We have specialized in providing industrial processing equipment for fine chemicals, pesticides, new energy,new materials, and pharmaceutical industries for more than 48 years.
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We have specialized in providing industrial processing equipment for fine chemicals, pesticides, new energy,new materials, and pharmaceutical industries for more than 48 years.
It has always been the best solution pursued by the pharmaceutical manufacturers that the process flow of production can be completed in the fully closed environment, because in this way, the entire process is isolated from external or artificial impurities, pollution and others, which can most effectively guarantee the drug quality and minimize the production impact on the environment. This is in line with the development trend in the world.
The application of some new technologies and new ideas in pharmaceutical engineering also provides technical means for drug production in the fully closed environment. Agitator nutsche filter dryer, commonly known as "Three-in-One", is the key for production. Here explains how to realize the production process of sterile APIs in the fully closed environment based on the development and application of some new technologies of the Three-in-One unit.
General Process Flow of Sterile APIs
Generally, the final pharmaceutical crystals are obtained through the crystallization process after the sterile API is refined or synthesized. The crystal suspension containing the drug product is firstly filtered to separate the crystal from the mother liquid, and the filter cake layer is obtained afterwards. Then the washing device is used to spray the washing liquid to soak or flush the filter cake for certain times required by the process. After the mother liquid is separated again, the crystal is dried (usually by vacuum heating or vacuum freeze-drying) for a certain period of time, and a sample is taken for inspection. If the result passes the test, then production process is basically done, and the final steps for drug products are unloading, transportation, quantitative packaging or sub-packaging.
At present, the process flows of sterile APIs in most domestic pharmaceutical factories are not complete and optimized, without functions well connected with each other. Especially for the transfer and transmission of powdery pharmaceutical materials, there is no good connection in actual production. The material is mostly delivered in bulk or in buckets and are moved by workers between the discharging and sub-packaging processes. In this way, the material generally will cross multiple purification rooms, which is likely to increase the risk of secondary pollution. If a fully enclosed delivery system is used, then above problems can be completely avoided, making the production process more in line with CGMP requirements.
It is difficult to strictly meet the sterile requirements during the loading or unloading process if material is delivered in bulk from the transport container (box or PE bag) to the production equipment (dryer, mixer, dispenser, etc.). Considering the strict requirements of pharmaceutical companies for hygiene and environmental protection, especially in the production of sterile products or products containing certain active ingredients, it is critical to choose the appropriate feeding and discharge methods, so changing the traditional transfer way in the process flow is the key to realize production in the fully closed environment.
Fully Closed Agitator Nutsche Filter Dryer/ “Three-in-One”
Gas Conveying and Discharging Technology
At present, the relatively developed conveying technology for powder material is to use high-speed airflow to fluidize the material, and then realize the powder transmission through a closed pipeline. It is not new for the advanced manufacturers of Three-in-One in the world, and they already started to apply it in the production of sterile APIs, which requires the redesign of the production system originally based on Three-in-One, adding this new and efficient air conveying technology.
Fully Closed “Three-in-One”
The fully enclosed Three-in-One continuous production system generally consists of “Three-in-One” unit with more than one agitator nutsche filter dryer, an air conveying system and a weighing and packaging system.
The fully enclosed Three-in-One production system can be operated and controlled automatically, details of which are introduced as follows:
1、
First seal the entire unit, fill it with sterile inert gas (such as N2 gas) for protection, add crystallization liquid to be processed from the crystallizer to the Three-in-One through the automatic valve, and close the feeding valve after reaching a certain volume.
2、
The inert gas is introduced to pressurize, and the solid-liquid separation of the crystallization liquid is realized through the large metal filter plate at the bottom.
3、
After the solid-liquid separation of the crystallization liquid, spray and wash the filter cake.
4、
After washing, the stirring device is lowered by the hydraulic device for mixing, and at the same time, the material layer is heated by the pipeline inside the stirring device. The temperature in the drying process should be strictly controlled, otherwise the drug will be degraded and invalid. While heating and drying, vacuumize the system to make the solvent evaporate quickly, and at the same time start the dust collector to ensure the ventilation of the vacuum system.
5、
After the material layer is dried and qualified (according to sampling test or process analytical technologies (PAT)), stop the vacuum process and start the automatic discharge program.
6、
Automatic discharge: fill high-pressure sterile inert gas (such as N2) near the discharge port, and at the same time vacuumize the side of the stock bin, then lower the stirring device, control the stirring and descending speed of the paddle to scrape and push the material, helping them enter the stock bin quickly through the discharge valve. Stop stirring and descend when the paddle is close to the metal filter plate layer, and then fill inert gas instantly to blow all the bottom material to the bin.
7、
After the material enters the stock bin, the level is detected, then the material is loaded into the metering bin in batches, and then quantitatively distributed through the weighing controller. Now the whole process of filtering, washing, drying and packaging of medicines is completed.
Fully Closed Conveying System
The main limitation of traditional flat-bottom filter (such as tank-type Three-in-One and vertical dryers) is that the operation of unloading at the end is complicated, and it is difficult to completely discharge the materials. It not only takes long time, but also a large amount of residuals are left behind, which lessens the yield and mixed batches of medicines may happen. The most important thing is that after discharge in the tradition equipment, the bulk materials are mostly moved by workers in buckets to the next sub-packaging process, crossing multiple purification rooms, which is likely to increase the risk of secondary pollution and not in line with the requirements of cGMP of sterile operation in the whole process flow.
The fully enclosed conveying system innovatively utilizes the principle of gas transportation and high-speed airflow cleaning technology to realize the fully automatic discharge in tank type Three-in-One, and the entire conveying process is in the closed condition, with simple discharge action, high efficiency, short operation time, complete discharge, and almost no residual, which basically fixes the disadvantage in the process design of the traditional Three-in-One, making it fully applicable to the production of sterile APIs.
Three stages
The first stage (main discharge stage): When the drying process is over, the automatic discharge program of Three-in-One is triggered. First open the discharge valve on the side of the tank bottom, and at the same time connect the vacuum system of the stock bin. When the discharge valve is opened, the N2 gas valve on the discharge net is opened simultaneously. N2 is blown in from the middle of the discharge valve to fully gasify the material powder inside, and flow through the discharge pipe to the stock bin at high speed. When the material powder reaches the bin, most of them falls to the bottom due to cyclone separation and gravity, and a small part reaches the upper filter with N2, trapped by the filter and recovered by the back blowing device.
During the discharge process, the agitator in Three-in-One moves at a slow speed, and gradually pushes the powder on the filter plate to the discharge valve until all the products are basically discharged. Some residuals are still left on the bottom where the paddle cannot be scraped by the agitation (the remaining material), then the discharge process enters the second stage, that is, the stage of removing the remaining material.
The second stage (residual removal stage): the stirring paddle stops, and then the high-pressure N2 gas valve on the top of the tank is opened, and a high-speed airflow is formed, blowing up all the remaining powdery materials at the bottom layer and changing them into aerosol form. After that, blow in low-pressure N2, so that all aerosols in the tank can be quickly discharged from the valve. The user can set the times of high-pressure gas injection according to the production requirements. When all the materials enter the stock bin, the next step of closed packaging of the powder can be carried out.
The third stage (weighing and sub-packaging stage): The material is discharged and enters the closed sub-packaging system, which can be accurately weighed on the batch container. For products packed in PE bags, it is directly connected to the outlet of the dryer. The materials pass through the vibrating screen, enter the vertical storage tube, and then are distributed through the vibrating tube. For the bucket filling system, the material is packed through the quantitative filling valve through the closed transmission system.
The working principle of the sub-packaging system is that after dried by Three-in-One, API powder passes the vibrating screen through the bottom valve of the stock bin, and under the vibration and shaking, the qualified fine powder is evenly screened into the metering bin and then dropped into the barrel-shaped container on the electronic scale through the closed soft connection and the sub-charging control valve at the outlet. The weighing and sub-packaging system detects the weight of the material on the scale, and the program controls the opening and closing of the sub-packaging valve, so that the distribution of a single barrel of medicinal powder can quickly achieve the basic filling amount in a short period of time, and then slowly and accurately load. When the weigh reaches the set value, the valve is closed, and the sub-packaging process ends.
Features of fully closed Three-in-One production system
1）
The production process is completed in fully closed environment. Due to the innovative application of the advanced conveying system, the production process from crystallization to sub-packaging can be completed in fully closed environment. This set of equipment is with a fully closed operating system, more in line with GMP requirements.
2）
Safety and environmental protection. Thanks to the operation in fully closed condition of this system, it can completely avoid the pollution of the solvent to the air in the operating environment during the production, and at the same time reduce poisoning accidents caused by contact with toxic substances. This advantage is even more important today when the calls for environmental protection and labor protection are rising day by day.
3）
The drug yield is high, and the solvent can be completely recovered. As the entire production system works in a fully closed condition, materials and solvents can be recovered almost 100%, which avoids waste caused by material omission, legacy and solvent volatilization and creates great economic benefits, especially in the treatment of high-value materials and solvent.
4）
It is highly automatic and easy to operate. Each process is carried out in stages, with considerate safety measures. Workers can take up the job after simple training, greatly reducing the workload.
5）
Thorough cleaning of materials. Since this equipment can re-stir and suspend the filter cake during the washing operation, the filter cake can be thoroughly cleaned.
6）
All operations can be done with the same system, including filtration, washing, drying, transmission, weighing, and sub-packaging. The connection of each stage runs smoothly, while the space is also used to the greatest extent.
7）
Clean production. This multifunctional filter dryer can work in a closed condition and is equipped with a dust collector to collect the dust generated after drying, which can meet the high requirements in cleanliness of production. In view of the above advantages of the fully closed Three-in-One production system, such production line is especially suitable for sterile pharmaceutical products, making its technical performance completely integrated and optimized with the pharmaceutical process system.
At present, with the general application of GMP regulations in the pharmaceutical production process, more and more companies are concerned about the process adaptability of their equipment, especially in the manufacturing stage of finished drug products, the norms and standards will become more and more strict, and the closed production process will be their best choice. The Three-in-One production system with fully closed conveying function can realize the entire pharmaceutical production process in then closed condition, including crystallization, filtering, washing, drying, discharging, screening and sub-packaging, so it is a very good solution for pharmaceutical companies, as well as a successful case to apply the new technology to the traditional equipment for integration and upgrading, and the profoundly glorious future of such application is seen.
