Pilot Plant Scale Up

PILOT PLANT SCALE UP
TECHNIQUES
PILOT PLANT SCALE UP TECHNIQUES
Pilot Plant
R&D Production
The requirements, training, reporting relationships & responsibilities of

personnel are also factors in successful product scale up
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What is pilot plant and scale up
• Pilot Plant:- It is the part of the pharmaceutical
industry where a lab scale formula is transformed
into a viable product by development of liable and
practical procedure of manufacture.
• Scale-up:- The art for designing of prototype using

the data obtained from the pilot plant model.
Why conduct Pilot Plant Studies?
(imp)
• 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
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Why conduct Pilot Plant Studies? (imp)
The pilot plant is a ‘hybrid’ of development facility and manufacturing unit,

which integrates development, early development activities, clinical supply
manufacture, technology evaluation, scale-up, and transfer to production
sites.
Pilot plant studies must include a current good manufacturing practices
(cGMPs) environment, 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 principles to those
in production.
Why conduct Pilot Plant Studies? (imp)
During this process, the availability of raw materials that
consistently comply with the specifications required to
produce the product must also be determined.
The physical space required and the layout of related functions

should be taken into consideration during the pilot plant phase
itself with the intent to provide short-term and long-term
efficiencies.
The requirements, training, reporting relationships, and

responsibilities of personnel are also factors, which must
Objective of pilot scale studies
• 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 it’s ability to

withstand Batch-scale and process modification.
• Evaluation and Validation for process and equipments
• To identify the critical features of the process. 7

Objective of pilot scale studies
• Guidelines for production and process controls.
• To provide master manufacturing formula with

instructions for manufacturing procedure.
• To avoid the scale-up problems

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A pilot plant can be used for (imp)
• 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 full-scale production process; and in the
case of a positive decision, designing and constructing a full-
size plant or modifying an existing plant
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A pilot plant can be used for (imp)
Key technical aspects that must be addressed during scale-up in the pilot plant
includes:
• Identification and control of critical component and formulation variables early
in development.
• Pilot plant equipment simulates as closely as possible to the equipment that
will be used at the manufacturing site.
• Identification of critical process parameters and operating ranges for the pilot
plant equipment through the use of statistically designed experiments.
• Collection of product and process data to adequately characterize each unit
operation.
• The facility design and the pilot plant staff involved in manufacturing operations
plays a key role in ensuring the smooth and timely transfer of process
technology to the manufacturing site.
Primary Functions of Pilot Plant
Ensure that product is produced
• Efficiently
• Economically
• Reproducibly
• Low production cost
• Rapid production rate
• Shorter production time
• Minimum equipment stress (wear and tear)
• Provide solutions to problems
• Evaluate new processing equipments
General Considerations
1. Reporting responsibilities
2. Personnel requirements
3. Space requirements
4. Review of formula
5. Raw material
6. Relevant processing equipments

7. Production rates
8. Process evaluation, optimization, performance and
validation
9. Preparation of master formula, BMR, IPQA-QC

General considerations
1. Reporting Responsibility
R & D group The formulator who developed

with the product can take into the
separate production and can provide
staffing support even after transition
into production has been
completed
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• Pilot plant functions can be part of a research and development group
with separate staffing. This arrangement is designed to provide a
hierarchy of responsibility to scale-up formulations that have been
developed by other formulators within research and development,
thereby providing an opportunity for critique of formula/process that is
independent of the initial formulation function.
• Alternatively, the formulators who developed the product can take it

into production and continue to provide support even after the
transition into production has been completed.
• The effectiveness of the pilot plant is determined by the ease with

which new products or processes are brought into routine production.
This can best 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, packaging, engineering, quality
assurance/control (QA/QC), regulatory, and marketing.
5. Raw material

7. Production rates
validation

2. Personnel
Requirement
The personnel required should have
a good theoretic knowledge as well
as some practical experience in
pharmaceutical industry
Scientists with 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 16
Personnel
Requirements
Scientist contribute fundamental strength
to understand the complex
interrelationship between processes and
chemical, physical, biochemical and
medicinal properties of dosage form
In addition, it is becoming increasingly

important for the group to contain
individuals who are knowledgeable in
both electronics and computers
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5. Raw material

7. Production rates
validation

SPACE REQUIREMENTS FOR PILOT
PLANT
Administration & Information

Physical testing area
Processing
Standard Pilot Plant

Equipment Floor Space
Storage area
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3. SPACE REQUIREMENTS
a. 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.
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b. PHYSICAL TESTING AREA
• An adequate working area in which samples can be laid out and examined
and physical test can be performed
• This area should provide permanent bench top space for routinely used
physical- testing equipment.
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c. 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.
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d. STORAGE AREA
• It should have two areas
divided as approved and
unapproved area for active
ingredient as well as excipient.
• Different areas should be
provided for the storage of the
in-process materials, finished
bulk products from the pilot-
plant & materials from the
experimental scale-up batches
made in the production.
• Storage area for the packing
material should also be
provided.
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5. Raw material

7. Production rates
validation

4. REVIEW OF THE FORMULA
• A thorough review of the each aspect of formulation is important.
• The purpose of each ingredient and it’s 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.
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5. Raw material

7. Production rates
validation

5. RAW MATERIALS
One purpose/responsibility of the pilot-plant is the approval &

validation of the active ingredient & excipients raw materials.
Why?
Raw materials used in the small scale production cannot necessarily

be the representative for the large scale production
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5. Raw material

7. Production rates
validation

6. 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 will take place.
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5. Raw material

7. Production rates
validation

7. PRODUCTION RATES
The immediate as well as the future market

trends/requirements are considered while
determining the production rates.
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5. Raw material

7. Production rates
validation

PROCESS EVALUATION, OPTIMIZATION, PERFORMANCE AND
VALIDATION
Order of mixing of
Drying temp. components Mixing
And drying time speed
Screen size Mixing

(solids) PARAMETERS
time
Filters size Rate of addition of

(liquids) granulating agents,
Heating and cooling solvents,
Rates solutions of drug etc.
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 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.
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5. Raw material

7. Production rates
validation

9. MASTER MANUFACTURING PROCEDURES
The three important aspects
Weight sheet Processing Manufacturing

directions procedure
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• 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.
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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.
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Solid Dosage Form
(Tablets)
SCALE UP OF SOLID DOSAGE FORMS
• For scaling up of tablets & capsules, from experimental laboratory to
intermediate to large scale, each stage should be carefully monitored.
• Process using the same equipment, can perform differently when size of
equipment & amount of material is increased.
• In most cases, scale-up occurs in several stages viz Small-scale laboratory

development from 0.5 to 2 kg can be scaled up to 5–10 kg and then 20–100 kg
on a pilot scale. Production scale can typically range from 200 kg to greater than
1000 kg.
• scale-up involves not just increasing the total number of unit doses produced. It
involves the transfer of technology and the transfer of the knowledge that has
been accumulated during the small-scale development of the product and
processes.
• From blending to film coating, each process has its own set of challenges. Each
operation to be categorized & well understood schematically.
SCALE UP OF SOLID DOSAGE FORMS
• Dry methods
– Direct compression
– Compression granulation
• Wet methods
– Wet granulation
DRY WET
DIRECT COMPRESSION GRANULATION GRANULATION
WEIGHING
WEIGHING WEIGHING SIZING
SIZING SIZING GRANULATION
BLENDING BLENDING DRYING
LUBRICATION COMPACTION SIZING
COMPRESSION MILLING BLENDING
COATING LUBRICATION LUBRICATION
COMPRESSION COMPRESSION
SCALE UP OF SOLID DOSAGE FORMS (tablets by wet
granulation)
a. Material handling :
• In laboratory, scooping or just pouring may be done. However on large scale,
the processes including lifts, vacuum loading systems, screw feed systems,
metering pumps.
• The type of system depends on characteristics of API & excipients for e.g.
density, static charges.
• Material handling system should deliver accurate amount of ingredient.
• In case of material loss there should accountability & compensation.
• Steps to be taken to avoid cross contamination.
• Validated cleaning procedures for the equipment should be established.

Vacuum loading machine
Screw feed system

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b. 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.
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• 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.
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V – cone blender Double cone blender
Types of
blenders
Ribbon blender
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Slant cone blender Types of
blenders
Bin blender
Orbiting screw blenders

c. 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
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• Wet granulation
can also be
prepared using
tumble blenders
equipped with
high-speed
chopper blades.
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• 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.
Multifunctional Processors – small space, less manpower, less

material handling, less human exposure, less exposure to
hazardous compounds 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 too much 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.
Occasionally Non-aqueous solvents – for poorly soluble drugs are used, more
volatile, therefore less energy to remove solvent, requires proper room and
equipment ventilation, safety precautions
Solvent recovery – EPA, OSHA
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Binders:
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.
d. 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.
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• 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.
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e. Reduction of Particle size
• Compression factors are affected by particle size distribution(PSD). PSD
decides the 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.
(16# / 18# , 40 # , 60# , 80# , 100# & then collecting plate).
• Desired Granules: Fines Ratio ranges from 40:60 to 70:30. preferably 50:50
& 60:40
• Granules --- Portion of blend retained on 60#
• Fines ---- Portion of blend passing through 60#
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Reduction of Particle size
 Higher proportion of granules can lead to:
 Improper filling of die cavity leading to weight fluctuations
 In case of coloured granules , coarser granules give mottled appearance to the
tablets.
 High proportion of fines can lead to:

 Weight variation due to improper flow
 Capping due to high speed & application of high compression pressure.
• 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 / multi mill with knife arrangement.
• In some instances dried granules are sifted through mechanical sieving device
and retained , oversized granules are passed through sizing devices.
• When screening procedure is adopted , final blending should be included to

ensure Content uniformity.
Reduction of Particle size
 Oscillatinggranulators are commonly used for oversized granules
lumps/aggregates which are not hard.
Multi-mills are commonly used for dry
sizing for rapid out put. PSD can be
controlled by screen size, speed, rate of
material feed & keeping knives forward.
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• 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.
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f. Blending
• Type of blending equipment often differs from that used in
laboratory.
• In any blending operation, both segregation and mixing occur

simultaneously. Both these processes depend on particle size,
shape, hardness, and density, and dynamics of the mixing
action.
• Fragile granules undergo abrasion leading to generation of fines

.
• Generation of fines can result in improper mixing leading to
flow, fill weight & CU issues
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Blending
Particle abrasion is more likely to occur when high-shear mixers
with spiral screws or blades are used. Generation of fines is less in
tumbler mixers compared to shear mixers. However on prolonged
blending fines are generated.
Bulk density of the blend has to be considered while deciding the

load as excessive batch size can lead to loss in blending efficiency
leading to poor CU, poor lubrication & improper color dispersion.
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
• Octagonal blender
• Nauta mixer
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Twin / Ribbon Octagonal blender
blender
Nauta mixer
• Dry methods
• Wet methods
– Wet granulation
DRY WET
WEIGHING
Tablets by Direct compression
Points to be written
a. Material handling (Simplest / most preferred, minimum handling & highly
economical. When exploring this option consideration to be given for particle
characteristics size, PSD, shape & static charges.)
b. Dry blending
• Blender load, optimum mixing time & speeds, to assure uniform distribution of
drug consistently in batch to batch. High load can reduce blending efficiency.
Low load can cause powder to slide rather than to roll resulting into increased
time for mixing / improper mixing
• Here optimization & validation of this process is important because less steps
are involved.
• Low dose ingredients to be sandwiched between 2 portion of DC excipients.
Order of addition of excipients is important.
• Auxiliary dispersion equipment (chopper blade ) within blender can remover

aggregates & improve uniformity
Tablets by Direct compression
• Size reduction
• Multi-mills are commonly used for dry sizing for rapid out put. PSD can be
controlled by screen size, speed, rate of material feed & keeping knives forward.
• 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.
• Dry methods
• Wet methods
– Wet granulation
DRY WET
WEIGHING
Slugging (Dry Granulation)
• Dry granulation is done when a dry powder blend cannot be directly compressed
because of poor flow or poor compression properties. It is also used when API is
moisture / solvent sensitive
a. Material handling
b. Dry Blending (DC)
c. Slugging
• This is done on a tablet press designed for slugging, which operates at pressures of
about 15 tons, compared with a normal tablet press, which operates at pressure of 4
tons or less.
• Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch
in diameter for materials that are more difficult to compress and require more
pressure per unit area to yield satisfactory compacts.
• If an excessive amount of fine powder is generated during the milling operation the
material must be screened & fines recycled through the slugging operation.
d. Size reduction (DC) 70
Dry Compaction (Dry Granulation)
Dry granulation is done when a dry powder blend cannot be directly compressed
because of poor flow or poor compression properties. It is also used when API is
moisture / solvent sensitive
a. Material handling
b. Dry Blending (DC)
c. Roller compaction/chilsonator
•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.
•If an excessive amount of fine powder is generated during the milling operation the material must be screened &
fines recycled through the slugging operation.
d. Size reduction 71
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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.
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• 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.
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• 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 s 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.
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• 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.
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• 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.
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HIGH SPEED ROTARY
MULTI ROTARY MACHINE
MACHINE
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DOUBLE ROTARY
UPPER PUNCH AND
MACHINE
LOWER PUNCH
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SINGLE ROTARY MACHINE
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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.
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• 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 & difference in
temperature and humidity to which tablets are exposed while
coating and drying process.
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Accumulation and
Partial Drying Coalescence and
Cohesion
Spreading
Wetting and Adherence
Coating solution moves through tubing to the coater by using the peristaltic pump.
Solution is then atomized by spray nozzles creating droplets.
Initially, wet droplets adhere to the tablet surface.
Coating solution disperses evenly and accumulates on the surface and partially dries.
Additional coating solution covers the tablet while drying.
Coalescence and final drying of the spraying solution yields a finished tablet.
Factors affecting coating
•
Scale up of liquid orals
Liquid orals
• 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
• The physical form of a drug product that is pourable displays
Newtonian or pseudo plastic flow behavior and conforms to
it’s container at room temperature
• Liquid orals are – non sterile solutions, suspensions and
emulsions
Steps of liquid manufacturing process -
General flow chart
Raw Materials Measured and
weighed
Mixing Purified water
• Planning of material
Filling
requirements
• Liquid preparation
Packing Finished products storage
• Filling and Packing
• Quality Control Quality Control

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Equipments
• Mixer
• Homogenizer
• Filtration
assembly
• Bottling assembly
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Quality Control
• Dissolution of drugs in solution
• Potency of drugs in suspension
• Temperature uniformity in emulsions
• Microbiological control
• Product uniformity
• Final volume
• Stability
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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 solutions
Protecting the API Buffers, antioxidants,

preservatives
Maintaining the appearance Colorings, stabilizers,
cosolvents, antimicrobial
preservatives
Taste/smell masking Sweetners, flavorings.
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Solutions
• Simple solutions are most straightforward to
scale up but require tanks of adequate size
and suitable mixing capacity.
• Most equipment should have heating and

cooling capabilities for rapid dissolution of
formulation components.
• Adequate transfer systems and filtration

equipment are required, but they must be
monitored to ensure that they can clarify the
product without removing active or adjuvant
ingredients.
• All equipment must be made of suitable,

non-reactive sanitary materials and be
designed and constructed to facilitate easy
cleaning.
Solutions
• Liquid pharmaceutical processing tanks, kettles,
pipes, mills, filter housings, are fabricated from
stainless steel. Of the three types commonly used in
the industry (304, 308, and 316), type 316 is most
often used because it is the least reactive.
• Stainless steel is virtually non-reactive but may

react with some acidic pharmaceutical liquids. This
problem can be minimized by treating the stainless
steel with acetic acid or nitric acid solution to
remove surface alkalinity. This process, known as
passivation.
• Interaction with metallic surfaces can be minimized

by using polytetrafluoroethylene (Teflon) liners.
Although Teflon is inert, these liners have the
potential disadvantages of cracking, breaking,
flaking, and peeling, with resulting product
contamination.
Solutions
• Dilute solutions of rapidly dissolving materials are
prepared by adding solute to the solvent and agitating
until the solution is homogeneous.
• Heat may be required for more concentrated solutions

or when the solute is slow to dissolve.
• Excipients are usually added in a specified order to

increase the rate of dissolution and to facilitate a rapid
approach to equilibrium. For this reason, menthol and
flavors are charged as alcoholic solutions to the batch.
• Solutes present in small concentrations, particularly
dyes and other intensely colored materials, should be
dissolved before mixing with the main portion of the
batch to ensure complete dissolution
• As a rule, complete solution should be confirmed at
every stage in the manufacture of a homogeneous
liquid.
Solutions
• In large-scale production, gravimetric means
of measurements are used. For this reason, all
liquids components of the formulation are
expressed in units of both volume and weight.
• Solutions must be filtered and clarified down
to removal of particulate matter of at least 3
µm this stage of the process is called
‘‘polishing.’’
• Filters used in the manufacturing, processing,
or packing of liquid drug products intended for
human use should not release fibers.
• Filter aids are commonly used to improve
clarity and increase the flow rate, thus
decreasing filtration time. The amount of filter
aid usually does not exceed 0.5 g/L. Examples :
diatomaceous earth, expanded perlite and
cellulose.
Formulation aspects of oral liquids
• Suspensions:
Purpose Agent
Facilitating the dispersion -wetting agents
between API and vehicle Salt formation ingredients
Protecting the API - Buffering-systems, polymers,
antioxidants
Maintaining the suspension Colorings, suspending agent,
appearance flocculating agent.
Masking the unpleasant Sweeteners, flavorings
taste/smell
100
Scale up aspects of suspensions
• Suspensions with respect to scale up are more
critical than simple solutions because of critical
processing needs.
• Addition of suspending agent and API, uniform

dispersion is a crucial step involved. Because on
production scale, large quantities are involved,
addition can be facilitated by use of vibrating feed
system. Powder eductor may be used for those
materials which have tendency to clump & are
difficult to disperse.
• Suspending agents can be incorporated in form of

slurry. Such a slurry helps in adequate hydration
of suspending agent. During scale up time should
be given for adequate hydration of suspending
agent as this step decides the rheological
characteristics of the suspension.
Suspensions
• Physical properties of API also affect its
dispersion characteristics. Problems not
anticipated during lab scale may arise during
scale up. It is necessary to study the drug
characteristics during preformulation studies so
that its dispersibility can be predicted.
• If API gets wetted adequately, simple addition

at appropriate manufacturing stage can be
done conveniently.
• If the drug has tendency to agglomerate/ has

static charges / poor wettability, judiciously
incorporate the step of preparation of drug
slurry.
• Slurry of API & wetting agent in vehicle can be
prepared using high shear mixer. This helps in
dispersion of drug & removal of any entrapped air &
agglomerates, prevents creaming and improves CU of
the suspension.
• Another method is to blend the API & surfactant along

with a suitable wetting liquid in the high shear powder
blender.
• By introducing this step, wettability is improved and

formation of dry agglomerates can be prevented.
• For large scale manufacture of suspensions, mixers,
pumps & mills have to be carefully selected.
• The equipment capacity is decided on the basis of size

of the batch, viscosity of the product.
• Use of undersized equipment can lead to
inadequate / non-uniform distribution or
excessive time for production.
• Mixing at high speed can result in entrapment of

air leading to chemical & physical instability.
Application of vacuum using Versator can remove
entrapped air.
• Unwanted foreign particles either from raw

materials or generated during manufacturing can
be removed by filtering batch through
appropriate screens.
• After completion of batch, filling should be

monitored. The suspensions are required to
mixed and recirculated constantly so that the
suspension does not settle down.
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
Taste/smell masking Sweetners, flavorings
105
Equipments
• Mixer
• Homogenizer
• Filteration assembly
• Bottling assembly
106
Emulsions
• Scale-up procedures from the laboratory to
manufacture can introduce a number of problems
due to the difficulties in matching the exact
conditions of mixing, and, because of entrapment of
air, especially in emulsions of high consistency.
• Along with being inelegant, even traces of

atmospheric air can cause decomposition in drugs or
excipients susceptible to oxidation.
• There are additional constraints when manufacturing

parenteral emulsions that must be sterile and of fine
particle size. Perfluorochemical and fat emulsions are
usually prepared by homogenization at high
temperature and pressure, as a large output of
energy is required to produce droplet sizes
considerably less than 1 µm.
Emulsions
• Although heat sterilization is widely used, this places a severe test on the stability, and
emulsions are sometimes prepared from sterile components under strict aseptic conditions
and further sterilized by filtration.
• Differences in manufacturing techniques such as the rate of the heating and cooling cycle,
the extent and order of mixing can cause variations in the consistency and rheology of the
resulting emulsions.
• The initial particle size of the emulsion depends on the emulsifiers used, the emulsification
equipment, the addition speed, and the phase volume.
Emulsion
• If the surfactant is placed in one of the
phases prior to emulsification, it will
migrate to the other to establish
equilibrium. Thus, emulsification
temperatures and cooling rates are
important and the time of the mixing
should be sufficient to allow the surfactant
to migrate to and equilibrate at the
interface throughout the process.
• Oil in water emulsions are sometimes

prepared by the phase inversion
technique, where the aqueous phase is
added to the oil phase to form a w/o
emulsion that inverts to an o/w emulsion
on addition of further amounts of water.
This process is claimed to give finer
emulsions.
Emulsion
• Preparation techniques, in particular cooling
rates and mixing procedures, have a marked
effect on initial and final consistencies of
emulsions prepared with nonionic
emulsifying waxes. For example, ‘‘shock’’
cooling and limited mixing initially produces
very mobile systems whereas slow cooling
with adequate mixing produces semisolid
emulsions.
• Mixing time, when the emulsifiers are in the

molten state, it influences the distribution of
surfactant within the molten masses and
bilayers and the relative lamellar order within
the system. With ionic emulsifying waxes,
different preparation techniques cause
comparatively minor variations in the
consistency of the final product.
Scale-up of semisolid dosage forms
Semisolids - Ointments
• Ointments can be manufactured by
incorporation and fusion. Mechanical mixers
are used to prepare ointments in large
quantities.
• SS kettle mixers may be used to manufacture

hydrocarbon and water-soluble base
ointments. The SS is jacketed for heating and
cooling and is equipped with a mixing
device.
• The kettle configuration is especially well-

suited for the melting and mixing of oils and
waxes and for complete bottom-emptying.
• Depending on the formulation to be

processed, the mixer may be either a
propeller or an anchor–agitator design. If the
formulation is primarily liquid, a propeller
mixer is more suitable.
Ointments
• If the formulation consists of solid waxes,
lanolin, petrolatum, and similar substances, a
kettle with a removable agitator is used.
• Planetary mixers are also used for large

scale preparations . Here, the finely divided
powdered materials are added slowly or
sifted into the vehicle (ointment base)
previously placed inside the rotating mixer.
• On achieving a uniform consistency, the

ointment preparation are processed through
the roller mill to ensure complete dispersion
and reduce the size of aggregates that may
have formed during processing.
Semi – solids Ointments
• The roller mills force the coarsely formed
ointments through stainless steel rollers to
produce ointments that are uniform in
composition and smooth in texture
• Substances may also be added by

levigating a portion of the base with the
milled drug to form a concentrate.
• The concentrate is then dispersed in the

remainder of the vehicle using steam-
jacketed vessel (on a large scale) and
allowed to cool and congeal. Once
congealed, the ointment is passed through
an ointment roller mill to ensure a uniform
and smooth texture.
Semi – solids Ointments
Semi – solids Creams
• Emulsions are prepared by means of a two-phase
heat system. In the first phase, the oil phase
ingredients are combined in a jacketed tank and
heated between 70 – 75°C to melt or liquefy all the
ingredients to a uniform state.
• In a separate tank, the second phase, aqueous phase

ingredients are heated together to slightly above
75°C. The aqueous phase is then slowly added to the
oil phase through constant agitation in case of o/w
emulsion.
• The mixture is cooled slowly with continuing

agitation as the emulsion is formed. The medicinal
ingredients may be added when the emulsion is in
the cooling stage.
• Usually, these ingredients are added as concentrated

slurry that has been previously milled to a finely
divided state.
• When the aqueous phase of the emulsion
system is larger, a large kettle may be required
with a more complex mixer. As the oil phase is
heated in a kettle, the aqueous phase is
prepared in a kettle almost twice the size of the
oil phase kettle. This size difference
accommodates the volume of the final
emulsion.
• In this case oil phase kettle is mounted directly

above the aqueous phase so as to introduce the
oil phase mixture into the lower emulsifying
unit. The oil phase is introduced into the
aqueous phase kettle in a relatively small
stream to allow rapid dispersion and
emulsification by an appropriately sized
agitator.
• For batch sizes of 500 L or less , a single
high-turbulence agitator may be used in
most cases. High turbulence emulsifier
consisting of three top entering coaxial
agitators including an anchor agitator
and self-adjusting Teflon scrapers for
thorough mixing of the preparation.
• For larger batches , a large-scale multi-

agitator mixer may be used that involves
a mixer emulsifier (for high degree of
shear), a high-speed disperser (to
disperse solids into viscous liquids), and
an anchor–agitator (to provide maximum
movement of product under low shear
conditions in the mix vessel).
• For large batches mixers with double-motion,
counter rotating agitation combined with a
homogenizing action that allows for versatility
in mixing applications may be used.
• After the addition of the phases, the rate of

cooling is generally slow to allow for adequate
mixing while the emulsion is still in liquid form.
• Cooling should be at a rate consistent with the

mixing of the emulsion and scraping of the
kettle walls to prevent formation of congealed
masses of ointment or cream, especially when
the semisolid contains a large amount of high-
melting substances.
• If drugs are introduced during the manufacture of the
product, oil-soluble drugs should be dissolved in the oil
phase and water soluble drugs in the aqueous phase.
• Preservative should be added while the emulsion is

still hot to effect complete solution.
• To improve the stability of the oil phase, colloid mills

may be used to disperse the oil phase further once the
emulsion is formed.
• Colloid mill operates by a shearing
action of a high-speed rotor against
a stationary stator with minimal
clearance .
• The colloid mill may also be located

outside of the kettle and the
emulsion pumped through it to the
filling equipment or holding tank.
• Homogenizer is also used to reduce

the size of the oil globules by
exerting a smearing action in which
the emulsion is forced through a
small orifice under high pressure.
The advantage of the homogenizer over the colloid mill is that it
does not incorporate air into the emulsion but the out put is less.
Another in-line method of emulsification is the ultrasonic process,

which uses a sonicator. This process uses a very high-intensity mixing
device that mechanically generates ultrasonic acoustic energy to
produce emulsions and dispersions.
• Liquid is pumped through a special orifice, forming a flat,
high-pressure stream. This jet impinges on the edge of a
flat blade enclosed in a tube, causing it to vibrate at
ultrasonic frequencies.
• Cavitation produces violent local pressure changes that

act on the liquid, causing instantaneous and intense
dispersion of immiscible liquids or insoluble particles.
• Transfer pumps should deliver viscous products without

applying excessive shear & incorporating air. For this
purpose positive displacement pumps are used.
Semi solids Creams
Precautionary measures for semi-solids
• The mixing equipment used must be capable of effectively &
continuously moving the mass from out side walls of vessel to the center
& from bottom to the top of the vessel. So as to enhance uniform
distribution of materials and rapid & efficient heat transfer.
• The motors used for mixing should take into account the changing
viscosity of the product on addition of ingredients and changes in
temperature.
• Temperature has to be monitored & controlled since all processes of

emulsification dispersion are controlled by this parameter. Sensors
should be located in vessels in such a manner that realistic picture of
temp. at all locations in the vessel. Failure to attain correct temp of both
phases can result in improperly dispersed wax, wide ranges of viscosity,
adverse effect on particle size.
Precautionary measures for semi-solids
• If temp is more than the required range it can result into
temporary increase in solubility of API yielding a metastable
product however on cooling recrystallization can occur due to
saturation. This recrystallized form may have different
polymorphic form or different crystal shape & size. This can lead
to grittiness, less elegant product, change in PSD, altered stability
& biological activity.
• Cream & gel formulations are thixotropic & sensitive to changes

in shear. Care should to be taken w.r.t changes in viscosity while
handling such products during transfer.
• Rheology of these products should studied thoroughly.

Scale-up for parenterals
127

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Pilot Plant Scale Up

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PILOT PLANT SCALE UP

The requirements, training, reporting relationships & responsibilities of

• Scale-up:- The art for designing of prototype using

• A pilot plant allows investigation of a product and

The pilot plant is a ‘hybrid’ of development facility and manufacturing unit,

The physical space required and the layout of related functions

The requirements, training, reporting relationships, and

• To try the process on a model of proposed plant before

• Examination of the formula to determine it’s ability to

• Evaluation and Validation for process and equipments

• To identify the critical features of the process. 7

• Guidelines for production and process controls.

• To provide master manufacturing formula with

• To avoid the scale-up problems

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

R & D group The formulator who developed

• Alternatively, the formulators who developed the product can take it

• The effectiveness of the pilot plant is determined by the ease with

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

In addition, it is becoming increasingly

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

Administration & Information

Standard Pilot Plant

• Adequate office and desk space should be provided for both

• Discreet pilot plant space, where the equipment needed for

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

• The purpose of each ingredient and it’s contribution to the final

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

One purpose/responsibility of the pilot-plant is the approval &

Raw materials used in the small scale production cannot necessarily

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

• The most economical and the simplest & efficient equipment

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

The immediate as well as the future market

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

Screen size Mixing

Filters size Rate of addition of

• The knowledge of the effects of

6. Relevant processing equipments

9. Preparation of master formula, BMR, IPQA-QC

The three important aspects

Weight sheet Processing Manufacturing

• The process directions should be precise and explicit.

• A manufacturing procedure should be written by the

• Various specifications like addition rates, mixing time,

• The primary objective of the pilot plant is the

• Hence each pilot batch representing the final

• Stability studies should be carried out in finished

• In most cases, scale-up occurs in several stages viz Small-scale laboratory

• Material handling system should deliver accurate amount of ingredient.

• In case of material loss there should accountability & compensation.

• Steps to be taken to avoid cross contamination.

• Validated cleaning procedures for the equipment should be established.

Screw feed system

• Inadequate blending at this stage could result in discrete portion of

• For these reasons, screening and/or milling of the ingredients