“A REVIEW ON COMPARATIVE

STUDY OF PILOT PLANT SCALE UP

TECHNIQUE”
A REPORT OF PROJECT WORK
Submitted to
RAJIV GANDHI PROUDYOGIKI
VISHWAVIDHALAYA, BHOPAL
In Partial Fulfillment of the Requirement for the
Degree of
BACHELOR OF PHARMAY

2021-2022

SUPERVISED BY:SUBMITTED BY:

Ms. PRIYANKA AHIRWAR QUAM
BABU
ASST. PROFESSOR B. PHARMACY
 VII SEMESTER

ENROLL NO:

0516PY181062

VIVEKANAND COLLEGE OF PHARMACY

VIP CAMPUS RATIBAD, SIKANDARABAD
BHOPAL, 462044
 VIVEKANAND COLLEGE OF PHARMACY
VIP CAMPUS RATIBAD, SIKANDARABAD BHOPAL, 462044

CERTIFICATE

This is to certify that Mr. QUAM BABU Enrollment No. 0516PY181062

a student of B.PHARMACY final year has satisfactorily submitted project
on “A REVIEW ON COMPARATIVE STUDY OF PILOT PLANT
SCALE UP TECHNIQUE " under my Supervision.

He has collected the literature very sincerely and methodically and his work his
authentic.

STUDEN
T
QUAM
BABU
ENROLLMENT
NO.0516PY181062
 FORWARDING LETTER

Mr. QUAM BABU has completed his project work entitled "A
REVIEW ON COMPARATIVE STUDY OF PILOT
PLANT SCALE UP TECHNIQUE
Under the Supervision and Guidence of Asst. Prof. Ms. PRIYANKA AHIRWAR
fulfillment for the degree of Bachelor of Pharmacy.

The project is forwarded to RGPV Examiner for evaluation.

Dr. VIVEKANAND
KATARE
Principal
 DECLARATION

This is to certify that the dissertation word entitled a "A REVIEW ON

COMPARATIVE
STUDY OF PILOT PLANT SCALE UP TECHNIQUE " for theaward of
carried by our laboratories and library under the guidance and supervision of DR.
VIVEKANAND KATARE.

It also declare that present work embody has not the basic award for any degree or
fellowship previously. The particular given in this Project or true to be best knowledge.

Dr. VIVEKANAND KATARE QUAM BABU

Principal Enrollment.
No.0516PY181098
 ACKNOWLEDGEMENT
The completion of any project depends upon the co-operation, co-ordination
and combined efforts of several resources of knowledge, inspiration and
energy. Therefore I approach the important matter of project through these
lines trying my best to give full credit where it deserves.

I wish to express my deep sense of gratitude to my guide, Asst.Prof. Miss.

PRIYANKA AHIRWAR, VCP Faculty of Pharmacy for his valuable
guidance and support for this major project. I am heartily thankful to him for
providing me his valuable suggestions and remarks to complete these major
projects. I think without his guidance this thesis work could not be so
successful.

I express my profound indebtedness to Dr. Vivekanand Katare, Principal

VCP Faculty of Pharmacy, Bhopal for providing all facilities required for
making the project successful It gives me an immense pleasure to thanks and
expresses my deep sense of gratitude to my Teaching staff of college, who has
been an invarable source of inspiration to me.

I am also thankful to my Non-Teaching Members, who always helped me in all

situations.

I express my sincere gratitude to my ever loving, affectionate, Parents, and my

friends who has been soils pillar of everlasting support and inspiration.
PILOT PLANT SCALE UP TECHNIQUE

Page 1
 INTRODUCTION

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
A pilot plant is a pre-commercial production system that employs new
production technology and/or produces small volumes of new technology-
based products, mainly for the purpose of learning about the new technology.
The knowledge obtained is then used for design of full-scale production
systems and commercial products, as well as for identification of further
research objectives and support of investment decisions. Other (non-technical)
purposes include gaining public support for new technologies and
questioning government regulations. Pilot plant studies must includes a close
examination of formula to determine its ability to withstand batch scale and
process modifications; it must includes a review of range of relevant
processing equipment also availability of raw materials meeting the
specification of product and

PILOT PLANT
Why conduct Pilot Plant Studies?
 A pilot plant allows investigation of a product and process on an
intermediate scale before large y 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 complex food 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-live and storage stability studies.
 Determining possible salable by-products or waste stream requiring
treatment before discharge.
 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.
Considerations in pilot plant development
 Kind and size – depends on goals; evaluating product and process;
producing samples of product for evaluation; market testing or
furnishing to potential customers.
 Location: near R&D facility? At an existing plant? Close liaison
between R&D and pilot plant staff is essential.
 Labor requirements and costs: engineering staff, skilled operations and
maintenance staff- pilot plant costs may exceed those of usual plant
production costs. The pilot plant may be used for training personnel
for a full- scale plant.
 Objective
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 with stand
Batch- scale and process modification.
 Evaluation and Validation for process and equipments
 To identify the critical features of the process
 Guidelines for production and process controls.
 To provide master manufacturing formula with
instructions for manufacturing procedure.
 To avoid the scale-up problems.
Significance of Pilot Plant
 Standardization of formulae.
 Review of range of relevant processing equipments.
 Optimization and control of production rate.
 Information on infrastructure of equipments during the scale up
batches physical space required.
 Identification of critical features to maintain quality of a product.
 Appropriate records and reports to support GMP.
PILOT PLANT DESIGN
 A pilot plant design should support three key strategic objectives :

 Formulation and process development .

 Clinical supply manufacture .

 Technology evaluation , scale up and transfer .

 Attributes playing a key role in achieving the above objectives are :

 cGMP Compliance .
 A flexible highly trained staff .
 Equipment to support multiple dosage form development .
 Equipment at multiple scales based on similar operating principles to those in
production .
 The pilot plant design should be according to cGMP norms . The layout should be
according to the need for flexibility (portable equipment installed , use of multipurpose
rooms) , restricted access , personnel flow and material flow. The facility and
equipment should be able to capture critical process information . Intermediate
sized and Full scale production equipment should be available in order to evaluate the
effects of scale up of research formulations . Adequate space required to carry out each
function smoothly (eg., cleaning of pilot plant equipments) . The final design should
result in a facility that support the key strategic objectives and should have low
maintenance and operating costs .
 Although the pilot plant design must simulate the manufacturing environment in which
the new product will ultimately be produced , there are many differences in operation
because of the specific objectives of the two types of facilities i.e. the pilot plant
facilitates product development activities , whereas the manufacturing plant routinely
fabricates products for the market place .
PILOT PLANT OPERATION

 Operational Aspects of Pilot Plant includes :

Validatio

n Training

Engineering

Support

Maintenance

Calibration

Material

Control

Inventory

Orders

Labeling

Process and Manufacturing Activities

 VALIDATION :

 A validation master plan should be develop that addresses—

 The design specifications

 Installation qualification

 Operational qualification

 Performance qualification

of all major utility systems , process equipment , and computer control systems .
A fully validated pilot plant should ensure compliance with cGMP and should
meet current FDA standards .

 TRAINING :Training in four major area required –-

 Compliance with quality standards such as cGMP

 Safety and environmental responsibilities

 Compliance with SOPs

 Technical skills and knowledge

 ENGINEERING SUPPORT : It is required for –-

 Design , construction , commissioning and validation of the pilot plant

facility

 Co-ordination , scheduling and direction of ongoing operations

 MAINTENANCE : It is required to –-

 Meet cGMP norms

 To ensure data integrity and equipment reliability during the development

process. The maintenance program should be documented and written
procedures established.
 CALIBRATION : Calibration of critical instruments/equipments is required for–-

 Compliance with cGMP

 Maintaining the integrity of data generated during the development

process Calibration should be performed by well trained and expert staff.

 MATERIAL CONTROL : More flexible and efficient computer based system is

required for material control in pilot plant .

 INVENTORY : Inventory should be maintained in a Computer Based

InventoryOrdering-Dispensing System

 ORDERS : All orders must be placed through the computer system . For placement of
the order , First In First Out (FIFO) criteria is followed .

 LABELING : Labels should comply with GMP-GLP requirements . Computer

system must be used for labeling

 PROCESS AND MANUFACTURING ACTIVITIES : It includes –

 Formulation and Process Development Studies

 Clinical supply manufacture

 Technology evaluation , scale up and transfer Precise documentation of each

trials have to be made .
 QUALITY ASSURANCE
QUALITY CONTROL :
QA Activities –-
  Auditing pilot plant

 Auditing and approval of component suppliers

 Reviewing , approving and maintaining batch records for clinical supplies

 Sampling and release of raw materials and components required for clinical
supplies

 Release of clinical supplies

 Maintaining and distributing facility and operating procedures (SOPs)

 Review and approval of validation and engineering documentation.

 QC Activities –-

 Release testing of finished products

 Physical , chemical , and microbiological testing of finished clinical

products, components and raw materials

 Testing for validation and revalidation programs

 QC in-process testing during development , scale up , and technology transfer

activities

 GENERAL CONSIDERATIONS

 PERSONNEL REQUIREMENTS : Personnel should have –-

Scientists with experience in pilot plant operations as well as in actual 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

 SPACE REQUIREMENTS

 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.

Physical testing area

This area should provide permanent bench top space for

routinely used physical- testing equipment.
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 pilot-plant & materials
from the experimental scale-up batches made in the production.
Storage area for the packing material should also be provided
 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 thesmall-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 recognize
 RAW MATERIALS

 One purpose/responsibility of the pilot-plant is the

approval& validation of the active ingredient & excipient
raw materials.
production area are the most preferable
  Raw materials used in the small scale production cannot
necessarily be the representative for the large scale production
 RELEVANT 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.

 PRODUCTION RATES :

 It can be determined by the immediate future market requirements.

 Equipment and the process should be chosen on the basis of production of a batch
at a frequency that takes into consideration :

1. Product loss in the equipment during manufacture .

2. The time required to clean the equipment between batches .

3. The number of batches that will need to be tested for release

 Order of mixing of
components

Filter size PARAMETERS Mixing speed

(liquids)

Heating and
cooling rates

 It is the basis of process validation Documentation of process is to be done . Process

is validated only if there are no changes in the formula , quality of the ingredients , or
the equipment configuration .

 Revalidation needs to be done to ensure that changes have not take place .

 PREPARATION OF MASTER MANUFACTURING PROCEDURES: It includes

 The chemical weigh sheet. It should clearly identify the chemicals required in
a batch and present the quantities and the order in which they will be used .

 The sampling directions

 In-process and finished product specifications

  Manufacturing directions should be in a language understandable by the operator
termed as SOP’s .

 Batch Record Directions should include specifications for addition rates , mixing
times , mixing speeds , heating and cooling rates , temperature .

 Proper documentation should be carried out.

 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 CONSIDERATIONS :

GMP items that should be a part of scale up are –-

 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

crosscontamination.

 TRANSFER OF ANALYTICAL METHODS TO QUALITY ASSURANCE :

Analytical methods developed in research must be transferred to QA department . Transfer

process includes -

1. Review the process to make sure that proper analytical instrument is available .

2. Personnel should be trained to perform the test .

3. Reliability of the test should be checked .

4. At last assay procedure should be reviewed before transfer .

SCALE – UP TECHNIQUES

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

STEPS IN SCALE UP
General flow chart
Raw Materials Measured and weighed

mixing Distilled

water Filling

Packing

Finished products storage

Quality Assurance

 General stability consideration for general guidance on

conducting stability studies, see the FDA Guideline for
Submitting Documentation for the Stability of Human Drugs
and Biologics.

 A commitment should be included to conduct long-term

stability studies through the expiration dating period, according
to the approved protocol.

 Production batches, and to report the results in subsequent annual

reports.
 Scale Up Process

Scale-up is defined as the process of increasing the batch size. Scale-up of

a process can also be viewed as a procedure for applying the same process
to different output volumes. Batch size enlargement does not always
translate into a size increase of the processing volume. In mixing
applications, scale-up is indeed concerned with increasing the linear
dimensions from the laboratory to the plant size. On the other hand,
processes exist (e.g., tableting) for which ―scale-up‖ simply means
enlarging the output by increasing the speed. In moving from R & D to
production scale, it is sometimes essential to have an intermediate batch
scale. This scale also makes possible the production of enough product for
clinical testing and samples for marketing. However, inserting an
intermediate step between R & D and production scales does not in itself
guarantee a smooth transition.

 Pilot plants: Destined for development

Pilot plants are on the verge of an unprecedented evolution. Read

about the 10 factors that’ll impact the design, construction and
operation of these next- generation units.

I have seen many changes in pilot plants over the course of my

career, but I predict that we are on the verge of an unprecedented
evolution of these units.

My crystal ball sees 10 key factors influencing next-generation pilot plants

1. Outsourcing;

2. Automation;

3. Fugitive emissions

4. Multiple trains;
5. Online analytical capabilities;

6. Safety and control system interaction;

7. Wireless technology;

8. Instrument availability;

9. Instrument multi-functionality;

10. Unit size. Let’s look at each of these and what they may spur

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

 Stages of Production of
Tablets

 Material handling
 Dry blending
 Granulation
 Drying
 Reduction of particle size
 Blending
 Direct compression
 Slugging (dry granulation)
 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 formulation. The More
sophisticated methods of handling materials are vacuum loading
systems, metering pumps, screw feed system. The types of the system
selected depend on the nature of the materials, e.g., density and static
change.

 Dry Blending
 Inadequate blending at this stage could result in discrete portion of
the batch being either higher low in potency. Steps should be taken
to ensure that all the ingredients are free from lump sand
agglomerates. For these reasons, screening and/or milling of the
ingredients usually makes the process more reliable and reproducible.
There are various equipment used in blending process they are V-
blender, double cone blender, Ribbon blender, Slant coneblender, Bin
blender, Orbiting screw blenders vertical and horizontal high
intensity mixers.

The blending will be optimized by following parameters

1. Time of blending.

2. Blender loading.

3. Size of blender

 Granulation
Sigma blade mixer, Heavy-duty planetary mixer. 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.
 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 is 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

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. As part of the scale-up of a milling or sieving operation, the
lubricants and glidants, in the laboratory are usually added directly to the final blend. This
is done because some of these additives, especially magnesium stearate, tend to agglomerate
when added enlarge quantities to the granulation in a blender.
 Blending

Type of blending equipment often differs from that using in laboratory scale.
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.

 Slugging (Dry Granulation)

 This is done on a tablet press designed for slugging, which operates at pressures of
about 15tons, 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.

 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 propertie
 Compression

 The ultimate test of a tablet formulation and granulation process is

whether the granulation can be compressed on a high speed tablet
press.
 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. The following parameters are optimized
during pilot plant techniques of Granulation feed rate, Delivery
system should not change the particle size distribution., 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.
 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.
 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 resulting a soft tablet,
decrease in wet ability 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.
 The machine used are high speed rotary machine, multi rotary
machine, double rotary machine, upper punch and lower punch
machine and single rotary machined.

 SCALE UP FOR BIOTECHNOLOGY-DERIVED PRODUCTS

The design and scale up of biological processes is very challenging (due to complexity
of biological systems and the physical and biochemical characteristics of the protein
products) .
The following parameters are to be considered for scale up of biotechnological products –-
 BIOREACTOR OPERATION : Usually stirred tank bioreactor is used Mixing
efficiency given by –
1. Impeller rate
2. Aeration rate
3. Hydrostatic pressure
4. Agitation rate
5. Mixing time
 FILTERATION OPERATION : The key process parameters for filteration scale up are
 –
1. Transmembrane pressure
2. Volume
3. Operating time
4. Temperature
5. Flux rate
6. Protein concentration
7. Solution viscosity
8. Retentate flow rate
9. Permeate flux

The fluid dynamic variables used in the scale up work are –

1. The length of the fibers (L , per stage)

2. The fiber diameter (D)

3. The number of fibres per catridge (n) 
4. The density of the culture ( )
5. The viscosity of the culture ( From these variables , scale up parameters such as
wall shear rate and its effect on flux are derived.

 CENTRIFUGATION :
At laboratory scale – batch centrifuge is used .
At production scale – continuous centrifuge is used . Low shear centrifuge used to
minimize the shear sensitivity of animal cells .
 CHROMATOGRAPHY :
Key parameters for chromatography scale up are
1.Gel capacity
2.Linear velocity
3. Buffer volume
4. Bed height
5.. Temperature
6. . Cleanability
 7.. Gel lifetime
8.. pH of the elution buffer
9. . conductivity of the elution buffer

 VIRAL
CLEARANCE :
Viral inactivation and/or removal steps are critical part of the process design for
biotechnology products derived from mammalian cell culture system .

 PRINCIPLES OF SIMILARITY
Equipments selected for pilot plant studies should preferably be similar in all respects to
those actually used in commercial production . If similarity exists then it helps in
effective process translation as well as in production of good quality product . In
actuality , approximations of similarity are often necessary due to departures from
ideality (e.g., differences in surface roughness , variations in temperature gradients ,
changes in mechanism) . Stress should be given on four types of similarity.
A. Geometric Similarity :
Similarity with respect to shape , height , thickness , breadth etc., Small scale model
equipments and large scale equipments must be in the scale ratio of 1:2 , 1:5 , 1:20
etc.
B. . Mechanical Similarity :
Mechanical similarity (the application of force to a stationary or moving system)
can be described in terms of Static , Kinematic or Dynamic similarity .

Static Similarity –- It is the deformation under constant stress of one body or

structure to that of another . It exists when geometric similarity is maintained .
Kinematic Similarity -- Geometrically similar moving systems will exhibit
kinematic similarity when corresponding particle takes geometrical similar path
in the corresponding time interval

Dynamic Similarity -- Forces (gravitational , centrifugal , pressure) which accelerate

or retard the motion of materials . Geometrically similar moving systems are
dynamically similar when the ratio of all forces is equal . It is useful in the prediction
of pressure drops , power consumption.
C. Thermal Similarity :
It is concerned with flow of heat (by radiation , conduction , convection , or the
bulk transfer of material) . Geometrically similar systems are thermally similar
when temperature difference bears constant ratio and in moving systems it must
have kinematic similarity .
D. Chemical Similarity :
It is the similarity concerned with the variation in chemical composition from point
to point as a function of time . It is related to the existence of comparable
concentration gradients . It is dependent upon both thermal and kinemtatic similarity
.
The relationship of key groups , key activities and development milestones
typically experienced during the transfer of formulation and process technology
from the pilot plant to the production facility .
 HOW TO SCALE-UP SCIENTIFICALLY
 A rational approach to scale-up is Dimensional Analysis which is a proven method
of developing functional relationships that describe any given process in a
dimensionless form to facilitate modeling and scale-up or scale-down .
 Dimensionless Analysis is a method for producing dimensionless numbers and
deriving functional relationships among them that completely characterize the
process . It was first systematically applied to fluid flow 90 years ago by Lord
Rayleigh on the basis of the principle of similitude referred to by Newton in one
of his early works .
Dimensionless Numbers :
Basic Dimensional Quantities : Length (L), Mass (M), Time (T) .

Dimensional Numbers have no dimensions . Such numbers are frequently used to describe the
ratios of various physical quantities .
nNewton (Ne) = P/( 3 d 5 )
Froude (Fr) = n2 d/g
Reynolds (Re) = d2 /n
in which P is power consumption (ML2 /T3 )
 is specific density of particles (M/L3 )
n is the impeller speed (T-1 )
d is the impeller diameter (L)
g is the gravitational constant (L/T2 )
 is the dynamic viscosity (M/LT)

 Ne is a measure of the power required to overcome friction in fluid flow in a stirred

reactor. In mixer granulation applications, this number can be calculated from the
power consumption of the impeller .
 Fr is described for powder blending and was suggested as a criterion for dynamic
similarity as well as scale-up parameter in wet granulation .
Re relates the inertial force to the viscous force, is used to describe mixing processes
IMPROVING THE LIKELYHOOD OF SCALABILITY
 Identifying the physical and chemical phenomena involved in pharmaceutical
manufacturing process
 Understanding whether and how these phenomena are affected by a change in. scale
(i.e. Are they dependent on volume , area or length .
 Identifying the predominant or controlling process mechanism .
 Identifying the critical process variables that affect scalability .
 Identifying or determining the physicochemical properties (eg: density , particle size
viscosity) of the formulation components and the products relevant to scalability .
 Using dimensional analysis to reduce the number of variables required to
characterize a process as the manufacturing scale changes
 Using software that enables the estimation of equipment performance and material
characteristics

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
it’s own pilot- plant personnel's.
 CONCLUSION

In order to scale up and transfer a process successfully from laboratory scale

to pilot scale and multiple commercial manufacturing scales, a thorough
understanding of the integration of scale factors , facility design , equipment
design and process performance is necessary .From the and presence of
lubricant and blending will play a important, role the development of pilot
scale up techniques to large scale production solid dosage form. above finding
it was concluded that the Pilot scale up techniques is one of the important tool
for the optimization of large scale production. The parameters such as
Granulation feed rate, compression
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