TABLET
PILOT PLANT SCALE UP
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
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