9,10.pilot Plant & Scale Up

PAPER-910201 CHAPTER-1,6,7 &8 PILOT PLANT & SCALE UP
By: Jignasha & Vijay
PILOT PLANT SCALE UP

TECHNIQUES
GUIDED BY:-
PREPARED BY:- Dr.R. K. Parikh
Vijay makwana
Roll no:-1
Jignasha R. Bhuria
Roll no:-5
M. Pharm Sem-1
YEAR:-2009-2010
DEPARTMENT OF PHARMACEUTICS AND

PHARMACEUTICAL TECHNOLOGY, 2009-2010
CONTENTS:
M.PHARM. SEM-I (2009-10)
L.M.COLLEGE OF PHARMACY, AHMEDABAD-9 PAGE: 1
INTRODUCTION ON PILOT PLANT AND SCALE UP

o PILOT PLANT DESIGN
o PILOT PLANT OPERATION
GENERAL CONSIDERATIONS ABOUT PILOT PLANT REQUIREMENTS
STEPS OF SCALE UP
SCALE UP FOR SOLID DOSAGE FORM (TABLET)
SCALE UP FOR PARENTERAL PRODUCT
SCALE UP CONSIDERATIONS FOR LIQUID ORALS
SCALE UP FOR SEMISOLID DOSAGE FORMS
SCALE UP FOR BIOTECHNOLOGY-DERIVED PRODUCTS
THEORY OF SIMILARITY
HOW TO SCALE UP SCIENTIFICALLY?
SCALE UP OF LIQUID & SEMISOLID MANUFACTURING PROCESS
SCALE UP OF POWDER BLENDING OPERATION
IMPROVING THE LIKELYHOOD OF SCALABILITY
CONCLUSION
REFERENCES AND QUESTION BANK
[1] 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
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 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 of scale up
“Find mistakes on small scale and make profit on large scale.”
To produce physically and chemically stable therapeutic dosage forms.
Review of the processing equipment.
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula.
Pilot plant studies include the close examination of the formula to determine :
Its ability to withstand batch scale .
Process modification .

Compatibility of the equipment with the formulation .

Cost factor .
Availability of raw materials meeting the specifications required to produce the
product .
Market requirement .
Physical space required and the layout of the related functions .
Thus , during the scale up efforts in the pilot plant :

Production and process controls are evaluated , validated and finalized .
Product reprocessing procedures are developed and validated .
Appropriate records and reports are issued to support cGMP .
In short , all critical features of a process must be identified so that as the

process is scaled up , it can be adequately monitored to provide assurance
that the process is under control and that the product produced at each
level of the scale up maintains the specified attributes originally intended .
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 :

Validation
Training
Engineering Support
Maintenance
Calibration
Material Control
Inventory
Orders
Labeling
Process and Manufacturing Activities
Quality Assurance and Quality Control
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 Inventory-

Ordering-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

[2] GENERAL CONSIDERATIONS

PERSONNEL REQUIREMENTS : Personnel should have –-
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
SPACE REQUIREMENTS :
Storage area
Separate provisions for API and excipients further segregated into approved and
unapproved areas according to GMP .
Storage area for in process materials , finished bulk products , retained samples ,
experimental production batches , packaging materials (segregated into approved
and unapproved areas) .
Controlled environment space allocated for storage of stability samples
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.
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
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 .
PROCESS EVALUATION :
Drying temp.
And drying time
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 cross-
contamination
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 .
[3] SCALE – UP TECHNIQUES

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

Design and construct a pilot plant including provisions for process a

nvironmental controls, cleaning and sanitizing systems, packaging a
waste handling systems, and meeting regulatory agency requiremen
Evaluate pilot plant results (product and process) including process

Economics to make any corrections and a decision on whether or no
to proceed with a full scale plant development
[4] 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:
Fluorescent lighting fixtures should be the ceiling flush type.
The various operating areas should have floor drains to simplify cleaning.
The area should be air-conditioned and humidity controlled.
High -density concrete floors should be installed.
The walls in the processing and packaging areas should be enamel cement finish on
concrete.
Equipment in the pharmaceutical pilot plant should be similar to that used by
production division- manufacture of tablets.
1)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.
2) 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.
3) 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.
Wet granulation can also be prepared using tumble blenders equipped with high-
speed 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.
Fluidized Bed Granulations :
1. Process Inlet Air Temperature
2. Atomization Air Pressure
3. Air Volume
4. Liquid Spray Rate
5. Nozzle Position and Number of Spray Heads

6. Product and Exhaust Air Temperature

7. Filter Porosity
8. Cleaning Frequency
9. Bowl Capacity
4) 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.
5) 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.
Tray Dryer-- Parameters to be considered for scale up are :
1. Air flow
2. Air temperature
3. Depth of the granulation on the trays
4. Monitoring of the drying process by the use of moisture and temperature
probes
5. Drying times at specified temperatures and air flow rates for each product
Fluidized Bed Dryer : Parameters to be considered for scale up are :
1. Optimum Load
2. Air Flow Rate
3. Inlet Air Temperature
4. Humidity of the Incoming Air

6) 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.
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.
7) 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.
In scale up of blending , following parameters should be considered -
1. Blender loads ,
2. Blender size ,
3. Mixing speeds ,
4. Mixing times ,
5. Bulk density of the raw material (must be considered in selecting blender and
in determining optimum blender load)
6. Characteristics of the material
8) Specialized Granulation procedures:
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 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 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.
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.
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.
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.
[5] 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 temperature-sensitive 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.
• Here, the water for injection equipment is located, as well as the technical installation
of the lyophilizer.
 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.

 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 a 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 water-
soluble 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.
[6] Scale up for Liquid orals

• The physical form of a drug product that is pourable displays Newtonian or
pseudoplastic flow behaviour and conforms to it’s 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.
Steps of liquid manufacturing process
1. Planning of material requirements:
2. Liquid preparation:
3. Filling and Packing:
4. 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.
SOLUTION :
Parameters to be considered are –-
1. Tank size ( diameter )

2. Impeller type
3. Impeller diameter
4. Rotational speed of the impeller
5. Number of impellers
6. Number of baffles
7. Mixing capability of impeller
8. Clearance between Impeller Blades and wall of the mixing tank
9. Height of the filled volume in the tank
10. Filteration equipment (should not remove active or adjuvant ingredients)
11. Transfer system
12. Passivation of SS (prereacting the SS with acetic acid or nitric acid solution to
remove the surface alkalinity of the SS)
SUSPENSION :
1. Addition and dispersion of suspending agents (Lab scale – sprinkling method &
Production scale – vibrating feed system)
2. Hydration/Wetting of suspending agent
3. Time and temperature required for hydration of suspending agent
4. Mixing speeds (High speed leads to air entrapment)
5. Selection of the equipment according to batch size
6. Versator (to avoid air entrapment)
7. Mesh size (the one which is chosen must be capable of removing the
unwanted foreign particulates but should not filter out any of the active
ingredients . Such a sieve can only be selected based on production batch
size trials.)
EMULSION :

1. Temperature
2. Mixing equipment
3. Homogenizing equipment
4. Inprocess or final product filters
5. Screens , pumps and filling equipment
6. Phase volumes
7. Phase viscosities
8. Phase densities
Formulation aspects of oral liquids

Solutions:
Protecting the API Buffers, antioxidants, preservatives
Maintaining the Colorings, stabilizers, co-solvents, antimicrobial preservatives

appearance
Taste/smell masking Sweetners, flavorings.
Suspensions:
Purpose Agent
Facilitating the connection between API -wetting agents

and vehicle
Salt formation ingredients
- Buffering-systems, polymers,
Protecting the API
antioxidants
Colorings, suspending agent, flocculating
Maintaining the suspension appearance
agent.
Sweeteners, flavorings
Masking the unpleasant taste/smell
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
[7] SCALE UP FOR SEMISOLID PRODUCTS

The following parameters are to be considered during the scale up of semisolid
products :
1. Mixing equipment (should effectively move semisolid mass from outside walls
to the center and from bottom to top of the kettle)
2. Motors (used to drive mixing system and must be sized to handle the product
at its most viscous stage.)
3. Mixing speed
4. Component homogenization
5. Heating and cooling process
6. Addition of active ingredients
7. Product transfer
8. Working temperature range (critical to the quality of the final product)
9. Shear during handling and transfer from manufacturing to holding tank to
filling lines
10. Transfer pumps (must be able to move viscous material without applying
excessive shear and without incorporating air)
11. While choosing the size and type of pump ,
a. Product viscosity
b. Pumping rate
c. Product compactibility with the pump surface
d. Pumping pressure
required should be considered .
[8] 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 4. Agitation rate

2. Aeration rate 5. Mixing time
3. Hydrostatic pressure
FILTERATION OPERATION : The key process parameters for filteration

scale up are -
1. Transmembrane pressure 6. Protein concentration
2. Volume 7. Solution viscosity
3. Operating time 8. Retentate flow rate
4. Temperature 9. Permeate flux
5. Flux rate
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 6. Cleanability
2. Linear velocity 7. Gel lifetime
3. Buffer volume 8. pH of the elution buffer
4. Bed height 9. conductivity of the elution buffer
5. Temperature
VIRAL CLEARANCE : Viral inactivation and/or removal steps are critical part of
the process design for biotechnology products derived from mammalian cell
culture system .
[9] 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 is shown below :

DEVELOPMENT MILESTONES
Key Groups Key Activities
Pharmaceutical Formulation
Marketing Formulation Defined
Identify critical process
Pharmaceutical Formulation Process Development and packaging parameters
Pharmaceutical Technology Pilot scale stability batch
Development manufacture
Development Report
Pharmaceutical Formulation
Pharmaceutical Technology Site selection

Scale-up/Stability/Clinical Supply
Development Initial large scale process
Batches
Manufacturing , Validation qualification studies
QA/QC
Scale-up report
Pharmaceutical Formulation Additional large scale

Pharmaceutical Technology NDA Submission process qualification
Development studies
Manufacturing , Validation Product transfer document
QA/QC issued
Product acceptance by
manufacturing
Manufacturing , Validation Validation protocol
QA/QC written
Pharmaceutical Technology Manufacture Validation Batches Preapproval inspection
Development by FDA
Manufacturing site
preparation

Validation report
Manufacturing NDA Approval
QA/QC FDA Approval to
Pharmaceutical Technology market product
Development
Production start up
[10] 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 .
Newton (Ne) = P/( n3 d5)
Froude (Fr) = n2d/g
Reynolds (Re) = d2n/
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 .
[11] SCALE-UP OF LIQUID AND SEMISOLID

MANUFACTURING PROCESSES
In mixing and semisolid manufacturing, mixing is an important unit operation .

Flow regimes in pharmaceutical system undergoing mixing process may range

from laminar to turbulent to transitional flow . The flow regime in the vicinity of an
impeller is often turbulent while the flow regime elsewhere in the system can be
laminar or transitional .
For turbulent flow regime, power is N3D2 (  = density ; N = rotational speed ; D =

Diameter of impeller ) .
For laminar flow regime, power is N2 (  = viscosity )
Scale-up of solutions : Three methods can be applied .
1. Power Law Approach :-

N2 = N1 ( 1  R )n
n is power law exponent
N1 & N2 are rotational speed of impeller
R is geometric scaling factor such as : D 1T1 or D2T2 (D = impeller

diameter and T is mixing tank diameter) ; Z 1T1 or Z2T2 (Z = height of
liquid in the mixing tank)
2. Dimensionless Numbers :-
Reynolds Number (the ratio of inertial to viscous forces in a flow)
Re = (D2N  )
Froude Number (the ratio of inertial stress to the gravitational force per
unit area in a liquid)
Fr = (DN2  g)
It is a means of correlating process characteristics at various production

scales .
D = Diameter of impeller ; N = Rotational speed of impeller ;
 = Viscosity ;  = density ; g = acceleration gravity
3. Scale of agitation approach :-

Applicable only if system show Newtonian flow and Geometric
similarity . The rheological behaviour of shear-thinning (pseudoplastic)
systems may be described by the ostawald-de Waele equation between
the shear rate extremes corresponding to the zero shear viscosity, 0
and to the infinite shear viscosity, 

T = Ka
In which T is the shear stress ,  is the rate of shear and K and a are
constants .
The ratio of :0 corresponding to the ratio of T:T 0 would then be used
to facilitate scaling .
[12] SCALE-UP OF POWDER BLENDING

OPERATIONS
Regarding scale-up requirements, blending processes can be classified into
two fundamentally different groups i.e. for Free flowing and cohesive
materials . Their blending requirements vary .
Free Flowing Materials :- They are powders and granulations in which

interparticle cohesive forces are small enough for particles to move
individually .
Both inter and intra shell mixing processes can be described by similar
equation such as : 2 = Ae-kN where
2 is mixture variance
N is number of revolutions
A is unspecified constant
K is rate constant .
The Froude Number : Fr = [2R/g] where
 is rotation rate
R is vessel radius
g is acceleration from gravity
is suggested for tumbling blender scale-up .
Cohesive Powders :- The effect of cohesion on powder flow and scale-up

in particular for blending operations is a problem . A cohesive powder can
be defined as a material in which the adhesive forces between particles
exceed the particle weight by at least an order of magnitude .
1. The cohesive effects are much stronger in smaller vessels and tend to
disappear in large vessels . This is because as the blender scale
increases gravitational and convective force increase, thereby
overwhelming cohesive force .
2. As the blender size increases, the chunk to blender size ratio shrinks.
Both arguments can be mathematically expressed in terms of

dimensionless cohesion number c

c = /gR = (/g)/R = S/R

in which  = effective cohesive stress (under actual conditions)
 = powder density under flow conditions
g = acceleration of gravity
R = Vessel Volume
S = /g is the chunk size which can be defined as the internal
length scale of flow driven by material properties .
As R increases , c decreases
Mixing rate for radially ( top-bottom ) segregated loading , is independent
and constant regardless of mixture cohesion and mixer size .
Mixing rate for axially (left-right) segregated loading , the scale-up factors
is depended on cohesion , indicating that scale-up is a mixture
dependent problem ( but this is at small scale ) .
The conclusion from these result is that laboratory scale experiments

for cohesive powders are of questionable validity for predicting full-scale
behaviour . Behaviour at small scales is likely to be strongly affected by
cohesive effects that are of much less intensity in the large scale .
The most common scale-up criterion for the application of shear via
impellers and I bars is to match the linear speed of the moving element .
[13] 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 .
[14] 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 .
[15]REFERENCES
The Theory and Practice of Industrial Pharmacy : Leon Lachman , Herbert A
Lieberman , Joseph L Kanig : Section IV : Chapter 23 : Pilot Plant Scale-Up
Techniques : Page No . 681 – 710 .
Encylopedia of Pharmaceutical Technology : James Swarbrick , James C Boylan :

Volume 12 : Pilot Plant Design : Page No . 171 – 186 .
Pilot Plant Operation : Page No . 187 – 208 .
Drugs and The Pharmaceutical Sciences : Pharmaceutical Process Scale-Up :

Marcel Dekker series : Michael Levin : Volume 118
Parenteral Drug Scale-Up : Page No. 43 – 56 .
Scale-Up Considerations for Biotechnology-Derived Products : Page No. 95 –

114
Powder Handling : Page No. 133 – 150 .
Scale-Up of Film Coating : Page No. 259 – 310 .
Scaling Up Manufacturing Processes : A Technology Primer : Supplement To

Pharmaceutical Technology 2005 .
POSSIBLE QUESTIONS
1. What is the difference between pilot scale and scale up ? [ 1 mark ]
2. Outline the Pilot Plant Operation and give brief note on each . [ 5 marks ]
3. Which parameters should be considered during the scale up of Tablet Coating ?
[2 marks ]
4. Give a brief note on Scale-Up of Biotechnology-Derived Products and Parenteral
Solutions . [ 5 marks ]
5. What are the steps involved in transfer of a formulation right from F&D to
Production facility ? [ 7.5 marks ]
6. Write a brief note on Dimensional Analysis . [ 2 marks ]
7. various approaches used for scale-up of solutions . [ 5 marks ]
8. Give a brief note on scale-up of blending operation . [ 5 marks ]
9. How will you improve the scalability ? [ 2 marks ]
10. Newton , Reynolds number and Froude number with its applications . [ 3
marks ]
11. Define Scale up techniques in pharmaceutical formulation.Discuss “similarities”
with a view to observe and solve scaling up problems,by giving suitable
illustrations.[2004]

12. Write a note on similarity.

13. Write note on pilot plant design and operation.[2005]
14. What are the general consideration for scale up operation and specifically oral
liquid dosage form scientifically.


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PAPER-910201 CHAPTER-1,6,7 &8 PILOT PLANT & SCALE UP

By: Jignasha & Vijay

PILOT PLANT SCALE UP

DEPARTMENT OF PHARMACEUTICS AND

INTRODUCTION ON PILOT PLANT AND SCALE UP

SCALE UP FOR SOLID DOSAGE FORM (TABLET)

SCALE UP FOR PARENTERAL PRODUCT

SCALE UP CONSIDERATIONS FOR LIQUID ORALS

SCALE UP FOR SEMISOLID DOSAGE FORMS

SCALE UP FOR BIOTECHNOLOGY-DERIVED PRODUCTS

HOW TO SCALE UP SCIENTIFICALLY?

SCALE UP OF LIQUID & SEMISOLID MANUFACTURING PROCESS

SCALE UP OF POWDER BLENDING OPERATION

IMPROVING THE LIKELYHOOD OF SCALABILITY

REFERENCES AND QUESTION BANK

M.PHARM. SEM-I (2009-10)

“Defined as a part of the pharmaceutical industry where a lab scale formula is

Why conduct Pilot Plant Studies?

A pilot plant can be used for

Considerations in pilot plant development

M.PHARM. SEM-I (2009-10)

Compatibility of the equipment with the formulation .

Thus , during the scale up efforts in the pilot plant :

In short , all critical features of a process must be identified so that as the

PILOT PLANT DESIGN

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

PILOT PLANT OPERATION

M.PHARM. SEM-I (2009-10)

Process and Manufacturing Activities

Quality Assurance and Quality Control

VALIDATION : A validation master plan should be develop that addresses--

TRAINING : Training in four major area required –-

Compliance with quality standards such as cGMP

ENGINEERING SUPPORT : It is required for –-

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

M.PHARM. SEM-I (2009-10)

Meet cGMP norms

CALIBRATION : Calibration of critical instruments/equipments is required for–-

Compliance with cGMP

MATERIAL CONTROL : More flexible and efficient computer based system is

INVENTORY : Inventory should be maintained in a Computer Based Inventory-

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

PROCESS AND MANUFACTURING ACTIVITIES : It includes –

Formulation and Process Development Studies

QUALITY ASSURANCE & QUALITY CONTROL :

Auditing pilot plant

Release testing of finished products

M.PHARM. SEM-I (2009-10)

[2] GENERAL CONSIDERATIONS

REVIEW OF THE FORMULA :

RELEVANT PROCESSING EQUIPMENT :

It can be determined by the immediate future market requirements.

M.PHARM. SEM-I (2009-10)

1. Product loss in the equipment during manufacture .

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

PREPARATION OF MASTER MANUFACTURING PROCEDURES: It includes-

Product stability and uniformity:-

M.PHARM. SEM-I (2009-10)

TRANSFER OF ANALYTICAL METHODS TO QUALITY ASSURANCE :