1. BY:-
Robin Gulati

2.  Introduction
 Objectives of the Pilot Plant
 Significance of pilot plant
 Pilot plant design for tablets
◦ Typical unit operations

3.  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.”
R&D
Pilot
Plant
Produ-
ction

4. Scale
up
 Art of designing of prototype using the data
obtained from the pilot plant model.

5. To produce physically and chemically stable
therapeutic dosage forms.
Review of the processing equipment.
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula.

6. Examination of formulae.
Review of range of relevant processing equipment.
Production rate adjustment.
Idea about physical space required.
Appropriate records and reports to support GMP.
Identification of critical features to maintain quality.

7.  Each stage considered carefully from
experimental lab batch size to intermediate
and large scale production.
 Same process, same equipment but
different performance when amount of
material increased significantly.
 May involve a major process change that
utilizes techniques and equipment that
were either unavailable or unsuitable on a
lab scale.

8.  Material handling
 Dry blending
 Granulation
 Drying
 Reduction of particle size
 Blending
◦ Dry blending
◦ Direct compression
◦ Slugging (Dry granulation)

9.  Granulation handling and feed system
 Compression
 Tablet coating

13.  In lab: materials scooped, dumped or
poured by hand.
 May work well for small or intermediate
scale productions.
 Large scale productions: mechanical means
necessary.
 Simple means: post hoist devices, devices
for lifting, and tilting drums.
 Sophisticated: vacuum loading systems,
screw feed systems and meter pumping
systems.

14.  Type of system selected depends on the
characteristics of the material, e.g., density.
 Material handling system should cause
no/minimum loss of material.
 Lengthy transfer more material loss.
 If one system being used for more than one
material  cross contamination should be
avoided.
 Accomplished by using validated cleaning
procedures.

15. Vacuum Loading Machine

16.  Powders granulated prior to tabletting well
blended to ensure proper mixing.
 Inadequate blending  drug content
uniformity variation (more when drug conc/n
is low)  high or low potency.
 Large batch blended in batches ensuring no
lump and agglomerate formations.

17.  Problems of improper blending:-
◦ Flow problem through the equipment
◦ Non-reproducible compression
◦ No content uniformity.
 Screening and/or milling of the ingredients
prior to blending done to make the process
more reliable and reproducible.

18.  Equipment used for blending are:
◦ V- blender
◦ Double cone blender
◦ Ribbon blender
◦ Slant cone blender
◦ Bin blender
◦ Orbiting screw blenders vertical and horizontal high
intensity mixers.
 Scale up considerations
◦ Time of blending .
◦ Blender loading.
◦ Size of blender.

19. V-cone Blender Double Cone Blender

20. Ribbon Blender

21.  The most common reasons given to justify
granulating are:
a) To impart good flow properties to the material,
b) To increase the apparent density of the powders,
c) To change the particle size distribution,
d) Uniform dispersion of active ingredient.
 Traditionally, wet granulation has been
carried out using:
◦ Sigma blade mixer
◦ Heavy-duty planetary mixer (100-200kgs)

22. Sigma Blade Mixer

23. Planetary Mixer

24.  Wet granulation
can also be
prepared using
tumble blenders
equipped with
high-speed
chopper blades.

25.  These greatly affect the granulating time as
well as the granulating fluid relative to that
used in experimental laboratories trials.
 High shear mixers often more effective in
densifying light powders, but require large
amount of energy and have limited load size.
 Now-a-days equipment involving
continuous process are in use.

26.  Advantages:-
◦ Less space and manpower.
◦ Less handling of materials since they are closed
systems.
◦ Reduce danger of personnel exposure to potent
materials.
◦ Prevent from potentially hazardous substances.

27.  Binders:
◦ 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 (when
dissolved in granulating solution) as a result
transfer of fluid becomes difficult.
◦ This problem can be overcome by adding some or
all binding agents in the dry powder prior to
granulation.

28.  Gelatin
 Acacia
 Tragacanth
 Methylcellulose
 Ethylcellulose
 Hydroxypropyl cellulose
 Polyvinylpyrolidone

29.  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.

30.  The most common conventional method
 circulating hot air oven, which is heated by
either steam or electricity.
 Scale-up considerations for an oven drying
operation are:
◦ airflow
◦ air temperature, and
◦ the depth of the granulation on the trays.

31.  Too deep or too dense bed makes the drying
process 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.

32.  Fluidized bed dryers are
an attractive alternative
to the circulating hot air
ovens.
 The important factor
considered as part of
scale up fluidized bed
dryer are optimum
loads, rate of airflow,
inlet air temperature and
humidity.

33. Uniformity of Content
tablet weight uniformity
Compressibility Tablet hardness
Compression Tablet color
Flowability
factors uniformity

34.  Problems due to improper particle size:
◦ Too large particle size- insufficient filling of the die
cavity- weight variation
◦ For colored granulation- coarser the granulation-
mottling
◦ Too many fines- flowability problems- wt variation
◦ Capping (also occurs if speed of the press in
increased).

35. Oscillating granulator
(for not too hard
oversized granulation)
Equipments Hammer mill
Mechanical sieving
device
Screening device

36. Speed of
the mill
Control
factors
Rate of Type of
material feed equipment

37. Oscillating type granulator Hammer mill

38.  Use of lubricants & glidants:
◦ In lab: added to the final blend
◦ Scale up: added to the dry granulation during size
reduction
◦ This is done because additives like magnesium
stearate, agglomerate when added in large
quantities to the granulation in a blender.
◦ Over mixing or under mixing should be avoided.

39. Blender Mixing
loads speed
Mixing
Design
Control time
factors

40. Particle size
Mixing
Shape
Hardness
Density
Dynamics of the
mixing action
Segregation

41.  Characteristics of the material:
◦ Fragile particles or agglomerates: more readily
abbraided  more fines  improper mixing  flow
problems, fill problems, content uniformity problems.
◦ Particle abbraision is more when high-shear mixing with
spiral screws or blades are used.
◦ Tumble blenders: for prolonged mixing
◦ Bulk density of raw materials considered in selection of
the blender and determining optimum blender load.
◦ Excessive granulation: poor content uniformity, poor
lubrication & improper color dispersion.

42.  “Direct Compression” is defined as the process by which
tablets are compressed directly from powder mixture of
API and suitable excipients.
 No pretreatment of the powder blend by wet or dry
granulation procedure is required.
 Direct compression is one of the most advanced
technologies to prepare tablets.
 Requires only blending and compression of excipients.
 Economical process.
 Suitable for heat and moisture sensitive API.
 Not suitable for very low and very high dose drugs.

45. Particle characteristics (mixing & segregation): size,
size distribution, shape, static charge
Blender load
Optimum mixing speed
Blending time
Optimizing the process and validation of its
performance

46.  Order of addition of components to the
blender
 Mixing speed: can be varied with the original
direction as necessary.
 Mixing time: excessive mixing may fracture
the fragile excipients and ruin their
compressibility.
 Use of auxiliary dispersion material within the
mixer (chopper blade in a twin shell mixer):
◦ Increase efficiency
◦ Reduce agglomerates

47.  Mixing action:
◦ Determined by the mechanics of the mixer.
◦ Changed by converting from one blender to the
other or by modifying the blender through addition
of baffles or plates, which would alter the mixing
characteristics.
 Blender load: affects efficiency
◦ Overload: reduced free flow of granules and
reduced efficiency
◦ Localized concentration: content uniformity
◦ Small load: sliding and rolling of powders in the
blender, no proper mixing & increased time for
mixing.

48. 1. Simple
2. Requires least complicated equipment
3. Requires minimum amount of handling and
operator time
4. Modification in the process is easy
5. Free flowing granules can be obtained without the
granulating solution.
6. Saves time and energy necessary to volatilize the
solvent used in conventional granulation powders

49. 7. Suitable for thermolabile and moisture sensitive
API’s
8. Chances of batch-to-batch variation are negligible,
because the unit operations required for
manufacturing processes is fewer.
9. Particle size uniformity

50.  Excipient Related
1. Problems in the uniform distribution of low dose
drugs.
2. High dose drugs having high bulk volume, poor
compressibility and poor flowability are not suitable
for direct compression. For example, Aluminium
Hydroxide, Magnesium Hydroxide
3. Direct compression diluents and binders must possess
both good compressibility and good flowability.
4. Many active ingredients are not compressible either in
crystalline or amorphous forms.
5. May lead to unblending because of difference in
particle size or density of drug and excipients.
Similarly the lack of moisture may give rise to static
charges, which may lead to unblending.
6. Non-uniform distribution of colour, especially in
tablets of deep colours.

51.  Process Related
i) Capping, lamination, splitting, or layering of tablets
related to air entrapment during direct
compression. When air is trapped, the resulting
tablets expand when the pressure of tablet is
released, resulting in splits or layers in the tablet.
ii) In some cases require greater sophistication in
blending and compression equipment.
iii) Expensive equipment

52.  For dry powder blend that cannot be directly
compressed because of poor flow or compression
properties.
 Done on a tablet press designed for slugging.
 Pressure of 15 tons; normal: 4 tons or less
 Speed is slow since poorly flowable powders require
more time to be compressed.
 Diameter of slugs:
◦ 1 inch for more easily slugged material
◦ ¾ inch for materials difficult to compress

53. Upper feed hopper
Vertical screw
Horizontal feed screw
Pressure applied Feed & recycle
Pre-break
Compaction rolls
Granulator
Screen
Screener Recycle system
Original powder
feed
Lower hopper
Finished
product Recycle

54.  Materials of very low density require roller
compaction to achieve a bulk density sufficient to
allow encapsulation or compression. E.g.-
densification of aluminium hydroxide

55.  Additional handling can affect content uniformity of
the drug and the particle size distribution.
 Segregation due to static charges may lead to flow
problems through tablet press hoppers and feed
frames.
 This affects tablet weight, thickness and hardness.
Finally poor content uniformity.
 More sophisticated equipment  cleaning problem.
 Equipment to be engineered for efficient and total
cleaning.
 Well written, documented and validated cleaning
procedures are essential for such systems.

56.  Functions of a tablet press:
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.
 Potential problems such as sticking to the punch
surface, tablet hardness, capping, and weight
variation detected.

57.  Control factors while selecting the speed of the press:
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 it should induce static charges.
 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 at high press speeds.

58.  Slowing down the press speed or using larger
compression rollers can often reduce capping in a
formulation.
 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.

59. Single Rotary Double Rotary
Press Press

64.  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 found to work well with a
particular tablet in small lab coating pan may be
totally unacceptable on a production scale.

65.  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.

68. THANK
YOU!