The document discusses the design and operation of a pilot plant for tablet and capsule production. It provides details on: 1) The purpose of a pilot plant is to transform a lab-scale formula into a viable product by developing reliable manufacturing methods. It helps evaluate scale-up and technology transfer. 2) Key considerations for pilot plant design include simulating production equipment, identifying critical parameters, and collecting data to characterize unit operations while following cGMP. 3) The document outlines various unit operations like blending, granulation, drying, milling and compression and important aspects to consider when scaling them up.

1. PILOT PLANT DESIGN FOR TABLETS AND
CAPSULES
by
Dr.P.Koteswari
Professor and HOD
Dept. of Pharmaceutics
Smt Sarojini Ramulamma College of Pharmcy

2. Introduction
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 reliable practical
method of manufacture.”
R & D Production
Pilot Plant
Scale-up
“The art of designing of prototype using the data
obtained from the pilot plant model.”

3. General considerations
Pilot plant is a hybrid development facility and manufacturing unit which
integrates development, clinical supply manufacture, technology evaluation,
scale-up and transfer to production sites.
Pilot plant study must include c GMPs, A flexible highly trained staff, a close
examination of the formula to determine its ability to withstand batch scale and
process modification, equipment to support multiple dosage form development
and equipment at multiple scales based on similar operating procedures to
those in production.
During this process the availability of raw materials that comply with the
specifications reqd. to produce the product must be detd.
The physical space reqd.must be taken into consideration

4. • The pilot plant plays a critical role in the technology evaluation, scale up and
transfer activities of new products a properly designed and operated pilot plant
can aid in the enhanced collection of scientific data necessary for the support of
internal transfer activities as well as regulatory submissions
• Key technical aspects that must be addressed during scale-up in the pilot plant
includes:
1. Identification and control of critical component and formulation variables early
in development
2. Pilot plant equipment simulates as closely as possible to the equipment that
will be used at the manufacturing site
3. Identification of critical process parameters and operating ranges for the pilot
plant equipment through the use of statistically designed experiments
4. Collection of product and process data to adequately characterize each unit
operation.
Who should be responsible for pilot plant studies?
R and D group with separate staffing.
But some companies prefer that the pilot plant and the technical service group are
organizationally separate from research and development. The advantage with this
group would more operations oriented, more pragmatic and more receptive to the
operations priorities.

5. Personnel requirements
• The qualification required for a position ina pilot plant include a blend of good
theoretical knowledge of pharmaceutics and some practical experience in the
pharmaceutical industry. In adition, the ability to communicate well and the
ability to develop good relationships with other people are important since
experience and knowledge are most useful when adequately and effectively
communicated.
• The number of people in a pilot plant depends upon the number of products
being supported and on the level support reqd.
• References to the 4p’s personnl, premises, plant and procedures as the essential
elements in any quality oriented industry
• There can be no doubt of these elements it is people that are the most important
actor in the assurance of quality
• In most cases quality of one department effect on the operations of the other.for
ex., tablet hardness.
Training
Each person engaged in the manufacture, processing, packaging and holding of a
drug product must receive GMP training and specific training depending on the
complexity of their jobs. employees who require training can be categorized into
three groups.

6. • New employees
• Those employees who are assigned a new job
• Those employees whose performance at a task falls below reqd
standards.
The training of hourly personnel is important since new employees
may find themselves in a relatively technical environment dealing
with potent or dangerous chemicals and working with a system of
weights and measures that are unfamiliar to them.
Written operating procedures are required under the regulations
and they are considered helpful in the employee training program.
Well documented system and standardized procedures not only help
in personnel training but also provide a basis for the development of
self inspection

7. • The pilot plant must be prepared to make a variety of dosageforms in response to
a wide range of product development program.
• Most importantly, the training program must be developed to meet the changing
priorities of the product development cycle while maintaining cGMP compliance
in the manufacture of clinical supplies.
Review of the formula
A thorough review of each aspect of the formula and the purpose of each ingredient
in the formula and its contribution for the final product must be understood.
The need to modify the formulation during the scale up is not unusual and this
should be done as early as possible in the phase III trials to allow long term stability
data in support of a proposed new drug application.
Raw materials
- One responsibility of pilot plant function is the approval and validation of active
and excipient raw materials used in the pharmaceutical products. This is necessary
because the raw materials used in small scale formulation trials may not be
representative of the large volume production. Ex., even though all analytic
specifications are met, the active ingredient may change in particle shape, size,
density , static charges rate of solubility etc. the quality of active ingredient
needs to be verified because having alternate suppliers is usually desirable.

8. Relevant processing equipment
The size of pilot plant equipment size should be such that experimental trials
can be run that are meaningful and relevant to the production sized batches
that will eventually be made. If the pilot plant equipment is too small, the
process developed will not scale up. If it is large excessive costs will be
incurred

9. Pilot plant study must include
• Examination of formulae.
• Review of range of relevant processing equipments.
• The specification of the raw materials.
• Production rates.
• The physical space required.
• Appropriate records and reports to support GMP.

10. Objectives of Pilot Plant
“Find mistakes on small scale and make profit on
large scale.”
• 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.

11. General considerations
Relevant processing equipment
- Economical ,simple and capable of consistently producing
product with in the specifications
- Size
- Ease of cleaning
Production rates
- Market requirements
- The equipment and process should be chosen to produce
batches at a desired frequency

12. Process evaluation
• Order of addition of components and their quantities
• Mixing speed
• Mixing time
• Rate of addition of granulating agents, solvents, solutions of
drugs, slurries
• Heating and cooling rates
• Filter sizes
• Screen sizes
• Drying tempearatures
• Drying time

13. Personnel requirements
- Good theoretical knowledge and practical experience in
pharma Industry
Space requirements
- Administration and information processing
- Physical testing area
- Std. pilot plant equipment floor space
- Storage area
Review of the formula
Raw materials
Preparation of master manufacturing procedures
GMP considerations
Transfer of analytical methods to quality assurance

14. Pilot Plant design 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.
• If possible, it should be located on the ground floor to
expedite the delivery and shipment of supplies.

15. 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.

18. 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.
• More sophisticated methods of handling materials such as
vacuum loading systems, metering pumps, screw feed system.

19. Vacuum loading machine
Where material is moved
to a short distance to one
destination

20. 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.

21. The 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.

22. Granulation
The most common reasons given to justify granulating are
• To impart good flow properties to the material,
• To increase the apparent density of the powders,
• To change the particle size distribution,
• Uniform dispersion of active ingredient.
Traditionally, wet granulation has been carried out using,
• Sigma blade mixer,
• Heavy-duty planetary mixer.
• Wet granulation can also be prepared using tumble
blenders equipped with high-speed chopper blades

23. WET GRANULATION

24. • 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.

25. 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 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.

26. • 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.

27. Oscillating type granulator Hammer mill

28. 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.
• The important factor to consider as part of scale-up of an
oven drying operation are airflow, air temperature, and the
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.

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

30. Reduction of Particle size
• 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.

31. • A granulation with too large a particle size and
insufficient fines is unable to fill die cavities leads
weight variation
• For colored granulation, the coarser the
granulation the more mottled the final tablets
• If too many fines are present tablet weight
variation occurs because of flow problems and is
further exaggerated when speed of the press
increased.
• Both undersized and over sized granulations can
adversely affect the drug content uniformity

32. • 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.

33. Blending
• Type of blending equipment often differs from that using in
laboratory.
• 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.

34. Equipments used for mixing
•Sigma blade mixer.
•Planetary mixer.
•Twin shell blender.
•High shear mixer

35. Direct compression
1. Grinding(drug is added to the granulator and grinded)
2. Blending or Mixing
3. Compression

36. Important aspects of direct compression
- The order of addition of components to the blender
- The mixing speed
- The mixing time
- The mixing action
- The blender load

37. Ideal characteristics of directly compressible vehicle
1. It should posses appreciable compressibility and flow
properties.
2. It should be physiologically inert.
3. Must be compatible with other tablet ingredients.
4. It should posses the appreciable disintegration
characteristics.
5. It should not hinder the release of drug from the
tablet.

38. Directly compressible vehicle
1. Soluble fillers/binders
Lactose,dextrose,mannitol, sucrose, sorbitol.
2. In soluble fillers/binders
Micro crystaline cellulose
Dicalcium phosphate,
Dicalcium phosphate dihydrate,
Tricalcium phosphate

39. Advantages
1. Direct compression technique is less time consuming
(No of steps are less) .
2.It requires less labor , equipment ,space hence economical.
3. Being a dry process, It is suitable for heat and moisture sensitive
substances.
4.The microbial contamination is prevented due to absence of water.
Disadvantages
1.Large dose drugs, which are not self compressible are not suitable for
direct compression.
2. Direct compression technique is not suitable for the drugs that exhibit
poor flow properties.
3. Chances for interaction between the drug and directely compressable
filler.
4.when components differ in their bulk densities and particle sizes
,stratification (segregation into layers ) occurs.

40. Slugging (dry granulation)
• A dry powder blend that cannot be directly compressed
• This is done on a tablet press designed which operates at
pressures of about 15 tons
• 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. Ex., 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.

42. Advantages
It uses less equipment and space.
It eliminates the need for binder solution, heavy mixing
equipment and time consuming drying step required for wet
granulation.
• For moisture sensitive material
• For heat sensitive material
• For improved disintegration since powder particles are not
bonded together by a binder
Disadvantages
• It requires a specialized heavy duty tablet press to form slug
• It does not permit uniform color distribution
• The process tends to create more dust than wet granulation,
increasing the potential contamination.

43. Dry granulation

44. 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. Pre-compression of granulation (optional).
3. Compression of granules.
4. Ejection of the tablet from the die cavity and take-off of
compressed tablet.

45. o Prolonged trial runs at press speeds equal to that to be used
in normal production should be tried.
o Only then are potential problems such as sticking to the
punch surface, tablet hardness, capping, and weight variation
detected.
o High-speed tablet compression depends on the ability of the
press to interact with granulation.
The parameters to be considered while choosing speed of 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.

46. - 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.
- For high-speed machines, induced die feed systems is
necessary.
- These are available with a variety of feed paddles and with
variable speed capabilities.
- So that optimum feed for every granulation can be obtained.
- 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.

47. - This cause the punches to penetrate into 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.

48. Hopper – This is connected to the feed shoe and it is where the
granules/powder mixtures are poured into prior to tabletting or
compression. The hopper can be filled manually or by using
mechanical equipment during subsequent tabletting.
Die cavity – The die cavity is where the powder granules are
compressed into tablets. The die determines;
The diameter of the tablet
The size of the tablet
To some extent the thickness of the tablet.
Punches – This comprises upper and lower punch and they
compress the powder into tablets of various shapes within the
die.
Cam track – This guides the position/movement of the punches.
Tablet adjuster – This is used to adjust the volume of the
powder to be compressed and so determines the weight of the
tablet.
Ejection adjuster – This facilitates the ejection of the tablet from
the die cavity after compression.
In the production of tablets using a single punch tabletting
machine, the upper punch compresses the powder into tablets
while the lower punch ejects the tablet.

50. 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 fluidized-bed 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.

51. • 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.

52. Capsules

53. • Capsules are solid dosage forms in which the drug
substance is enclosed in either a hard or soft soluble
container or shell of a suitable form of gelatin.
Steps in capsule production
• Mixing of ingredient
• Granulation and lubrication
• Making of capsules
• Filling of capsules
• Uniformity testing
• Packing and labeling

54. The powder blend must have the uniform particle size
distribution, bulk density & compressibility
Composition of capsule shell
Gelatin
• Prepared by the hydrolysis of collagen.
• There are two basic types of gelatin:
• Type – A and Type – B.
• The two types can be differentiated by their isoelectric
points (7.0 – 9.0 for type A and 4.8 – 5.0 for type B) and by
their viscosity and film forming characteristics
• Combination of pork skin and bone gelatin are often used to
optimize shell characteristics.
• The bloom strength and viscosity.

55. Colorants
• Identifying the product, improving patient compliance.
Ex., synthetic dyes (“coal tar dyes”) and insoluble pigments
Opaquing agents
• Titanium dioxide may be included to render the shell opaque.
• Opaque capsules may be employed to provide protection
against light or to conceal the contents.
Preservatives
Ex., parabens
Shell manufacture
Dipping
Rotation
Drying
Stripping
Trimming
Joining

56. Sealing
• Capsules are sealed and somewhat reshaped in the
Etaseal process.
• This thermal welding process forms an indented ring
around the waist of the capsule where the cap
overlaps the body.
Storage
• Finished capsules normally contain an equilibrium
moisture content of 13-16%.
• To maintain a relative humidity of 35-65% when
handling and storing capsules.

57. Sizes and shapes
 For human use, empty gelatin capsules are manufactured
in eight sizes, ranging from 000 to 5.
Capsule capacities in table
Size Volume Fill weight(g) at 0.8
g/cm3 powder density
000 1.37 1.096
00 0.95 0.760
0 0.68 0.544
1 0.50 0.400
2 0.37 0.296
3 0.30 0.240
4 0.21 0.168
5 0.15 0.104

58. Zanasi or Martelli encapsulator
•Capable of handling
powders, pellets, tablets.
•Some models allow the
insertion of smaller capsules,
paste or liquid filling
•Bulk density, powder
flow, compressibility, and
lubricant distribution.
•Overly lubricated granules
are responsible for delaying
capsule disintegration and
dissolution.

59. Manufacture of Soft Gelatin Capsules
Composition of the shell
• gelatin + plasticizer
• 0.3-1.0 - very hard shell
• 1.0-1.8 - very soft shell.
• Up to 5% sugar may be included to give a “chewable”
quality to the shell.
• The residual shell moisture content of finished capsules
will be in the range of 6-10%.
Formulation
• Formulation for soft gelatin capsules involves liquid,
rather than powder technology.
• The pH of the liquid can be between 2.5 and 7.5.
• Emulsion can not be filled because water will be released
that will affect the shell.

60. The types of vehicles used in soft gelatin capsules fall in to two
main groups:
Water immiscible- volatile liquids such as vegetable oils,
mineral oils, medium-chain triglycerides and acetylated
glycerides.
Water miscible, nonvolatile liquids such as low molecular
weight PEG have come in to use more recently because
of their ability to mix with water readily and accelerate
dissolution of dissolved or suspended drugs.
All liquids used for filling must flow by gravity at a
temperature of 350c or less.
The sealing temperature of gelatin films is 37-400C.

61. Manufacture process
Plate process
• Placing the upper half of a plasticized gelatin sheet over a
die plate containing numerous die pockets,
• Application of vacuum to draw the sheet in to the die
pockets,
• Filling the pockets with liquor or paste,
• Folding the lower half of gelatin sheet back over the filled
pockets, and
• Inserting the “ sandwich” under a die press where the
capsules are formed and cut out.

64. This process is developed in the year 1933. The
capsule prepared by this process have
uniformly filled medications with accurate
doses.
It is fully automatic continuous process in which
liquid gelatin is made to flow from an
overhead tank to form two gelatin sheets on
two different rotating drums. These gelatin
sheets are conveyed between two rotating
dies from opposite direction. As the sheets
comes in between the dies, the metered
filling materials is injected which creates
pockets in the sheets. simultaneously, these
formed pockets are sealed by pressure and
heat and are cut off from the sheets as
capsules.
the capsuels so formed are adhered with mineral
lubricants applied on gelatin sheeets for ease
in movement. These lubricants are removed
by passing the capsules through naphtha
bath. The capsules are then passed through
air dryers under pressure to rinse off the
excess moisture. Finally they are proceeded
for packaging
Rotary die press

65. Bubble method
The Globex Mark II capsulator produces truly seamless, one-
piece soft gelatin capsules by a “bubble method”.
• A concentric tube dispenser
simultaneously discharges the molten
gelatin from the outer annulus and the
liquid content from the tube.
• By means of a pulsating pump
mechanism, the liquids are discharged
from the concentric tube orifice into a
chilled-oil column as droplets that
consists of a liquid medicament core
within a molten gelatin envelop.
• The droplets assume a spherical shape
under surface tension forces and the
gelatin congeals on cooling.
• The finished capsules must be
degreased and dried.

66. Semi solid/Liquid-filled hard gelatin capsules
• Important reason: the standard for liquid filled capsules
was inability to prevent leakage from hard gelatin capsules.
• As banding and of self-locking hard gelatin capsules,
together with the development of high-resting state
viscosity fills, has now made liquid/semisolid-filled hard
gelatin capsules.
• As with soft gelatin capsules, any materials filled into hard
capsules must not dissolve, alter or otherwise adversely
affect the integrity of the shell.
• Generally, the fill material must be pumpable.

67. • Three formulation strategies based on having a high resting
viscosity after filling have been described.
• Thixotropic formulations,
• Thermal-setting formulations,
• Mixed thermal-Thixotropic systems.
• The more lipophilic contents, the slower the release rate.
• Thus, by selecting excipients with varying HLB balance,
varying release rate may be achieved.