This is very useful presentation for UG and PG students of Pharmacy

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CONTENTS
 Definition
 Significance
 General Considerations
 GMP Considerations
 Product Considerations
 Advantages
 Disadvantages
 References
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 Plant:- It is a place where the 3 M’s that are Man,
Material and Money are brought together for the
manufacturing of products.
 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 practical procedure of
manufacturing.
 Scale-up:- The art for designing of prototype using the
data obtained from the pilot plant model.
DEFINITIONS
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SIGNIFICANCE
 Permits close examination of formulae to determine its
ability to withstand batch scale and process
modification.
 Review of Equipment - most compatible with the
formulation & most economical, simple and reliable in
producing product.
 Raw materials - consistently meet the specifications
required to produce the product can be determined.
 Production rate adjustment after considering marketing
requirements.
 Give rough idea about physical space required and of
related functions.
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 Appropriate records and reports are issued to support
good manufacturing practices.
 Procedure can be developed and validated.
Cont….
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GENERAL
CONSIDERATIONS
1. Reporting Responsibility:-
R & D group
with separate
staffing
The formulator who developed the
product can take into the production
and can provide support even after
transition into production has been
completed
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* 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.
* Engineering principles
* Knowledge of computers &
electronics
2. Personnel Requirement:-
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3. Space Requirements:-
Administration
and information
processing
Physical
testing area
Standard
equipment
floor space
Storage
area
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 Adequate office and desk space should be provided for
both scientist and technicians.
 The space should be adjacent to the working area.
 Computers.
3.1 Administration And Information Process:-
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3.2 Physical Testing Area:-
 This area should provide permanent bench top space for routinely
used physical - testing equipment.
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 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.
3.3 Standard Pilot-plant Equipment Floor Space :-
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 It should have two areas,
1.Approved area and
2.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 packaging
material should also be provided.
3.4 Storage Area:-
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 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.
4. Review of the formula:-
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 One purpose/responsibility of the pilot-plant is the
approval & validation of the active ingredient &
excipients raw materials.
 Raw materials used in the small scale production cannot
necessarily be the representative for the large scale
production.
 Ingredients may change in particle size, shape or
morphology which result in differences in bulk density,
static charges, rate of solubility, flow properties, color,
etc.
5. Raw materials :-
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6. Equipment:-
 The most economical, 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 too small the process developed will not scale up.
 If too big then the wastage of the expensive active
ingredients.
 Ease of cleaning
 Time of cleaning
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 The immediate as well as the future market trends /
requirements are considered while determining the
production rates.
7. Production Rates:-
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PARAMETERS
Order of mixing of
components Mixing
speed
Mixing
time
Rate of addition of
granulating agents,
solvents,
solutions of drug etc.
Heating and cooling
Rates
Filters size
(liquids)
Screen size
(solids)
Drying temp.
And drying time
8. Process Evaluation:-
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The three important aspects
Weight sheet Processing &
Sampling
directions
Manufacturing
procedure
9. Master Manufacturing Procedures:-
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 The weight sheet should clearly identify the chemicals
required in a batch. To prevent confusion the names and
identifying numbers 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.
Cont….
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 During the scale-up of a new product, the analytic test
methods developed in research must be transferred to the
quality assurance department.
 Early in the transfer process, the quality assurance staff
should review the process to make sure that the proper
analytic instrumentation is available and that personnel are
trained to perform the tests.
Transfer of Analytical Method to
Quality Assurance
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 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.
10. Product Stability And Uniformity:-
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GMP CONSIDERATION
 Equipment qualification
 Process validation
 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
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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.
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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.
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 SOLID DOSAGE FORM
1. Material Handling
Laboratory Scale
Deliver accurate amount to the destination
Large Scale
* Lifting drums
* More Sophisticated Methods
-Vacuum Loading System
-Metering Pumps
Prevent Cross Contamination by Validation Cleaning
Procedures.
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2. Dry Blending
Powders should be used for encapsulation or to be
granulated prior to tabletting must be well blend to
ensure good drug distribution.
Inadequate blending could result in drug content
uniformity variation, especially when the tablet or capsule
is small & the drug concentration is relatively low.
Ingredients should be lumps free, otherwise it could cause
flow problems.
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3. Granulations
 Reasons :-
* To improve the flow properties.
* To increase the apparent density of the powder.
* To change the particle size distribution so that the
binding properties on compaction can be improved.
 Types :-
a) Wet Granulation
b) Dry Granulation
c) Direct Compression Method
 A small amount potent active ingredient can be dispersed
most effectively in a carrier granulation, when the drug is
dissolved in granulating solution and added during the
granulating process.
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 Wet granulation has been carried out by using,
- Sigma Blades
- Heavy-duty planetary mixture
-Tumble Blenders
-High Speed Chopper Blades used in mixing of light
powders.
 Multifunctional Processors,
dry blending, wet granulation, drying, sizing &
lubricating.
 Effect of Binding Agent.
Cont….
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4. Drying
 Hot Air Oven
* air temperature
* rate of air flow
* depth of granulation on the trays
 Fluidized Bed Dryer
* optimum loads
* rate of airflow
* inlet air temperature
* humidity
Data used for small scale batches(1-5 kg) cannot be
extrapolate processing conditions for intermediated scale
(100 kg) or large batches.
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5. Reduction In Particle Size
 Particle size to particle size distribution is important to
the compression characteristics of a granulation.
 Compression factors that may affected by the particle
size distribution are flow ability, compressibility,
uniformity of tablet weight, content uniformity, tablet
hardness, tablet color uniformity.
 Equipments :-
* oscillating granulator a mechanical sieving device
* a hammer mill
* screening device
 If too large particle size :-
* weight variation
* mottling
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 If too fines particle size,
* weight variation
* capping
 Both oversized and undersized granulation can adversely
affect tablet content uniformity.
 Lubricants & Gildants are added at final blend
Cont….
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6. Blending
Consequent attention should be paid to scale up of the
right design is used and blender loads, mixing speeds,
mixing timing are properly established.
In any blending operation segregation and mixing occurs
simultaneously, both processes are a function a particle
size, shape, hardness, density and dynamics of the mixing
action.
Low dose active ingredients – directly compressed.
Equipments :-
* Planetory type mixer
* Twin shell mixture
* Cone type
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 Over loading in blender –
* retards the free flow of granules
* reduce the efficiency
* cause content un-uniformity
 If the load is to small –
* powder blend slides rather than roll in blender
* improper mixing
Cont….
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7. Slugging
 A dry powder blend that can not be directly compressed
because of poor flow properties may in some instances be
processed using a slugging operation.
 Instruments :-
* Tablet press – which operates at pressure of 15 tons,
compared with a normal tablet press, which operates at
pressure of 4 tons or less.
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8. Compression
 The ultimate test of the tablet formulation and
granulation can be compressed on a high-speed tablet
press.
 Steps involved during compression,
* Filling empty die cavity with granulation
* Pre compression of granules
* Compression of granules
* Ejection of tablet from the die cavity
 Compression characteristics can be evaluated by press
speed equal to normal production speed.
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 Then detect the problems such as,
* sticking to punch surface
* tablet hardness
* capping
* weight variation
 Granules must be delivered at adequate rate.
 During compression, the granules are compacted, and in
order for a tablet to form, bonds within the compressible
materials must be formed.
Cont….
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TABLET COATING
 Equipments :-
* conventional coating pan
* perforated pans of fluidized-bed coating column
 Types :-
1. Sugar coating
2. Film coating
 Tablet must be sufficiently hard to withstand the the
tumbling to which they are subjected while coating.
 Operation conditions to be established for pan or column
operation are optimum tablet load, operating tablet, bed
temperature, drying air flow rate, temperature, solution
application rate.
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CAPSULES
 To produce capsules on high-speed equipment, the
powder blend must have,
* uniform particle size distribution
* bulk density
* formation of compact of the right size and of sufficient
cohesiveness to be filled into capsule shells.
 Equipments :-
1. Zanasi or Mertalli – Dosator(hollow tube)
2. Hoflinger – Karg – Tamping pins
 Weight variation problem can be encountered with these
two methods.
 Overly lubricated granules – delaying disintegration.
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 Humidity affect moisture content of –
* granulation
* on the empty gelatin capsules
 Empty gelatin capsules have a recommended storage
condition of 15-25 ºC temperature & humidity 35-65 %
RH.
 At high humidity – capsule swells make separation of the
capsule parts difficult to interfere with the transport of the
capsule through the process.
 At low humidity – capsule brittle increased static charge
interfere with the encapsulation operation.
Cont….
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LIQUID ORALS
 Simple solutions are the straight forward to scale up but
they require tanks of adequate size and suitable mixing
capability.
 Most equipment has heating or cooling capabilities to
effect rapid disollution of components of the system.
 All the equipments must be made up of suitable non-
reactive material and be designed and constructed to
facilitate easy cleaning.
 Liquid pharmaceutical processing tank, kettles, pipes,
mills, filter houses etc. are most frequently fabricated
from stainless steel
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 Two types of steel –
1. 308
2. 316
 Stainless steel is most non reactive, however it does react
with some acidic pharmaceutical liquids, this problem can
be minimized by PASSIVATION.
 Interaction with metallic surfaces can be minimized by
use of glass or Teflon coating.
 Although they are highly inert materials, they have the
disadvantages of cracking, breaking and flaking with
resultant product contamination.
Cont….
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 Equipments :-
* tankage
* piping
* ancillary equipment for liquid mixing
* filteration, transfer and related equipments.
 The majority of the equipments are composed of 300
series austenitic stainless steel, with glass lined
vessels employed for preparation of formulations
sensitive to iron and other metal ions.
 The vessels can be equiped with external jackets for
heating and/or cooling and various types of agitators,
depending upon the mixing requirements of the
individual formulation.
Cont….
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SUSPENSIONS
 Suspensions require more attention during scale up than
simple solutions because of additional processing needs.
 Equipments :-
* vibrating feed system and power for production scale.
* high shear mixing equipment
 Slurries facilitate rapid and complete hydration of
suspending agent when added to large portion of the
vehicle.
 Active ingredients must be uniformly dispersed
throughout the batch.
 Mixing at too high speed can result in entrapment of air,
which may affect physical or chemical stability of the
product.
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VACUUM UNIT VERSATOR
 Filteration – remove unwanted particles.
 Screens of 150 mesh, having 100 microns are used.
 Active ingredients – particle size 10 – 25 microns.
 Transfer and filling of finished suspension should be
carefully monitored.
 It should be constantly mixed during transfer to maintain
uniform distribution of the active ingredients.
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EMULSIONS
 Manufacturing of liquid emulsion products entails
specialized procedures as result scale up into production
equipment involves extensive process development and
validation.
 Equipments :-
* mixing equipment
* homogenizing equipment
* screens
* pumps
* filling equipment
 High shear mixers may lead to air entrapment, this
problem can be avoid by carrying out operation under
controlled vacuum.
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SEMI SOLID PRODUCTS
 The main difference of semi solid formulation with
comparison to suspensions, liquids and emulsions is their
higher viscosity.
 Viscosity renders certain aspects of the scale-up of semi
solid products more critical.
 Equipments :-
* blenders
* mixers
* pressure filling equipments
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SUPPOSITORIES
 The manufacturing of suppositories on a laboratory scale
usually involves,
* the preparation of a molten mass
* the dispersion of drug in the molten base
* casting of suppositories in a suitable mold
* cooling of the mold
* opened & remove the suppositories
 More no. of moulds & large size Pan for melting of drug
& base.
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CONTRACT MANUFACTURE
 On occasional, scale-up or manufacture of a product
may need to be done at an outside, contract
manufacturer.
 The reasons for considering contract manufacture
include the needs for additional manufacturing
capacity, high specialized technology or specialized
equipments.
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