Amiodarone hydrochloride injection production and processing technology

Abstract

The invention discloses an amiodarone hydrochloride injection production and processing technology which comprises the following steps: washing and drying a bottle, weighing and preparing a solution: A, opening a nitrogen valve of a western medicine dilute solution preparation tank, introducing nitrogen into the western medicine dilute solution preparation tank, injecting about 60% of water for injection according to the prescription dosage into the western medicine dilute solution preparation tank, starting stirring to 30HZ, adding a proper amount of water for injection according to the prescription dosage, and adding a proper amount of water for injection according to the prescription dosage of about 60% into the western medicine dilute solution preparation tank; and introducing circulating cooling water into the interlayer, cooling the temperature of the injection water in the tank to 60-65 DEG C, discharging the circulating cooling water in the interlayer, and filtering: after an intermediate product is qualified, filtering a sample through a 10-inch 0.22 mu m PES filter element (Combite) by adopting nitrogen, performing terminal filtering through the 10-inch 0.22 mu m PES filter element (Combite), filling and sealing, performing light inspection and leakage detection, and packaging. According to the amiodarone hydrochloride injection production and processing technology, in order to solve the problem that an amiodarone hydrochloride injection prepared through an existing amiodarone hydrochloride injection production and processing technology is low in quality and safety, operation is carried out strictly according to a bottle washing procedure, and the cleanliness degree of an ampoule bottle is ensured.

Description

Technical Field

[0001] The invention relates to the technical field of amiodarone hydrochloride injection, in particular to a production and processing technology of amiodarone hydrochloride injection. Background Art

[0002] Amiodarone hydrochloride injection is indicated for the treatment of severe arrhythmias when oral administration is not suitable, and is particularly suitable for the following situations: atrial arrhythmias with rapid ventricular rhythms; tachycardia in WPW syndrome; severe ventricular arrhythmias; cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest that is ineffective with external defibrillation. The quality and safety of amiodarone hydrochloride injection produced by the existing production and processing technology of amiodarone hydrochloride injection are relatively low, and therefore a production and processing technology of amiodarone hydrochloride injection is proposed. Summary of the invention

[0003] The object of the present invention is to provide a production and processing technology of amiodarone hydrochloride injection to solve the problem of low quality and safety of amiodarone hydrochloride injection produced by the existing production and processing technology of amiodarone hydrochloride injection proposed in the above background technology.

[0004] To achieve the above object, the present invention provides the following technical solution: a production and processing technology of amiodarone hydrochloride injection, comprising the following steps:

[0005] (1) Washing and drying bottles: Use an ampoule ultrasonic cleaner and an ampoule tunnel sterilization and drying machine for washing and drying operations;

[0006] (2) Weighing: Check the name, batch number, and quantity of the raw and auxiliary materials received according to the batch production instructions and the inspection report. According to the standard operating procedures for weighing positions, weigh the prescribed amount of amiodarone hydrochloride, polysorbate 80 (II), and benzyl alcohol, place them in a clean container, and hang a label on the outside of the container, indicating the product name, batch number, weight, date, and operator;

[0007] (3) Liquid preparation: The liquid preparation process includes the following steps: A. Open the nitrogen valve of the western medicine dilution tank, introduce nitrogen into the western medicine dilution tank, inject about 60% of the prescribed amount of water for injection (60.0 kg, the allowable range is 60.0 ± 0.5 kg) into the western medicine dilution tank, start stirring at 30HZ, introduce circulating cooling water into the interlayer to cool the temperature of the water for injection in the tank to 60°C to 65°C, and discharge the circulating cooling water in the interlayer; B. Open the upper cover of the feed inlet, slowly add the prescribed amount of polysorbate 80 into the western medicine dilution tank, take about 3kg of hot water for injection to rinse the stainless steel barrel three times, transfer the rinsing liquid into the western medicine dilution tank, and fill it with Stir for 3 minutes to completely dissolve the polysorbate 80; C. Turn off the nitrogen, slowly add the prescribed amount of amiodarone hydrochloride to the western medicine dilution tank, turn on the nitrogen, and completely dissolve the amiodarone hydrochloride; D. Slowly add the prescribed amount of benzyl alcohol to the western medicine dilution tank, take about 3kg of hot injection water to rinse the stainless steel barrel 3 times, transfer the rinse solution to the western medicine dilution tank, and stir to mix the liquid evenly; E. Slowly inject hot injection water to the full volume and stir for 5 minutes. After the volume is fixed, turn on the small circulation again to mix the liquid, turn off the circulation, and record the pressure difference between the upstream and downstream of the filter; F. Adjust the speed to 15HZ, turn on the circulating cooling water to cool the liquid to 25℃±5℃;

[0008] (4) Filtration: After the intermediate product is qualified, the sample is filtered through a 10-inch 0.22 μm PES filter element (Cobetter) using nitrogen, and then through a 10-inch 0.22 μm PES filter element (Cobetter) for terminal filtration;

[0009] (5) Filling and sealing: Confirm that the machine is running normally, start the filling and sealing machine, and use 2L of liquid medicine to rinse the pipes and filter element before filling. Nitrogen should be filled before and after the filling process. The residual oxygen content after filling should be ≤5%. The filling and sealing quality should be checked at any time during the sealing process. The liquid properties and filling volume should be checked every 1 hour during the filling and sealing process;

[0010] (6) Light inspection and leak detection: The light inspection and leak detection includes the following steps: A. According to the standard operating procedures of the bottle hot and water-throwing machine, the operator rinses the semi-finished products through the bottle hot machine (65±5℃), and the rinsing process does not exceed 5 minutes; B. Turn on the power of the fully automatic ampoule light inspection and leak detection machine, set the product name, specification, and batch number, set the discharge voltage of the four stations to 18KV, and the leakage upper limit to 1.3V; C. The products to be inspected are sent to the fully automatic ampoule light inspection and leak detection machine for light inspection and leak detection, and are divided into qualified products, unqualified products in light inspection, and unqualified products in leak detection. After the unqualified products in the first machine inspection are inspected by the whole batch of products, they need to be manually re-inspected twice. The qualified products in the two re-inspections can be put into the qualified products of this batch, and the unqualified products in the re-inspection are directly destroyed;

[0011] (7) Packaging: During the packaging process, the quality controller shall check the quality of printing and labeling, boxing and packing for each batch, and conduct random inspection every hour. The inspection shall be in compliance with the regulations. After packaging, the batches shall be sent to the warehouse for inspection.

[0012] Preferably, the operation requirements of the ampoule ultrasonic cleaning machine are as follows: after the ampoule is injected with circulating water filtered by a 0.45μm filter element and enters the ultrasonic cleaning machine, it is cleaned with circulating water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, cleaned with degraded water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, and then cleaned with injection water filtered by a 0.22μm filter element and blown with compressed air filtered by a 0.01μm filter element, and then transported to a tunnel-type sterilizing dryer through a conveyor belt. During this period, 20 ampoules are extracted every 2 hours to check the cleanliness, which should be qualified; the operation requirements of the ampoule tunnel sterilizing dryer are as follows: the sterilization temperature is set to 300°C, the mesh belt speed is ≤250mm / min, the cleaned ampoules are sent to the sterilization tunnel oven, and the drying and sterilization time is not less than 10 minutes.

[0013] Through the above technical solution: ensure the cleanliness of the ampoule bottle.

[0014] Preferably, the filling speed is controlled at 260 bottles / minute to 300 bottles / minute, the target filling volume is 3.30 ml, and the filling volume is controlled by the volumetric method with an allowable range of 3.20 ml to 3.40 ml, which should meet the filling volume requirements.

[0015] Through the above technical solution: improving filling efficiency.

[0016] Compared with the prior art, the invention has the following beneficial effects: the production and processing technology of amiodarone hydrochloride injection is

[0017] The device is designed to solve the problem of low quality and safety of amiodarone hydrochloride injection produced by the existing amiodarone hydrochloride injection production and processing technology. By strictly following the bottle washing procedure, the cleanliness of the ampoule bottle is ensured, and the path of visible foreign matter, insoluble particles, etc. is controlled, so as to ensure the high quality of the preparation. By adopting a segmented liquid preparation process, injection water is added first, then the auxiliary materials are added, and finally the raw materials are added. Each step is rinsed to make the materials completely transferred to the liquid preparation tank. High-temperature liquid preparation can better dissolve the active ingredients, and the main drug, auxiliary materials and injection water form a stable homogeneous system to ensure the uniformity of the content of the drug solution. The nitrogen pressure delivery of the drug solution can reduce the content of dissolved oxygen in the drug solution, ensure that the quality of the drug solution batch remains uniform, and further ensure the quality. The high-voltage discharge method established by the fully automatic light inspection and leak detection integrated machine has high sensitivity, high accuracy and good precision. It can better eliminate defective bottles than conventional inverted vacuum leak detection and color water leak detection, ensure the sterility level of the drug, and further improve the safety of the drug solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a schematic diagram of the process flow of the present invention. DETAILED DESCRIPTION

[0019] 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.

[0020] See also Figure 1 The present invention provides a technical solution: a production and processing technology of amiodarone hydrochloride injection, according to Figure 1 As shown, a production process of amiodarone hydrochloride injection includes the following steps:

[0021] (1) Washing and drying bottles: Use an ampoule ultrasonic cleaning machine and an ampoule tunnel sterilization and drying machine for washing and drying operations; the operation requirements of the ampoule ultrasonic cleaning machine are as follows: the ampoules conveyed after bottle unscrambling are injected with circulating water filtered by a 0.45μm filter element and then enter the ultrasonic cleaning machine, and are then cleaned with circulating water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, cleaned with degraded water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, and then cleaned with injection water filtered by a 0.22μm filter element and blown with compressed air filtered by a 0.01μm filter element, and then transported to the tunnel sterilization and drying machine through a conveyor belt. During this period, 20 ampoules are extracted every 2 hours to check the cleanliness, which should be qualified; the ampoule tunnel Sterilization dryer operation requirements: Set the sterilization temperature to 300°C, the mesh belt speed ≤250mm / min, send the washed ampoules into the sterilization tunnel oven, the drying and sterilization time is not less than 10 minutes, and extract 20 ampoules every 2 hours to check the dryness, which should be qualified; through the above scheme, strictly follow the bottle washing procedure to ensure the cleanliness of the ampoules, strictly follow the ampoule high-temperature sterilization procedure, remove the pyrogens carried by the inner packaging material, ensure the sterility level of the ampoules, control the production of visible foreign matter, insoluble particles, etc., thereby ensuring the high quality of the preparation, the ampoule ultrasonic cleaning machine is the existing technology model AQCL28 / 4, and the ampoule tunnel sterilization dryer is the existing technology model KSZ620 / 75.

[0022] (2) Weighing: Verify the name, batch number, and quantity of the raw and auxiliary materials received according to the batch production instructions and the inspection report. According to the standard operating procedures for the weighing position, weigh the prescribed amount of amiodarone hydrochloride, polysorbate 80 (II), and benzyl alcohol, place them in a clean container, and hang a label on the outside of the container, indicating the name, batch number, weight, date, and operator. Before weighing, the raw and auxiliary materials need to be cleaned and unpacked, and then wiped with 75% ethanol for sterilization.

[0023] (3) Liquid preparation: The liquid preparation process includes the following steps:

[0024] A. Before preparation, confirm that there is no liquid in the interlayer of the western medicine dilution tank, confirm the status of the weighing system, reset the online scale of the western medicine dilution tank to zero, the western medicine dilution tank is the existing technology, the model is 200L, open the nitrogen valve of the western medicine dilution tank, pass nitrogen into the western medicine dilution tank, inject about 60% of the prescription amount of water for injection (60.0kg, the allowable range is 60.0±0.5kg) into the western medicine dilution tank, start stirring to 30HZ, pass circulating cooling water into the interlayer, cool the temperature of the water for injection in the tank to 60℃~65℃, and discharge the circulating cooling water in the interlayer; B. Open the upper cover of the feed inlet, slowly add the prescription amount of polysorbate 80 into the western medicine dilution tank, take about 3kg of hot injection water to rinse the stainless steel barrel 3 times, and transfer the rinse liquid into the western medicine dilution tank together. , stir thoroughly to completely dissolve polysorbate 80, stir for 10 minutes; C. Turn off nitrogen, slowly add the prescribed amount of amiodarone hydrochloride to the western medicine dilution tank, turn on nitrogen, stir and dissolve at 60±5℃ for 2h to completely dissolve amiodarone hydrochloride; D. Slowly add the prescribed amount of benzyl alcohol to the western medicine dilution tank, take about 3kg of hot injection water to rinse the stainless steel barrel 3 times, transfer the rinse liquid to the western medicine dilution tank, stir to mix the medicine solution evenly, and stir for 10 minutes; E. Slowly inject hot injection water to make up to the full volume (the density of the medicine solution is 1.03g / ml, and the final fixed volume allowable range is 103.0kg±0.5kg) and stir for 5 minutes. After making up to the volume, open the small circulation again at 60±5℃, circulate through a 10-inch 0.22μm PES filter element (the filter element is for single use) for 5 minutes to mix the medicine solution (filtration pressure difference: ≤0.2MPa), close the circulation, and record the pressure difference between the upstream and downstream of the filter. ; F. Adjust the speed to 15HZ, start the circulating cooling water to cool the liquid to 25℃±5℃; The above operation solves the solubility problem of amiodarone hydrochloride, adopts a segmented liquid preparation process, first add water for injection, then add excipients and finally add raw materials, and each step is rinsed to make the materials completely transferred to the liquid preparation tank. High-temperature liquid preparation can better dissolve the active ingredients, and the main drug, excipients and water for injection form a stable homogeneous system to ensure the uniformity of the content of the liquid.

[0025] (4) Filtration: After the intermediate product is qualified, the sample is filtered through a 10-inch 0.22μm PES filter element (Cobetter) with nitrogen, and then through a 10-inch 0.22μm PES filter element (Cobetter) for terminal filtration (the filter element is for single use, and the liquid delivery pressure is ≤0.30MPa; the sterilizing filter pressure and pressure difference should be monitored during filtration, and the filtration pressure difference is ≤0.2MPa). Before and after filtration, the two 10-inch 0.22μm PES cartridge filters (Cobetter) for sterilizing filtration should pass the integrity test, and the bubbling point before and after filtration should be ≥0.32MPa (moistened with water for injection).

[0026] (5) Filling and sealing: Confirm that the machine is running normally and start the filling and sealing machine. The filling and sealing machine model is AGFGL20 / 14. Before filling, use 2L of liquid medicine to clean the pipes and filter element. Fill with nitrogen before and after the filling process. The residual oxygen content after filling is ≤5%. During the filling and sealing process, the filling speed is controlled at 260 bottles / minute to 300 bottles / minute. The target filling volume is 3.30ml, and the filling volume is controlled by the volume method with an allowable range of 3.20ml to 3.40ml, which should comply with the specified filling volume requirements. The filling quality should be checked at any time during the sealing process. The properties and filling volume of the drug solution should be checked every hour during the filling process. The properties are colorless to light yellow clear liquid, and the allowable filling volume range is 3.20ml to 3.40ml. Visible foreign matter should be checked every hour, and the visible foreign matter should comply with regulations. Through the above operation, nitrogen pressure delivery of the drug solution can reduce the content of dissolved oxygen in the drug solution, ensure that the quality of the drug solution batch remains uniform, and further ensure the quality; discarding the terminal filter element after a single use can prevent filter element perforation, further reducing the production risk of amiodarone hydrochloride injection.

[0027] (6) Light inspection and leak detection: Light inspection and leak detection include the following steps: A. Operate according to the standard operating procedures of the bottle hot and water-throwing machine. The operator rinses the semi-finished products through the bottle hot machine (65±5℃), and the rinsing process does not exceed 5 minutes; B. Turn on the power of the fully automatic ampoule light inspection and leak detection machine. The model of the fully automatic ampoule light inspection and leak detection machine is JAYL600. Set the product name, specification, and batch number. Set the discharge voltage of the four stations to 18KV and the upper limit of leakage to 1.3V; C. After the products to be inspected are sent to the fully automatic ampoule light inspection and leak detection machine for light inspection and leak detection, they are separated. For qualified products, unqualified products in light inspection and unqualified products in leak detection, D. Unqualified products in one machine inspection shall be manually re-inspected twice after the light inspection of the whole batch of products is completed. The qualified products in the two re-inspections can be put into the qualified products in this batch, and the unqualified products in the re-inspection shall be directly destroyed; the high-voltage discharge method established by the fully automatic light inspection and leak detection machine through the above operation has high sensitivity, high accuracy and good precision. It can better eliminate defective bottles than conventional inverted vacuum leak detection and color water leak detection, ensure the sterility level of medicines, further improve the safety of liquid medicines, and meet people's needs for medicines.

[0028] (7) Packaging: This product is packaged in ampoules with the packaging specifications of 3 ml / tube, 6 tubes / box. The ampoule labeling, printing of small boxes, boxing and cartoning shall be carried out in accordance with standard operating procedures. During the packaging process, the quality control personnel shall check the quality of printing and labeling, boxing and cartoning for each batch. Spot checks shall be conducted every hour and shall comply with the regulations. After packaging, the products shall be sent to the warehouse for inspection. The round bottle labeling machine can be model A205 or RH01.

[0029] 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.

[0030] 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 production and processing technology of amiodarone hydrochloride injection, characterized in that: The following steps are involved: (1) Washing and drying bottles: Use an ampoule ultrasonic cleaner and an ampoule tunnel sterilization and drying machine for washing and drying operations; (2) Weighing: Check the name, batch number, and quantity of the raw and auxiliary materials received according to the batch production instructions and the inspection report. According to the standard operating procedures for weighing positions, weigh the prescribed amount of amiodarone hydrochloride, polysorbate 80 (II), and benzyl alcohol, place them in a clean container, and hang a label on the outside of the container, indicating the product name, batch number, weight, date, and operator; (3) Liquid preparation: The liquid preparation process includes the following steps: A. Open the nitrogen valve of the western medicine dilution tank, introduce nitrogen into the western medicine dilution tank, inject about 60% of the prescribed amount of water for injection (60.0kg, the allowable range is 60.0±0.5kg) into the western medicine dilution tank, start stirring to 30HZ, introduce circulating cooling water into the interlayer, cool the temperature of the water for injection in the tank to 60℃~65℃, and drain the circulating cooling water in the interlayer; B. Open the upper cover of the feed inlet, slowly add the prescribed amount of polysorbate 80 into the western medicine dilution tank, take about 3kg of hot injection water to rinse the stainless steel barrel 3 times, transfer the rinse solution into the western medicine dilution tank, and stir well to make polysorbate 80 0 completely dissolved; C. Turn off the nitrogen, slowly add the prescribed amount of amiodarone hydrochloride to the western medicine dilution tank, turn on the nitrogen, and completely dissolve the amiodarone hydrochloride; D. Slowly add the prescribed amount of benzyl alcohol to the western medicine dilution tank, take about 3kg of hot injection water to rinse the stainless steel barrel 3 times, transfer the rinse solution to the western medicine dilution tank, and stir to mix the liquid evenly; E. Slowly inject hot injection water to the full volume and stir for 5 minutes. After the volume is fixed, turn on the small circulation again to mix the liquid, turn off the circulation, and record the pressure difference between the upstream and downstream of the filter; F. Adjust the speed to 15HZ, turn on the circulating cooling water to cool the liquid to 25℃±5℃; (4) Filtration: After the intermediate product is qualified, the sample is filtered through a 10-inch 0.22 μm PES filter element (Cobetter) using nitrogen, and then through a 10-inch 0.22 μm PES filter element (Cobetter) for terminal filtration; (5) Filling and sealing: Confirm that the machine is running normally, start the filling and sealing machine, and use 2L of liquid medicine to rinse the pipes and filter element before filling. Nitrogen should be filled before and after the filling process. The residual oxygen content after filling should be ≤5%. The filling and sealing quality should be checked at any time during the sealing process. The liquid properties and filling volume should be checked every 1 hour during the filling and sealing process; (6) Light inspection and leak detection: The light inspection and leak detection includes the following steps: A. According to the standard operating procedures of the bottle hot and water-throwing machine, the operator rinses the semi-finished products through the bottle hot machine (65±5℃), and the rinsing process does not exceed 5 minutes; B. Turn on the power of the fully automatic ampoule light inspection and leak detection machine, set the product name, specification, and batch number, set the discharge voltage of the four stations to 18KV, and the leakage upper limit to 1.3V; C. The products to be inspected are sent to the fully automatic ampoule light inspection and leak detection machine for light inspection and leak detection, and are divided into qualified products, unqualified products in light inspection, and unqualified products in leak detection. After the unqualified products in the first machine inspection are inspected by the whole batch of products, they need to be manually re-inspected twice. The qualified products in the two re-inspections can be put into the qualified products of this batch, and the unqualified products in the re-inspection are directly destroyed; (7) Packaging: During the packaging process, the quality control personnel shall check the quality of printing and labeling, boxing and packing for each batch, and conduct random inspections every hour. The inspections shall comply with the regulations. After packaging, the batches shall be sent to the warehouse for inspection.

2. The production and processing technology of amiodarone hydrochloride injection according to claim 1, characterized in that: The operation requirements of the ampoule ultrasonic cleaning machine are as follows: after the ampoule is injected with circulating water filtered by a 0.45μm filter element and enters the ultrasonic cleaning machine, it is cleaned with circulating water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, cleaned with degraded water filtered by a 0.45μm filter element, blown with compressed air filtered by a 0.01μm filter element, and then cleaned with injection water filtered by a 0.22μm filter element and blown with compressed air filtered by a 0.01μm filter element, and then transported to the tunnel sterilization dryer through a conveyor belt. During this period, 20 ampoules are extracted every 2 hours to check the cleanliness, which should be qualified; the operation requirements of the ampoule tunnel sterilization dryer are as follows: the sterilization temperature is set to 300°C, the mesh belt speed is ≤250mm / min, the cleaned ampoules are sent to the sterilization tunnel oven, and the drying and sterilization time is not less than 10 minutes.

3. The production and processing technology of amiodarone hydrochloride injection according to claim 1, characterized in that: The filling speed is controlled at 260 bottles / minute to 300 bottles / minute, the target filling volume is 3.30 ml, the filling volume is controlled by the volume method, and the allowable range is 3.20 ml to 3.40 ml, which should comply with the filling volume requirements.

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