Continuous manufacturing has been making its way into pharmaceutical and nutritional production for almost 20 years. It is associated with a wide range of advantages: integrated processes increase both process reliability and efficiency; process times are reduced compared to batch processes, while the specific production output increases; market launches can be realized more quickly, and production becomes more flexible overall.
In tablet production, continuous direct compression is meeting with growing acceptance, as it appears attractive in terms of process technology and enables a leaner plant design compared to batch-to-batch production. The reasons for the still dominant role of batch production are manifold and lie, among other things, in well-known reservations.
Overcoming economic reservations
One central concern can be traced back to observations of existing continuous facilities: these often take up a lot of floor space and room height, which usually requires prior modifications to existing buildings or even new builds. In addition, there are concerns about long lead times for design and manufacturing and the tendency for high investments as plants have to be customized. The complexity also makes many manufacturers shy away, as scientific personnel are required for setup and specially-trained users for operation. During operation, interested parties also fear long downtimes due to the time-consuming cleaning and retooling processes.
Conversely, conclusions for economic continuous manufacturing can also be derived from these “pain points.” This involves less complex and easier-to-adapt systems based on a simplified process chain. The direct compression process creates optimal conditions for this.
Compact and flexible overall system
Building on these conclusions, Fette Compacting has rethought continuous manufacturing for tablet production from the ground up. The result is the continuous direct compression system. It comprises a closed dosing-mixing unit FE CPS including powder transport system, an FE 55 tablet press, and an operator terminal. The entire system can be integrated into existing production areas on a single level. Structural investments are thus reduced to a minimum.
The FE CPS processes a wide range of formulations with throughputs from about five to 200 kg per hour. It thus offers a high degree of process flexibility: from product development to smaller batches and large-volume production. The FE 55 tablet press has three compression stations instead of two, enabling longer pressure holding times at lower pressure. This results in gentler processing and an even more flexible tableting process. Such a setup is also suitable for a multiple unit pellet system (MUPS), as segregation processes can be effectively reduced.
Focus on safety and simplicity
During development of the FE CPS, the focus was on operator safety. The process area was designed to be dust-tight. Additional protection is provided by the enclosed design, which is also supported by sealed glass panels and a vacuum in the process area.
Until now, cleaning and retooling were considered critical work steps in continuous systems, as they consist of much more than a hundred individual parts. The new dosing-mixing unit, on the other hand, features significantly fewer parts and interfaces and has separate process and technical areas which are easily accessible. For this purpose, it was divided in such a way that the process parts of the refilling stations, the dosing stations and the specially-developed mixer are located in the process area. The technical area, which is dust-tight and separate from the process area, houses the drives, the electronics and the cabling, among other things. All components can be easily removed from the process area for cleaning.
Furthermore, the system follows a design principle that consistently focuses on simplicity in terms of operation, changeover and maintenance. At its heart is the human-machine interface (HMI), which provides the operator with an overview of all parameters for dosing, mixing, tableting, and process analysis. In future, a single terminal will be sufficient to record the entire continuous process, including recipes, protocols, events and diagnostics. Handling of the HMI is learned in a short time, so that the qualification threshold for operation in continuous operation is significantly lowered.
Fully-integrated process analysis
The material properties and the machine and process design have a major influence on the stability of the continuous process. This is where the continuous direct compression system sets new standards. To monitor the decisive quality attributes, it has a new type of technology for inline process analysis (embedded Process Analytical Technology, ePAT), in which sophisticated sensors are integrated into the process units. They can be positioned at four points to continuously monitor relevant production parameters: at the outlet of the mixer, at the inlet of the tablet press, at the Fill-O-Matic, and in the process chamber of the tablet press. For example, the sensor at the mixer checks mixing homogeneity. Such inline measurements, which take place directly in the production flow, allow swift reactions in the case of quality deviations and direct adjustment of the production process.
With data acquisition and analysis in real time, the FE CPS also sets new standards in terms of measurement and reaction speed. When it comes to measurement methods, near-infrared spectroscopy (NIRS) has proven to be particularly efficient. Its advantage lies in the fact that it is good at detecting many active substances in this spectral range. The infrared rays penetrate deep into the tablet without damaging it. NIRS enables ultra-fast quality checks on larger sample quantities, making it ideal for high-performance tablet presses such as the FE 55 and the upstream mixer. Depending on requirements, Fette Compacting works with users to determine an individual PAT solution to exploit the full efficiency potential of continuous tableting.
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