Granulation Technology for Pharma Applications
Gral High Shear Granulators
Whether the customer’s requirement is for high shear mixing or granulation, GEA has a solution for every processing challenge and can help select the technology that is most suitable for your Pharma application.
Unique process design
The key to success is the unique design of vessel and mixing tools. The angled position of the mixing blades combined with the rounded edges at the bottom of the vessel guarantee the typical rope-type movement for optimal flow of product during granulation. Several binder liquid spray systems are available to suit your process. Bowl and mixing blades are shaped and mounted to minimize clearance for maximum yield, without locally overheating the product. During a discharge cycle, the centrifugal force created by the rotation of the mixing arm will push the product in a natural way to a proportionally regulated outlet valve at the side without compacting the wet granules. This way we can accurately dose the finished granules to a calibration unit, connected to the outlet. GEA Pharma is the perfect partner for the development of a granulation process from formulation up to full-scale production. With capacities from 10 to 1200 liter, the (Ultima)Gral range can cover all requirements, from development over clinical batch production for scale-up trials to large scale production for marketed products.
User-friendly operation
Many features of the (Ultima)Gral ensure that the equipment is easy to operate. Loading the powders can be executed by gravity. An inspection window or video is incorporated in the bowl cover for visual process monitoring. The height of the bowl outlet allows for an open discharge in the product vessel of the dryer or for an inline connection with a calibrating unit and vacuum transfer piece for closed transport of the wet granules to the Fluid Bed Dryer. Process controls and automation are available by means of PLC and operating panel, with optional recipe control.
Cleanibility, safety and maintenance
The top driven design ensures that the shaft seals are not in contact with the product. The shaft seals are dry running and mounted in a cartridge, which eliminates cross-contamination and allows easy cleaning and inspection. The construction is extremely robust and requires hardly any maintenance. All mechanical and electrical parts are easily accessible from the technical area behind the machine. The machine can be executed as fully enclosed and free-standing in the room or can alternatively be built through-the-wall. The machine complies with the most stringent safety regulations and can be equipped for granulation with organic solvents.
Comparison Gral & UltimaGral
| Gral | UltimaGral | |
| Vessel, Impeller, Chopper, all parts in contact with product | SAME | SAME |
| Removable Process Vessel | YES | NO |
| Plunger outlet valve (one movement) | YES | NO |
| Swing away outlet valve (2 movements) | NO | YES |
| Surrounding cabinet for improved GMP | NO | YES |
| Pressure Shock Resistant | NO | YES |
| CIP | NO | YES |
| WIP | YES | YES |
| Torque Measurement | YES | YES |
| Nitrogen inerting | YES | YES |
| vacuum loading | YES | YES |
| Integrated wet mill | YES | YES |
| Closed Integration with Fluid Bed | YES | YES |
Production Capacities
| Gral / UltimaGral size | 10 | 25 | 75 | 150 | 300 | 400 | 600 | 900 | 1200 |
| Bowl Volume (Litres) | 7.9 | 27 | 77 | 153 | 303 | 400 | 614 | 900 | 1166 |
| Typical Batch Weight @ 0.6 g/ml (kg) | 3 | 11 | 30 | 60 | 120 | 160 | 240 | 350 | 480 |
Plant Design
Customized Plant DesignUsing standard components, GEA can supply both simplicity and flexibility in high shear granulator plant design for the pharmaceutical industry. User selected process options, control systems and liquid preparation units combine to exactly meet process requirements. This approach ensures that qualification and validation efforts are kept to a minimum.Through-the-wall configuration
Through-the-wall offers the best option in terms of cleanliness, maintenance and explosion protection. The Through-the-wall configuration provides a sealed separation between technical and GMP space by the machine itself. This offers a clear containment concept including
explosion area separation that fulfills the latest requirements like ATEX. By keeping technical components out of the process room, the equipment is much easier to clean. Maintenance is carried out from the technical area, reducing the need for the maintenance engineer to work in a GMP area. This reduces downtime and the risk of contamination. For ATEX, the design allows the technical area to be classified as safe.
Loading
Depending on the layout of the production area, several options for loading the powders are available. When the processing room is sufficiently high, gravity loading is applicable, using post hoists to lift the IBC on top of the (Ultima)Gral. Alternatively gravity loading with the IBC located on a docking station on the floor above the machine is possible if a multiple floor installation is preferred. In height-restricted areas however, vacuum loading can be used. In this case the product is sucked into the processing vessel from an IBC located close to the machine on the floor.
Moveable Head
The (Ultima)Gral can be equipped with a ‘Movable Head’ to enhance flexibility. This feature allows operators to lower the closed bowl to enable better accessibility and easy loading. The closed bowl can also be raised for dust free discharging. This option is extremely useful in height-constrained processing areas.
Binder solution addition
In a wet granulation process, binder addition is one of the critical phases determining product quality. A range of binder addition systems is available to give the optimum binder liquid droplet size. This ensures an even distribution throughout the powder mass, for different viscosities. The liquid is transferred to the mixing bowl using a peristaltic pump or pressure vessel, while the rate and amount is controlled by a loss in weight system, or a mass flow meter.
Design for Cleanability and Maintenance
Manufacturing compliance depends on efficient, effective cleaning. Automation of the cleaning process ensures repeatability, allows validation and minimizes down-time. In recognition of the fundamental role played in today’ s advanced pharmaceutical powder processing industry by automated clean-in-place procedures, GEA has developed a unique approach to CIP.
CIP and WIP
The (Ultima)Gral can be supplied with a wide range of washing-in-place and fully automated cleaning-in-place options. These include spray nozzles adapted for most effective cleaning of product feed, product filter, granulation vessel, lid and discharge valve (for example retractable spray nozzles for the lid). Even downstream equipment, such as a mill, can be incorporated in the cleaning system.
Easy Maintenance
The through the wall design of the (Ultima)Gral™ ensures that technical interventions can be easily carried out without having to access the processing area and disturbing the clean environment. Even the concealed service lines can be easily accessed via sealed doors in the machine encasement.
Gral
First introduced in 1975, the Gral high shear mixer granulator is a fine example of GEA's experience in manufacturing high quality equipment for the pharmaceutical industry.
Standard Features
- Top driven mixer and chopper: No seals in direct contact with the product
- Unique bowl design for optimal granulation
- Full opening discharge for easy unloading of difficult products
- Free standing machine OR through-the-wall design (only for 75 L or larger)
- Easy to wash-in-place
- Built to GMP-standards
- Removable bowl concept: A bowl trolley is available for easy removal of the bowl
- Twin speed chopper and mixer
- Full interlocked guarding
- Easy access for maintenance
Optional Features
- Movable head
- Explosion proof design
- Automated WIP system
- Automation / PC / PLC controls
- Granulation endpoint determination by torque measurement
- Variable speed mixer and chopper motors
- Jacketed / insulated bowl
- Video monitoring of the process
- Closed link to wet screening unit and fluid bed
- Total containment through up- and downstream split valves
- Liquid addition system (peristaltic pump / pressure vessel / mass flow meter)
- Fill-O-Matic (vacuum) or gravity loading system
- Validation documentation and assistance based on GAMP
UltimaGral
Using proven standard components of the Gral range, GEA can supply both simplicity and flexibility in plant design with the UltimaGral.
Main features
With bowl capacities of 10–1200 L (useful bowl content up to 2/3 of gross capacity), the UltimaGral range can cover all requirements after the formulation stage. From clinical batch production for scale-up trials to large-scale production for marketed products, scalability is key to the system’s success. The most important features of this design are the top-driven mixer and chopper, the optimized design to ensure easy cleaning & GMP compliance, and the through-the-wall installation of the larger machines.
Additional features
- Easy to wash-in-place (WIP)
- Built to GMP-standards
- Total containment of the product
- Variable speed chopper and impeller
- Operator control panel on the machine
- Automation/PC/PLC controls
- Controlled product discharge
- Automatic end point detection with PROCOLL-software
- Explosion proof design
- Heating and cooling units
- Fill-O-Matic (vacuum) or gravity loading system.
- EC type approved for pressure shock resistant integrated systems and 16-bar pressure shock resistant high shear granulators
Concealed services
The design of the UltimaGral ensures that lines and hoses for the utilities on the machine (water, electricity, hydraulics, etc.) are concealed in the machine encasement. This creates an uncluttered working space and avoids hoses being run to the machine within the process area.
Integrated Lines
Our complete range of process equipment is designed with system integration in mind.
Integrated line of a top-drive granulator (Gral) and a fluid bed dryer
Fluid bed dryer Integration
Integrating a high shear mixer with a fluid bed processor is the most common configuration used on an industrial scale for the production of pharmaceutical granules. This system allows full integration with upstream and downstream equipment, and even includes a wet mill between the granulator and dryer.
With modern control systems, it is easy to load, mix and granulate a second batch in the high shear granulator whilst drying the previous batch in the fluid bed prior to discharge.
All equipment can be cleaned in place in a single automatic process.
Improved safety for integrated granulation and drying suites
Extensive safety testing confirms pressure enhancement effects and identifies safe design limits for integrated systems. GEA in conjunction with the FSA, the safety specialist centre in Germany, have carried out an extensive test programme involving over 100 test explosions. This research has shown conclusively that should an explosion occur during the transfer operation in an integrated system where a granulator is connected directly to a fluid bed dryer without an explosion isolation valve, the secondary explosion pressures in the granulator can be significantly higher than in the fluid bed. These tests have enabled GEA to gain full EC type approval for a range of pressure shock resistant integrated systems and 16-bar pressure shock resistant high shear granulators ...
Containment Integration
During most of the manufacturing process, the APIs are inside machines or vessels which are more or less tight. The main risk of material escaping into the environment exists whenever a connection between those pieces of equipment needs to be made or broken, when a sample needs to be taken, and last, but not least, when the machines need to be cleaned after the end of a manufacturing campaign.
Whether the High Shear Granulator is stand-alone, or integrated with drying equipment; several features can be incorporated into the process line to ensure completely contained processing:
- For loading and unloading Buck® containment valves can be mounted on the product feed and on the discharge valve.
- Flexible containment with Hicoflex® disposable system.
- Within a complete contained integrated system, transfer of product takes place using a vacuum transfer system.
A sampling valve that allows the operator to take samples during the process without having to stop the machine, open the bowl, or even open a port in the lid, can be integrated into the processing vessel and adapted to different containment levels. The sample container is completely contained allowing the sample to be transported to the QC lab without exposure to the atmosphere.
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関連製品
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