Pilotplantscale uptechniques by kailash vilegave

“Make your mistakes on a small scale
and our profits on a large one”.

Mr. Kailash Vilegave
M Pharma
Lecturer, Dept of Pharmaceutics
Shivajirao S. Jondhle College of Pharmacy
Asangaon
1 DEPT OF PHARMACEUTICS 3/15/2013

CONTENTS

 Definition
 Significance
 General Considerations
 GMP Considerations
 Product Considerations
 Advantages
 Disadvantages
 References

3/15/2013 DEPT OF PHARMACEUTICS 2

DEFINITIONS
3

 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.

DEPT OF PHARMACEUTICS 3/15/2013

SIGNIFICANCE
4

 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.

5
Cont….
 Appropriate records and reports are issued to
support good manufacturing practices.
 Procedure can be developed and validated.
 To evaluate the effect on the process of a large
change in the scale of operation and to gather
other data so that a good design of a larger unit
may be made with a high probability of commercial
success.
 To produce trial lot quantities of the material in
question so that its properties may be critically
examined.
 To find and examine all by – products or waste.
These may not be seen in laboratory scale. By the
use of pilot plant, it is possible to minimize the
waste, hence better yield of prescribed dosage
3/15/2013 form. DEPT OF PHARMACEUTICS

GENERAL
6 CONSIDERATIONS
1. Reporting Responsibility:-

R & D group The formulator who developed the
with separate product can take into the production
staffing and can provide support even after
transition into production has been
completed


2. Personnel Requirement:-

7

* 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
3/15/2013 DEPT OF PHARMACEUTICS

8

3. Space Requirements:-

Administration Physical Standard Storage
and information testing area equipment area
processing floor space


a) Administration And Information Process:-
9

 Adequate office and desk space should be provided
for both scientist and technicians.
 The space should be adjacent to the working area.
 Computers.

3/15/2013 DEPT OF PHARMACEUTICS

b) Physical Testing Area:-
10
 This area should provide permanent bench top
space for routinely used physical - testing
equipment.


c) Standard Pilot-plant Equipment Floor
Space :-
11

 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.

d) Storage Area:-

 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 DEPT OF PHARMACEUTICS
3/15/2013 12

4. Review of the formula:-
13

 A thorough review of the each aspect of formulation is important
and carried out early in the scale up process.
 The purpose of each ingredient and it’s contribution to the final
product manufactured on the small-scale laboratory equipment
should be understood.
 If any modification in the formula, it should be done as early as
possible in phase III trial .
 To allow time to generate meaningful long term stability in support
of a proposed new drug application (NDA)
 Then the effect of scale-up using equipment that may subject the
product to stresses of different types and degrees can more readily
be predicted or recognized.


5. Raw materials :-

14

 One purpose/responsibility of the pilot-plant is the
approval & validation of the active ingredient &
excipient 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.
 Quality of active ingredients needs to be verified

6. Equipment:-
15

 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

A. Non sterile equipments
16

 Heating and cooling capability

 Adequate transfer system (filtration equipment)

 Made of suitable non reactive sanitary materials

 Processing tanks, kettles, pipes, mills, filter
housing, are mostly fabricated from stainless still if
interaction occurs then use poly poly tetra flouro
ethane liners .

B. Suspention
17

 For addition & dispersion of suspending agent
required vibratinf feed system

 Pumps and mills

 Filling equipment

 Homogenising equipments

 Mixing equipment

7. Production Rates:-
18

 The immediate as well as the future market trends /
requirements are considered while determining the
production rates.


8. Process Evaluation:-
….items that should be examined including
19 the following order of components including

adjustments of their amounts…….
Order of mixing of
Drying temp. components Mixing
And drying time speed

Mixing
Screen size PARAMETERS time
(solids)
Rate of addition of
granulating agents,
Filters size solvents,
(liquids) solutions of drug etc.
Heating and cooling
Rates


 Why to carry out process
evaluation????
20

 The knowledge of the effects of various
process parameters on in-process and
finished product quality is the basis for
process optimization and validation.

 The purpose of process validation is to
confirm that the selected manufacturing
procedure assure the quality of the product
at various critical stages in the process and
in finished form.

 The manufacturing process & quality control
information should be revived on annual
basis. DEPT OF PHARMACEUTICS 3/15/2013

9. Master Manufacturing Procedures:-
21

The Three important aspects

Weight sheet Processing & Manufacturing
Sampling procedure
directions
Finished product
spacifacation


Cont….
22

 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 PHARMACEUTICS in3/15/2013
DEPT OF mentioned the batch record

Transfer of Analytical Method to
23
Quality Assurance

 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.


10. Product Stability And Uniformity:-
24

 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. OF PHARMACEUTICS 3/15/2013
DEPT

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


ADVANTAGES
26

 Members of the production and quality control
divisions can readily observe scale up runs.

 Supplies of excipient & 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 3/15/2013
DEPT OF PHARMACEUTICS repair.

DISADVANTAGES
27

 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.


 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.

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.


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
31 granulating process. 3/15/2013
DEPT OF PHARMACEUTICS

Cont….

 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.


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.
33

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

Cont….

 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


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

Cont….

 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


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.


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.


Cont….

 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.

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.

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.

Cont….

 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.

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

Cont….

 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.

PARENTERALS

DEPT OF PHARMACEUTICS
46 3/15/2013

Cont….

 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.

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.

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.

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.

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


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
52
& base. DEPT OF PHARMACEUTICS 3/15/2013

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.


IMPORTANT QUESTIONS
I. What do you mean by pilot plant scale up and give examples ? (May ‘06)
II. What is the significance of pilot plant scale up with routine production procedure ? (May
‘07)
III. Explain the procedure for pilot plant scale up for liquid orals. (Sep ‘07 & Apr ‘08)
IV. Pilot plant scale up for tablets. (May ‘09)
V. Pilot plant scale up for liquid dosage forms. (Oct ‘09)
VI. Write in detail pilot plant scale up concepts & techniques for parenterals. (May ‘11)
VII. Explain the concepts of pilot plant scale up for tablets.
(Nov ‘11)


REFERENCE
55

1. The theory & practice of industrial pharmacy
by Leon Lachman, Herbert A.
Lieberman, Joseph L. Kenig, 3rd
edition, published by Varghese Publishing
house.

2. www.google.co.in


56


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