Three in one to realize fully enclosed production

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"Three in one" in the pharmaceutical process to achieve fully enclosed production

the fully enclosed production process in pharmaceutical production has always been the best production mode pursued by drug manufacturers. In this way, the drug production process is not affected by external or man-made impurities, pollution, etc., which can most effectively ensure the drug quality, and the production has the least impact on the environment. This mode of production is in line with the development trend of cleaner production in the world

the application of some new technologies and new ideas in pharmaceutical engineering also provides technical means for the fully enclosed production of drugs. As long as the key equipment commonly used in production is the filter washing dryer, which is commonly known as the "three in one" equipment, combined with the development and application of some new technologies of the three in one unit, this paper explains how to comprehensively utilize the new technological progress of the three in one unit to realize the fully closed production process of sterile API

general production process of sterile API

generally, the final drug crystal is obtained through the crystallization process after the refining or synthesis process of sterile API. The crystalline suspension containing drug crystals shall be filtered first to realize the solid-liquid separation between the crystal and mother liquor and obtain the filter cake layer. Then, the washing device shall be used to spray the washing liquid to soak or rinse the filter cake. After a certain number of washing times as required by the process, the mother liquor shall be separated again, and then the crystals shall be dried (generally vacuum heating or vacuum freeze-drying). After drying for a certain time, samples shall be taken for inspection, The qualified products will become finished drugs. Finally, unloading, transportation, quantitative packaging or sub packaging shall be carried out

at present, in the production process of sterile API in most domestic pharmaceutical factories, the production process system as a whole has not been fully and reliably connected and optimized. Especially for the transportation and transmission of powdered drug materials, there has been no good connection and transmission mode in the actual production. The materials are mostly transported in bulk or in barrels. The non-contact video extensometer can avoid these problems and the manual handling between the sub packaging of Shandong Hongwang's annual output of 1.2 million tons of nickel based composite materials project. In this transfer mode, materials generally need to cross multiple purification rooms, which is easy to cause secondary pollution of materials during the transfer process, thus greatly reducing the startup cost. If the fully enclosed conveying system is adopted, the above problems can be completely avoided, making the production process more in line with cGMP requirements

the traditional bulk material transportation method is difficult to strictly ensure the sterility requirements during the loading or unloading process between the transportation container (box, barrel or PE bag) and the production equipment (dryer, mixer, sub packer, etc.). As the requirements for hygiene, environmental protection and cleanliness level of pharmaceutical enterprises are very strict, especially in the production of sterile preparations or products containing some active ingredients in the pharmaceutical industry, such requirements are more stringent. How to select the appropriate loading and unloading methods is very important. Therefore, to realize the full closed production process, it is the key to change the material transportation mode in the traditional production process

fully enclosed three in one production system

* gas conveying and discharging technology

at present, the more mature method of conveying powdery materials is to use high-speed air flow to fluidize powdery materials, and then realize the conveying of powdery materials through closed pipes. International advanced three in one equipment manufacturers have adopted this technology and have begun to apply it in the production of sterile APIs. Therefore, it is necessary to redesign the API production system based on three in one equipment, and make use of new and efficient gas transportation technology to form a fully closed production system

* fully enclosed three in one production system

a fully enclosed three in one continuous production system generally consists of more than one filtration, washing and drying three in one unit, gas conveying silo system and weighing and sub packaging system

the fully enclosed three in one production system can realize complete automatic operation control. The production process of the system is introduced as follows:

1) first seal the whole unit system, fill it with sterile inert gas (such as N2 gas) for protection, add the crystal solution to be treated from the crystallizer to the three in one through the automatic valve, and close the feed valve after reaching a certain volume

2) inject inert gas for pressurization, and realize solid-liquid separation of crystal liquid through the large metal filter plate at the bottom

3) spray and wash the filter cake after solid-liquid separation of crystallization liquid

4) after washing, drop the mixing device through the hydraulic device for mixing, at the same time, use the heating pipeline system inside the mixing to heat the material layer, and strictly control the temperature during the drying process, otherwise it will cause degradation failure of the drug. While heating and drying, the system shall be vacuumized to make the solvent evaporate rapidly. Meanwhile, the automatic operation of the dust collector shall be started to ensure the normal ventilation of the vacuum system

5) after the drying of the material layer is qualified (sampling detection or automatic process analysis pat is available), stop the vacuum and enter the automatic discharge procedure

6) automatic discharge: inject high-pressure sterile inert gas (such as N2 gas) near the discharge port, vacuumize at the side of the silo, then lower the mixing device, control the mixing speed and the falling speed of the mixing blade to scrape and feed the powdery materials quickly into the silo through the discharge valve, stop mixing and falling when the mixing is scraped close to the metal filter plate layer, and then inject the inert gas instantly, Blow all the bottom materials to the silo

7) after entering the silo, the material level shall be detected, and the material shall be unloaded to the metering silo in batches, and then the quantitative sub loading shall be carried out through the weighing controller. So far, the whole process of drug filtration, washing, drying and sub packaging has been completed

* fully enclosed material conveying system

the main limitation of traditional flat bottom filtration equipment such as tank type three in one and vertical dryer is that when the materials are finally unloaded, the operation is complex, and it is difficult to completely discharge the materials. Each unloading process not only takes a long time, but also causes a large number of material residues, affects the yield, and is easy to cause the phenomenon of mixed batches between drugs. The most important thing is that most of the bulk materials formed after the unloading of the above traditional equipment are transported to the next sub loading process by manual barrels. In this way, the materials span multiple purification rooms, which is easy to cause secondary pollution of the materials during the transfer process, thus not meeting the requirements of cGMP for the whole process of sterile operation

the fully enclosed material conveying system innovatively uses the gas transportation principle and high-speed air flow cleaning technology to realize the fully automatic discharge of tank type three in one. Moreover, the whole material conveying process is closed, with simple discharge action, high efficiency, short time, complete discharge and basically no residue. It completely solves the weakness in the process design of the traditional three in one equipment, making it fully applicable to the production of finished products of sterile API

three stages

* the first stage (main discharge stage): when the drying process is completed, the three in one enters the automatic discharge procedure, first open the discharge valve on the side of the tank bottom, and at the same time, connect the vacuum system of the silo. In addition, when the discharge valve is opened, the N2 gas valve on the discharge valve is also opened at the same time. N2 gas is blown in from the middle of the discharge valve to fully aerate the powder in the discharge valve and flow to the receiving silo at a high speed through the discharge pipeline. When the material powder arrives at the silo, most of the material powder will fall to the bottom of the silo due to the cyclone separation and gravity, and a small part will reach the upper filter with N2 gas, which will be intercepted by the filter and recycled by the back blowing device

during the discharging process, the three in one mixing shall be kept at a slow speed, and the powder on the three in one filter plate shall be gradually pushed to the discharge valve port until all products are basically discharged. When the bottom layer of materials (residual materials) that cannot be scraped by the mixing is left, the discharging shall enter the second stage, that is, the residual material removal stage

* the second stage (residual material removal stage): the mixing stops rotating, and then the high-pressure N2 gas injection valve on the top of the tank starts, so that the high-pressure N2 gas forms a high-speed rotating air flow, blowing up all the remaining powdery materials at the bottom layer to form aerosol form, and then blowing in the low-pressure N2 gas, so that all aerosols in the tank can be quickly discharged from the discharge valve. The user can set the high-pressure injection times according to the production residue requirements to completely eliminate the residues

when all the materials enter the silo, the next step of closed sub loading of powder can be carried out

* the third stage (weighing and repacking stage): the materials are discharged into the closed repacking system and can be weighed accurately on batch containers. For the products supplied in PE bags, they are directly connected with the outlet of the dryer, the materials pass through the vibrating screen and enter the vertical storage pipe, and then the materials are sub packed through the vibrating pipe. For the drum sub charging system, the materials are sub charged through the quantitative sub charging valve through the closed transmission system

the working principle of the dispensing system is as follows: the three in one dried API powder enters the oscillating screen through the bottom valve of the silo. Under the oscillation and shaking of the oscillating screen, the qualified fine powder is evenly screened into the metering silo, and then the fine powder falls into the barrel container above the electronic scale through the closed soft connection through the dispensing control valve at the outlet of the metering silo. By detecting the weight of the materials on the scale, the weighing and sub charging system controls the opening and closing of the sub charging valve by program, so that the sub charging of a single barrel of powder can quickly achieve the basic loading in a very short time, and then slowly and accurately. When the weighing reaches the set value, the valve is closed to end a sub packaging process. The composition of the whole device is shown in Figure 2

characteristics of fully enclosed three in one production system

1) the production system process is fully enclosed. Because of the fully enclosed objects 2. The innovative application of the classified material conveying system according to the loading method can completely realize the fully enclosed production process from the beginning of crystallization to the end of sub packaging. This set of equipment is a fully enclosed system, and the production process is more in line with cGMP requirements

2) safety and environmental protection. Because the production system is fully closed, it can completely avoid the pollution of solvents to the operating environment air during the production process, and reduce the occurrence of poisoning accidents of operators due to contact with toxic substances. Today, with the growing voice of environmental protection and labor protection, this advantage is even more important

3) high drug yield and complete solvent recovery. Because the whole production system is a fully closed system, the materials and solvents can be almost 100% fully recovered to avoid waste caused by material omission, residue and solvent volatilization, which has great economic benefits, especially when the value of materials and solvents is high

4) high degree of automation and easy to master. Each process is carried out in stages with complete safety measures. The operators can complete the operation after simple training, and the work intensity is greatly reduced

5) complete the thorough cleaning of materials. Because this equipment can stir and suspend the filter cake again during washing operation, the filter cake can be thoroughly cleaned

6) all operations can be completed with the same system. Filtration, washing, drying, transportation, weighing and sub packaging can be completed in the same system. The connection of each stage is very natural and smooth, and the space is also maximized

7) clean production. This multi-functional filtering and drying equipment can be operated in a closed manner, and is equipped with a dust collector to completely collect the dust generated after drying, which can meet the production and operation requirements of high cleanliness

in view of the above advantages of the fully enclosed three in one production system, the production line formed by it is particularly suitable for the production of sterile pharmaceutical products, making the three in one equipment technically

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