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1. Pilot Plant Scale-Up Techniques
for Solid Dosage Forms
Presented by:
Elaheh Entezar-Almahdi, Pharm-D
Ph.D Candidate of Pharmaceutics, Shiraz University of Medical Sciences
April 2016

2. References
1) The Theory and Practice of Industrial Pharmacy, Lachman, L. Lieberman, H. Kanig, J.
(1986).
2) Pharmaceutics, The Science of Dosage Form Design, Aulton, M. 2nd edition. (2002).
3) Pharmaceutical Dosage Forms Tablets, Vol. 1-3, Lachman, L. Lieberman, H. Schwartz, J.
(1989).
4) Yu LX. Pharmaceutical quality by design: product and process development, understanding,
and control. Pharm Res. 2008;25(4):781-91.
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3. QbT vs. QbD paradigms
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QbTQbD
Some of the QbD elements may
include:
- Define target product quality
profile
- Design and develop product and
manufacturing processes
- Identify critical quality attributes,
process parameters, and sources of
variability
- Control manufacturing processes
to produce consistent quality over
time

4. 1. Material Handling
 Laboratory scale
 Large scale
 Lifting and tilting drum
 More sophisticated methods (vacuum loading system, screw feed system, and metering
pump)
 If the system is used to transfer materials for more than one product, steps must be taken to
prevent cross-contamination by the use of validated cleaning procedures for the equipment.
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5. 2. Blending
 Powders to be used for
encapsulation, or to be granulated
prior to tabletting or encapsulation,
must be well blended to ensure good
drug distribution.
 Inadequate blending at this stage
could result in drug content
uniformity variation, especially if the
tablet or capsule is small and the drug
concentration is relatively low in the
blend.
 Ingredients should be free of lumps
and agglomerates, otherwise it could
cause flow problem.
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6. Cont’D
Overloading in blender
 Retards the free flow of granules
 Reduce the efficiency
 Cause content un-uniformity
If the load is to small
 Powder blend slides rather than roll in
blender
 Improper mixing
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7. Some Industrial Equipment for Mixing
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Process parameters:
- Type and geometry of mixer
- Order of addition
- Mixer load level
- Number of rotation (time and
speed)
- Agitation bar (on/off pattern)

8. 3. Granulations
To improve the flow properties
To increase the apparent
density of the powders
To change the particle size
distribution so that the binding
properties on compaction can
be improved
Use of the granulation process
to disperse an active ingredient
Reasons
Types
Wet granulation
Direct compression
method
Dry granulation
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Process parameters for wet granulation:
- High shear granulation
- Pre-binder addition mix time
- Impeller speed, configuration, and location
- Chopper speed, configuration
- Spray nozzle type and location
- Method of binder addition
- Binder fluid temperature
- Binder addition rate and time
- Post granulation mix time
- Bowel temperature
- Fluid bed granulation
- Mixing time
- Spray nozzle
- Method of binder addition
- Binder fluid temperature
- Binder fluid addition rate and time
- Inlet air flow rate, volume, temperature and
dew point
- Exhaust air temperature
- Filter properties and size
- Shaking intervals
- Product temperature

9. Multifunctional “processor”
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 Dry blending, wet granulation, drying, sizing, and lubrication in a continuous process in a single piece of
equipment
 The advantages to using such equipment during scale-up of a product can be significant in terms of space
and manpower requirements. Closed continuous systems have the added advantage of materials, thereby
reducing the danger of personnel exposure to potent materials. This is especially important when potent
and potentially hazardous compounds are involved.

10. 4. drying
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Hot Air Oven
• Air temperature
• Rate of air flow
• Depth of granulation on the trays
Fluidized Bed Dryer
• Optimum loads
• Rate of airflow
• Inlet air temperature
• Humidity
Data used for small-scale batches (1 to 5 kg)
cannot be used to extrapolate processing
conditions for intermediate-scale (100 kg) or
larger batches.

11. 5. Reduction of particle size
 Particle size and especially particle size distribution
are important to the compression characteristics of a
granulation.
 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.
 Equipment: Oscillating granulator, Hammer mill,
Screening device
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12. 5. Reduction of particle size (cont’D)
 Too large particle size result in: Weight variation and Mottling
 Too fine particle size result in: Weight variation, Capping and Lamination
 Both oversized and undersized granulation can adversely affect tablet content uniformity.
 Lubricants and glidants are added at final blend.
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Process parameters:
- impact/cutting/screening mills
 Mill type
 Speed
 Blade configuration and type
 Screen size and type
 Feeding rate

13. 7. Slugging
 A dry powder blend that cannot be directly compressed because of
poor flow or compression properties may in some instances be
processed using a slugging operation.
 Materials of very low density require roller compaction to achieve
a bulk density sufficient to allow encapsulation or compression.
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14. 8. Compression
 The ultimate test of a tablet formulation and granulation process is whether the granulation
can be compressed on a high-speed tablet press.
 Steps involved during compression:
1. Filling of empty die cavity with granulation.
2. Precompression of granulation (optional)***.
3. Compression of granulation.
4. Ejection of the tablet from the die cavity and take-off of compressed tablet
*** courtoy has developed a tablet press that is capable of minimizing capping by a unique
compression system. Instead of the pressure profile being the customery sine wave, it becomes
more of a square wave.
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15. 15
Process parameters:
- Compression speed and force
- Pre-compression force
- Feed frame type and speed
- Hopper design, height, and vibration
- Tablet weight and thickness
- Depth of fill
- Punch penetration depth

16. Tablet Coating
 Equipment: Conventional coating pan, perforated pans
or fluidized-bed coating column
 Types: sugar coating, film coating
 Tablets must be sufficiently hard to withstand the
tumbling.
 Conditions: optimum tablet load, operating tablet, bed
temperature, drying air flow rate, temperature, solution
application rate
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Process parameters:
- Product temperature
- Spray nozzle (type, quantity, pattern,
configuration
- Individual gun spray rate
- Total spray rate
- Pan rotation speed
- Atomization air pressure
- Pattern air pressure
- Inlet air flow, temperature, dew point
- Exhaust air temperature, air flow
- Total coating time

17. Capsules
To produce capsules on high-speed equipment, the
powder blend must have:
 Uniform particle size distribution
 Bulk density
 Compressibility required to promote good flow
characteristics
equipment:
 Zanasi or Martelli form slugs in a dosator ( a hollow
tube with a plunger to eject the capsule plug)
 Hoflinger-Karg --- Tamping pins
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18. Cont’D
 Overly lubricated granules---- delaying capsule disintegration and dissolution
 Granulation moisture content can be important to chemical or physical stability of the
finished product.
 Empty gelatin capsule have a recommended storage condition of 15 to 25 degree and a RH
of between 35 and 65%.
 High humidity conditions--- the capsules may swell because of the moisture absorbed.
 Low humidity conditions--- the capsules may brittle and increase their static charge.
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