PILOT PLANT SCALE UP FOR TABLETS
What is Pilot plant??
“Defined as a part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by the development of liable practical procedure for manufacture.”
• Pilot plant scale-up techniques involve reproducible manufacture of an experimental formulation on high-speed production equipment, in a cost effective manner
• It is a part of the pharmaceutical industry where the same processes used during Research and Development (R&D) of dosage forms are applied to different output volumes; usually greater than that obtained during R&D
PILOT PLANT SCALE UP FOR TABLETS
• The primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale
• The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness
• Should be located on the ground floor to expedite the delivery and shipment of supplies
• Extraneous and microbiological contamination must be guarded against by incorporating the following features in the pilot plant design:
– Fluorescent lighting fixtures should be the ceiling flush type
– The various operating areas should have floor drains to simplify cleaning
– The area should be air-conditioned and humidity controlled
– High -density concrete floors should be installed
– The walls in the processing and packaging areas should be enamel cement finish on concrete
– Equipment in the pharmaceutical pilot plant should be similar to that used by production division- manufacture of tablets
1) Material handling system
• In the laboratory, materials are simply scooped or poured by hand, but in intermediate- or large-scale operations, handling of this materials often become necessary
• If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination
• Any material handling system must deliver the accurate amount of the ingredient to the destination
• The type of system selected also depends on the characteristics of the materials
2) Dry blending
• Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution
• Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency
• Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates
• For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible
V blenders/ Twin shell blenders
Double cone blenders
Tumble blenders/ Conta blenders
SCALE UP CONSIDERATIONS
• Time of blending
• Blender loading
• Size of blender
• Speed of blender
3) Granulation
The most common reasons given to justify granulating are:
1. To impart good flow properties to the material
2. To increase the apparent density of the powders
3. To change the particle size distribution
4. Uniform dispersion of active ingredient
• Wet granulation can also be prepared using tumble blenders equipped with highspeed chopper blades.
• More recently, the use of multifunctional “processors” that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment
Sigma Blade Mixers
Planetary Mixers
High shear mixer/ granulator
SCALE UP CONSIDERATIONS
• Process Inlet Air Temperature
• Atomization Air Pressure
• Air Volume
• Liquid Spray Rate
• Nozzle Position and Number of Spray Heads
• Product and Exhaust Air Temperature
• Filter Porosity
• Cleaning frequency
• Bowl capacity
Use of binders
• Binders are used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling
• In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult this problem can be overcome by adding some or all binding agents in the dry powder prior to granulation
• Some granulation, when prepared in production sized equipment, take on a dough like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.
• This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all
4) Drying
• The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity
• Fluidized bed dryers are an attractive alternative to the circulating hot air ovens.
SCALE UP CONSIDERATIONS- Hot air oven
• Airflow
• Air temperature
• Depth of the granulation on the trays
-If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules
-Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load
Hot air Oven
SCALE UP CONSIDERATIONS- Tray dryer
1. Air flow
2. Air temperature
3. Depth of the granulation on the trays
4. Monitoring of the drying process by the use of moisture and temperature probes
5. Drying times at specified temperatures and air flow rates for each product
Tray Dryer
SCALE UP CONSIDERATIONS- Fluidized bed dryer
1. Air flow
2. Air temperature
3. Material to be dried
4. Quantity of material
5) Size reduction
• Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity
• First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings
• Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device
• As part of the scale-up of a milling or sieving operation, the lubricants and glidants, which in the laboratory are usually added directly to the final blend, are usually added to the dried granulation during the sizing operation
• This is done because some of these additives, especially magnesium stearate, tend to agglomerate when added in large quantities to the granulation in a blender
Hammer Mill
Oscillating Granulator
6) Blending
• In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action
• Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used
• When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender
SCALE UP CONSIDERATIONS- Blender
1. Blender loads
2. Blender size
3. Mixing speeds
4. Mixing times
5. Bulk density of the raw material (must be considered in selecting blender and in determining optimum blender load)
6. Characteristics of the material
7) Specialized Granulation procedures: Slugging (Dry Granulation)
• A dry powder blend that cannot be directly compressed because of poor flow or compression properties
• This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less
• Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts
• If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation
• Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch
• Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression
E.g densification of aluminum hydroxide.
• Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties
8) Tablet Compression
• The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press
• During compression, the tablet press performs the following functions:
1. Filling of empty die cavity with granulation.
2. Precompression of granulation (optional).
3. Compression of granules.
4. Ejection of the tablet from the die cavity and take-off of compressed tablet
Tablet compression machine
• When evaluating the compression characteristics of a particular formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be tried.
• Only then are potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected
• High-speed tablet compression depends on the ability of the press to interact with granulation
SCALE UP CONSIDERATIONS- Tablet compression
1. Granulation feed rate
2. Delivery system should not change the particle size distribution
3. System should not cause segregation of coarse and fine particles, nor should it induce static charges
4. Speed of Rotation
• The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame
• The smaller the tablet, the more difficult it is to get a uniform fill a high press speeds
• For high-speed machines, induced die feed systems is necessary
• These are available with a variety of feed paddles and with variable speed capabilities
• After the die cavities are filled, the excess is removed by the feed frame to the center of the die table
• Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers
• This cause the punches to the penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between the punches
• The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers
• Larger the compressions roller, the more gradually compression force is applied and released
• Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation
• The final event is ejection of compressed tablets from die cavity
• During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking
• High level of lubricant or over blending can result in a soft tablet, decrease in wettability of the powder and an extension of the dissolution time
• Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the center in order to relieve pressure during ejection
9) Tablet Coating
• Sugar coating is carried out in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations
• The conventional sugar coating pan has given way to perforated pans or fluidizedbed coating columns
• The development of new polymeric materials has resulted in a change from aqueous sugar coating and more recently, to aqueous film coating
• The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column
• Some tablet core materials are naturally hydrophobic, and in these cases, film coating with an aqueous system may require special formulation of the tablet core and/or the coating solution
• A film coating solution may have been found to work well with a particular tablet in small lab coating pan but may be totally unacceptable on a production scale
• This is because of increased pressure & abrasion to which tablets are subjected when batch size is large & different in temperature and humidity to which tablets are exposed while coating and drying process
Tablet coating Pan
SCALE UP CONSIDERATIONS- Tablet Coating
1. Pan load
2. Bed Temperature
3. Spray inlet temp
4. Atomization air pressure/ spray pattern
5. Bulk density of the raw material (must be considered in selecting blender and in determining optimum blender load)
6. Liquid Spray Rate
7. Gun to bed distance
Challenges in Tablet Scale-Up
Scaling up tablet formulations presents various challenges, including:
Uniformity: Achieving uniformity in tablet weight, drug content, and hardness in larger batches.
Tooling and Compression: Adapting tablet press tooling and compression parameters for larger-scale production.
Quality Assurance: Ensuring stringent quality control throughout the scale-up process is essential.
FAQ
What is pilot plant scale-up in the context of tablet manufacturing?
Pilot plant scale-up is the process of transitioning from laboratory-scale development and testing of pharmaceutical tablets to producing larger quantities suitable for commercial distribution.
Why is pilot plant scale-up important in the pharmaceutical industry?
Pilot plant scale-up is crucial because it ensures that pharmaceutical companies can efficiently produce high-quality tablets at a scale that meets market demand while adhering to regulatory standards.
What are the key considerations when scaling up tablet manufacturing?
Key considerations include formulation optimization, equipment selection, process validation, and maintaining tablet quality and consistency during the scaling process.
What are the challenges associated with scaling up tablet formulations?
Challenges include achieving uniformity in tablet weight, drug content, and hardness in larger batches, adapting tablet press tooling and compression parameters, and maintaining stringent quality control.
What are some best practices for a successful pilot plant scale-up of tablet manufacturing?
Best practices include comprehensive planning, risk assessment, continuous monitoring and testing, and strict adherence to regulatory guidelines.
How does pilot plant scale-up impact the cost efficiency of tablet production?
Scaling up allows for the production of larger batches, which typically reduces manufacturing costs per tablet, making the process more cost-effective.
Why is regulatory compliance crucial during pilot plant scale-up?
Regulatory compliance is essential to ensure that the final tablets meet safety and efficacy standards, allowing for their approval and distribution in the market.
What are the benefits of successful pilot plant scale-up for tablet manufacturing?
Benefits include cost-efficient production, consistent tablet quality, compliance with regulatory requirements, and timely availability of medications in the market.
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