To make the factory environment and the design layout of the workshop suitable for the requirements of injection production, obtain a clean production environment, and effectively avoid the influence of cross-contamination and other factors on the quality of medicines, the production of injections should be based on the requirements of GMP to select the location of the plant and the structure of the workshop design. Depending on the different type of injection, there are different requirements for the production workshop design.
The design, production process and environmental zone division of terminal sterilization small-volume injection workshop
The production process of terminally sterilized small-volume injections includes the preparation, compounding, filling and sealing, sterilization, quality inspection, packaging and other steps of raw and auxiliary materials. According to different types of process equipment, it can be divided into two types: stand-alone production process and linked production process. The process and environmental division are shown in the figure below:
The general key points of the design of terminal sterilization small-volume injection workshop include the following aspects:
(1) According to GMP regulations, the final sterilization small-volume injection production environment is divided into four areas: general production area, class D clean area, class C clean area, and partial class A clean area under the background of class C. The general production area includes external cleaning of ampoules, sterilization and leak detection of semi-finished products, foreign substance inspection, and package printing; Class D clean area includes material weighing, concentration, quality inspection, washing and drying of ampoules, washing of work clothes, etc.; Class C clean area includes rare-mixing, fine filtration; Filling and sealing is a partial class A clean area under a C-level background. The area with high cleanliness level should maintain a positive pressure difference of not less than 10Pa compared to the area with low cleanliness level.
The temperature of the general clean area is 18~26℃, and the relative humidity is 45%~65% if no special requirements,.
(2) Workshop should implement the principle of separation of people and logistics. When personnel enter the production workshops of various levels, they must first change clothes, and the production areas of different levels need to have corresponding levels of clothing purification measures. The production area should be arranged in strict accordance with the production process. The production areas of the same level are relatively concentrated, and the transfer windows or buffer rooms are set up in the interconnection of rooms with different clean levels to make the material transfer route as short and smooth as possible.
One line of the logistics route is raw and auxiliary materials, and the materials are processed by external cleaning for concentration and dilution mixing; the other line is ampoules. After the ampoules are processed by external cleaning, they enter the washing, filling and sealing linkage line for cleaning, drying. Converged in the filling and sealing process. The filled ampoule is sterilized, leaked, bottle wiped, foreign body checked, and finally outsourced to complete the entire production process.
(2) Inside the plant, storage areas for raw materials, auxiliary materials, semi-finished products, and finished products that are compatible with the scale of production are set up, and placed in the production areas nearby and in contact with them, to reduce toxicity and pollution during transportation.
The storage area should be arranged in the waiting area, the qualified product area and the unqualified product area; the storage weighing room, the quality inspection room, the tool cleaning storage room, the cleaning tool washing storage room, the clean work clothes washing and drying room, etc. should be around the process production The layout should be conducive to production management; the air-conditioning room, pump room, power distribution room office, and control room should be located outside the clean area, and should be conducive to the layout of public pipelines including air-conditioning ducts.
(3) The water needle production workshop needs to exhaust heat and moisture in the room with concentration and dilution mixing rooms, tool cleaning room, sterilization room, bottle washing room, sanitary ware room, etc. Ventilation should be considered for sterilization and leak detection. The professional design of public works, including water supply and drainage, gas supply, heating, strong and weak electricity, cooling and ventilation, and heating, should comply with GMP principles.
(4) The floor in the water jet production workshop is generally made of clean-resistant epoxy artesian floor. The partition wall is made of light color steel plate, and the joints between the wall and the wall, the wall and the ground, and the wall and the ceiling are treated with arc corners. There are dead ends.
Design of large-volume injection workshop for terminal sterilization. Production process and environmental zone division
The production process of large-volume injections (large infusion) is an important part of the workshop design. The production process generally includes the preparation of raw and auxiliary materials, concentrated mixing, dilution mixing, packaging material processing (bottle washing, rough washing, fine washing, etc.), filling Sealing, sterilization, light inspection, packaging and other processes. The containers for infusion include glass bottles, polyethylene plastic bottles, composite films, etc., but the production process is different for different packaging containers. The infusion process of composite membrane, glass bottle and plastic container and the division of environmental area are shown in the following figure.
General points for the design of terminally sterilized large-volume injection (large infusion) workshop
1. The design should be clearly divided. According to GMP regulations, it can be seen from the schematic diagram of the large infusion production process and environmental area division that the large infusion production is divided into general production areas, class D clean areas, class C and partial class A clean areas. The general production area includes bottle washing, particle treatment, sterilization, light inspection, packaging, etc.; class D clean area includes bottle rough washing, capping, etc.; class C clean area includes bottle fine washing, preparation, filtration, filling, pressing Stopper, where the exposed part of the bottle after fine washing to the filling and sealing process needs to be partial A grade. The functional areas related to production should be close to each other in order to achieve smooth logistics and short pipelines, such as material flow: raw and auxiliary materials weighing, concentrated mixing, thin mixing, and potting processes are as close as possible.
When designing the workshop, people and logistics should be arranged reasonably, and the intersection of people and logistics should be avoided as much as possible. The flow of people includes people entering the general production area, class D clean area, and class C clean area through different dressings; the logistics of entering and leaving the workshop are generally as follows: the entry of bottles or plastic particles, the entry of raw materials and the entry of outsourcing materials And the export of finished products.
2. Mastering the process production equipment is the key to designing the infusion workshop. Different infusion packaging containers have different production processes, resulting in different production equipment. Even for the infusion of the same packaging container, the production line has different options. For example, the bottle washing process for glass bottled infusion includes a drum-type bottle washer that includes coarse and fine washing and a box-type bottle washer that integrates coarse and fine washing. . Differences in process equipment necessitate different workshop layouts, and current infusion production uses linkage lines.
3. Arrange the auxiliary rooms reasonably. Auxiliary rooms are an important part of production quality assurance and GMP certification in large infusion workshops. The proper layout of auxiliary rooms is the key to the success or failure of workshop design. General auxiliary rooms of large infusion production workshops include C-level tool cleaning storage room, D-level tool cleaning storage room, laboratory, bottle washing water preparation room, non-conforming product storage room, sanitary ware room, etc.
General technical requirements for terminal sterilization large-volume injection workshop
1. The control area of the large infusion workshop includes Class D clean area, Class C clean area, and local Class A under the background of Class C. The temperature of the control area is 18~26℃, and the relative humidity is 45%~65%. Ultraviolet lamps should be installed in each process.
2. Generally, the height of the clean production area is about 2.7m. Various pipelines including air ducts are arranged in the upper ceiling and maintenance needs are considered. The internal height of the ceiling needs to be 2.5m. Clean floor drains are required for clean production areas, and no floor drains are allowed in Class A areas.
3. The floor in the large infusion production workshop is generally made of clean-resistant epoxy artesian floor. The partition wall is made of light-weight color steel plate. The joints between the wall and the wall, the wall and the ground, and the wall and the ceiling are treated with arc corners, and no dead corners are allowed. .
4. Concentrated room, rare room, tool cleaning room, sterilization room, bottle washing room, sanitary ware room need to exhaust heat and moisture. In the process of making bottles and caps of plastic pellets, more heat is generated. In addition to the use of low-temperature water system cooling, the air conditioning system should consider the corresponding load, and the feeding system of plastic pellets must consider dust removal measures. Anti-corrosion and ventilation should be considered in the bottle washing water preparation room.
5. Different environmental areas should maintain a pressure difference of no less than 10Pa.
6. The purified water pipeline can be designed with loop circulation, and the water for injection can be looped with an insulation loop above 70°C. The pipeline installation slope is generally 0.1%~0.35 (1%0~3%0), stainless steel. The length of the blind section of the branch pipe should not be More than 6 times the diameter of the circulating main pipe.
Design of aseptic powder injection workshop
The production process of aseptic dispensing powder injection includes scrubbing and disinfection of raw and auxiliary materials, rough washing of vials, fine washing, sterilization and drying, rubber stopper treatment and sterilization, washing and sterilization of aluminum caps, dispensing, capping, and light inspection According to GMP regulations, the air cleanliness level of the production area is divided into A, B and D under the background of B level. Among them, aseptic filling, stoppering, capping of the vial out of the tunnel oven, rubber stopper out of the sterilizer and storage, etc. require a level A under the background of a local level B, scrubbing and disinfection of raw and auxiliary materials, final cleaning of the bottle stopper, and bottle The plug is dried and sterilized as Class D.
The general key points and technical requirements for the design of the aseptic powder injection workshop are as follows:
(1) The design of the workshop should be based on the principle of separating people and logistics, according to the process flow and the correlation of the production process, organically arrange the functional areas with different cleanliness requirements to make the material flow short and smooth. The logistics of the powder injection workshop basically has the following types: raw materials, vials, rubber stoppers, aluminum caps, outsourcing materials and finished products out of the workshop. Personnel entering the workshop must go through different degrees of change to enter the Class D and Class B clean areas.
(2) The workshop is equipped with purification air conditioning and comfort air conditioning systems that can effectively control temperature and humidity, and can ensure the temperature and humidity requirements of the cultivation room; if there are no special process requirements, the temperature in the control area is 18~26℃, and the relative humidity is 45%~65% . Each process needs to install ultraviolet lamps for sterilization.
(3) The processes that need to remove heat and moisture in the workshop generally include bottle washing area, tunnel oven sterilization room, rubber plug aluminum cover room, rubber plug sterilization room, tool cleaning room, sanitary ware room, etc.
(4) Maintain a pressure difference of no less than 10Pa between clean areas of different levels, and each room should have a pressure measuring device. If it is to produce penicillin or other highly allergenic drugs, the filling room should maintain a relatively negative pressure.
Design points of freeze-dried powder injection workshop
The production process of freeze-dried powder injection includes bottle washing and drying and sterilization, rubber stopper treatment and sterilization, aluminum cap washing and sterilization, sub-packaging and half-stopping, freeze-drying, capping, packaging, etc. As shown below.
The general key points and technical requirements of freeze-dried powder injection workshop design are as follows:
(1) According to GMP regulations, the air cleanliness level of its production area is divided into A, B, C and D under the background of B level. Among them, the filling and half stoppering, lyophilization, capping, and clean bottle stopper storage are classified as Class A under a Class B environment, preparation and filtration are Class C, and the bottle stopper is cleaned and dried and sterilized as Class D.
(2) The workshop design strives to have a reasonable layout, follow the principle of separation of people and logistics, and do not cross backflow. Personnel entering the workshop must go through different levels of purification procedures to enter the Class D, Class C and Class B clean areas respectively. Those entering the Class A area under the background of Class B must wear sterile work clothes. The air pressure in the aseptic work area is higher than other areas, and the aseptic work area should be arranged in the center of the workshop as much as possible, so that the air pressure will flow from the higher room to the lower room.
(3) The purification air-conditioning and comfort air-conditioning system in the workshop can effectively control the temperature and humidity; and can ensure the temperature and humidity requirements of the cultivation room; the temperature of the control zone is 18~26℃, and the relative humidity is 45%~65%. UV lamps must be installed in each process.
(4) The layout of auxiliary rooms should be reasonable. The cleaning tool room and the container cleaning room should be located outside the aseptic operation area, and the non-sterile process operations cannot be arranged in the aseptic operation area. When materials or other items enter the aseptic work area, sterilization rooms or sterilization equipment should be set up for the disinfection or sterilization of materials and items. The containers and utensils after washing should be disinfected or sterilized before entering the aseptic work area.
(5) Arrange the pipelines of pure water and water for injection in accordance with GMP regulations.
(6) If there is a live bacteria culture such as a freeze-drying workshop for biological vaccine products, it is required to strictly divide the clean area into a live bacteria area and a dead bacteria area, and control and treat the air discharge in the live bacteria area and sewage with live bacteria.