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1. Material Handling
In large-scale operations, mechanical devices such as drum lifting and tilting machines and more sophisticated methods of material handling such as screw feed systems, vacuum loading systems and metering pumps become necessary, unlike in the laboratory where materials are simply scooped. , dump or pour by hand.
Any material handling system used must deliver the correct amount of material to the intended destination with minimal damage. Long transfer lines may cause material damage, for which this must be compensated.
2. Dry Blending
All ingredients (use and active ingredients) are meant to be free of lumps and coagulants prior to dry mixing. Failure to remove or isolate all aggregates can cause flow problems through the equipment creating a non-reproducible compression.
Screening and/or milling of ingredients should be done before mixing to make the process more reliable and reproducible. Powders used for encapsulation or granulation should be well mixed to ensure good drug distribution before tableting. Inadequate mixing can result in isolated parts of the batch being either high or low strength.
3. Granulation
Wet granulation can be achieved using sigma blades or heavy-duty planetary mixers. Equipped with large motors of 7 to 10 horsepower, this type of production equipment can process material from 100 to 200 kg. The granulation time used in experimental laboratory trials and the amount of granulating fluid required can be affected by the weight of the material and the large shear forces generated by these powerful units.
Wet granulation can also be made using a tumble blender equipped with high-speed chopper blades. High shear mixers are more effective at thickening lighter powders. However, they demand a lot of energy. They have a limited load size. Some equipment combines this high shear mixing action required for good densification with the advantage of high-speed choppers that break up aggregates and ensure uniform distribution of granulated fluid and more controlled grain sizes.
There are also multi-functional processors capable of performing all the tasks required to prepare finished granulations such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single piece of equipment.
The advantage of such equipment in product scale-up is the space and manpower requirements. The viscosity of the granulating solution can be adjusted if problems with the addition of binder in the powder process are anticipated. Binding agents sometimes impart considerable viscosity to granular solutions, making fluid transfer by pumping or pouring difficult. One way to solve this problem is to disperse some or all of the binding agent into the dry powder prior to granulation, and the granulating liquid containing any residual binder can thus be easily pumped and metered in batches during granulation.
Some grains take on a dough-like consistency when prepared in production-size equipment and may need to be broken up into a more granular and porous mass to facilitate drying. Screen or a hammer call with a suitable large screen.
4. Drying
During the scale-up of this operation, the depth of the granulation bed should be carefully controlled and the drying process should be monitored using moisture and or temperature probes in the granulation. Important factors to consider as part of the scale-up of oven drying operations are airflow, air temperature and grain depth in trays.
If the granular bed is too dense, the drying process will be ineffective. Dye migration to the grain surface may also occur if soluble dyes are involved. The drying process can be monitored by frequent multi-point sampling of the granulation for moisture content throughout the drying phase. Drying times must be established at specific temperatures and airflow rates for each product and for each specific oven load.
In scale-up of a fluidized bed drying operation, the optimum load must first be established. Also, airflow rate and inlet air temperature, as well as incoming air humidity, must be established, as these affect drying time. The main advantage of fluidized bed dryers is reduced drying time.
Fluidized bed drying times are typically less than 1 hour, compared to 8 hours or more in conventional ovens. However, scale-up of a fluidized bed drying operation is more involved than scale-up of a circulating hot air furnace process. For example, large seasonal changes in temperature and humidity can alter the drying process if air drawn from outside the plant is not conditioned.
5. Reduction of Particle Size
In the laboratory, hand screening or short-time handling with a small-scale milling equipment is used to obtain the desired particle size distribution prior to compression or encapsulation. When such a process is expanded to accommodate larger, high-speed presses with more elaborate feed systems, it is essential that the sorting equipment gives the desired output while controlling particle size and size distribution, which are important characteristics of a granule.
Particle size reduction of dry granules of production size batches can be achieved by bypassing all material through an oscillating granulator, a hammer mill, a mechanical sieving device or a screening device. Oscillating granulators work well when the granulate is not too hard with lumps or aggregates. Care should be taken not to overfeed the equipment to avoid excessive fines.
Hammer mills are also often used to produce dry granules in a specific size distribution. They have a rapid output and the particle size distribution can be controlled by changing screen size, mill speed, type and number of hammers, blades used and material feeding rate.
The most suitable milling equipment for granule particle size reduction can be selected by first determining the characteristics of the unmilled granulation and then selecting the equipment to produce the required particle size distribution for optimum performance during the compression or encapsulation stage.
Compression factors that may be affected by particle size distribution are flowability, compressibility, tablet weight uniformity, content uniformity, tablet hardness, and tablet content uniformity. For example, a grain with too large a particle size and insufficient fineness is unable to fill the die cavities evenly during compression. The tablet weight will, therefore, fluctuate considerably.
As part of the scale-up of a milling or sieving operation, lubricants and glidants that are added directly to the final mixture (in the laboratory) are now added to the dry granules during the sizing operation. This is done because some of these additives, especially magnesium stearate, form clumps when added in large quantities to the granules in a blender.
6. Blending
Attention should be paid to the scale-up of this operation so that properly designed equipment is used, blender loads, mixing speeds and mixing times are properly established. This is important because the type of mixing equipment used in manufacturing operations differs from that used in the laboratory, especially in size. A good understanding of the properties of the material to be mixed helps make a full-scale manufacturing processing operation successful and more efficient. For example, a product with brittle particles or agglomerates can be easily eroded or crushed resulting in excessive fines.
These fines can mix incorrectly causing flow problems, fill weight and content uniformity problems. In any mixing operation, both separation and mixing occur simultaneously. Both processes depend on particle size, shape, hardness, concentration and mixing dynamics. Therefore the characteristics of the different powders in the mixture must be known and the reason for segregation understood so that the reason for the mixing operation can be optimized to produce a uniform mixture.
7. Granulation handling and feed system
Studies are needed to determine the effect of additional handling (in large-scale operations) on drug content uniformity and particle size distribution. Separation due to static charges during granulation mechanical handling can cause material flow problems through tablet press hoppers and feed frames.
This flow problem can lead to uneven tablet weight, thickness, hardness and ultimately poor content control. In the laboratory, handling a finished granulation can be a simple operation such as hand scooping material from a drum into a press hopper. For large operations, a sophisticated, automated handling system using mechanical systems can be employed to convey the granules.
8. Compression
When evaluating the compression properties of a particular formulation an attempt should be made to run prolonged trials at press speeds similar to those used in normal production. This is done to identify potential problems such as hardness, capping and weight variation of the punched surface tablets.
These pre-production trials in pilot plants are essential to identify these problems early in the scale-up process so that changes can be made easily. Such changes will be more difficult during later production, as marketing requirements may make it difficult to interrupt the production schedule to modify the formulation. Compression of a granulation in a high-speed tablet press is the ultimate test of a tablet formulation and granulation process.
