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Production process of ampoule/vial bottle in purification workshop

2023-09-04

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Marya

Usually, the raw and auxiliary materials for small volume injections are consistent with those for large volume injections. Injection grade specifications are generally required for injection raw materials. If they cannot meet the requirements, they can be refined themselves to meet the injection grade requirements; Injection raw materials have control requirements for microbial limits, pyrogens, etc.

Part 1 Weighing of raw and auxiliary materials in ampoule/vial washing drying filling sealing (capping) linkage production line purification workshop

 

Usually, the raw and auxiliary materials for small volume injections are consistent with those for large volume injections. Injection grade specifications are generally required for injection raw materials. If they cannot meet the requirements, they can be refined themselves to meet the injection grade requirements; Injection raw materials have control requirements for microbial limits, pyrogens, etc.

For liquid formulations that cannot be sterile filtered and sterile powder injection directly packaged formulations, sterile grade raw materials need to be used, and the formulation and sterile filling production should be carried out according to sterile processes; For products that cannot undergo final sterilization after filling, aseptic filling (or packaging) production should also be carried out according to aseptic processes. If the product can withstand the final sterilization conditions, the final sterilization process should be given priority and sterile processes should not be used as a substitute for the final sterilization process. At the same time, the raw and auxiliary materials of the injection must be weighed in a clean area to avoid environmental pollution; According to the physical characteristics and biological activity of the raw materials, their weighing should be completed in a completely independent area (independent airflow protection and dust capture). Select a D-level, C-level, or A-level weighing environment based on the requirements of the feeding environment level or the results of the process risk assessment. Sterile materials are weighed in a sterilized container under Class A conditions, and then transferred to a liquid container under Class A cleanliness level. The background environment must meet the requirements of Class B cleanliness level. Due to the presence of dust (from solid materials) or particles in the air, which may affect personnel, personnel must be protected during the material handling process; When weighing sterile materials, personnel must dress in accordance with the requirements of Class B cleanliness level, which not only reduces the risk of material sterility, but also plays a role in protecting personnel.

There are two methods for weighing raw and auxiliary materials: one method is to set up a raw and auxiliary material processing and weighing room with the same cleanliness level as the production environment near the raw and auxiliary material warehouse. The raw and auxiliary materials required for production are taken out from the warehouse, and weighed and packaged according to the product prescription and production batch. The packaged raw and auxiliary materials are sealed in a double-layer plastic bag and placed in a covered plastic bucket, According to the feeding amount of each batch, it is sent to the weighing room in the production area for review, confirmation, feeding, and liquid preparation. Another method is to retrieve a certain amount of raw and auxiliary materials from the warehouse according to their packaging size, and place them in the temporary storage room of the production area. According to the batch production instructions, the raw and auxiliary materials required for the batch production are taken out from the temporary storage room of the raw and auxiliary materials. Under the unidirectional flow in the weighing room of the production area, appropriate precision measuring devices are selected to weigh and recheck the raw and auxiliary materials, and they are stored in double-layer plastic bags sealed for backup.

 

  

 

Part 2 Cleaning and sterilization of ampoules/vial bottles


①Process introduction:

The automation level of ampoule bottle cleaning and sterilization is relatively high. Currently, the use of ampoule/vial washing drying filling sealing (capping) linkage production line can effectively improve bottle washing efficiency and avoid pollution during the production process. During the production process, regular sampling of ampoules/penicillin bottles should be carried out to check cleanliness, control bottle washing speed, check injection water pressure, clean compressed air pressure, monitor the temperature, pressure difference, mesh belt speed, etc. of the tunnel oven, and regularly monitor the suspended particles in the tunnel oven. It is recommended to specify the usage time limit of ampoules/penicillin bottles after sterilization. Zhongjing Global Purification can provide consulting, planning, design, construction, installation and renovation services for purification workshops and sterile workshops. The basic process flow of the washing and drying part is as follows: ultrasonic cleaning → coarse washing of the inner and outer walls of the penicillin bottle with circulating injection water → compressed air washing → fine washing of the inner walls with injection water → compressed air washing of the inner and outer walls → tunnel oven sterilization.


②Process points:

cleanliness inspection of ampoule/penicillin bottles; Observation and recording of temperature during the sterilization process; Regularly replace the filter elements of air and water filters; Pressure control during air and water filtration.
 

③Verification key points:

confirmation of cleaning and sterilization time; Confirmation of air pressure and cleaning water pressure; Confirmation of water temperature; Number of cycles; Confirmation of cleanliness of one-way flow of sterilization equipment; Confirmation of pyrogens.


Part 3 Preparation process of ampoule/vial washing drying filling sealing (capping) linkage production line purification workshop


Preparation is the process of mixing various raw materials and solvents evenly before filling, including simple liquid mixing, dissolution of solid raw materials, and complex operations such as emulsification; For liquid injection formulations, water for injection is often used as a solvent, and an appropriate amount of solvent is added to the mixing tank according to the process requirements to the appropriate temperature; Put the weighed raw and auxiliary materials into the mixing tank according to the process requirements, stir the liquid evenly to dissolve, and adjust the pH to meet the process requirements; After meeting the quality standards for intermediates, the liquid is filtered through 0.45um and 0.22um filters in sequence and then transferred to a storage tank to complete the preparation process; The preparation process of small volume injections is consistent with that of large volume injections. For liquid formulations that cannot undergo sterile filtration, sterile grade raw materials need to be used, and the formulation and sterile filling production should be carried out according to sterile processes.

 

    

 

Part 4 Filling process of ampoule/vial washing drying filling sealing (capping) linkage production line purification workshop


For final sterilized small volume injections, filling and sealing can generally be carried out in a C-level environment. For final sterilized products with high pollution risks, it is generally required to fill and seal in local A-level environments under a C-level background. For non terminally sterilized liquid filling (such as freeze-dried powder needle products), due to the inability to sterilize the filled products, this type of filling operation must be carried out in the A-level background of the B-level area. Considering the particularity of sterile production processes, material transfer generally needs to be sealed in the B-level background or transferred in the B+A environment. Non terminally sterilized liquid filling must be carried out in a sterile environment and automated filling systems should be used as much as possible. If the automation equipment is installed inside the isolator, it will greatly reduce the risk of pollution and can reduce the environmental level of the background area.


①Process introduction:

 

For aseptic filling processes, penicillin/ampoule bottles protected by the A-level zone (or RABS) are transported into the filling machine; The temporary storage room for instruments has sterilized various instruments (such as filling needles, filling hoses, and filling pump components). Open the inner packaging in the one-way flow A-level area or RABS, connect the inlet pump of the filling machine, and start the filling machine. Transfer the rubber stopper to the stopper and pour it into the stopper under unidirectional flow or RABS; The partially stoppered penicillin bottle is sent to the freeze-drying machine under unidirectional flow protection; After the feeding is completed, insert the layer probe, close the freeze-drying machine door, and carry out the freeze-drying process according to the specified freeze-drying curve; After the freeze-drying is completed, open the door of the drying oven, and under unidirectional flow protection, take out the fully compressed dried semi-finished products from the drying oven of the freeze-drying machine in sequence from bottom to top, and send them to the capping buffer table. The liquid filling, semi stoppering, freeze-drying, capping and other processes of penicillin bottles can achieve a fully automated linkage line, and the freeze-drying machine can adopt a fully automatic material transfer and inlet and outlet system. The liquid filling, dispensing, and filling processes for penicillin and ampoule bottles are the same, but the sealing process is different: the liquid formulation of penicillin bottles needs to be fully stoppered and capped; The penicillin bottle freeze-dried powder injection preparation needs to be partially stoppered, freeze-dried, stoppered, and capped; Ampoule bottles for liquid formulations do not require stoppage or capping, and can be directly melted and sealed. For the filling of final sterilized products in ampoules/penicillin bottles, strict aseptic processes are not required. For penicillin bottle products that do not require freeze-drying, the full stoppering process is used, and the capping is directly removed, followed by product sterilization. For ampoule bottle filling, there is no need to add stoppers or caps. After filling, it is directly heated and sealed, and then subjected to final sterilization.

 

   


②Key points of the process: 


a. Filling preparation: Clean and sterilize the filling pipeline and needle with injection water before use, and use hoses that do not shed particles; Gases that come into direct contact with liquids should be monitored and meet the requirements. Before use, ensure that they undergo sterile filtration treatment. The insoluble particles, sterile, and oil-free items they contain should meet the requirements. If inert gas is used, the purity should meet the specified standards, and the filling equipment (pump unit, needle, pipeline, protective gas filter, and liquid distributor) should be installed according to aseptic operation. The cleaning equipment and tunnel oven should be checked (parameters such as medium pressure, temperature, specifications, speed, etc.); When the laminar flow device and unidirectional flow protection cover in the A-level area fail, emergency measures should be taken to prevent pollution during the filling process, and appropriate sampling should be taken. The products produced at the time of the failure should be placed separately and marked. Only when the investigation results prove that the failure has not had a quality impact on the product quality can the products at the time of the failure be included in the same batch. 
b. Filling process: During the filling process, the filling amount should be regularly checked and adjusted in a timely manner in case of deviation; Control the quality of the pressure plug; According to the evaluation results, it is necessary to discard an appropriate amount of products from the beginning stage of filling production (debugging stage). Environmental monitoring of suspended particles, airborne floating bacteria, settling bacteria, and surface microorganisms (personnel, equipment, factories) during the production process is required; Cleaning and sterilization of plant equipment and facilities such as ampoule/vial filling machines, operating tables, floors, and walls after filling; Operators should have good hygiene and behavioral habits, and the number of personnel in the clean area should be controlled.