Pellet Production Customized Granulation Line: Precision Work in Pellet Production
Losan Pharma adds a new granulation line for pellet manufacturing to an existing production: The process of upgrading existing inventory means an intervention into existing production facilities, so it requires surgical precision. The combination of existing machinery with new equipment, which can only be allowed to take up an extremely limited amount of space, is a real challenge for everyone involved in the project. The practice report describes the concept design and installation of a mixer/granulator for pellet production.
Pharmaceuticals company Losan Pharma has specialized in the development and production of modern drugs with optimized active ingredient performance. As an internationally recognized partner of the pharmaceutical industry for contract development work and contract manufacturing, Losan offers a wide range of solutions and services. Already at the end of 2016, the ever-increasing order volumes in basic manufacturing prompted the management to plan forward-looking technical investments at the Neuenburg plant in order to increase production capacity.
One area of the capacity increase was focused on expanding pellet production. The main task here was to integrate machine components from the already existing inventory into the new production line — all the while delivering a high degree of automation and achieving both high product quality and high yield.
Challenge: Lack of Space for Technical Zone
The installation of, among other things, a new granulation plant was carried out in the center of the existing production inventory. Due to building restrictions such as installation floor space, room height, and the surface load on the floor slabs, it was necessary to adapt the design of the granulator to the existing conditions in production in order to allow the machinery to be moved into place and subsequently installed.
Since there was no space for a technical zone behind the machinery, the majority of components such as the control cabinets, the cleaning equipment (Wash-in-Place) and the vacuum pumps were positioned on an intermediate floor above the installation. In addition, practical traffic routes needed to be available on the plant to enable effective working processes.
All of these challenges were met exceptionally well. The plant was taken into operation on time and without any problems. It was not necessary to interrupt operations in adjacent production areas, among other things because the mixer/granulator from equipment manufacturer Diosna was disassembled when it was moved into place. The teams of machine builders and the other trades worked closely together — with excellent motivation and coordination courtesy of the Losan project management.
The new granulator can be used to manufacture up to 400 kg of wet granulate. This meant that the previously established batch sizes could be increased by a factor of three. The scale-up procedure for product transfer from the existing equipment to the new wet granulator was completed without any issues.
Challenge: Upgrading the Existing Inventory
Once the original idea of installing a completely new line in the periphery of a newer building tract had been discarded, various options were investigated for carrying out the building work in the existing inventory. It needed to be taken into account in the planning that only a relatively small amount of floor space was available in the production cabinet for the mixer that was to be supplied by Diosna.
Originally, an advantageous “through the wall” installation of the mixer was targeted. However, the limited space and lack of an adjacent technical zone meant that this was impossible. A joint effort was made to find a hybrid solution that would fit perfectly in the room yet still offer the “through the wall” advantages.
The machine frame of the mixer serves not only as an operating level, but also as access to a directly adjacent operating platform with the downstream equipment, resulting in an exceedingly small overall footprint for the mixer and the complete production line. The frame of the mixer is enclosed all the way down to the floor, which makes external cleaning of the system much easier.
Instead of installing a new fluidized bed dryer, the decision was taken to use an existing dryer and to install the other core components of the plant in an immediately adjacent position, i.e. the mixer/granulator and other systems for further processing of the granulate into the required intermediate stage prior to the actual drying.
The decision to opt for the equipment from Diosna was based in particular on the details of the mixing and granulation technology — the Diosna granulator tends to operate with the impeller at lower rotational speeds. In return, the projected surface area in the flow direction is comparatively large. The bottom line is a large specific swept volume (i.e. the volume that is moved or “swept” per second, divided by the overall volume), whereby the vanes of the tool are positioned tangentially on the drive shaft/displacer in the middle of the impeller. Together with the special geometry of the vessel (with a tendency for larger diameters and lower vessel heights) and the tried-and-tested chopper construction, this delivers an intensive granulation process that can be controlled very well.
The material flow throughout the entire production line was adapted for the given space and installation conditions. A gravity-fed charging system was therefore only of limited usefulness.
Coordinated Parameters for High Pellet Quality
All of the plant components are carefully coordinated with each other and automated for the most part. A combination of pneumatic and gravity-fed product transfer enabled the plant components to be arranged in close proximity to each other despite the relatively low room height. The plant operates virtually continuously in shift mode with high hourly output rates.
The foundations for the high quality of the pellet product are already laid during wet granulation. The carefully coordinated geometries and rotational speeds of the impeller and the chopper guarantee consistent wetting and compaction of the granules.
The solids are initially sucked in via a powerful conveyor system. In order to reduce the time it takes to charge the granulator, two large stainless steel filters with a small mesh size are arranged on the mixer lid. They also allow the conveying of micronized powder and can be cleaned with WIP systems. Nonetheless, they ensure complete separation of particles from the conveying air that is sucked in.
With the aid of two different pumps that are integrated in the mixer frame — one peristaltic pump and one sinusoidal pump — the required granulating fluids can be added individually depending on the viscosity and the requirements of the particular recipe. The rates of addition for the fluids and the rotational speeds of the impeller and chopper were optimized and coordinated with each other. Since the height of the powder bed changes during the course of the granulation process, height-adjustable nozzles adapt the injection point depending on the fill height and product properties.
Depending on the product, the mixing and granulation process is either partially or fully automated. Although manual operator interventions were optimized upfront with an updated process design, on some products they still cannot be completely avoided. Here, the operator can be guided safely through the process with notification windows or fixed work instructions that are saved in the recipe.
The final step for granulation is calibration, i.e. breaking the granulate with the aid of a conical screen mill during emptying of the mixer. Here, it was agreed between Losan and Diosna that fill level sensors should be installed in a connected buffer container. The discharge function is thus largely automated. The mixer empties itself automatically — as directed by the recipe and based on demand.
Control Via Two Redundant Operating Stations
The granulator was designed with two redundant operating stations. A display next to the granulator enables the operator to observe and control the direct process sequence in and on the granulator during process transfers and for new developments. The second operating station of the granulator is combined with further operating stations such as those of the fluid bed dryer and the MES terminal into a control center. As a result, the operator can keep an eye at all times on all processes that are taking place and can control the entire line from a central position.
Connection of the production line to the IT infrastructure of Losan was also an important topic for the project. User administration is implemented via a domain server.
The batch reports generated by the plant are automatically saved and backed up to a dedicated path on the internal network. Subject to appropriate authorization levels, this permits individual reviews of the process data and allows the data to be printed out via a network printer or appended electronically as a batch report. In addition, the foundations were also laid for subsequent direct use of process data in the MES system.
WIP (Cleaning) and CIP-capable shaft seal
Just like the manufacturing process, WIP is also mostly automated, with online submission of the WIP report to the IT department of Losan. Cleaning of the mixer is performed with the aid of a WIP station, which was installed at some distance to the mixer on account of space issues. The operators place particular importance on perfect cleaning of the shaft seals, therefore the seals were specifically designed to be suitable for CIP.
In addition, the impeller can be lifted pneumatically in order to verify cleaning success. This function has also proved extremely successful during optimization of the cleaning program and during qualification. Instead of long cleaning cycles with unnecessary reserves, a relatively short cleaning program has been developed that is tailored to the products. Here, it helps to be able to check the heart of the machine, i.e. the impeller with its seal.
Teamwork Guarantees Timely Completion
Within the last two years, it has been possible to finalize the concept for the new granulating line, install all components of the line within the existing setup, carry out a process transfer including process optimization, and manufacture corresponding validation batches. Within the installation phase from April 2019 until the start of the first process validation runs in October 2019, the project management team at Losan Pharma coordinated more than ten different suppliers and trades side-by-side, all the while preparing the first GMP activities such as the qualification of the equipment or the cleaning validations.
Thanks to the excellent internal communication between all persons involved and the experience gained from previous machinery projects, the plant was completed on time. In the form of Diosna, a manufacturer was chosen for the granulator who was perfectly capable of delivering the required functional performance as well as meeting the requirements in terms of space usage and moving the equipment into place among the existing inventory. The granulating line described above has now been running in production operation for a number of months — with the mixer from Diosna at the heart of the new system.