1. Production and Scale-up
Techniques- Suspensions and
Emulsions
Syam Perla (M.Pharmacy )
syamsundhar222@gmail.com
1

2. Involve large amount of
materials and commercial
scale equipment costly to
operate
Product development
scientist
Large organisation Scientist is
responsible
for first few
batches
Small pharmaceutical manufacturing
company
Pilot plant
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3. drug product is developed in the research laboratory at a very small scale
successful in terms of efficacy, safety and stability
needs to be produced at very large scale
but there is substantial difference in the kind of conditions as well as the nature of
equipment and facilities between the research laboratory (standard and limited
capacity equipments and instruments)and large scale manufacturing
Formulation scientist while developing the product is unable to consider these
factors
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4. thus a lot of problems are encountered in transferring the product directly from
laboratory to production scale
which may affect the efficacy, safety ,stability and reproducibility of the product
In order to study and tackle above product transfer related problems the
concept of pilot plant facility has emerged
Pilot plant is a hybrid manufacturing and development facility allows
successful transfer of the experimental formulations obtained in laboratory to
the production scale so that viable and robust product by the development of
a reliable and practical method of manufacture is possible
Scale-up:- The art for designing of prototype using the data obtained
from the pilot plant model. 4

5. PILOT PLANT FUNCTIONS
Review of product formula
Selection of raw material
Selection of processing equipments
Scale up batches
documentation
Technology transfer
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6. Pilot plant operations
Type of organizational structure
Research personnel responsible for initial scale up and initial
production runs
Technology transfer
The product development scientist is responsible for the scale up and technology transfer
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7. Advantages
Disavantages
Product scientist knows most
Person from R&D
about the product
department is not familier
Various product related
with the production divisions
information stability data etc
equipment facilities and
are best conveyed by
operations
formulator
Time consuming for product
scientist
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8. Pharmaceutical pilot plant controlled by pharmaceutical research
Provides pilot plant as apart of R&D with separate staffing
This arrangement is designed to provide the research scientist a responsibility to
scale up the formulations that have been developed by other formulators with in
research and development
Advantage Scale up runs is under research division
Any scale up problems in the development process corrective measures can be
taken up immediately
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9. Pharmaceutical pilot plant controlled by production
Product scientist Pilot plant personnel
establish practicality responsibility is process
of formula and development and technology
manufacturing transfer
procedure in a pilot
plant facility
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10. Production R&D for development and QA/QC for raw
technology evaluation materials and
transfer final product
manufacturing testing
support and
trouble shooting
Manufactures and
suppliers for evaluation Drug regulatory
of raw materials affairs for
excipients equipments documentation and
submission of data
for various
regulatory agencies
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Pilot plant inter disciplinary interaction

11. Pilot plant staff and training requirements
RESUME
Good theoretical knowledge
Practical experience
Good communication skills
Formulation experience
Process and equipment experience
Engineer capability
Knowledge in both electronics and computers
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12. TRAINING OF PILOT PLANT PERSONNEL
Technical skills
Compliance with quality standards
compliance with S.O.P
Safety and environmental
responsibilities
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13. Sree rama
LARGE
ORGANISATION
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14. Sree rama
PILOT PLANT LAYOUT
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15. Design of a pharmaceutical pilot plant facility
A well designed pilot plant facility minimizes the labour, time and cost the key factors
which influence the design of a pilot plant are product type, product quantity and
activity based considerations
Product type: the type of dosage form developed, evaluated and manufactured in a pilot
plant facility and the technology that is going to be employed have an important bearing
on the design of pilot plant
Product type Typical requirements
Solid dosage forms Weighing area ,mixing and granulation areas compression and encapsulation area and coating
facility specialized exhaust and dust collector systems
Liquids and semisolids Shear stirring facility, bottle filling facility, purified water facility ,filling and packaging facility
Preparation of gelatin mass, gelatin mass storage area ,facility for loading of the gelatin of the
Soft gelatin capsules gelatin mass into encapsulation area dedicated temperature and humidity and humidity
controlled area for drying of the capsules
High shear mixing and stirring facility, sterilization and aseptic processing of the in-process and
Parenterals finished product (aseptic mixing units, special handling units for control of microbial and cross
contamination )
Biologically derived products sterile manufacturing areas, extensive air handling equipment and environmental controls
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16. Batch size: a pilot plant is supposed to be designed to manufacture
wide array of batch sizes meant for different purposes such as product
development, analytical development, and stability testing which are
typically few kg or liters in size a pilot plant facility must be operated
under good manufacturing practices
Activity based considerations: guidelines for the maintenance of the
pilot plant must be exactly the same as that of manufacturing facility
ideally large scale equipment in the pilot plant should approach 25-
100% of the capacity of full scale equipment
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17. Layout of a pharmaceutical pilot plant
Layout must compliance with cGMP guidelines following factors must be taken into
account
a) Space requirements and allocation
b) Process flow
c) Construction
d) Safety and environmental considerations
e) Operational costs
Space requirements and allocation
generally a pilot plant facility has following four types of space requirements.
major considerations in assessing the
floor space requirements are
a) Space for equipment
b) Provision for additional portable equipments
c) Dedicated equipment cleaning area
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18. Testing facility this area
should provide permanent
bench top space for
routinely used physical
testing equipments
Storage facility there should be a separate and appropriate space for storage various purposes
a) Storage of active ingredients and excipients
b) Storage of in-process materials, finished bulk products from the pilot plant
c) Storage of stability samples in controlled environment
d) Storage of packing materials in bulk
Documentation and
administration
effective monitoring and
documentation of each specific
activity is extremely important
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19. Process flow plan
a) Materials flow
b) Controlled access for the materials and components used in
manufacturing clinical supplies
c) Sampling of potent substances (specially designed rooms with air locks)
d) Receipt, sampling ,solvent dispensing and quarantine storage of
flammable solvents also need consideration
e) Temporary handling of flammable waste products as well as other waste
material
Personnel flow: size of rest room,
locker growing and shower areas
a proper provision in the layout
must be made for the cleaning,
disposal and storage
Ware house layout the ware house layout of a pilot plant facility depends
on the manufacturing capacity type of the product to be manufactured and
the storage requirements, requirements of special storage conditions
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20. Construction features taken into consideration
a) High density concrete floors should be installed
b) the walls in the packaging area should be enamel cement
finish
c) connections between the wall and window frames need to be
carefully constructed to prevent moisture damage and
enhance cleanability
d) light fixtures should be washable and allow for easy
maintenance
Building systems and utilities
The pilot plant HVAC system (heating ,ventilation and air conditioning)
It functions to maintain constant temperature and humidity it must be
suitable to consistently produce a quality product
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21. Water used during processing of the
product as well as for cleaning of
equipments and areas water quality is
divided into two types compendial
(USP Purified water and water for
injection)and noncompendial water
(portable water)
Processed air arrangements for specialized gases and breathing
air are also required for certain specialized process or handling
of some sensitive materials
Control systems controlling and monitoring of air, temperature
as well as relative humidity is the prime concern the other area
where monitoring and control may be desirable include
exhaust duct monitoring for lower explosives limits in solvent
processes 21

22. Safety and environmental considerations
Environmental discharges
Necessary provisions are always incorporated in the
pilot plant layout for isolation and pretreatment or
an alternate means of disposal of waste water will
likely be required if highly potent or toxic compounds are to be processed in the pilot plant
Handling of certain special (potent or toxic) materials
Certain specific arrangements in the building layout are
required to maintain a safe environment inside and
outside the facility
a) light and dark room conditions with lights of specific
wave length for photosensitive materials
b) Humidity controls for moisture sensitive materials
c) Temperature controls for thermo sensitive materials
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23. Handling and prevention of
explosives
Explosions are unavoidable thus
the pilot plant layout must
include arrangements for
suppressing, isolating or venting
an explosion in such a way to
protect operators and minimize
damage to the equipment and
facility.
Operational costs
Operational costs for maintaining sterile product facility is much more expensive to
operate than a pilot plant manufacturing solid oral dosage forms
Maintenance, calibration, engineering housekeeping, security, validation, QA,
microbiology, QC shipping receiving and training can be shared
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24. FULL SCALE MANUFACTURING
PILOT PLANT
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25. Preparation of relevant documents and technology
transfer to production
Documents and reports prepared in pilot plant
Lab note books
Scale up report
Validation protocol and report
Master manufacturing instructions
a) weighment sheet : exact quantities of raw materials
b) Stepwise manufacturing instructions : for each unit operation
c) Clearly specified time points: for sampling in process and finished products
Pilot plant transfers the technology to the shop floor for routine
mfg of the product at commercial scale
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26. Liquid pharmaceuticals encountered in the pilot plant are defined as non sterile
solutions ,suspensions or emulsions
are the most straight forward to scale up require tanks of adequate size and suitable mixing
capability and heating/cooling capabilities for rapid dissolution all equipment must be of
suitable nonreactive , sanitary materials and to be designed and constructed to facilitate easy
cleaning. Liquid processing tanks ,kettles pipes mills filter housing and so forth are most
fabricated from stainless steel
Stainless steel used in the industry type (308 and 316 ) most often used in the industry is 316
because of its unreactive nature
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27. Disadvantage surface alkalinity of the stainless steel
minimized by pre reacting the stain less steel with an
acetic acid or nitric acid this procedure is known as
passivation may need to be repeated at periodic
intervals
Interaction with metallic surfaces can be minimized by
the use of glass or polytetrafluoro ethylene liners.
Although these are highly inert surface materials they
have the obvious disadvantages of cracking breaking
flacking and peeling which results in product
contamination
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28. suspensions require more attention during scale up studies than do
simple solutions because of additional processing needs
Addition and dispersion of suspending agents
Lab scale sprinkling the material into the liquid vortex
Production scale require vibrating feed systems
Powder materials tends to clump during the process or that is difficult
to disperse
but these can be successfully incorporated by making a slurry with the
portion of the vehicle by using high shear mixer or powder blender
this converts a bulky material which is difficult to handle because of
static charges to a dense readily wettable powder which is much
easier to handle 28

29. Mixing at too high speed can result in the
incorporation of an excessive amount of air
into the product
Removal of Air bubbles is
difficult and time consuming
If air bubbles are not removed physical and
stability problems(reproducibility of filling )
Air can be removed using a
vacuum unit such as the versator
Product is drawn
into a vacuum
chamber through
an inlet line
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30. In preparing pharmaceutical suspensions the type of
mixers , pumps and mills and the horse power of the
motors should be carefully selected based on scale up
performance
example use of an
appropriate type of mixer
is important because if the
mixer is undersized obvious
problems of inadequate
distribution or excessive
production time result
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31. where it is spread on to
the center of high speed
rotating disc.
The centrifugal force produced by the
rotation of the disc causes the product
to form a thin film on the disc surface
as the film thins and moves toward the
outer edge of the vacuum chamber the
entrapped air is drawn off
deaerated product is collected from
the outer edge of the vacuum
chamber
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32. Selection of filters the mesh size
chosen must be capable of
removing the unwanted foreign
particulates but should not filter
out any of the active ingredients
If suspensions are not constantly mixed or recirculated during transfer process
they may settle out and there by adversely affect the uniform distribution of the
active ingredient 32

33. processing parameters of emulsions include temperature
mixing equipment homogenizing equipment final product
filters pumps and filling equipment
Mixing equipment are more likely to lead to air entrapment.
So use of vessels can be operated with the contents under a
controlled vacuum avoids the problem of unwanted aeration
Filtration equipment the unwanted particulates are most
efficiently removed by filtering the separate oil and water
phase before emulsification 33

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35. Sree rama
Created by SYAM PERLA
References N.K.Jain Pharmaceutical
Product Development pgno 379-418
Theory and Practice Of Industrial
Pharmacy Leon Lachman, Herbert
A. Lieberman pgno 681-710
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