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Fluid Bed Granulation, Drying, and Coating

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Purpose designed for cGMP processing of fine powders, pellets, granules, crystals and tablets.

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GEA Pharma Systems Lighthouse Probe™ Technology Airflow in Batch FluidBed Processing by Dilip M. Parikh: reprinted from Pharmaceutical Technology, March 1991. Fluid-Bed Processing in the 1990s by Dilip M. Parikh: reprinted from Pharmaceutical Technology Supplement, October 1996 Fluid Bed Processor for Granulation, Coating, Pelletization, and Solution Layering

Fluid bed drying

Gentle, rapid drying of powders and particles The product to be dried is fluidized by passing hot air through it. The process achieves fast heat transfer making it very efficient, yet gentle on the product. Capacity: from 50g to several ton/batch or several ton/hr. History and description of batch fluid bed processors Batch fluid bed processing has been used in the pharmaceutical industry for the past 30 years. Figure 1 shows the components of a typical fluid bed processor. The technology was originally developed specifically for rapid drying. Over the years, fluid bed processing has come into routine use for other applications such as granulation, agglomeration, air suspension coating, rotary pelletization, and powder and solution layering, but the principle of the fluid bed processor has not changed.

Figure 1: Typical Components of a Fluid Bed Processor for Granulation, Coating, Pelletization, and Solution Layering

A fluidized bed is a bed of solid particles with a stream of air or gas passing upward through the particles at a rate great enough to set them in motion. As the air travels through the particle bed, it imparts unique properties to the bed. For example, the bed behaves as a liquid. It is possible to propagate wave motion, which creates the potential for improved mixing. In a bubbling fluidized bed, no temperature gradient exists within the mass of the fluidized particles. This isothermal property results from the intense particle activity in the system. Thus, the fluid bed can be used to dry the wet product, agglomerate particles, improve flow properties, instantize the product, or produce coated particles for controlled release or taste masking. Modular systems designed to carry out multiple processes in which only a container change is necessary to change the type of unit operation being performed have been developed by all the manufacturers of fluid bed processors. Although the basic process of the fluid bed has not changed much, the versatility of fluid bed processing has evolved over the past 30 years in response to the demands of the pharmaceutical industry, the guidance of regulatory agencies, and competitive innovation on the part of equipment manufacturers.

Advances in Hardware Components that make up a fluid bed processor have not changed substantially. However, the shape of the fluid bed in the early days was quite different from the design offered by most manufacturers today. Figure 2 shows the shorter design that was prevalent in the industry before the 1970s. Late in that decade, several factors changed the design of fluid bed processors. FDA introduced GMP guidelines in the United States; controlled-release products that required uniform particle

coating were developed; and as machinery manufacturers developed modular fluid bed units, pharmaceutical manufacturers began to carry out agglomerating, coating, pelletization, and tablet coating in the processor. These changes required taller processing unitl. Figure 3 shows a current design of typical fluid bed processor. Ten-bar design Fluid bed processing involves fine dust and dry process air, which can cause an explosion triggered by a static charge. Such an explosion creates a momentary overpressure in the processor. Until late in the 1970s, the typical fluid bed processor was capable of withstanding only 2 bar overpressure. A 2-bar unit required a pressure-relief duct to vent the over-pressure in case of an explosion. The processor had to protrude through the roof or be installed near the outside wall of the facility to minimize the length of the pressure-relief duct. The processor required doors equipped with gaskets, posing a cleaning problem. It was thought that a machine capable of withstanding higher pressure was very expensive to make. However, 10-bar, pilot-size units were introduced by some manufacturers in the late 1970s. A 10-bar unit does not require a pressure-relief duct and thus can be installed anywhere Figure 3 Current Figure 2 Fluid Bed within the building. Design of a Processor with the Old This also meant that typical Fluid Bed Design the pressure-relief Processor duct, doors, door gaskets, and cleaning problems due to doors and gaskets were eliminated. In the 1990s one can obtain a production unit with a 10-bar shock resistance. Air-handling unit For a fluid bed processor used in manufacturing, process air is generally drawn from the outside of the building. The conditioning of this air to a constant humidity and dew point is now considered essential. The drying capacity of the air depends on its temperature, humidity, and volume. Because of the globalization of the pharmaceutical industry, fluid bed processes must be able to be transferred from one location to another anywhere in the world. To ensure the consistency of the process conditions and thus the product produced, it is important that

the quality of the process air be consistent and re-producible. The recent trend is to have an air-handling unit that can produce air of consistent quality with the desired dew point throughout the year. Distributor design The process air brought into the fluid bed processor must be distributed so that the product is uniformly fluidized. This was formerly achieved by means of perforated stainless steel plates with an open area of 4 - 30%. But because the fluid bed process deals with fine powder, a fine screen of 60-325 mesh had to be used in conjunction with the perforated plate. This arrangement was satisfactory from the process point of view. However, cleaning the sandwich construction was difficult.

Figure 5 GILL PLATE™ Air Distributor

The assurance of proper cleaning was always questioned, and screen ripping was common. In 1990, a new design of the air distributor called the overlap GILL PLATE™ was introduced. Figure 5 shows the newer design of the air distributors. The basic concept of this design, the GILL PLATE™, is widely used in the continuous fluid bed dryer. The design was modified to address the batch fluid bed process requirements. The NON-SIFTING GILL PLATE™ has the same capability of distributing air as the previous design. However, unlike the previously used sandwich-type air distributor, the overlap GILL PLATE™ is easier to clean and, in fact, can be cleaned in place. These NON-SIFTING GILL PLATE™ air distributors are usually suitable for a unit in which the container is stationary and product discharge is by gravity or pneumatic means. Process filters Filters retain the product in the processor. The early design was a single filter bag with a number of socks attached to the filter frame, which, in

turn, was attached to an air piston, used to mechanically shake the filter bag during processing. In the single-stroke shaker, filter shaking is accompanied by a loss of fluidization. This creates an intermittent process. In the coating process, the loss of fluidization could cause agglomeration. To provide continuous fluidization of the product, a split filter bag with two separate filter-shaking pistons was introduced in the 1980s. Cleaning of these filter bags was a concern throughout the industry. To prevent cross-contamination between products, pharmaceutical manufacturers used separate filters for each product. The washing of these bags was cumbersome. The bags were made of polypropylene, polyester, or nylon. Because filter bags are generally hand sewn and have numerous seams, they can tear upon repeated use. If the tear happens during processing, product can be lost. Moreover, filter bag handling and cleaning poses a problem of operator safety when a potent compound is processed. To partially address these issues, manufacturers of fluid bed equipment introduced cartridge filters. The cartridge is cleaned by pulses of air during the operation, with no interruption of fluidization. Inclined and vertical designs have emerged. It is claimed that the inclined cartridge allows easy access and can be taken in or out of the processor by placing it in a plastic bag. These cartridges are made up of Gore-Tex laminated polyester felt material and can be cleaned manually or ultrasonically. However, processing potent compounds required a cleanin-place system. A pleated stainless steel cartridge made of three layers of wire screen was introduced in 1991. These cartridges were made of stainless steel because other construction materials were not capable of withstanding the repeated cleaning required during product changeovers. The introduction of stainless steel cartridges for the first time provided the opportunity for cleaning in place of a fluid bed processor. Clean-in-place design Cleaning of process equipment used for different products has been discussed extensively in the literature. Formerly, to clean fluid bed processing equipment, the filter bags and the air distributor with sandwiched construction had to be removed from the unit and disassembled, The cleaning required 8 - 10 hours, and the assurance of cleaning was sometimes operator-dependent. In 1993 a patent was granted for a true clean-in-place (CIP) system. The introduction of overlap GILL PLATE™ air distributors and stainless steel filter cartridges provided the possibility of cleaning all the components of the fluid bed in place. Because this system can be automated, cleaning can be performed without operator intervention. This automation makes it easy

to validate the cleaning procedure. By providing a tank washer for the processor, strategically placed cleaning nozzles, and a cartridge-filter cleaning system, the fluid bed can be cleaned in place. The unique cartridge-cleaning system involves cartridges that can be raised and lowered during the cleaning cycle, a spray nozzle at the top of the cartridge, and annular nozzles around the cartridge tower base. The pleats of the cartridge get cleaned as the cartridges are moved up and down and the force of the spray rotates the cartridges. At the same time, the nozzle at the top of the cartridge tower sprays liquid through the cartridge filter media and backflushes the cartridge. The lower plenum and overlap gill air distributor is cleaned by a nozzle placed in the lower plenum. The cleaning regimen is determined in the early stages of cleaning method development and programmed to provide consistency in cleaning. Process Advances The fluid bed process was originally used for the drying of pharmaceutical granulations. However, over the years, agglomeration and air-suspension coating have been introduced. Researchers have discussed the incorporation of microwave technology in the laboratory fluid bed processor. A rapid drying is claimed to be the advantage of this system. There is no commercial installation of this development to date. Fluid bed processes using organic solvent require an inert gas, such as nitrogen, to replace the air as the medium of fluidization and a solvent recovery system to condense out the sol-vent and recycle the gas. In 1989, a vacuum fluid bed system was presented by Luy et al. A fluidized bed was generated and sustained under vacuum, thereby eliminating the use of inert gas. The developers claim several advantages for this sys-tem, such as considerable emission reduction, increased recovery rate of the solvent, and an application for oxygen-sensitive materials. Introduction of a rotor module for the fluid bed by various manufacturers has made possible the production of pellets of a broad size distribution, along with the layering of a drug sub-stance (powder, solution, or suspension) on an inert substrate. Coating of particles and pellets has been carried out in the fluid bed for the last 30 years using air suspension techniques. The Wurster process is the most popular method for coating particles. However, the technology has certain disadvantages, such as nozzle inaccessibility, prolonged process time, and a mini-mum volume requirement. In 1995, the PRECISION COATER™ ( Patented ), incorporating a modified air suspension technique, was introduced by Niro (Aeromatic-Fielder Division, Columbia, MD; 19). It was designed to allow easy removal of the nozzles for cleaning, faster process time

because of a patented particle accelerator, good utilization of thermal and kinetic energies, and scalability from a single-column to a multiplecolumn setup. A trend in the pharmaceutical industry is to use the fluid bed processor to mask the taste of bitter particles by granulating them with melted waxes or coating them with powdered wax. The end point of a fluid bed drying or granulating process has customarily been determined by monitoring the temperature of the exhaust gas stream. The reproducibility of the process is determined by a combination of bed temperature, exhaust air temperature, and drying time. During drying, the product passes through three distinct temperature phases. At the beginning of the process, the material heats up from the ambient temperature to approximately the wet-bulb temperature of the air in the dryer. This temperature is maintained until the product moisture content is reduced to a critical level. When the surface water is no longer present, the product temperature rises further. The termination of the drying process is thus determined by plotting drying curves and by performing experiments. Efforts to measure product moisture as it changes during agglomeration or drying have been made by using infrared moisture measurement . The unit discussed by these authors operates in the near infrared region using five wavelengths. The unit does need to be calibrated every time a new product is to be processed.

Figure 9 PLC Based Control Screen

Automation and Controls: Fluid bed processing requires accurate and reliable control of all the process parameters. Earlier designs of process control systems used pneumatic controls, which provided safe operation in hazardous areas but relied on operator actions to achieve repeatable product quality and accurate data acquisition. Current designs use programmable logic controllers (PLCs) and personal computers to achieve sophisticated control and data acquisition. Access to all user-configured data is protected by security levels, with passwords permitting individuals access only to selected functions. Figure 9 shows the typical PLC-based control screen. For further information about our control systems and how we address

FDA's Process Analytical Technology initiative (PAT), please access the Real Time Process Determination (RTPD) page. Real Time Process Determination is a comprehensive software solution that tracks process conditions. It acts as your most experienced operator and provides concise advice on how to run the process. It is an integrated suite of programs that work along with a Niro Pharma Systems fluid bed processor control system. This includes a program that runs during a fluid bed process and a program for the post batch analysis of the data collected. The most important sensors for control of the drying process are sensors for inlet and exhaust air temperature and an airflow sensor located in the air transport system. Other important parameters that must be sensed for agglomeration and coating are product temperature, atomizing air pressure, air dew point or humidity, and spray rate of the binder solution. Less critical variables are filter and product-bed pressure drop and filter cleaning frequency. All of these sensors provide constant feedback of the information to the operator and the control system. The signals are stored electronically and recalled as a batch report, either as a printout or an electronic batch report. With this ability to recall data analysis, a greater insight can be gained into the process. A high-shear mixer can be placed in line with a fluid bed processor. After the mixture is granulated in a high-shear mixer, the dense material is transported to the fluid bed dryer to dry. These two unit operations and the transfer between them can be controlled by a single controller. Such a system optimizes containment, minimizes material-handling requirements, and reduces the footprint of the machines. Summary: Over the past 30 years, fluid bed technology has progressed from a process to dry a product quickly to a more sophisticated technology that can be used for granulation, drying, particle coating, and pelletization. The improvement in the technology is driven by the pharmaceutical industry and the manufacturers of the equipment. Changes in the pharmaceutical industry require an efficient manufacturing operation, and continuing enhancements in fluid bed technology can certainly assist in that effort.

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