Abstract: Starting from the basic structure and working principle of Wuxi Zhanghua Pharmaceutical Equipment’s cone-shaped agitated nutsche filter dryer (“Three-in-One” Equipment) and taking the clean-grade product as an example, the advantages of the equipment in the production of APIs are discussed from four aspects: product purity, process adaptability, automation and real-time monitoring, and multi-directional CIP.
Key words: cone-shaped agitated nutsche filter dryer (“Three-in-One” Equipment); API production; advantages; new GMP
In the production process of AIPs, in order to reduce the material loss and avoid environment pollution that may be caused by the material transfer after crystallization, the subsequent filtration, washing and drying processes of the material are usually completed in one single piece of equipment, which is called “Three-in-One” for short. The most common “Three-in-One” used in drug production is with flat bottom, and there is no doubt that it has advantages in the production of sterile APIs, however, certain defects in another side as well, including small filter area in the circular flat bottom, side discharge (there is always material left behind), poor drying performance, small movement of material during the drying process, and low efficient heat transfer, more limits of drying, etc.
The prototype development of cone-shaped agitated nutsche filter dryer (hereinafter referred to as “cone-shaped ‘Three-in-One’”) began around 1993. On the basis of comprehensive analysis of the advantages and disadvantages of domestic "Three-in-One" equipment, after five generations, it has developed into the current clean-grade model, already successfully used in the production of APIs for more than 10 years.
With the increasing environmental awareness and higher production quality standards of APIs in China, the cone-shaped "Three-in-one"has its significant advantages. Taking the clean-grade cone-shaped "Three-in-one"of Wuxi Zhanghua Pharmaceutical Equipment as an example, we here briefly introduce its basic structure and working principle and focus on its advantages in the production of APIs.
1 Basic Structure and Working Principle of Wuxi Zhanghua Pharmaceutical Equipment’s Cone-shaped "Three-in-one"
The cone-shaped “Three-in-One” can complete a series of processes in one single piece of equipment, including solid-liquid separation and filtration, filter cake washing and material drying processes.
1.1 Basic Structure
Taking the clean-grade cone-shaped "Three-in-One" for the production of APIs as an example, its main structure is shown in Figure
Figure 1 Structure of Clean-grade Cone-shaped "Three-in-One"
a - Dust-proof mechanism b - Explosion-proof transmission mechanism
c - Rack mechanism d - Spray mechanism
e - Main shaft to stir and built-in heat exchange system
f - Main body g - Auxiliary maintenance mechanism
h - Filtering mechanism i – Automatic downward expansion discharge valve
a is the dust-proof mechanism, which meets the requirements of the clean area and helps to avoid dust pollution caused by transmission parts.
b is the explosion-proof transmission mechanism, including an explosion-proof main motor and a reducer. Its hardened gear reducer can strengthen the transmission capacity and ensure stable operation of the equipment.
c is the rack mechanism, with clean-grade mechanical seal of main shaft and multi-support layout.
d is the spray mechanism, including components for material washing and CIP.
e is the main shaft to stir and built-in heat exchange system, using a ribbon-type suspended stirring mechanism (no fulcrum at the bottom).
f is the main body of the equipment, including the heat exchange jacket and outer insulation components.
g is the auxiliary maintenance mechanism, which is used to assist the cone parts to go up and down, making it easy for disassembly and maintenance.
h is the filtering mechanism, including components for filtering medium and Reverse CIP (RCIP).
i is an automatic downward expansion discharge valve, which can realize fully automatic operation. It uses a valve cover with flat bottom, no dead corner for accumulated material, and can be completely cleaned in place.
1.2 Working principle
An intermittent process flow is applied toWuxi Zhanghua Pharmaceutical Equipment’s cone-shaped "Three-in-One", of which typical operation process is “feeding-filtering-washing-drying-discharging-CIP”, as shown in Figure 2.
The equipment generally adopts either pressure filtration or vacuum filtration, and there is huge difference between these two ways according to the characteristics of materials and filter cakes, which needs to be confirmed by small tests.
During the vacuum drying process, the equipment has a built-in heat medium circulation system. When the heat medium is added, at the same time, with vacuum pumping, the ribbon-type stirring mechanism rotates forward to lift the material for flipping in all the directions to realize the complete heat exchange, and the drying status of materials can be monitored by a vacuum online sampler.
After the drying process is completed and the internal environment of the equipment returns to normal pressure, the discharge valve is opened, and the stirring mechanism rotates forward to discharge most of the materials, and the rest small number of residuals are forced out by the stirring mechanism in reverse.
After the discharge is completed, the equipment is cleaned in multiple directions: the washing system will clean the inner part and the ribbon-type stirring mechanism; RCIP system will clean the residual layer, filter medium and the valve; CIP system will clean the valve cover and the connecting nozzle.
Figure 2 Operation Flow of Cone-shaped "Three-in-One"
2 Advantagesof Wuxi Zhanghua Pharmaceutical Equipment’s Cone-shaped "Three-in-One" in the Production of APIs
The new version of GMP puts forward higher requirements for the production of APIs and related equipment. It is obvious that equipment is the key to ensuring the quality of APIs and their production stability. The following will explain the advantages of cone-shaped "Three-in-One" in the production of API in combination with the relevant requirements in the new GMP.
2.1 High Product Purity
2.1.1 No Impurities Allowed to Be Mixed in the Material
After the material enters, parts in the equipment that are directly exposed to the material include the functional nozzle, the inner wall, the stirring mechanism, the filtering mechanism, the filtrate channel, the filtering component and the discharge valve mechanism. Among them, except for the stirring mechanism, the others are all static. Equipped by the correct materials, with proper manufacturing process, these parts will not bring any foreign matter into the process. However, the stirring mechanism is moving. First, it needs to use clean-grade mechanical seal of main shaft to realize good sealing performance. An isolation cavity is set in the mechanical seal to prevent any impurities that may be generated by the environment or the mechanical seal itself from entering the equipment. Secondly, as there is no rotating fulcrum at the bottom of cone-shaped "Three-in-One" for stirring mechanism, which is designed with suspension concept, it fundamentally eliminates the possibility of contamination by impurities.
2.1.2 Ensure the Safe and Clean Environment
The equipment is fully sealed, which not only ensures the cleanliness of the product during the process, but also protects the production environment. Especially for cases with volatile or dangerous solutions in the process, the equipment can ensure the safety of the environment and operators.
The ribbon-type stirring mechanism uses an axially fixed structure that does not move up and down, and maintains a settled and stable safe distance from the equipment, ensuring production safety without routine maintenance.
2.2 Advantages of Adaptability
2.2.1 High Filtering Efficiency
(1) Large filter area: The filter medium of "Three-in-One" is cone-shaped, equipped on the wall of the tank, as shown in Figure 3. Taking the size of the device with an inner diameter of about 1 m as an example, the standard conical filter area is about 1.6 m 2 , and the effective filter area is about three times that of the "Three-in-One" with the same diameter, but flat bottom.
Figure 3 Filter Medium Structure of Cone-shaped "Three-in-One"
(2) Small nominal thickness of the filter cake: There are many studies on filtration theory. Due to the large difference in the properties of material particles, there are many factors that affect the filtration rate. A semi-empirical model based on Darcy's Law and Poiseuille Equation figures out that thickness of the filter cake is one of the factors, which is inversely proportional to the filtration rate  : with the correct selection of filter medium, the filter cake layer should be formed and play a stable bridging role within a reasonable time to improve the filtration performance. The thinner the filter cake layer is, the faster the filtration speed is.
(3) In the cone-shaped "Three-in-One", the distance between the filter medium and the stirring mechanism is the nominal thickness of the filter cake. The ribbon-type stirring mechanism continuously change the inner cake, the thin layer of filter cake retained on the surface of the filter medium will form a stable filter strengthening layer. At the same time, the replacement process can also smooth the gaps in the filter cake, creating a stable pressure difference, thereby obtaining a filter cake with a lower moisture content.
2.2.2 Efficient Washing
The internal ribbon-type stirring mechanism of cone-shaped "Three-in-One" can quickly repulp the material after adding an appropriate amount of washing liquid. The thorough contact between the filter cake and the washing liquid will greatly improve the washing and replacement efficiency. Compared with the general blade-type and anchor-type stirring mechanism, the ribbon-type one obviously has better repulping performance.
2.2.3 Large heat transfer area and efficient drying
The cone-shaped "Three-in-One" has a large heat transfer area, including the heat transfer area of the main body (equipped with a high-efficiency heat transfer jacket) and the internal overall stirring heat transfer area. The super large heat exchange area not only ensures its drying performance, but more importantly, it makes effective use of the heat exchange area. The exchange contact between the material and the heat exchange parts is the most critical factor.
The ribbon-type stirring mechanism in the cone-shaped "Three-in-One" has better performance in mixing materials: the ribbon-type stirring mechanism rotates from the bottom to the top to lift the material, and then falls back to the bottom, with a long travel. The simulation of the mixing performance of materials in the cone-shaped "Three-in-One" is shown in Figure 4. The software is used to simulate the actual material moving state, and the light-colored particles are selected as the tracking samples.
Taking the design of MX-F-II mixing mechanism in a 5 m3 cone-shaped "Three in One" as an example, the feeding coefficient is 40%, the rotating speed is 35 r/min, and the samples are tracked in a short time, and it is found that they can move uniformly and contact with the heat exchange surface. For different materials, combined with the mixing performance and the need of crystal shape, there are a variety of types in the design database, and customized equipment is also optional. In case of special circumstances, the stirring mechanism can also be attached with corresponding mechanisms to meet the requirements, such as for the material with serious agglomeration, the forced crushing device can be equipped.
Figure 4 Simulation of Material Mixing Performance of Cone-shaped "Three-in-One"
2.3 Automation and real-time monitoring
In the process of large-scale pharmaceutical production, if the operation process of a single device is manually controlled, there will inevitably be some errors. In order to ensure the consistency of products between batches in terms of process flow, the cone-shaped “Three-in-One” can be controlled automatically, easy to operate and integrate into the central control system (PLC or DCS, etc.), which greatly reduces the labors for equipment operation, improves production efficiency, and effectively guarantees the high quality and stability and products.
In addition, it is also very important to monitor the product status inside the equipment for the control of the process flow. The sampler equipped inside can operate online in vacuum during the drying process to ensure continuity of production and effectively monitor the drying performance.
2.4 Multi-directional CIP
For the cone-shaped"Three-in-One"to produceAPIs, the internal part in direct contact with the material is polished, and its roughness is Ra≤0.4 μm.After the completion of a batch of products, discharge will be carried out. As the bottom of the equipment is designed as conical, the discharge port is set at the lowest position, no dead corner for accumulated material. After the discharge valve is opened, most of the materials in the forward rotation mixing mechanism will be discharged smoothly (in order to avoid the uncontrolled mass discharge of materials once the valve is opened, the stirring mechanism plays a certain bridging role, and once the material is rotated, it will be automatically discharged by gravity); At the later stage of discharging, the reverse rotation of the stirring mechanism further plays a role in pushing the material, which can almost discharge the remaining material in the equipment.
To fix the problem of a small number of residuals, there is an auxiliary cleaning program:
(1) The internal CIP of the equipment, the customized spray ring has holes in all the directions, and the inner wall of the equipment and the nozzle part of the head can also be cleaned in place. Meanwhile, there are different optional dropping angles for the ribbon-type stirring mechanism according to the characteristics of the materials. When the process is completed, most of the materials can be discharged, and a small number of residuals can be cleaned by the shower nozzle.
(2) Reverse Clean-in-Place (RCIP) program for filter medium: For the problem of residuals, most of API production processes use metal multi-layer sintered plates as filter medium. The safety gap between the outer edge of the ribbon and the filter medium is where the final residuals are, the amount of which varies with the characteristics of the material. The RCIP mechanism is located between the filter medium and the filtrate channel, as shown in Figure 5. RCIP is carried out within a short distance (generally 2~3 cm), the flushing pressure can reach 0.6 MPa. The residual layer is generally sticked as a whole and can be crushed down by the friction of the stirring mechanism after being partially washed. At the same time, CIP can effectively wash the filter medium and maintain the filtration rate of each batch for extremely fine or viscous materials. Regarding the replacement and maintenance of filter medium, the cone-shaped "Three-in-One" is equipped with auxiliary maintenance mechanism, including lifting system, cone lifting components, etc., which is easy to operate and maintain.
Figure 5-- Fliter Medium of Cone-shaped "Three-in-One"
Schematic Diagram of Reverse Clean-in-Place (RCIP)
The cone-shaped "Three-in-One"was born to meet the market demand and has obtained a number of national patents. It has been developed and applied for more than 20 years, and the clean-grade cone-shaped version for the compliance of API production is already the fifth-generation, which closely follows the corresponding regulatory requirements of the pharmaceutical industry, from structural design to application, and has been used in pharmaceutical companies for more than 10 years. With the increasing environmental awareness and the expanding API market, it is essential to upgrade the pharmaceutical equipment. The cone-shaped "Three-in-One" will significantly improve product quality, protect the production environment, and bring considerable benefits to the enterprises.