ensuring the safety of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 It is a front view structural schematic diagram of the liquid dispensing device of the present invention;

[0045] Figure 2 This is a schematic diagram of the three-dimensional structure of the filter assembly of the present invention;

[0046] Figure 3This is a front view structural schematic diagram of the bottle washing device of the present invention;

[0047] Figure 4 This is a schematic diagram of the front view of the plug cleaning device of the present invention;

[0048] Figure 5 This is a working flow chart of the filling and capping device of the present invention;

[0049] Figure 6 It is a process flow chart of the present invention;

[0050] Figure 7 This is a diagram of the formula of nimodipine injection of the present invention.

[0051] In the figure: 1, liquid dispensing tank; 2, rack; 201, mounting seat; 3, stirring assembly; 4, feed head; 5, liquid inlet head; 6, sampling head; 7, solenoid valve; 8, filter box; 801, solenoid column; 9, pressure detector; 10, filter assembly; 1001, vertical plate; 1002, placing frame; 1003, first filter element; 1004, second filter element; 1005, third filter element; 1006, plug hole; 1007, handle; 11, three-way valve; 12, first circulation pipe; 13, first circulation pump; 14, infusion pipe; 15, liquid pump; 16, liquid storage tank; 17 , delivery pump; 18, first connecting pipe; 19, large infusion ultrasonic rough cleaning machine; 20, auger bottle washing machine; 21, rinsing tank; 2101, liquid level meter; 22, second connecting pipe; 23, switch valve; 24, first filter; 25, feeding port; 26, second circulation pipe; 27, second filter; 28, second circulation pump; 29, drain valve; 30, discharge port; 31, sealing plate; 32, filling and plugging machine; 33, large infusion bottle capping machine; 34, water bath sterilizer; 35, DJS100 / 500 light inspection line; 36, MFY-01 sealing tester. DETAILED DESCRIPTION

[0052] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0053] See also Figure 1-7 The present invention provides a technical solution: a nimodipine injection production equipment, according to Figure 1 , Figure 2 , Figure 6 and Figure 7As shown, the liquid dispensing device includes a liquid dispensing tank 1, and the outer side of the lower end of the liquid dispensing tank 1 is connected to the inner side of the upper end of the frame 2. The liquid dispensing tank 1 is a prior art, and its model is 1000L. At the same time, the middle of the rear side of the frame 2 is connected to the filter box 8 through a mounting seat 201. A stirring assembly 3 is arranged in the middle of the upper end of the liquid dispensing tank 1, and a feed head 4 and a liquid inlet head 5 are arranged on both sides of the upper end of the liquid dispensing tank 1. At the same time, a sampling head 6 is arranged in the middle of the front of the liquid dispensing tank 1. The bottom of the lower end of the liquid dispensing tank 1 is connected to the upper end of the filter box 8 through an electromagnetic valve 7, and a pressure detector 9 is arranged on one side of the top of the upper end of the filter box 8. The front of the filter box 8 is detachably connected to the filter assembly 10 through a plurality of electromagnetic columns 801. The filter assembly 10 includes a vertical plate 1001, a placement frame 1002, a first filter element 1003, a second filter element 1004 and a third filter element 1005. The vertical plate 1001 is provided with a plurality of plug holes 1006 at equal intervals, and the positions of the plug holes 1006 are arranged one by one corresponding to the positions of the electromagnetic columns 801. At the same time, a handle 1007 is arranged in the middle of the front of the vertical plate 1001, and a plurality of placement frames 1002 are arranged at equal intervals on the back of the vertical plate 1001, and the placement frames 1002 are arranged at equal intervals. The first filter element 1003, the second filter element 1004 and the third filter element 1005 are respectively arranged on the frame 1002, and the first filter element 1003, the second filter element 1004 and the third filter element 1005 are detachably connected to the corresponding placement frame 1002. The first filter element 1003, the second filter element 1004 and the third filter element 1005 are all 10-inch polyethersulfone microporous filter elements, and the pore size of the first filter element 1003 is 0.45μm, and the pore size of the second filter element 1004 and the third filter element 1005 are both 0.22μm. 04 and the third filter element 1005 are both single-use, so that the filter element is discarded after a single use to prevent filter element perforation, further reducing the production risk of nimodipine injection. The lower end of the filter box 8 is connected to the first circulation pipe 12 and the infusion pipe 14 through the three-way valve 11, and the first circulation pipe 12 is provided with a first circulation pump 13. At the same time, the other end of the first circulation pipe 12 is connected to the upper end of one side of the filter box 8, and the other end of the infusion pipe 14 is connected to the bottom of the lower end of the liquid storage tank 16 through the liquid pump 15, and the middle of the upper end of the liquid storage tank 16 is connected to the first connecting pipe 18 through the delivery pump 17.

[0054] To further explain, the liquid preparation device adopts a segmented liquid preparation process, first adding water for injection, then adding auxiliary materials and finally adding raw materials, and each step is rinsed to allow the materials to be completely transferred to the liquid preparation tank 1.

[0055] according to Figure 3 , Figure 4 and Figure 6As shown, the cleaning device includes a bottle washing device and a plug washing device, and the bottle washing device includes a large infusion ultrasonic rough washing machine 19 and an auger bottle washing machine 20, which are convenient for cleaning the bottle body. The large infusion ultrasonic rough washing machine 19 is a prior art, and its model is SQCL50 / 500. The auger bottle washing machine 20 is a prior art, and its model is CJP. At the same time, the plug washing device is used to continue to clean the butyl rubber plug. The plug washing device includes a rinsing tank 21, and a liquid level meter 2101 is installed on one side of the front of the rinsing tank 21. At the same time, second connecting The first filter 24 is provided with a first filter 28 and a second circulating pump 28. The first filter 24 and the second filter 27 are both polypropylene cartridge filter elements, and the pore sizes of the first filter 24 and the second filter 27 are both 0.22 μm. At the same time, a drain valve 29 and a discharge port 30 are respectively provided on both sides of the lower end of the rinsing tank 21, and a sealing plate 31 is slidably connected to the middle of the discharge port 30.

[0056] according to Figure 5 and Figure 6 As shown, the filling and capping device includes a filling and stoppering machine 32, a large infusion bottle capping machine 33, a water bath sterilizer 34 and a detection device. The filling and stoppering machine 32 is a prior art, and its model is KGSG01 / 01. The large infusion bottle capping machine 33 is a prior art, and its model is SYZ(X)8. The water bath sterilizer 34 is a prior art, and its model is PSMSB-DC-4. The detection device includes a DJS100 / 500 light inspection line 35 and a MFY-01 sealing tester 36, which are used for filling, sealing and sterilizing the liquid medicine and detecting the finished product.

[0057] A nimodipine injection production process comprises the following steps:

[0058] (I) Liquid preparation and filtration

[0059] Liquid preparation: Add the prescribed amount of polyethylene glycol 400 (for injection) and ethanol into the liquid preparation tank, turn on the preparation stirring (stirring speed is not less than 60 rpm, the same below) and turn it off after 5 minutes, add nimodipine (API) into the liquid preparation tank, stir for 25 minutes, add water for injection (below 40°C, the same below) to about 90% of the total preparation amount, stir in a cycle for 5 minutes, add anhydrous citric acid and sodium citrate, stir in a cycle for 5 minutes, add water for injection to the full amount, stir in a cycle for 10 minutes, and take samples to test the properties, pH and content of the intermediate product;

[0060] Filtration: After the intermediate product properties, pH and content are qualified, turn on the liquid medicine pump to circulate the liquid medicine back, so that the liquid medicine circulates through the liquid medicine system for more than 10 minutes. The liquid medicine adopts three-stage filtration: the first stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.45μm; the second stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm; the third stage filtration (terminal filtration) uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm;

[0061] The filter elements used in this product are all single-use, and the filtration pressure difference shall not exceed 0.2MPa. The filter element integrity check (bubble point method) shall be carried out before and after use. The critical value of the bubble point before and after filtration shall be ≥0.32MPa;

[0062] (ii) Bottle washing

[0063] Rough washing: put the bottle body on the conveyor belt of the bottle storage platform, remove the unqualified products with obvious damage or cracks, the ultrasonic current value should be ≥2A, and the cleaning time should be ≥30s; turn on the conveyor belt of the bottle storage platform to keep the movement speed of the bottle body within 80 bottles / minute; fine washing: the bottle body after rough washing is sent to the clean area auger-type bottle washing machine for fine washing by the conveyor belt. The fine washing is divided into three levels of flushing, the first level of circulating water immersion, the second level of circulating water internal and external flushing, and the third level of injection water flushing. The pressure of the washing water shall not be less than 0.1MPa, the immersion time shall be ≥14s, the number of flushing times shall be 12 times, and the flushing time shall be 0.5s / time; visible foreign matter after cleaning shall meet the requirements;

[0064] (III) Washing the plug

[0065] Use a φ600 rinse tank for the plug washing process.

[0066] Pour the butyl rubber plugs to be cleaned into the rinsing tank, ≤ 15,000 per pot, and inject the injection water into the rinsing tank after the temperature drops to 40-60°C; when the water level in the rinsing tank is appropriate, close the injection water inlet valve, turn on the circulation pump, and keep the pressure of the filter after the pump not less than 0.1MPa, so that the butyl rubber plugs roll gently in the rinsing tank, rinse for 10 minutes, and drain. Repeat the above operation, continue rinsing for 2 times, take the washing water to check whether the visible foreign matter meets the regulations, and the visible foreign matter of the butyl rubber plugs after cleaning should meet the regulations;

[0067] (IV) Filling

[0068] Use KGSG01 / 01 filling and plugging machine to fill and plug the liquid, and drain the whole machine 3 times before filling (about 1200ml of liquid is discarded);

[0069] Adjust the filling machine to keep the filling volume stably at 51.0-55.0ml, with the target filling volume at 51.5ml; the filling machine speed should be within 80 bottles / minute, and the filling volume and visible foreign matter should be checked once every hour, which should meet the requirements;

[0070] (V) Capping

[0071] The SYZ(X)8 large infusion bottle capping machine is used for the capping process. The operating speed of the capping machine is within 80 bottles / minute, which matches the filling speed. The capping quality is checked every hour during the capping process. The seal should be firm and not loose after capping, and the appearance of the aluminum cap should meet the requirements;

[0072] Microbial limit test: 4 bottles of each batch of products are sampled at the end of capping for microbial limit test before sterilization; the acceptable standard is ≤100cfu / 100ml;

[0073] (VI) Sterilization

[0074] Use PSMSB-DC-4 water bath sterilizer for sterilization process, with common steam pressure of 0.3~0.5MPa and compressed air pressure of 0.4~0.8MPa;

[0075] Loading method: Full load, each sterilizer can be loaded with 4 vehicles, each vehicle is loaded with 6 layers, each layer is loaded with 495 bottles, each vehicle is loaded with 2970 bottles, and the maximum full load of each cabinet is 11880 bottles; when the actual batch exceeds the full load of the sterilizer, the excess samples will be destroyed and the destruction records will be kept; if it is not fully loaded, the same specification of nimodipine injection with distinguishing marks (aluminum caps of different colors) will be used as filling bottles;

[0076] Sterilization conditions: sterilization temperature 121℃, sterilization time 15 minutes, F0 value ≥15, out-of-cabinet temperature ≤65℃;

[0077] (VII) Light inspection and sealing test

[0078] Use DJS100 / 500 light inspection line for light inspection process, the illumination should be 2000~3000Lx, and remove white spots, white blocks, color spots, color blocks, glass scraps, fibers, turbidity, loose capping, all or part of the aluminum cap falling off, loose capping, insufficient filling, inferior bottles and other unqualified products during inspection;

[0079] Use MFY-01 sealing tester to check the sealing performance: randomly select products before, during and after the light inspection from each cabinet, and use the bubble release method (vacuum degree 67kPa, holding time 5 minutes) to check the sealing performance. Take 20 bottles each time, and take 60 bottles in total for each batch. No bottle shall be loosely sealed. If continuous bubbles are observed in the sample during the vacuum holding time (except for a small amount of interfering bubbles), it is judged as leakage.

[0080] (VIII) Packaging

[0081] Labeled, packed in carton, 1 piece per box.

[0082] The directions or positional relationships indicated by terms such as "center", "longitudinal", "lateral", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" are based on the directions or positional relationships shown in the accompanying drawings. They are merely simplified descriptions for the convenience of describing the present invention, and do not indicate or imply that the devices or elements referred to must have a specific direction, be constructed and operated in a specific direction. Therefore, they should not be understood as limitations on the protection content of the present invention.

[0083] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A nimodipine injection production equipment, comprising a liquid preparation device, a cleaning device and a filling and capping device, characterized in that: The liquid dispensing device comprises a liquid dispensing tank (1), wherein the outer side of the lower end of the liquid dispensing tank (1) is connected to the inner side of the upper end of the frame (2), and the middle of the rear side of the frame (2) is connected to the filter box (8) through a mounting seat (201), a stirring assembly (3) is arranged in the middle of the upper end of the liquid dispensing tank (1), and a feed head (4) and a liquid feed head (5) are arranged on both sides of the upper end of the liquid dispensing tank (1), and a sampling head (6) is arranged in the middle of the front of the liquid dispensing tank (1), the bottom of the lower end of the liquid dispensing tank (1) is connected to the upper end of the filter box (8) through an electromagnetic valve (7), and a pressure detector (9) is arranged on one side of the top of the upper end of the filter box (8) , and the front of the filter box (8) is detachably connected to the filter assembly (10) through a plurality of electromagnetic columns (801); the lower end of the filter box (8) is connected to the first circulation pipe (12) and the liquid infusion pipe (14) through a three-way valve (11), and the first circulation pipe (12) is provided with a first circulation pump (13); and the other end of the first circulation pipe (12) is connected to the upper end of one side of the filter box (8); the other end of the liquid infusion pipe (14) is connected to the bottom of the lower end of the liquid storage box (16) through a liquid pump (15), and the middle of the upper end of the liquid storage box (16) is connected to the first connecting pipe (18) through a delivery pump (17); The cleaning device comprises a bottle washing device and a plug washing device, and the bottle washing device comprises a large infusion ultrasonic rough washing machine (19) and an auger-type bottle washing machine (20), which are convenient for cleaning the bottle body, and the plug washing device is used to continue cleaning the butyl rubber plug; The filling and capping device comprises a filling and capping integrated machine (32), a large infusion bottle capping machine (33), a water bath sterilizer (34) and a detection device, and the detection device comprises a DJS100 / 500 light inspection line (35) and a MFY-01 sealing tester (36), which are used for filling, sealing and sterilizing the liquid medicine and for finished product detection.

2. The nimodipine injection production equipment according to claim 1, characterized in that: The liquid preparation device adopts a segmented liquid preparation process, first adding injection water, then adding auxiliary materials and finally adding raw materials, and each step is rinsed to allow the materials to be completely transferred to the liquid preparation tank (1).

3. The nimodipine injection production equipment according to claim 1, characterized in that: The filter assembly (10) comprises a vertical plate (1001), a placement frame (1002), a first filter element (1003), a second filter element (1004) and a third filter element (1005); a plurality of plug holes (1006) are equidistantly provided on the vertical plate (1001), and the positions of the plug holes (1006) are arranged in a one-to-one correspondence with the positions of the electromagnetic columns (801); a handle (1007) is arranged in the middle of the front side of the vertical plate (1001); a plurality of placement frames (1002) are equidistantly provided on the back side of the vertical plate (1001), and the first filter element (1003), the second filter element (1004) and the third filter element (1005) are respectively arranged on the placement frames (1002); and the first filter element (1003), the second filter element (1004) and the third filter element (1005) are detachably connected to the corresponding placement frames (1002).

4. The nimodipine injection production equipment according to claim 3, characterized in that: The first filter element (1003), the second filter element (1004) and the third filter element (1005) are all 10-inch polyethersulfone microporous filter elements, and the pore size of the first filter element (1003) is 0.45 μm, while the pore size of the second filter element (1004) and the third filter element (1005) are both 0.22 μm.

5. The nimodipine injection production equipment according to claim 3, characterized in that: The first filter element (1003), the second filter element (1004) and the third filter element (1005) are all single-use, so that the filter elements are discarded after a single use to prevent filter element perforation, further reducing the production risk of nimodipine injection.

6. The nimodipine injection production equipment according to claim 1, characterized in that: The plug cleaning device comprises a rinsing tank (21), and a liquid level meter (2101) is installed on one side of the front of the rinsing tank (21), and a second connecting pipe (22) and a feeding port (25) are respectively arranged on both sides of the upper end of the rinsing tank (21), and a switch valve (23) and a first filter (24) are installed on the second connecting pipe (22), a second circulation pipe (26) is arranged on one side of the rinsing tank (21), and a second filter (27) and a second circulation pump (28) are arranged on the second circulation pipe (26), and a drain valve (29) and a discharge port (30) are respectively arranged on both sides of the lower end of the rinsing tank (21), and a sealing plate (31) is slidably connected in the middle of the discharge port (30).

7. The nimodipine injection production equipment according to claim 6, characterized in that: The first filter (24) and the second filter (27) are both polypropylene cartridge filters, and the pore sizes of the first filter (24) and the second filter (27) are both 0.22 μm.

8. A production process of nimodipine injection, characterized in that: The following steps are involved: (I) Liquid preparation and filtration Liquid preparation: Add the prescribed amount of polyethylene glycol 400 (for injection) and ethanol into the liquid preparation tank, turn on the preparation stirring (stirring speed is not less than 60 rpm, the same below) and turn it off after 5 minutes, add nimodipine (API) into the liquid preparation tank, stir for 25 minutes, add water for injection (below 40°C, the same below) to about 90% of the total preparation amount, stir in a cycle for 5 minutes, add anhydrous citric acid and sodium citrate, stir in a cycle for 5 minutes, add water for injection to the full amount, stir in a cycle for 10 minutes, and take samples to test the properties, pH and content of the intermediate product; Filtration: After the intermediate product properties, pH and content are qualified, start the liquid medicine pump to circulate the liquid medicine back, so that the liquid medicine circulates through the liquid medicine system for more than 10 minutes. The liquid medicine adopts three-stage filtration: the first stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.45μm; the second stage filtration uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm; The third stage filtration (terminal filtration) uses a 10-inch polyethersulfone microporous filter element with a pore size of 0.22μm; The filter elements used in this product are all single-use, and the filtration pressure difference shall not exceed 0.2MPa. The filter element integrity check (bubble point method) shall be carried out before and after use. The critical value of the bubble point before and after filtration shall be ≥0.32MPa; (ii) Bottle washing Rough cleaning: put the bottles on the conveyor belt of the bottle storage platform, remove the unqualified products with obvious damage or cracks, the ultrasonic current value should be ≥2A, and the cleaning time should be ≥30s; turn on the conveyor belt of the bottle storage platform to keep the movement speed of the bottles within 80 bottles / minute; Fine washing: After rough washing, the bottle body is sent to the clean area by the conveyor belt for fine washing by the auger-type bottle washing machine. Fine washing is divided into three levels of flushing: the first level is circulating water immersion, the second level is circulating water internal and external flushing, and the third level is injection water flushing. The pressure of the washing water shall not be less than 0.1MPa, the immersion time shall be ≥14s, the flushing times shall be 12 times, and the flushing time shall be 0.5s / time; visible foreign matter after cleaning shall meet the requirements; (III) Washing the plug Use φ600 rinsing tank for plug washing process; Pour the butyl rubber plugs to be cleaned into the rinsing tank, ≤ 15,000 per pot, and inject the injection water into the rinsing tank after the temperature drops to 40-60°C; when the water level in the rinsing tank is appropriate, close the injection water inlet valve, turn on the circulation pump, and keep the pressure of the filter after the pump not less than 0.1MPa, so that the butyl rubber plugs roll gently in the rinsing tank, rinse for 10 minutes, and drain. Repeat the above operation, continue rinsing for 2 times, take the washing water to check whether the visible foreign matter meets the regulations, and the visible foreign matter of the butyl rubber plugs after cleaning should meet the regulations; (IV) Filling Use KGSG01 / 01 filling and plugging machine to fill and plug the liquid, and drain the whole machine 3 times before filling (about 1200ml of liquid is discarded); Adjust the filling machine to keep the filling volume stably at 51.0-55.0ml, with the target filling volume at 51.5ml; the filling machine speed should be within 80 bottles / minute, and the filling volume and visible foreign matter should be checked once every hour, which should meet the requirements; (V) Capping The SYZ(X)8 large infusion bottle capping machine is used for the capping process. The operating speed of the capping machine is within 80 bottles / minute, which matches the filling speed. The capping quality is checked every hour during the capping process. The seal should be firm and not loose after capping, and the appearance of the aluminum cap should meet the requirements; Microbial limit test: 4 bottles of each batch of products are sampled at the end of capping for microbial limit test before sterilization; the acceptable standard is ≤100cfu / 100ml; (VI) Sterilization Use PSMSB-DC-4 water bath sterilizer for sterilization process, with common steam pressure of 0.3~0.5MPa and compressed air pressure of 0.4~0.8MPa; Loading method: Full load, each sterilizer can be loaded with 4 vehicles, each vehicle is loaded with 6 layers, each layer is loaded with 495 bottles, each vehicle is loaded with 2970 bottles, and the maximum full load of each cabinet is 11880 bottles; when the actual batch exceeds the full load of the sterilizer, the excess samples will be destroyed and the destruction records will be kept; if it is not fully loaded, the same specification of nimodipine injection with distinguishing marks (aluminum caps of different colors) will be used as filling bottles; Sterilization conditions: sterilization temperature 121℃, sterilization time 15 minutes, F0 value ≥15, out-of-cabinet temperature ≤65℃; (VII) Light inspection and sealing test Use DJS100 / 500 light inspection line for light inspection process, the illumination should be 2000~3000Lx, and remove white spots, white blocks, color spots, color blocks, glass scraps, fibers, turbidity, loose capping, all or part of the aluminum cap falling off, loose capping, insufficient filling, inferior bottles and other unqualified products during inspection; Use MFY-01 sealing tester to check the sealing performance: randomly select products before, during and after the light inspection from each cabinet, and use the bubble release method (vacuum degree 67kPa, holding time 5 minutes) to check the sealing performance. Take 20 bottles each time, and take 60 bottles in total for each batch. No bottle shall be loosely sealed. If continuous bubbles are observed in the sample during the vacuum holding time (except for a small amount of interfering bubbles), it is judged as leakage. (VIII) Packaging Labeled, packed in carton, 1 piece per box.

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