Famotidine injection production device and production processing technology thereof

Abstract

The invention discloses a famotidine injection production device which comprises a liquid preparation device, a cleaning device and a detection labeling device, the liquid preparation device comprises a lactic acid treatment assembly, and a material tank arranged in the lactic acid treatment assembly is connected with a placement rack; the bottom of the lower end of the material containing tank penetrates through the vertical pressure steam sterilization cabinet through a treatment bottle and is connected with one end of a first conveying pipe, and the first conveying pipe is connected with a diluting tank. According to the production device for the motidine injection, a swing motor drives a driving gear, a driven gear and a fixing frame to swing back and forth, lactic acid in a material containing tank and water for injection are shaken up, and then the evenly-shaken lactic acid is conveyed into a treatment bottle and heated through a vertical pressure steam sterilization cabinet; the problem of polymers in lactic acid is solved in a heat treatment mode, the content of lactic acid in a finished product is ensured, meanwhile, before liquid preparation, nitrogen charging, discharging and nitrogen charging are conducted on all tanks and pipelines in front of a terminal filter element, dissolved oxygen control over liquid medicine is facilitated, and then the high quality of the finished product is ensured.

Description

Technical Field

[0001] The invention relates to the technical field related to the production of famotidine injection, and in particular to a famotidine injection production device and a production and processing technology thereof. Background Art

[0002] Famotidine injection is a chemical drug injection with famotidine as the active ingredient. Famotidine is a histamine-2 receptor antagonist that can effectively inhibit gastric acid secretion and pepsin secretion. Clinically, this product is often used to treat patients with peptic ulcer complicated by upper gastrointestinal bleeding, or gastric and duodenal mucosal erosion and bleeding, when gastric acid secretion must be reduced and patients are not suitable for oral administration. Certain equipment is required in the production process of famotidine injection, such as liquid preparation equipment, cleaning and drying equipment, filling equipment and detection equipment, etc. The above equipment is collectively referred to as production equipment.

[0003] When the existing production equipment is in use, the problem of polymers in lactic acid is not solved, the lactic acid content in the finished product cannot be ensured, and the dissolved oxygen in the liquid medicine is not controlled, thus affecting the quality of the finished product. To address 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 famotidine injection production device and its production and processing technology, so as to solve the problem that the existing production device proposed in the above background technology does not solve the problem of polymer in lactic acid when in use, cannot ensure the lactic acid content in the finished product, and does not control the dissolved oxygen in the drug solution, thereby affecting the quality of the finished product.

[0005] To achieve the above-mentioned purpose, the present invention provides the following technical solutions: a famotidine injection production device and a production process thereof, comprising a liquid preparation device, a cleaning device and a detection and labeling device,

[0006] The liquid dispensing device comprises a lactic acid processing component, a nitrogen storage tank, a configuration device and a dilution tank, and the lactic acid processing component and the dilution tank are installed at the upper end of the base, and the lactic acid processing component comprises a material placement tank, the material placement tank is connected to the placement rack, and the bottom of the lower end of the material placement tank passes through the interior of the vertical pressure steam sterilizer through the processing bottle and is connected to one end of the first conveying pipe, the other end of the first conveying pipe passes through one side of the vertical pressure steam sterilizer and is connected to the dilution tank, and a cooling fan is installed on the other side of the vertical pressure steam sterilizer, the nitrogen storage tank and the configuration device are installed on the upper end of the placement top plate, and one side of the lower end of the placement top plate is connected to the upper end of one side of the placement rack, and the other side of the lower end of the placement top plate is connected to the upper end of the base through a supporting vertical plate, a concentrated preparation tank is arranged at the rear side of the dilution tank, and the dilution tank is connected to the filter pressure box through the third conveying pipe away from the lactic acid processing component, and the other side of the filter pressure box is connected to the liquid dispenser arranged inside the ampoule filling machine;

[0007] The cleaning device includes a vertical ultrasonic cleaning machine and a tunnel-type sterilizing and drying machine, which is convenient for cleaning, sterilizing and drying the ampoule bottles;

[0008] The detection and labeling device includes a fully automatic ampoule light detection and leak detection integrated machine and a round bottle labeling machine & automatic tray loading machine, which are used to detect the sealing of the ampoule bottle after filling and label and package it.

[0009] Preferably, the placing frame includes a fixed frame, and the middle of the fixed frame is detachably connected to the outer side of the material storage tank, and corresponding positioning bearings are passed through both sides of the fixed frame and are connected to corresponding support frames, the lower end of the support frame is connected to the upper end of the placing seat, and the placing seat is placed on the upper end of the vertical pressure steam sterilizer, a driven gear is provided at the outer end of one side of the fixed frame, and the lower end of the driven gear is meshed and connected with a driving gear, and the driving gear is connected to the output end of the swing motor.

[0010] Preferably, the front of the nitrogen storage tank is connected to the material tank, the first conveying pipe, the configuration device, the dilute tank, the concentrated tank and the third conveying pipe through pipelines, and the material tank, the first conveying pipe, the configuration device, the dilute tank, the concentrated tank and the third conveying pipe are connected to the back of the storage tank through pipelines.

[0011] Preferably, the configuration device comprises a configuration box, a first stirring assembly and a second conveying pipe, and the first stirring assembly is arranged inside the configuration box, and the lower end of one side of the configuration box is connected to the dilution tank through the second conveying pipe.

[0012] Preferably, a first liquid inlet is provided on one side of the front of the dilution tank, and a first nitrogen inlet is provided on the other side of the upper end of the dilution tank, and a sampling tube is provided at the lower end of the front of the dilution tank, a sampling pump is installed on the sampling tube, and the other end of the sampling tube is connected to a detection device provided at the upper end of the base, a second stirring assembly is provided inside the dilution tank, and the second stirring assembly is connected to the first stirring assembly through a driving assembly, and the second stirring assembly and the first stirring assembly have the same structure.

[0013] Preferably, a second liquid inlet is provided on one side of the back of the concentrated preparation tank, and an electric heater is provided in the middle of the back of the concentrated preparation tank, and a temperature detector is provided on the back of the concentrated preparation tank above the electric heater, a second nitrogen inlet is provided on one side of the upper end of the concentrated preparation tank, and a second delivery pipe provided on one side of the upper end of the concentrated preparation tank is connected to a first delivery pipe provided on one side of the upper end of the dilute preparation tank through a delivery pump.

[0014] Preferably, a plurality of filter elements are arranged inside the filter pressure box, and the filter elements are 0.45 μm polyethersulfone filter elements and 0.22 μm polyethersulfone filter elements.

[0015] 8. A production and processing technology of famotidine injection, comprising the following steps:

[0016] 1. Liquid preparation and filtration

[0017] (1) Lactic acid pretreatment:

[0018] Preparation of 10% lactic acid: Calculate according to 100,000 ml batch, weigh 0.35 kg lactic acid, add water for injection to 3.5 kg, shake well, place in a vertical pressure steam sterilizer, treat at 121°C for 2 hours, and cool to room temperature;

[0019] (2) Weighing and preparing materials:

[0020] Weigh famotidine, niacinamide, vitamin C, and mannitol according to the prescribed amount for later use;

[0021] (3) Preparation:

[0022] Preparation of pH adjuster (4% sodium hydroxide solution): weigh 0.132 kg of sodium hydroxide, add 3.168 kg of water for injection, stir to dissolve, and set aside;

[0023] A. First, fill the tanks and pipelines in front of the terminal filter element with nitrogen to a pressure of about 0.15MPa, discharge, refill with nitrogen, and discharge again. This operation is repeated three times in total and then sealed. Fill the terminal filter element, silicone tube, and liquid distributor with nitrogen for about 10 minutes and seal.

[0024] B. Add water for injection above 60℃ (more than 100L) to the concentrated preparation tank, fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, reduce the temperature of the water for injection to 20℃~30℃ and then introduce it into the diluted preparation tank, add about 80L (about 80kg) of water for injection of 80% of the prescription volume to the diluted preparation tank; start the tank stirring, set the speed to 45Hz, and fill with nitrogen until the dissolved oxygen is ≤0.2mg / L;

[0025] C. Add 10% lactic acid solution, niacinamide, mannitol, vitamin C, and famotidine in the prescribed amount, and stir until the mixture is uniformly mixed;

[0026] D. Use 4% sodium hydroxide solution to adjust the pH to between 6.0 and 6.1;

[0027] Use injection water to make the volume to 100L, pass through a 0.45μm (5-inch) polyethersulfone filter element and a 0.22μm (5-inch) polyethersulfone filter element, fill with nitrogen and stir in a cycle, take samples every 10 minutes for intermediate product testing (properties, pH value, vitamin C, content), continue to fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, and then maintain nitrogen pressure in the dilution tank;

[0028] (4) Filter press

[0029] After the intermediate product is qualified, adjust the nitrogen valve on the dilution tank to control the pressure not to exceed 0.30MPa. The liquid is filtered through a 0.45μm polyethersulfone filter element (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0045HSF05SP, size: 5 inches) and two 0.22μm polyethersulfone filter elements (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0022HSCG05SP, size: 5 inches) to the dispenser of the filling machine. The filtration temperature range is 20-30℃, the pressure difference between upstream and downstream of the filtration is ≤0.2Mpa, the filtration speed is 20-50L / h, and the filtration time is not more than 10 hours. Before the end of production, take samples from the 0.45μm filter element for microbial contamination level inspection, and the microbial limit is ≤10cfu / 100ml;

[0030] The integrity test of 0.22μm polyethersulfone filter element is carried out before and after filtration. The critical value of the bubble point before and after filtration should be ≥0.32MPa (the wetting medium is water for injection). 0.45μm and 0.22μm filter elements shall not be reused after being used once. The pressure difference between upstream and downstream of filtration is ≤0.2MPa.

[0031] 2. Wash and dry the bottle

[0032] Set circulating water pressure: ≥0.2MPa; fine washing water (injection water) pressure: ≥0.20MPa; compressed air pressure: ≥0.30MPa; ultrasonic power: ≥300W, high temperature section temperature of the oven during high temperature sterilization of ampoules: ≥300℃, sterilization time: ≥10min; mesh belt speed ≤250mm / min; the cleanliness level of the sterilized ampoules should be exposed under a Class A laminar flow hood, and the effective storage time limit for ampoule sterilization is 2 hours;

[0033] 3. Filling

[0034] The potting process and liquid filtration device are carried out in a Class A laminar flow hood;

[0035] Adjust the filling volume (target filling volume: 2.15 ml, the filling volume range is controlled within the range of 2.10-2.20 ml), and the headspace residual oxygen content is less than 0.7%;

[0036] The filling machine should discharge no less than 2L of liquid before formal filling, and filling should start after the product filling volume and residual oxygen content are qualified;

[0037] Check dissolved oxygen and headspace residual oxygen once at the beginning, middle and end of filling. Dissolved oxygen ≤ 0.5 mg / L, headspace residual oxygen < 0.7%. Filling speed is about 27,000 bottles / hour, and the yield of filling process is ≥ 75%;

[0038] 4. Light inspection and sealing test

[0039] The parameters of the light inspection machine are as follows: high voltage setting is 19KV, leakage upper limit is 1.7V. Before using the light inspection machine, 20 positive bottles (5 bottles for each of the 4 parts), 20 defective bottles (5 bottles for each of the filling amount, white spots, fibers, and glass chips) and 10 negative bottles need to be randomly placed on the bottle feeding dial wheel. All positive bottles need to enter the leakage defective product channel, all negative bottles need to enter the qualified product channel, and all defective bottles need to enter the foreign body defective product channel. In this way, the stability of the equipment is confirmed, and the parameters are adjusted according to the light inspection test results. Those that exceed the parameter setting range are rejected. After the foreign body defective products of the machine inspection are inspected once, they need to be manually re-inspected twice, with an illumination of 1000~1500lx. The qualified products of the two re-inspections can be put into the qualified products of this batch, and the unqualified products of the re-inspection are directly destroyed;

[0040] The high-voltage charge method is used to conduct online leak detection of the sealing integrity of packaging materials during the production process. The online leak detection sensitivity is 3μm, and products that exceed the leakage voltage threshold will be rejected;

[0041] 5. Packaging

[0042] 2ml / tube, 10 tubes / box, packaged, stored.

[0043] Compared with the prior art, the beneficial effects of the present invention are: the famotidine injection production device and its production and processing technology,

[0044] (1) In order to solve the problem that the existing production device does not solve the polymer problem in lactic acid when in use, cannot ensure the lactic acid content in the finished product, and does not control the dissolved oxygen of the drug solution, thereby affecting the quality of the finished product, the present application drives the driving gear, the driven gear and the fixed frame to swing back and forth by a swing motor, so as to facilitate the shaking of the lactic acid and the injection water in the material tank, and then transports the shaken lactic acid to the inside of the treatment bottle and heats it in a vertical pressure steam sterilizer. The problem of polymer in lactic acid is solved by heat treatment, and the lactic acid content in the finished product is ensured. At the same time, before the liquid is prepared, the operations of nitrogen filling, discharge and nitrogen filling of each tank and pipeline in front of the terminal filter element are beneficial to the dissolved oxygen control of the drug solution, thereby ensuring the high quality of the finished product.

[0045] (2) In order to solve the problem that in the existing production equipment, during the production process, the drug solution is directly extracted and sampled for testing. When it comes into contact with the air, the oxygen in the air will oxidize the vitamin C, which in turn leads to inaccurate test results and poor use effects, the present application uses a sampling tube and a sampling pump to directly transport the drug solution in the dilution tank to the inside of the detection device, thereby avoiding contact between the drug solution and the air during sampling, so that the oxygen in the air will not oxidize the vitamin C, thereby improving the accuracy of the test results. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1It is a front view structural schematic diagram of the liquid dispensing device of the present invention;

[0047] Figure 2 It is a rear view structural schematic diagram of the liquid dispensing device of the present invention;

[0048] Figure 3 It is a front view structural schematic diagram of the lactic acid treatment component of the present invention;

[0049] Figure 4 This is a schematic diagram of the front view structure of the configuration device and the dilution tank of the present invention;

[0050] Figure 5 This is a schematic diagram of the rear view structure of the concentrated preparation tank of the present invention;

[0051] Figure 6 This is a filling production flow chart of the present invention;

[0052] Figure 7 This is a production process flow chart of the present invention;

[0053] Figure 8 The famotidine injection formula of the present invention is:

[0054] Fig. 9 This is the quality standard table of famotidine injection of the present invention;

[0055] Fig.10 This is the quality standard table of famotidine injection of the present invention;

[0056] Fig.11 This is the quality standard table of famotidine injection of the present invention;

[0057] Fig.12 This is the quality standard table of famotidine injection of the present invention.

[0058] In the figure: 1. base; 2. lactic acid treatment component; 201. material storage tank; 202. fixing frame; 203. positioning bearing; 204. support frame; 205. placement seat; 206. driven gear; 207. driving gear; 208. swing motor; 209. treatment bottle; 210. vertical pressure steam sterilizer; 211. first conveying pipe; 212. cooling fan; 3. placement top plate; 4. support vertical plate; 5. nitrogen storage tank; 6. configuration device; 601. configuration box; 602. first stirring component; 603. second conveying pipe; 7. dilution tank; 701. first liquid inlet; 702. first Nitrogen inlet; 703, first delivery pipe; 704, sampling tube; 705, sampling pump; 706, second stirring assembly; 707, driving assembly; 8, concentration tank; 801, second liquid inlet; 802, electric heater; 803, temperature detector; 804, second nitrogen inlet; 805, delivery pump; 806, second delivery pipe; 9, detection device; 10, third delivery pipe; 11, filter press box; 12, ampoule filling machine; 13, ampoule bottle; 14, vertical ultrasonic cleaning machine; 15, tunnel type sterilization and drying machine; 16, fully automatic ampoule light inspection and leak detection machine; 17, round bottle labeling machine & automatic tray loading machine. DETAILED DESCRIPTION

[0059] 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.

[0060] See also Figure 1-12 The present invention provides a technical solution: a famotidine injection production device, according to Figure 1 , Figure 2 , Figure 3 , Figure 7 and Figure 8As shown, the liquid preparation device includes a lactic acid processing component 2, a nitrogen storage tank 5, a preparation device 6 and a dilution tank 7, and the lactic acid processing component 2 and the dilution tank 7 are installed on the upper end of the base 1, and the lactic acid processing component 2 includes a material placement tank 201, and the material placement tank 201 is connected to the placement rack, and the placement rack includes a fixed frame 202, and the middle of the fixed frame 202 is detachably connected to the outer side of the material placement tank 201, and at the same time, the two sides of the fixed frame 202 penetrate the corresponding positioning bearings 203 and are connected to the corresponding support frame 204, the lower end of the support frame 204 is connected to the upper end of the placement seat 205, and the placement seat 205 is placed on the upper end of the vertical pressure steam sterilizer 210, and the outer end of one side of the fixed frame 202 is provided with a driven gear The driven gear 206 is meshed with a driving gear 207 at the lower end thereof, and the driving gear 207 is connected to the output end of the swing motor 208. The bottom of the lower end of the material storage tank 201 passes through the processing bottle 209 and penetrates the interior of the vertical pressure steam sterilizer 210 to be connected to one end of the first conveying pipe 211. The other end of the first conveying pipe 211 passes through one side of the vertical pressure steam sterilizer 210 and is connected to the dilution tank 7. A cooling fan 212 is installed on the other side of the vertical pressure steam sterilizer 210. Through the cooling fan 212, the vertical pressure steam sterilizer 210 can quickly cool down the lactic acid inside the processing bottle 209 after the processing is completed, thereby shortening the processing time and improving the processing efficiency.

[0061] according to Figure 1 , Figure 2 , Figure 4 , Figure 7 and Figure 8As shown, the nitrogen storage tank 5 and the configuration device 6 are installed on the upper end of the placement top plate 3, and the front of the nitrogen storage tank 5 is connected to the material tank 201, the first conveying pipe 211, the configuration device 6, the dilute tank 7, the concentrated tank 8 and the third conveying pipe 10 through a pipeline, and the material tank 201, the first conveying pipe 211, the configuration device 6, the dilute tank 7, the concentrated tank 8 and the third conveying pipe 10 are connected to the back of the storage tank 5 through a pipeline, and one side of the lower end of the placement top plate 3 is connected to the upper end of one side of the placement frame, and the configuration device 6 includes a configuration box 601, a first stirring component 602 and a second conveying pipe 603, and the configuration box 601 is provided with a first stirring component 602, and at the same time, the lower end of one side of the configuration box 601 is connected to the dilute tank 7 through the second conveying pipe 603, and at the same time, the other side of the lower end of the placement top plate 3 is connected to the base 1 through the support vertical plate 4. The upper end is connected, a first liquid inlet 701 is provided on one side of the front of the dilution tank 7, and a first nitrogen inlet 702 is provided on the other side of the upper end of the dilution tank 7, and a sampling tube 704 is provided at the lower end of the front of the dilution tank 7, a sampling pump 705 is installed on the sampling tube 704, and the other end of the sampling tube 704 is connected to the detection device 9 provided at the upper end of the base 1, a second stirring component 706 is provided inside the dilution tank 7, and the second stirring component 706 is connected to the first stirring component 602 through a driving component 707, and the second stirring component 706 and the first stirring component 602 have the same structure, and the first stirring component 602 and the second stirring component 706 are driven by the driving component 707 to rotate simultaneously, so as to facilitate the configuration of the 4% sodium hydroxide solution in the configuration device 6 and the uniform mixing of the product materials inside the dilution tank 7.

[0062] according to Figure 1 , Figure 2 and Figure 5 As shown, a concentrated preparation tank 8 is arranged at the rear side of the dilute preparation tank 7, a second liquid inlet 801 is arranged on one side of the back of the concentrated preparation tank 8, and an electric heater 802 is arranged in the middle of the back of the concentrated preparation tank 8, and a temperature detector 803 is arranged on the back of the concentrated preparation tank 8 above the electric heater 802, a second nitrogen inlet 804 is arranged on one side of the upper end of the concentrated preparation tank 8, and a second delivery pipe 806 arranged on one side of the upper end of the concentrated preparation tank 8 is connected with the first delivery pipe 703 arranged on one side of the upper end of the dilute preparation tank 7 through a delivery pump 805, and the side of the dilute preparation tank 7 away from the lactic acid treatment component 2 is connected with the filter pressure box 11 through the third delivery pipe 10, a plurality of filter elements are arranged inside the filter pressure box 11, and the filter elements are 0.45μm polyethersulfone filter elements and 0.22μm polyethersulfone filter elements, and the other side of the filter pressure box 11 is connected to a liquid dispenser arranged inside the ampoule filling machine 12.

[0063] according to Figure 6 and Figure 7As shown, the cleaning device includes a vertical ultrasonic cleaning machine 14 and a tunnel-type sterilizing and drying machine 15, which are convenient for cleaning, sterilizing and drying the ampoule bottle 13. The vertical ultrasonic cleaning machine 14 and the tunnel-type sterilizing and drying machine 15 are both prior arts. The model of the vertical ultrasonic cleaning machine 14 is AQCL28 / 4, and the model of the tunnel-type sterilizing and drying machine 15 is KSZ620 / 75B. The detection and labeling device includes a fully automatic ampoule light detection and leak detection all-in-one machine 16 and a round bottle labeling machine & automatic tray loading machine 17, which are used to detect the sealing of the ampoule bottle 13 after filling and label and package it. The fully automatic ampoule light detection and leak detection all-in-one machine 16 and the round bottle labeling machine & automatic tray loading machine 17 are both prior arts. The model of the fully automatic ampoule light detection and leak detection all-in-one machine 16 is JAYL-600, and the model of the round bottle labeling machine & automatic tray loading machine 17 is A205 & RH01.

[0064] A production and processing technology of famotidine injection comprises the following steps:

[0065] 1. Liquid preparation and filtration

[0066] (1) Lactic acid pretreatment:

[0067] Preparation of 10% lactic acid: Calculate according to 100,000 ml batch, weigh 0.35 kg lactic acid, add water for injection to 3.5 kg, shake well, place in a vertical pressure steam sterilizer, treat at 121°C for 2 hours, cool to room temperature, and solve the polymer problem in lactic acid by heat treatment to ensure the lactic acid content in the finished product;

[0068] (2) Weighing and preparing materials:

[0069] Weigh famotidine, niacinamide, vitamin C, and mannitol according to the prescribed amount for later use;

[0070] (3) Preparation:

[0071] Preparation of pH adjuster (4% sodium hydroxide solution): weigh 0.132 kg of sodium hydroxide, add 3.168 kg of water for injection, stir to dissolve, and set aside;

[0072] A. First, fill each tank and pipeline in front of the terminal filter element with nitrogen, with a pressure of about 0.15MPa, discharge, refill with nitrogen, and discharge again, for a total of 3 times, and seal; fill the terminal filter element, silicone tube, and liquid distributor with nitrogen for about 10 minutes, and seal. Through this operation mode, before the formal liquid preparation, the operation of filling, discharging, and refilling nitrogen in each tank and pipeline in front of the terminal filter element is beneficial to the dissolved oxygen control of the liquid, thereby ensuring the high quality of the finished product;

[0073] B. Add water for injection above 60℃ (more than 100L) to the concentrated preparation tank, fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, reduce the temperature of the water for injection to 20℃~30℃ and then introduce it into the diluted preparation tank, add about 80L (about 80kg) of water for injection of 80% of the prescription volume to the diluted preparation tank; start the tank stirring, set the speed to 45Hz, and fill with nitrogen until the dissolved oxygen is ≤0.2mg / L;

[0074] C. Add 10% lactic acid solution, niacinamide, mannitol, vitamin C, and famotidine in the prescribed amount, and stir until the mixture is uniformly mixed;

[0075] D. Use 4% sodium hydroxide solution to adjust the pH to between 6.0 and 6.1;

[0076] Use water for injection to make the volume to 100L, pass through a 0.45μm (5-inch) polyethersulfone filter element and a 0.22μm (5-inch) polyethersulfone filter element, fill with nitrogen and stir in a cycle, take samples every 10 minutes for intermediate product testing (properties, pH value, vitamin C, content), continue to fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, then maintain nitrogen pressure in the dilution tank, add water for injection, then add auxiliary materials and finally raw materials, and rinse each step to ensure that the materials are completely transferred to the liquid preparation tank;

[0077] (4) Filter press

[0078] After the intermediate product is qualified, adjust the nitrogen valve on the dilution tank to control the pressure not to exceed 0.30MPa. The liquid is filtered through a 0.45μm polyethersulfone filter element (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0045HSF05SP, size: 5 inches) and two 0.22μm polyethersulfone filter elements (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0022HSCG05SP, size: 5 inches) to the dispenser of the filling machine. The filtration temperature range is 20-30℃, the pressure difference between upstream and downstream of the filtration is ≤0.2Mpa, the filtration speed is 20-50L / h, and the filtration time is not more than 10 hours. Before the end of production, take samples from the 0.45μm filter element for microbial contamination level inspection, and the microbial limit is ≤10cfu / 100ml;

[0079] Conduct integrity tests on 0.22μm polyethersulfone filter elements before and after filtration. The critical value of the bubble point before and after filtration should be ≥0.32MPa (the wetting medium is water for injection). 0.45μm and 0.22μm filter elements should not be reused after one use. The pressure difference between upstream and downstream of the filtration should be ≤0.2MPa. Discarding the filter element after a single use can prevent filter element perforation and further reduce the production risk of famotidine injection.

[0080] 2. Wash and dry the bottle

[0081] Set circulating water pressure: ≥0.2MPa; fine washing water (injection water) pressure: ≥0.20MPa; compressed air pressure: ≥0.30MPa; ultrasonic power: ≥300W, high temperature section temperature of the oven during high temperature sterilization of ampoules: ≥300℃, sterilization time: ≥10min; mesh belt speed ≤250mm / min; the cleanliness level of the sterilized ampoules should be exposed under a Class A laminar flow hood, and the effective storage time limit for ampoule sterilization is 2 hours;

[0082] Strictly follow the bottle washing procedures to ensure the cleanliness of the ampoules and control the generation of visible foreign matter and insoluble particles, thereby ensuring the high quality of the preparation.

[0083] 3. Filling

[0084] The potting process and liquid filtration device are carried out in a Class A laminar flow hood;

[0085] Adjust the filling volume (target filling volume: 2.15 ml, the filling volume range is controlled within the range of 2.10-2.20 ml), and the headspace residual oxygen content is less than 0.7%;

[0086] The filling machine should discharge no less than 2L of liquid before formal filling, and filling should start after the product filling volume and residual oxygen content are qualified;

[0087] Check dissolved oxygen and headspace residual oxygen once at the beginning, middle and end of filling. Dissolved oxygen ≤ 0.5 mg / L, headspace residual oxygen < 0.7%. Filling speed is about 27,000 bottles / hour, and the yield of filling process is ≥ 75%;

[0088] Strictly control the product filling volume and residual oxygen content in accordance with the requirements of the reference preparation to ensure the quality consistency of the generic preparation.

[0089] 4. Light inspection and sealing test

[0090] The parameters of the light inspection machine are as follows: high voltage setting is 19KV, leakage upper limit is 1.7V. Before using the light inspection machine, 20 positive bottles (5 bottles for each of the 4 parts), 20 defective bottles (5 bottles for each of the filling amount, white spots, fibers, and glass chips) and 10 negative bottles need to be randomly placed on the bottle feeding dial wheel. All positive bottles need to enter the leakage defective product channel, all negative bottles need to enter the qualified product channel, and all defective bottles need to enter the foreign body defective product channel. In this way, the stability of the equipment is confirmed, and the parameters are adjusted according to the light inspection test results. Those that exceed the parameter setting range are rejected. After the foreign body defective products of the machine inspection are inspected once, they need to be manually re-inspected twice, with an illumination of 1000~1500lx. The qualified products of the two re-inspections can be put into the qualified products of this batch, and the unqualified products of the re-inspection are directly destroyed;

[0091] The high-voltage charge method is used to conduct online leak detection of the sealing integrity of packaging materials during the production process. The online leak detection sensitivity is 3μm, and products that exceed the leakage voltage threshold will be rejected;

[0092] 5. Packaging

[0093] 2ml / tube, 10 tubes / box, packaged, stored.

[0094] according to Fig. 9 , Fig.10 , Fig.11 and Fig.12 As shown in the figure, the shelf life standard of famotidine injection is formulated with reference to the standards of various countries. The most stringent control requirements are adopted for each item of the quality standard, such as strict control on properties and appearance, which puts forward higher requirements on the quality of the drug solution; the control limits of related substances are tightened with reference to the most stringent standards of each sub-item, and the product quality is strictly controlled, thereby improving the safety of product quality within the validity period; in addition, on the basis of the shelf life quality standard of famotidine injection, the product release standard is further formulated, and the solution color, the limits of related substance inspection items and the content limits are tightened, and stricter standards are put forward for the control of drug solution quality, thereby further ensuring the safety of drug use.

[0095] 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.

[0096] 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 famotidine injection production device, comprising a liquid preparation device, a cleaning device and a detection and labeling device, characterized in that: The liquid preparation device comprises a lactic acid treatment component (2), a nitrogen storage tank (5), a preparation device (6) and a dilution preparation tank (7), and the lactic acid treatment component (2) and the dilution preparation tank (7) are installed on the upper end of the base (1), and the lactic acid treatment component (2) comprises a material placement tank (201), the material placement tank (201) is connected to the placement rack, and the bottom of the lower end of the material placement tank (201) passes through the interior of the vertical pressure steam sterilizer (210) through a treatment bottle (209) and is connected to one end of a first conveying pipe (211), and the other end of the first conveying pipe (211) passes through one side of the vertical pressure steam sterilizer (210) and is connected to the dilution preparation tank (7), and the vertical pressure steam sterilizer (210) is connected to the dilution preparation tank (7). A cooling fan (212) is installed on the other side of the pressure steam sterilizer (210), the nitrogen storage tank (5) and the configuration device (6) are installed on the upper end of the placement top plate (3), and one side of the lower end of the placement top plate (3) is connected to the upper end of one side of the placement frame, and the other side of the lower end of the placement top plate (3) is connected to the upper end of the base (1) through a supporting vertical plate (4), a concentrated preparation tank (8) is arranged on the rear side of the dilution preparation tank (7), and the side of the dilution preparation tank (7) away from the lactic acid treatment component (2) is connected to the filter pressure box (11) through a third transmission pipe (10), and the other side of the filter pressure box (11) is connected to a liquid distributor arranged inside the ampoule filling machine (12); The cleaning device comprises a vertical ultrasonic cleaning machine (14) and a tunnel-type sterilizing and drying machine (15), which is convenient for cleaning, sterilizing and drying the ampoule bottle (13); The detection and labeling device comprises a fully automatic ampoule light detection and leak detection integrated machine (16) and a round bottle labeling machine & automatic tray loading machine (17), which are used to detect the sealing of the ampoule bottle (13) after filling and to label and package it.

2. The famotidine injection production device according to claim 1, characterized in that: The placing frame comprises a fixed frame (202), and the middle of the fixed frame (202) is detachably connected to the outer side of the material placing tank (201), and corresponding positioning bearings (203) are passed through the two sides of the fixed frame (202) and connected to the corresponding supporting frames (204), the lower end of the supporting frame (204) is connected to the upper end of the placing seat (205), and the placing seat (205) is placed on the upper end of the vertical pressure steam sterilizer (210), and a driven gear (206) is arranged at the outer end of one side of the fixed frame (202), and the lower end of the driven gear (206) is meshedly connected with a driving gear (207), and the driving gear (207) is connected to the output end of the swing motor (208).

3. The famotidine injection production device according to claim 1, characterized in that: The front side of the nitrogen storage tank (5) is connected to the material tank (201), the first conveying pipe (211), the configuration device (6), the dilution tank (7), the concentration tank (8) and the third conveying pipe (10) through pipelines, and the material tank (201), the first conveying pipe (211), the configuration device (6), the dilution tank (7), the concentration tank (8) and the third conveying pipe (10) are connected to the back side of the storage tank (5) through pipelines.

4. The famotidine injection production device according to claim 1, characterized in that: The configuration device (6) comprises a configuration box (601), a first stirring component (602) and a second conveying pipe (603), and the first stirring component (602) is arranged inside the configuration box (601), and the lower end of one side of the configuration box (601) is connected to the dilution tank (7) through the second conveying pipe (603).

5. The famotidine injection production device according to claim 1, characterized in that: A first liquid inlet (701) is provided on one side of the front of the dilution tank (7), and a first nitrogen inlet (702) is provided on the other side of the upper end of the dilution tank (7). A sampling tube (704) is provided at the lower end of the front of the dilution tank (7). A sampling pump (705) is installed on the sampling tube (704), and the other end of the sampling tube (704) is connected to a detection device (9) provided at the upper end of the base (1). A second stirring component (706) is provided inside the dilution tank (7), and the second stirring component (706) is connected to the first stirring component (602) via a driving component (707). The second stirring component (706) and the first stirring component (602) have the same structure.

6. The famotidine injection production device according to claim 1, characterized in that: A second liquid inlet (801) is provided on one side of the back of the concentrated preparation tank (8), and an electric heater (802) is provided in the middle of the back of the concentrated preparation tank (8). A temperature detector (803) is provided on the back of the concentrated preparation tank (8) above the electric heater (802). A second nitrogen inlet (804) is provided on one side of the upper end of the concentrated preparation tank (8), and a second delivery pipe (806) provided on one side of the upper end of the concentrated preparation tank (8) is connected to a first delivery pipe (703) provided on one side of the upper end of the dilute preparation tank (7) via a delivery pump (805).

7. The famotidine injection production device according to claim 1, characterized in that: The filter pressure box (11) is provided with a plurality of filter elements inside, and the filter elements are 0.45 μm polyethersulfone filter elements and 0.22 μm polyethersulfone filter elements.

8. A production and processing technology of famotidine injection, comprising the following steps:

1. Liquid preparation and filtration (1) Lactic acid pretreatment: Preparation of 10% lactic acid: Calculate according to 100,000 ml batch, weigh 0.35 kg lactic acid, add water for injection to 3.5 kg, shake well, place in a vertical pressure steam sterilizer, treat at 121°C for 2 hours, and cool to room temperature; (2) Weighing and preparing materials: Weigh famotidine, niacinamide, vitamin C, and mannitol according to the prescribed amount for later use; (3) Preparation: Preparation of pH adjuster (4% sodium hydroxide solution): weigh 0.132 kg of sodium hydroxide, add 3.168 kg of water for injection, stir to dissolve, and set aside; A. First, fill the tanks and pipelines in front of the terminal filter element with nitrogen to a pressure of about 0.15MPa, discharge, refill with nitrogen, and discharge again. This operation is repeated three times in total and then sealed. Fill the terminal filter element, silicone tube, and liquid distributor with nitrogen for about 10 minutes and seal. B. Add water for injection above 60℃ (more than 100L) to the concentrated preparation tank, fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, reduce the temperature of the water for injection to 20℃~30℃ and then introduce it into the diluted preparation tank, add about 80L (about 80kg) of water for injection of 80% of the prescription volume to the diluted preparation tank; start the tank stirring, set the speed to 45Hz, and fill with nitrogen until the dissolved oxygen is ≤0.2mg / L; C. Add 10% lactic acid solution, niacinamide, mannitol, vitamin C, and famotidine in the prescribed amount, and stir until the mixture is uniformly mixed; D. Use 4% sodium hydroxide solution to adjust the pH to between 6.0 and 6.1; Use injection water to make the volume to 100L, pass through a 0.45μm (5-inch) polyethersulfone filter element and a 0.22μm (5-inch) polyethersulfone filter element, fill with nitrogen and stir in a cycle, take samples every 10 minutes for intermediate product testing (properties, pH value, vitamin C, content), continue to fill with nitrogen until the dissolved oxygen is ≤0.2mg / L, and then maintain nitrogen pressure in the dilution tank; (4) Filter press After the intermediate product is qualified, adjust the nitrogen valve on the dilution tank to control the pressure not to exceed 0.30MPa. The liquid is filtered through a 0.45μm polyethersulfone filter element (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0045HSF05SP, size: 5 inches) and two 0.22μm polyethersulfone filter elements (manufacturer: Hangzhou Kebet Filter Equipment Co., Ltd., model: SPSHSM0022HSCG05SP, size: 5 inches) to the dispenser of the filling machine. The filtration temperature range is 20-30℃, the pressure difference between upstream and downstream of the filtration is ≤0.2Mpa, the filtration speed is 20-50L / h, and the filtration time is not more than 10 hours. Before the end of production, take samples from the 0.45μm filter element for microbial contamination level inspection, and the microbial limit is ≤10cfu / 100ml; The integrity test of 0.22μm polyethersulfone filter element is carried out before and after filtration. The critical value of the bubble point before and after filtration should be ≥0.32MPa (the wetting medium is water for injection). 0.45μm and 0.22μm filter elements shall not be reused after being used once. The pressure difference between upstream and downstream of filtration is ≤0.2MPa.

2. Wash and dry the bottle Set the circulating water pressure: ≥0.2MPa; fine washing water (injection water) pressure: ≥0.20MPa; compressed air pressure: ≥0.30MPa; ultrasonic power: ≥300W, ampoule high temperature sterilization stage, oven high temperature section temperature: ≥300℃, sterilization time: ≥10min; The speed of mesh belt is ≤250mm / min; the clean level of the sterilized ampoule should be exposed under a Class A laminar flow hood, and the effective storage time limit of ampoule sterilization is 2 hours; 3. Filling The potting process and liquid filtration device are carried out in a Class A laminar flow hood; Adjust the filling volume (target filling volume: 2.15 ml, the filling volume range is controlled within the range of 2.10-2.20 ml), and the headspace residual oxygen content is less than 0.7%; The filling machine should discharge no less than 2L of liquid before formal filling, and filling should start after the product filling volume and residual oxygen content are qualified; Check dissolved oxygen and headspace residual oxygen once at the beginning, middle and end of filling. Dissolved oxygen ≤ 0.5 mg / L, headspace residual oxygen < 0.7%. Filling speed is about 27,000 bottles / hour, and the yield of filling process is ≥ 75%; 4. Light inspection and sealing test The parameters of the light inspection machine are as follows: high voltage setting is 19KV, leakage upper limit is 1.7V. Before using the light inspection machine, 20 positive bottles (5 bottles for each of the 4 parts), 20 defective bottles (5 bottles for each of the filling amount, white spots, fibers, and glass chips) and 10 negative bottles need to be randomly placed on the bottle feeding dial wheel. All positive bottles need to enter the leakage defective product channel, all negative bottles need to enter the qualified product channel, and all defective bottles need to enter the foreign body defective product channel. In this way, the stability of the equipment is confirmed, and the parameters are adjusted according to the light inspection test results. Those that exceed the parameter setting range are rejected. After the foreign body defective products of the machine inspection are inspected once, they need to be manually re-inspected twice, with an illumination of 1000~1500lx. The qualified products of the two re-inspections can be put into the qualified products of this batch, and the unqualified products of the re-inspection are directly destroyed; The high-voltage charge method is used to conduct online leak detection of the sealing integrity of packaging materials during the production process. The online leak detection sensitivity is 3μm, and products that exceed the leakage voltage threshold will be rejected; 5. Packaging 2ml / tube, 10 tubes / box, packaged, stored.

Images