PILOT PLANT

SCALE- UP TECHNIQUE
SUNEEL KUMAR PANDEY
RAVI KESHARI
M.PHARM(PHARMACEUTICS)
PSIT, (KANPUR)

Contents
Definition
Objectives
Steps in scale-up
General considerations
GMP considerations
Advantages and Disadvantages
References

Definitions
Plant:- It is a place were the 5 Ms like money,
material, man, method and machine are brought
together for the manufacturing of the products.
Pilot Plant:- It is the part of the pharmaceutical
industry where a lab scale formula is transformed
into a viable[practical] product by development of
liable

[accountable]

and

practical procedure

of

manufacture.
Scale-up:- The art for designing of prototype[model]
using the data obtained from the pilot plant model.

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 liable practical procedure for manufacture.
R & D Production
Pilot Plant
Scale-up :
The art of designing of prototype using the data
obtained from the pilot plant model.

Objectives of Pilot Plant

Find mistakes on small scale and make profit on large scale.
To try the process on a model of proposed plant before
committing large sum of money on a production unit.
Examination of the formula to determine its ability to
withstand Batch-scale and process modification.
Evaluation and Validation for process and equipment's
To produce physically and chemically stable therapeutic
dosage forms.
Review of the processing equipment.

Objective
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula with instructions
for manufacturing procedure.
To identify the critical features of the process.
To avoid the scale-up problems.

REASONS FOR BUILDING A PILOT PLANT

To evaluate on process of large change in scale up
operation.
To find and examine all by-products or waste .
To produce a path for obtain lot of quantities of material.
Clinical studies, analytical development, process
development, stability testing.

Significance/Importance of Pilot Plant

Examination of formulae.
Review of range of relevant processing equipments.
The specification of the raw materials.
Idea about process requirements
Production rates.
The physical space required.
Appropriate records and reports to support GMP.

STEPS IN SCALE UP

Steps in Scale-Up
Define product economics based on projected market
size and competitive selling and provide guidance for
allowable manufacturing costs
Conduct laboratory studies and scale-up planning at

the same time

Define key rate-controlling steps in the proposed
process
Conduct preliminary larger-than-laboratory studies
with equipment to be used in rate-controlling step to
aid in plant design
Design and construct a pilot plant including provisions

for process and environmental controls, cleaning and

sanitizing systems, packaging and waste handling
systems, and meeting regulatory agency requirements

Define product economics based on projected market size and

competitive selling and provide guidance for allowable manufacturing costs

Conduct laboratory studies and scale-up planning at the same time

Define key rate-controlling steps in the proposed process

Conduct preliminary larger-than-laboratory studies with equipment

to be used in rate-controlling step to aid in plant design

Design and construct a pilot plant including provisions for process and
environmental controls, cleaning and sanitizing systems, packaging and
waste handling systems, and meeting regulatory agency requirements

Evaluate pilot plant results (product and process) including process

Economics to make any corrections and a decision on whether or not
to proceed with a full scale plant development

Why conduct Pilot Plant

Studies?
A pilot plant allows investigation of a product and
process on an intermediate scale before large
amounts of money are committed to full-scale
production
It is usually not possible to predict the effects of a
many-fold increase in scale
It is not possible to design a large scale
processing plant from laboratory data alone with
any degree of success

A pilot plant can be used for

Evaluating the results of laboratory studies and
making product and process corrections and
improvements
Producing small quantities of product for sensory,
chemical, microbiological evaluations, limited
market testing or furnishing samples to potential
customers, shelf-life and storage stability studies
Providing data that can be used in making a
decision on whether or not to proceed to a fullscale production process; and in the case of a
positive decision, designing and constructing a
full-size plant or modifying an existing plant

General considerations
1.

Reporting Responsibility

R&D
group with
separate
staffing

The formulator who

developed the product can
take into the production
and can provide support
even after transition into
production has been
completed

 Pilot plant functions can be part of a research and

development group with separate staffing.
This arrangement is designed to provide a
responsibility to scale up formulations with in
research and development ,there by providing an
opportunity for critique of formulation process that is
independent of the initial formulation function, the
formulators who developed the product can take it
into production has been completed.
Some companies prefer to have the pilot plant and
technical service group organizationally separate
from research and reporting instead to operations
side of the business

 What ever the reporting arrangement ,the goal of

a pilot plant is to facilitate the transfer of a
product from the laboratory into production. The
effectiveness of the pilot plant is determined by
the ease with which new products or processes
are brought into routine production.
This can be achieved if a good relationship exists
between the pilot plant group and the other
groups with which they interact ,namely,
research and development, processing
,packing ,engineering , quality assurance
,regulatory and marketing

2. Personnel Requirement:Scientists with qualification

& experience in pilot plant
operations as well as in
actual production area are
the most preferable
As they have to understand
the intent of the formulator
as well as understand the
perspective of the
production personnel.
The group should have some
personnel with engineering
knowledge as well as scale
up also involves
engineering principles

3.

Space Requirements

Administration
and information
processing

Physical
testing
area

Standard
equipment
floor space

Storage
area

 Administration and information

process:
Adequate office and desk space should be
provided for both scientist and technicians.
The space should be adjacent to the
working area, computer terminal for
convenient data entry and retrieval as well
as archives for stability data protocols and
historical files.
.

 Physical testing area: The second required area is an adequate working area in which
samples can be laid out and examined and where physical tests
on these samples can be performed.
This area should provide permanent bench top space for
routinely used physical- testing equipment. (e.g,balance ,
ph meter , and viscometer)

 Standard pilot-plant equipment floor space: Discreet pilot plant space, where the equipment needed for
manufacturing all types of dosage form is located.
Intermediate sized and full scale production equipment is
essential in evaluating the effects of scale-up of research
formulations and processes
Equipments used should be made portable where ever possible.
So that after use it can be stored in the small store room.
Space for cleaning of the equipment should be also provided.
Utilization of this area is most efficient when it is sub divided in
to areas for solid dosage forms, semi solid dosage forms , liquid
preparation and sterile products

 Storage Area: It should have two areas

divided as approved and
unapproved area for active
ingredient as well as excipient.
Different areas should
provided for the storage of the
in-process materials, finished
bulk products from the pilotplant & materials from the
experimental scale-up batches
made in the production.
Storage area for the packing
material should also be
provided.
These should be further
segregated in to approved and
un approved areas according
to GMPs .

4. Review of the formula:

A thorough review of the each aspect of
formulation is important.
The purpose of each ingredient and its
contribution to the final product
manufactured on the small-scale laboratory
equipment should be understood.
Then the effect of scale-up using
equipment that may subject the product to
stresses of different types and degrees can
more readily be predicted, or recognized.

5. Raw materials: One purpose/responsibility of the pilot-plant is

the approval & validation of the active ingredient &
excipients raw materials.

Necessary because Raw materials used in the

small scale production cannot necessarily be the
representative for the large scale production

6. Processing Equipment: The most economical and the simplest &

efficient equipment which are capable of producing
product within the proposed specifications are
used.
The size of the equipment should be such that the
experimental trials run should be relevant to the
production sized batches.

If the equipment is too small the process

developed will not scale up,

Whereas if equipment is too big then the

wastage of the expensive active ingredients.

 7. Production Rates:

The immediate as well as the future market

trends/requirements are considered while
determining the production rates.

The equipment and process should be chosen so

as to produce batches at a frequency that takes
into consideration product loss in the equipment
during manufacturing

8. Process Evaluation:This step is to evaluate the process critically and to

optimize its performance based on the evaluation
items that should be examined include the following
Order of mixing of components
Mixing speed
Mixing time
Rate of addition of granulating agents, solvents,
solutions of drug etc.
Heating and cooling Rates
Filters size (liquids) Screen size(solids) Drying
temp.And drying time

8. Process Evaluation:-

Drying temp.
And drying time

Screen size
(solids)
Filters size
(liquids)

Order of mixing of
components

PARAMETERS

Heating and cooling

Rates

Mixing
speed
Mixing
time
Rate of addition of
granulating agents,
solvents,
solutions of drug etc.

Why to carry out process

evaluation????
The knowledge of the effects of
various process parameters as
few mentioned above form the
basis for process optimization
and validation.

9. Master Manufacturing Procedures:The three important aspects

Weight sheet

Processing
directions or
sample
direction

Manufacturing
process

 The weight sheet should clearly identify the chemicals

required In a batch. To prevent confusion the names
and identifying nos. for the ingredients should be used
on batch records.
The process directions should be precise and explicit.
A manufacturing procedure should be written by the
actual operator.
Various specifications like addition rates, mixing time,
mixing speed, heating, and cooling rates, temperature,
storing of the finished product samples should be
mentioned in the batch record directions.

10. Product stability and uniformity: The primary objective of the pilot plant is the
physical as well as chemical stability of the
products.

Hence each pilot batch representing the final

formulation and manufacturing procedure should
be studied for stability.

Stability studies should be carried out in

finished packages as well.

 GMP are FDA guidelines to follow for industries: A check

list of GMP items
Equipment qualification
Process validation
Regularly schedule preventative maintenance
Regularly process review & revalidation
Relevant written standard operating procedures
The use of competent technically qualified personnel
Adequate provision for training of personnel
A well-defined technology transfer system
Validated cleaning procedures.
An orderly arrangement of equipment so as to ease material
flow & prevent cross- contamination

Advantages
Members of the production and quality
control divisions can readily observe scale
up runs.
Supplies of excipients & drugs, cleared by
the quality control division, can be drawn
from the more spacious areas provided to
the production division.
Access to engineering department
personnel is provided for equipment
installation, maintenance and repair.

Disadvantages
The frequency of direct interaction of the
formulator with the production personnel
in the manufacturing area will be
reduced.
Any problem in manufacturing will be
directed towards its own pilot-plant
personnel's.

PILOT PLANT DESIGN FOR

TABLETS AND CAPSULES

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.

Extraneous and microbiological contamination must be guarded

against by incorporating the following features in the pilot plant
design:
1.Fluorescent lighting fixtures should be the ceiling flush type.
2.The various operating areas should have floor drains to simplify
cleaning.
3.The area should be air-conditioned and humidity controlled.
4.High -density concrete floors should be installed.
5.The walls in the processing and packaging areas should be
enamel cement finish on concrete.
6.Equipment in the pharmaceutical pilot plant should be similar to
that used by production division- manufacture of tablets.

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.

Vacuum loading machine

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.

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.

V cone blender

Double cone blender

Ribbon blender

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.
Traditionally, wet granulation has been carried out using,
.Sigma blade mixer,
.Heavy-duty planetary mixer.

Sigma blade mixer

Planetary mixer

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.

10/4/16

Dept. of Pharmaceutics

52

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.

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.

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.

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.

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.

Oscillating type granulator

Hammer mill

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.

Equipments used for mixing

Sigma blade mixer.
Planetary mixer.
Twin shell blender.
High shear mixer

METHODS
DRY BLENDING

WET
GRANULATION

WEIGHING
SIZING
BLENDING
LUBRICATION
COMPRESSION
COATING

WEIGHING
SIZING
GRANULATION
DRYING
BLENDING
LUBRICATION
COMPRESSION

DRY
GRANULATION

WEIGHING
SIZING
BLENDING
COMPACTION
MILLING
LUBRICATION
COMPRESSION

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 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.

Dry Compaction
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.
One of the best examples of this process is the 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.

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.

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.
Following are 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.

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.
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.
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.

DIFFERENT PUNCHES &DIES

HIGH SPEED ROTARY

MACHINE

MULTI ROTARY MACHINE

DOUBLE ROTARY
MACHINE

UPPER PUNCH AND

LOWER PUNCH

SINGLE ROTARY MACHINE

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.

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.

Pilot Plant scale-up techniques for

Capsule
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
1.Mixing of ingredient
2.Granulation and lubrication
3.Making of capsules
4.Filling of capsules
5.Uniformity testing
6.Packing and labeling

The manufacturing process for capsulated products often

same to that tablets.
Both tablets & capsules are produced from ingredients
that may be either dry blended or wet granulated to
produce a dry powder or granule mix with uniformly
dispersed active ingredients.
To produce capsules on high speed equipment ,the
powder blend must have the uniform particle size
distribution, bulk density & compressibility required to
promote good flow properties & result in the formation of
compact of the right size and sufficient cohesiveness to
be filled in to capsule shells.

Manufacture of Hard Gelatin Capsules

1. Shell composition :
Gelatin :
. Prepared by the hydrolysis of collagen.
. Gelatin in its chemical and physical properties, depending
upon the source of the collagen and extraction.
. 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 physicochemical properties of gelatin of most interest to
shell manufactures are the bloom strength and viscosity.
Colorants :
Various soluble synthetic dyes (coal tar dyes) and insoluble
pigments are used.
Not only play a role in identifying the product, but also may
play a role in improving patient compliance.
E.g., white, analgesia; lavender, hallucinogenic effects; orange or
yellow, stimulants and antidepressants.

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 :
When preservatives are employed, parabens are often selected.

2)

Shell manufacture :

I. Dipping :
. Pairs of the stainless steel pins are dipped into the dipping
solution to simultaneously form the caps and bodies.
. The pins are at ambient temperature; whereas the dipping
solution is maintained at a temperature of about 500C in a
heated, jacketed dipping pan.
. The length of time to cast the film has been reported to be
about 12 sec.
II. Rotation :
. After dipping, pins are elevated and rotated 2-1/2 times until
they are facing upward.
. This rotation helps to distribute the gelatin over the pins
uniformly and to avoid the formation of a bead at the capsule
ends.

III. Drying :

. The racks of gelatin coated pins then pass into a

series of four drying oven.
. Drying is mainly done by dehumidification.
. A temperature elevation of only a less degrees is
permissible to prevent film melting.
. Under drying will leave the films too sticky for
subsequent operation.
IV. Stripping :
. A series of bronze jaws strip the cap and body
portions of the capsules from the pins.

V. Trimming :
. The stripped cap and body portions are delivered to collects in which
they are firmly held.
. As the collects rotate, knives are brought against the shells to trim
them to the required length.
VI. Joining :
. The cap and body portions are aligned concentrically in channels and
the two portions are slowly pushed together.

3)

Sorting :

. The moisture content of the capsules as they are from the

machine will be in the range of 15 18% w/w.
. During sorting, the capsules passing on a lighted moving
conveyor are examined visually by inspectors.
. Defects are generally classified according to their nature and
potential to cause problems in use.
4) Printing :
. In general, capsules are printed before filling.
. Generally, printing is done on offset rotary presses having
throughput capabilities as high as three-quarter million
capsules per hour.

5) Sizes and shapes :

. For human use, empty gelatin capsules are
manufactured in eight sizes, ranging from
000 to 5.
Size
Volume
Fill weight(g) at
. Capsule
capacities
in table: 0.8
g/cm3 powder
density
000
00
0
1
2
3

1.37
0.95
0.68
0.50
0.37
0.30

1.096
0.760
0.544
0.400
0.296
0.240

Three larger size are available for veterinary use: 10,

11, and 12 having capacities of about 30, 15, and 7.5
g, respectively.
The largest size normally acceptable to patient is a
No: 0.
The standard shape of capsules is traditional,
symmetrical bullet shape.
Some manufactures have employed distinctive shapes.
e.g. Lillys pulvule
tapers to a bluntly pointed end.
Smith Kline Beachams spansule capsules taper at
both the cap and body ends.

6) 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.
7) Storage :
. Finished capsules normally contain an equilibrium moisture content
of 13-16%.
. To maintain a relative humidity of 40-60% when handling and storing
capsules.

Filling of hard gelatin capsules

Equipment used in capsule filling operations involves one often of two
types of filling systems.
Zanasi or Martelli encapsulator:
Forms slugs in a dosatar which is a hollow tube with a plunger to eject
capsule plug.
Hofliger-Karg machine:
Formation of compacts in a die plate using tamping pins to form a
compact.

ZANASI AUTOMATIC
CAPSULE FILLING MACHINE

HOFLIGER KARG AUTOMATIC

CAPSULE FILLING MACHINE

In this both system, the scale-up process involve bulk density, powder
flow, compressibility, and lubricant distribution.
Overly lubricated granules are responsible for delaying capsule
disintegration and dissolution.

OSAKA MODEL R-180

SEMI AUTOMATIC CAPSULE
FILLING MACHINE

Manufacture of Soft Gelatin

Capsules
I.

Composition of the shell:

. Similar to hard gelatin shells, the basic component of

soft gelatin shell is gelatin; however, the shell has been
plasticized.
. The ratio of dry plasticizer to dry gelatin determines the
hardness of the shell and can vary from 0.3-1.0 for
very hard shell to 1.0-1.8 for 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%.

II.

Formulation :

. Formulation for soft gelatin capsules involves liquid,

rather than powder technology.
. Materials are generally formulated to produce the
smallest possible capsule consistent with maximum
stability, therapeutic effectiveness and manufacture
efficiency.
. The liquids are limited to those that do not have an
adverse effect on gelatin walls.
. The pH of the lipid can be between 2.5 and 7.5.
. Emulsion can not be filled because water will be
released that will affect the shell.

The types of vehicles used in soft gelatin capsules fall in to two

main groups:
1. Water immiscible, volatile or more likely more volatile
liquids such as vegetable oils, mineral oils, medium-chain
triglycerides and acetylated glycerides.
2. 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.

III. Manufacture process :

A. Plate process :
The process involved

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.

B. Rotary die press:

. In this process, the die cavities are machined in to the
outer surface of the two rollers.
. The die pockets on the left hand roller form the left side
of the capsule and the die pockets on the right hand
roller form the right side of the capsule.
. Two plasticized gelatin ribbons are continuously and
simultaneously fed with the liquid or paste fill between
the rollers of the rotary die mechanism.
. As the die rolls rotate, the convergence of the matching
die pockets seals and cuts out the filled capsules.

C. Accogel process:
. In general, this is another rotary process involving
A measuring roll,
A die roll, and
A sealing roll.
. As the measuring roll and die rolls rotate, the measured doses
are transferred to the gelatin-linked pockets of the die roll.
. The continued rotation of the filled die converges with the
rotating sealing roll where a second gelatin sheet is applied
to form the other half of the capsule.
. Pressure developed between the die roll and sealing roll seals
and cuts out the capsules.

4. 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.

IV. Soft/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.

 Three formulation strategies based on having a high resting

viscosity after filling have been described.
1. Thixotropic formulations,
2. Thermal-setting formulations,
3. 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.

CAPSULE
POLISHING
MACHINE

AUTO MATIC
CAPSULE
ARRANGEMNT

ORAL LIQUIDS:

Liquid orals
The physical form of a drug product that is pourable
displays Newtonian or pseudoplastic flow behaviour and
conforms to its container at room temperature.
Liquid dosage forms may be dispersed systems or
solutions.
In dispersed systems there are two or more phases, where
one phase is distributed in another.
A solution refers two or more substances mixed
homogeneously.

General flow chart

Measured and
weighed

Raw Materials

Mixing

Distilled water

Filling

Packing

Finished products storage

Quality Assurance

Steps of liquid manufacturing process

Planning of material requirements:
Liquid preparation:
Filling and Packing:
Quality assurance:

Critical aspects of liquid manufacturing

Physical Plant:
Heating, ventilation and air controlling system:
the effect of long processing times at suboptimal
temperatures should be considered in terms of consequences
on the physical or chemical stability of ingredients as well as
product.

Formulation aspects of oral

liquids
Suspensions:
Purpose
Facilitating the connection
between API and vehicle

Agent
-wetting agents
Salt formation ingredients

Protecting the API

- Buffering-systems, polymers,
antioxidants

Maintaining the suspension

appearance

Colorings, suspending agent,

flocculating agent.

Masking the unpleasant

taste/smell

Sweeteners, flavorings

 Emulsions:
Purpose

Agent

Particle Size

Solid particles, Droplet

particles

Protecting the API

Buffering-systems,
antioxidants, polymers

Maintaining the appearance

Colorings, Emulsifying
agents, Penetration
enhancers, gelling agents
Sweetners, flavorings

Taste/smell masking

 Solutions:

Protecting the API

Buffers, antioxidants,
preservatives

Maintaining the
appearance

Colorings, stabilizers,
cosolvents, antimicrobial
preservatives

Taste/smell masking

Sweetners, flavorings.

Layout of the pilot plant

Equipments
Mixer
Homogenizer
Filtration assembly
Bottling assembly

Filtration assembly

Quality assurance
Dissolution of drugs in solution
Potency of drugs in suspension
Temperature uniformity in emulsions
Microbiological control
Product uniformity
Final volume
Stability

Scale-up of semisolid dosage forms

Semisolid dosage forms

In general, semisolid dosage forms are complex
formulations having complex structural elements.
Often they are composed of two phases (oil and water),
one of which is a continuous (external) phase, and the
other of which is a dispersed (internal) phase.
The active ingredient is often dissolved in one phase,
although occasionally the drug is not fully soluble in the
system and is dispersed in one or both phases, thus
creating a three-phase system.

Semisolid dosage forms

The physical properties of the dosage form depend
upon various factors, including the size of the
dispersed particles, the interfacial tension between the
phases, the partition coefficient of the active ingredient
between the phases, and the product rheology.
These factors combine to determine the release
characteristics of the drug, as well as other
characteristics, such as viscosity.

Critical manufacturing
parameters
For a true solution, the order in which solutes are added
to the solvent is usually unimportant.
The same cannot be said for dispersed formulations,
however, because dispersed matter can distribute
differently depending on to which phase a particulate
substance is added.
In a typical manufacturing process, the critical points are
generally the initial separation of a one-phase system
into two phases and the point at which the active
ingredient is added.

Critical manufacturing
parameters
Because the solubility of each added ingredient is
important for determining whether a mixture is visually
a single homogeneous phase, such data, possibly
supported by optical microscopy, should usually be
available for review.
This is particularly important for solutes added to the
formulation at a concentration near or exceeding that of
their solubility at any temperature to which the product
may be exposed.

Critical manufacturing
parameters
Variations in the manufacturing procedure that occur after
either of these events are likely to be critical to the
characteristics of the finished product.
This is especially true of any process intended to increase
the degree of dispersion through reducing droplet or
particle size (e.g., homogenization).
Aging of the finished bulk formulation prior to
packaging is critical and should be specifically addressed
in process validation studies.
General stability consideration

General stability consideration

The effect that SUPAC changes may have on the stability of the drug
product should be evaluated. For general guidance on conducting
stability studies, see the FDA Guideline for Submitting Documentation
for the Stability of Human Drugs and Biologics.

General stability consideration

For SUPAC submissions, the following points should
also be considered:
1. In most cases, except those involving scale-up,
stability data from pilot scale batches will be
acceptable to support the proposed change.
2. Where stability data show a trend towards potency
loss or degradant increase under accelerated
conditions, it is recommended that historical
accelerated stability data from a representative
prechange batch be submitted for comparison.

General stability consideration

It is also recommended that under these circumstances, all available
long-term data on test batches from ongoing studies be provided in the
supplement.
Submission of historical accelerated and available long-term data would
facilitate review and approval of the supplement.

General stability consideration

3. A commitment should be included to conduct long-term stability
studies through the expiration dating period, according to the
approved protocol, on either the first or first three (see section III-VI
for details) production batches, and to report the results in subsequent
annual reports.

The Role of In Vitro Release

Testing
The key parameter for any drug product is its efficacy
as demonstrated in controlled clinical trials.
The time and expense associated with such trials make
them unsuitable as routine quality control methods.
Therefore, in vitro surrogate tests are often used to
assure that product quality and performance are
maintained over time and in the presence of change.

The Role of In Vitro Release

Testing
A variety of physical and chemical tests commonly
performed on semisolid products and their components
(e.g., solubility, particle size and crystalline form of the
active component, viscosity, and homogeneity of the
product) have historically provided reasonable evidence
of consistent performance.
More recently, in vitro release testing has shown
promise as a means to comprehensively assure
consistent delivery of the active component(s) from
semisolid products.

The Role of In Vitro Release

Testing
An in vitro release rate can reflect the combined effect of several
physical and chemical parameters, including solubility and particle size
of the active ingredient and rheological properties of the dosage form. In
most cases, in vitro release rate is a useful test to assess product
sameness between prechange and postchange products.

The Role of In Vitro Release

Testing
However, there may be instances where it is not suitable for this purpose.
In such cases, other physical and chemical tests to be used as measures of
sameness should be proposed and discussed with the Agency.
With any test, the metrics and statistical approaches to documentation of
sameness in quality attributes should be considered

The Role of In Vitro Release

Testing
The evidence available at this time for the in vitro-in
vivo correlation of release tests for semisolid dosage
forms is not as convincing as that for in vitro
dissolution as a surrogate for in vivo bioavailability of
solid oral dosage forms.
Therefore, the Centers current position concerning in
vitro release testing is as follows:

The Role of In Vitro Release

Testing
1. In vitro release testing is a useful test to assess
product sameness under certain scale-up and
postapproval changes for semisolid products.
2. The development and validation of an in vitro release
test are not required for approval of an NDA, ANDA
or AADA nor is the in vitro release test required as a
routine batch-to-batch quality control test.

The Role of In Vitro Release

Testing
In vitro release testing, alone, is not a surrogate test
for in vivo bioavailability or bioequivalence.

3.

4. The in vitro release rate should not be used for

comparing
different
formulations
across
manufacturers.

Contract manufacturing

Definition of contract
manufacturing

Production of goods by one firm, under the label or brand of another firm.
Contract
manufacturers provide such
service to
several
(even competing) firms based on their
own or
the customers' designs, formulas, and/or specifications. Also called private
label manufacturing.

Contract manufacturing
Contract manufacturing is a process that established a working
agreement between two companies.
As part of the agreement, one company will custom produce parts or
other materials on behalf of their client.
In most cases, the manufacturer will also handle the ordering and
shipment processes for the client.
As a result, the client does not have to maintain manufacturing facilities,
purchase raw materials, or hire labour in order to produce the finished
goods.

Contract manufacturing.
The basic working model used by contract manufacturers translates
well into many different industries.
Since the process is essentially outsourcing production to a partner
who will privately brand the end product, there are a number of
different business ventures that can make use of a contract
manufacturing arrangement.
There are a number of examples of pharmaceutical contract
manufacturing currently functioning today, as well as similar
arrangements
in
food
manufacturing,
the
creation
of computer components and other forms of electronic contract
manufacturing.

Contract manufacturing
Even industries like personal care and hygiene products, automotive
parts, and medical supplies are often created under the terms of a
contract manufacture agreement.
In order to secure contract manufacturing jobs, the contract manufacturer
usually initiates discussions with the potential client.
The task is to convince the prospective customer that the manufacturer
can use their facilities to produce quality goods that will meet or exceed
the expectations of the customer.

Contract manufacturing
At the same time, the manufacturer will demonstrate how the
overall unit cost of production to the customer will be less than
any current production strategies in use, thus increasing the
amount of profit that will be earned from each unit sold
There are several advantages to a contract manufacturing
arrangement.
For the manufacturer, there is the guarantee of steady work.
Having contracts in place that commit to certain levels of
production for one, two and even five year periods makes it much
easier to forecast the future financial stability of the company.

Contract manufacturing
For the client, there is no need to purchase or rent
production facilities, buy equipment, purchase raw
materials, or hire and train employees to produce the
goods.
There are also no headaches from dealing with
employees who fail to report to work, equipment
that breaks down, or any of the other minor details
that any manufacturing company must face daily.

Contract manufacturing
All the client has to do is generate sales, forward orders to the
manufacturer, and keep accurate records of all income and expenses
associated with the business venture.
The general concept of contract manufacturing is not limited to the
production of goods. Services such as telecommunications, Internet
access, and cellular services can also be supplied by a central vendor
and private branded for other customers who wish to sell those
services.
Doing so allows the customer to establish a buy rate from the
vendor, then resell the services at a profit to their own client base

Scopes of contract
manufacturing
The
scope
of
the Contract
Manufacturing
Procurement business scenario outlined in this
documentation only concerns the customer side (OED
-The Office of Enterprise Development ).
This business scenario does not cover how an ERP
(Enterprise Relationship Management) system
on the supplier's side (that is, the contract manufacturer's
side) receives messages sent by the customer, and how it
deals with the additional information (for example,
components) submitted with these messages.

Scopes of contract
manufacturing
Mappings are only provided for A2A communication (between
the OED's ERP system and SAP* SNC*) from IDoc to XML
and vice versa.
This business scenario does not cover the tracking of the
manufacturing process (production phases) that takes place at
the contract manufacturer's site - it does not take into account
the current production phase at the contract manufacturer' site.
Consequently, the OED planner cannot predict the supply
situation of finished goods.
* SAP- Supply Network Planning
* SNC- Supply Network Collaboration

Limits of contract manufacturing

The Contract Manufacturing Procurement business scenario has the
following limitations:
Once a schedule line in the ERP purchase order is changed, the date and quantity data
originally requested are lost. Even if the information is stored in SAP SNC, it is not
possible to send this information to the CM.

The Contract Manufacturing Procurement business scenario is based on functions

introduced in SAP ERP 6.0. For lower releases, you need to develop a customer
modification.

Limits of contract manufacturing

No data import control functions are provided for
messages sent from the CM to SAP SNC.
The bill of material (BOM) is not available in SAP SNC.
New purchase order items cannot be created in SAP SNC.
Product substitution is not supported.
Scheduling agreements for the subcontracted material are
not allowed.

Limits of contract manufacturing

A supplier should be able to update the component consumption in SAP SNC
until a good receipt has been posted in the customer ERP back-end system.
The subcontracting scenario of the Rosetta Network Order Management Program
as described in the PIPs* 7B5 (Notify of Manufacturing Work Order), 7B6
(Notify of Manufacturing Work Order Reply), and 7B1 (Work In Process
Notification) is not included in the scope of SAP SCM*.
* PIP- Partner Interface Process
* SCM- Supply Chain Management

Scale-up for parenterals

Injectables
The majority of the parenteral solutions are
solutions requiring a variety of tankage,
piping and ancillary equipment for liquid
mixing, filteration, transfer and related
activities.
The majority of the equipments are
composed of 300 series austenitic stainless
steel, with tantalum or glass lined vessels
employed for preparation of formulations
sensitive to iron and other metal ions.
The vessels can be equipped with external
jackets for heating and/or cooling and
various types of agitators, depending upon
the mixing requirements of the individual
formulation.

Working area of a parenteral

pilot plant
Incoming goods are stored in special areas for
Quarantine, Released and Rejected status.
A cold room is available for storage of temperaturesensitive products. Entrance into the warehouse and
production areas is restricted to authorized personnel.
Sampling and weighing of the raw material is
performed in a dedicated sampling area and a central
weighing suite, respectively.
The route for final products is separated from the
incoming goods; storage of final products is done in
designated areas in the warehouse while they are
awaiting shipment.
Several clothing and cleaning procedures in the
controlled transport zone and production area ensure
full quality compliance.
In addition, a technical area is located in between the
production zone and the area for formulation
development.

Lay-out of the pilot-plant

Facility Design
To provide the control of microbial, pyrogen
and particles controls over the production
environment are essential.
Warehousing:
All samples should be aseptically taken,
which mandates unidirectional airflow and
full operator gowning.
These measures reduce the potential for
contamination ingress into materials that are
yet to receive any processing at any site.

Preparation Area:
The materials utilized for the production of
the sterile products move toward the
preparation area through a series of
progressively cleaner environments.

First the materials are passed through class 100,000 i.e. grade D
environment for presterilization.

Transfer of materials are carried out in air-locks

to avoid cross contamination

The preparation areas are supplied with HEPA filters.

There should be more than 20 air changes per hour

The preparation place is Class 100 area.

Production area

Compounding area:
The manufacture of parenterals is carried
out in class 10,000 (Grade C) controlled
environments in which class 100
unidirectional flow hoods are utilized to
provide greater environmental control
during material addition.
These areas are designed to minimize the
microbial, pyrogen, and particulate
contamination to the formulation prior to
sterilization.

Aseptic filling rooms:

The filling of the formulations is performed in an Class 100
environment.
Capping and Crimp sealing areas:
The air supply in the capping line should be of Class 100
Corridors:
They serve to interconnect the various rooms. Fill rooms, air
locks and gowning rooms are assessed from the corridor.
Aseptic storage rooms.
Air-locks and pass-throughs:
Air locks serve as a transition points between one environment
and another.
They are fitted with the UltraViolet lights, spray systems, or
other devices that may be effectively utilized for
decontamination of materials.

Formulation aspects
Solvent:
The most widely used solvent used for
parenteral production is water for injection.
WFI is prepared by by distillation or
reverse osmosis. Sterile water for injection
is used as a vehicle for reconstitution of
sterile solid products before administration
and is terminally sterilized by autoclaving
Solubilizers:
They are used to enhance and maintain
the aqueous solubility of poorly watersoluble drugs.

Solubilizing agents used in sterile products include:

1. co-solvents: glycerine, ethanol, sorbitol, etc.
2. Surface active agents: polysorbate 80,
polysorbate 20, lecithin.
3. Complexing agents: cyclodextrins etc
They act by reducing the dielectric constant
properties of the solvent system, thereby reducing
the electrical, conductance capabilities of the
solvent and thus increase the solubility.
Antimicrobial preservative agents:

 Buffers:
They are used to maintain the pH level of
a solution in the range that provides either
maximum stability of the drug against
hydrolytic degradation or maximum or
optimal solubility of the drug in solution.
Antioxidants:
Antioxidants function by reacting
prefentially with molecular oxygen and
minimizing or terminating the free the free
radical auto-oxidation reaction. Examples
phenol (0.065-0.5%), m-cresol (0.16-0.3%)
etc.

Instrumentation
Mixer
Homogenizer
Filteration assembly
Filling machinery

Mixer/Homogenizer

Filtration assembly

Bottling/Filling machinery

Sterilization and
Depyrogenation

Steam sterilization
Dry-heat sterilization and depyrogenation
Gas and vapour sterilization
Radiation sterilization
Sterilization by filteration

Aseptic processing control and evaluation

In-process Testing:
End-product Testing:
Process simulations:
Quality Assurance

Particulate matter
Pyrogen test
Stability test

Particulate matter detector

Liquid orals
The physical form of a drug product that is
pourable displays Newtonian or pseudoplastic
flow behaviour and conforms to its container
at room temperature.
Liquid dosage forms may be dispersed
systems or solutions.
In dispersed systems there are two or more
phases, where one phase is distributed in
another.
A solution refers two or more substances
mixed homogeneously.

Technology Transfer:

Reference
The theory & practice of industrial pharmacy by Leon Lachman, Herbert
A. Lieberman, Joseph L. kenig, 3rd edition, published by Varghese
Publishing house.
Lachman L. The Theory and practice of industrial pharmacy. 3 rd Edition.
Varghese publication house.
www.google.com

References
1. The theory and practice of industrial pharmacy. Leon
Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third
edition. Varghese publishing house. Page no. 681-703.
2. Pharmaceutical dosage forms: Tablets. Volume 3. second
edition. Leon Lachman, Herbert A. Lieberman, Joseph B.
Schwartz. Page no. 303-365.
3. Pharmaceutical process scale up edited by Michael Levin.
4. Modern pharmaceutics. Edited by Gilbert S. Banker &
Christopher T. Rhodes. 4th edition.
5. www.google.com

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