Production Process Of Injection Purification Workshop

Production process of small-capacity injection purification workshop for ampoules and vials.

Part 1 Weighing Of Raw Materials And Excipients In Injection Purification Workshop

Generally, the requirements for the raw and auxiliary materials of small-volume injections are consistent with those of large-volume injections. The raw materials of injections are generally required to use injection-grade specifications. If they fail to meet the requirements, they can be re-refined to meet the requirements of injection-grade; , Pyrogen, etc. have control requirements.

For liquid preparations that cannot be sterile filtered and sterile powder preparations for direct subpackaging, sterile grade raw materials and auxiliary materials must be used, and the liquid preparation and aseptic filling production should be carried out according to the aseptic process; for the filled products, the final Sterilized ones also need to be produced by aseptic filling (or sub-packaging) according to the aseptic process. If the product can withstand the terminal sterilization conditions, the terminal sterilization process shall be used first, and the aseptic process shall not replace the terminal sterilization process. At the same time, raw and auxiliary materials for injections must be weighed in a clean area to avoid environmental pollution; according to the physical characteristics and biological activity of raw and auxiliary materials, the weighing should be completed in a completely independent area (independent airflow protection and dust collection) . According to the requirements of the feeding environment level or the process risk assessment results, select D-level, C-level or A-level weighing environment.

Sterile substances are weighed in the sterilized container under Class A conditions, and then transferred to the liquid container under Class A cleanliness level, and the background environment must meet the requirements of Class B cleanliness level. Since the air will contain dust (from solid materials) or particles, which may affect personnel, personnel must be protected during material handling; when weighing sterile materials, personnel must dress in accordance with the requirements of Class B cleanliness, except In addition to reducing the sterility risk of personnel to materials, it also plays a role in personnel protection.

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 near the raw and auxiliary material warehouse with the same cleanliness level as the production environment, and take out the raw and auxiliary materials required for production from the warehouse, and follow the product prescription and production In batches, the raw and auxiliary materials are weighed and subpackaged, and the subpackaged raw and auxiliary materials are sealed in double-layer plastic bags and placed in covered plastic buckets, and sent to the weighing room in the production area according to the amount of each batch of feeding. Check and confirm, feeding and dosing. Another method is to take a certain amount of raw and auxiliary materials from the warehouse according to the packaging size of the raw and auxiliary materials, and place them in the raw and auxiliary material temporary storage room in the production area. Auxiliary materials, in the one-way flow in the weighing room of the production area, select a metering device with appropriate accuracy to weigh and check the raw and auxiliary materials respectively, and store them in double-layer plastic bags and seal them for later use.

Part 2 Cleaning, Sterilization, And Transfer Of Packaging Materials (Bottles, Stoppers) And Utensils In The Injection Purification Workshop

1 Cleaning And Sterilization Of Rubber Stoppers

① Process introduction: The cleaning, silicification, sterilization, drying and other treatments of rubber stoppers play a vital role in the product quality, and the quality of each step should be strictly monitored, such as detecting insoluble particles and visible particles in the cleaning water during the cleaning process. For foreign matter, carry out silicification according to the verification requirements, confirm the amount of silicone oil, silicification time, etc., strictly monitor the sterilization and drying time, temperature, pressure, etc., monitor the sterility of the rubber stopper, and test the inner element to meet the requirements.

At present, most enterprises choose rubber stopper cleaning and sterilizing machines. The steps of cleaning, silicification, sterilization and drying of rubber stoppers can be completed at the same time, which can better meet the needs of production. Many companies have also begun to choose ready-to-use or disposable rubber stoppers (cleaned by the supplier), and the injection purification workshop can be put into use after only being sterilized; injection purification workshops that do not have the sterilization conditions can also directly purchase free plugs. Wash the sterile rubber stopper.

The processing of rubber stoppers should go through procedures such as cleaning, sterilization, drying, etc. These procedures can be separated or combined into a continuous processing system to eliminate or reduce the risk of recontamination that may occur during the processing of rubber stoppers, such as There is also a siliconization process if necessary. At present, automatic rubber stopper cleaning machines can be used to realize the cleaning, siliconization, sterilization and drying functions of rubber stoppers. It is necessary to specify and verify the cleaning procedures according to the use requirements of rubber stoppers.

②Key points of the cleaning and sterilization process of rubber stoppers: Observation of the cleanliness of rubber stoppers and rinse water: Observation and recording of temperature during the cleaning and sterilization process: The rubber stoppers to be used after cleaning should be protected from secondary pollution during storage Measures; to reduce the risk of contamination, use up within the proven storage time.

③Key points of cleaning and sterilization verification of rubber stoppers: confirmation of cleaning, sterilization and drying time; Confirmation of the storage conditions and storage time of the rubber stoppers to be used.

The rubber stoppers after cleaning and sterilization must be transferred under the same conditions as the filling environment; the rubber stoppers for aseptic filling must be placed in a B+A environment or at the outlet of the rubber stopper washing machine in RABS. The sterilized and dried rubber stoppers are divided into double-layer sterile bags. Transport the rubber stoppers packed in double-layer aseptic bags to the RABS of the filling machine by trolley, remove the first layer of packaging in the buffer zone of the RABS rubber stoppers of the filling machine, enter the RABS, and open the second layer in the RABS Package. The operator operates through the glove box at the material port and pours the rubber plug into the rubber plug hopper of the filling machine.

The filling of vials requires rubber stoppers and aluminum caps, while the filling of ampoules does not require rubber stoppers and aluminum caps.

2 Washing And Sterilization Of Ampoules And Vials

①Process introduction: The automation of ampoule cleaning and sterilization is relatively high. At present, the washing, drying, filling and sealing (rolling) linkage production line is adopted, which can effectively improve the efficiency of bottle washing and avoid pollution in the production process. During the production process, ampoules/vials should be extracted regularly to check the cleanliness, control the speed of bottle washing, check the pressure of injection water, the pressure of clean compressed air, monitor the temperature, pressure difference, and mesh belt speed of the tunnel oven. To monitor the suspended particles in the tunnel oven, it is advisable to specify the use time limit of ampoules/vials after sterilization. Zhongjing Global Purification can provide supporting services such as consultation, planning, design, construction, installation and transformation of purification workshops and aseptic workshops.

The washing and drying process is basically as follows: Ultrasonic cleaning → rough washing of the inner and outer walls of the vial with circulating water for injection → air washing with compressed air → fine washing of the inner wall with water for injection → air washing of the inner and outer walls with compressed air → tunnel oven sterilization.

②Key points of the process: cleanliness inspection of ampoules/vials; temperature observation and recording during the sterilization process; regular replacement of air and water filter elements; pressure control during air and water filtration.

③Key points of verification: confirmation of cleaning and sterilization time; confirmation of air pressure and pressure of cleaning water; confirmation of water temperature; number of cycles; confirmation of cleanliness of one-way flow of sterilization equipment; confirmation of pyrogen.

Part 3 Preparation Process Of Injection Purification Workshop

Preparation is the process of uniformly mixing various raw materials and solvents before filling, including simple liquid mixing, dissolution of solid raw materials, etc., as well as complex operations such as emulsification; for liquid injection preparations, water for injection is often used as a solvent To use, add an appropriate amount of solvent to the blending tank according to the process requirements to the appropriate temperature; put the weighed raw and auxiliary materials into the blending tank according to the feeding order of the process requirements, stir the liquid to dissolve evenly, and adjust the pH to the process requirements; After the quality standard of the intermediate, the liquid is filtered through 0.45um and 0.22um filters in turn and put into the storage tank to complete the preparation process operation; the preparation process of the small-volume injection is consistent with the preparation process of the large-volume injection.

For liquid preparations that cannot be sterile filtered, it is necessary to use sterile grade raw and auxiliary materials, and carry out liquid preparation and aseptic filling production according to the aseptic process.

Part 4 Filling Process Of Injection Purification Workshop

For terminally sterilized small-volume injections, generally filling and sealing can be carried out in a Class C environment, and for terminally sterilized products with high contamination risks, it is generally required to perform filling and sealing in a local Class A environment under a Class C background.

For non-terminal sterilized liquid filling (such as freeze-dried powder injection products), since the filled product cannot be sterilized, this type of filling operation must be carried out at level A under the background of level B area, and taking into account Due to the particularity of the aseptic production process, material transfer generally needs to be transferred in a closed environment under a B-level background, or under a B+A environment. Non-terminal sterilized liquid filling must be carried out in a sterile environment, and an automated filling system should be used as much as possible. If the automation equipment is installed in the isolator, the risk of contamination will be minimized and the environmental level in the background area can be reduced.

① Process Introduction: For the aseptic filling process, the vials/ampoules under the protection of the A-level area (or in RABS) enter the filling machine through transmission; the temporary storage room for the equipment has sterilized various equipment (such as filling needles , filling hose, filling pump assembly), open the inner packaging in the one-way flow A-level area or RABS, connect the filling machine inlet pump, and start the filling machine. Transfer the rubber stopper to the side of the stopper, and pour the rubber stopper onto the stopper under one-way flow or RABS; the semi-stoppered vial is sent to the lyophilizer under the protection of one-way flow; after feeding , insert the layer probe, close the door of the freeze dryer, and carry out the freeze-drying process according to the specified freeze-drying curve; The semi-finished product is taken out from the drying box of the freeze dryer and sent to the capping buffer table.

Vial liquid filling, semi-stoppering, freeze-drying, capping and other processes can realize a fully automatic linkage line, and the freeze dryer can adopt a fully automatic material transfer and feeding and discharging system.

The liquid filling, dosing process and filling process of vials and ampoules are the same, but the sealing process is different: liquid preparations in vials need to be fully stoppered and capped; vials of lyophilized powder preparations need to be half stoppered , freeze-drying, plugging, and capping; liquid preparations in ampoules do not need to be plugged or capped, and can be directly melt-sealed.

For the filling of terminally sterilized products in ampoules/vials, strict aseptic processes are not required.

For vial products that do not need to be freeze-dried, the full stoppering process is adopted, and the cap is directly removed, and then the product is sterilized.

For the filling of ampoules, there is no need to add stoppers and caps. After filling, it is directly heat-melted and sealed, and then terminally sterilized.

② Process Points:

1. Filling Preparation:the filling pipes and needles should be cleaned and sterilized with water for injection before use, and hoses that do not shed particles should be used; gases that directly contact liquids should be monitored and meet the requirements, and ensure that they are sterile filtered before use , the insoluble particles, sterile, and oil-free items contained in it should meet the requirements. If inert gas is used, the purity should meet the specified standards, install the filling equipment (pump set, needle, pipeline, protective gas filter and liquid distributor) according to aseptic operation, check the cleaning equipment and tunnel oven (medium pressure, Temperature, specifications, speed and other parameters); check the laminar flow device in the A-level area. When the one-way flow protective cover fails, emergency measures should be taken to prevent pollution during the filling process, and appropriate sampling will be taken to produce The products should be placed separately and marked. When the investigation results prove that the failure has no quality impact on the product quality, the products at the time of the failure can be merged into the same batch.

1. Filling Process:During the filling process, the filling volume should be checked regularly, and should be adjusted in time when there is a deviation; the quality of the plugging should be controlled; according to the evaluation results, appropriate amount of products in the initial stage of filling production (debugging stage) should be discarded. It is necessary to carry out environmental monitoring of suspended particles, airborne bacteria, sedimentation bacteria, and surface microorganisms (personnel, equipment, plant) during the production process; after filling, the plant equipment and facilities such as filling machines, operating tables, floors, and walls are cleaned and sterilized. bacteria; operators should have good hygiene and behavioral habits, and the number of personnel in the clean area should be controlled.