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PILOT PLANT
PILOT PLANT
SCALE-UP TECHNIQUES
SCALE-UP TECHNIQUES
Mr.Sagar Kishor Savale
Mr.Sagar Kishor Savale
Department of Pharmaceutics
Department of Pharmaceutics
avengersagar16@gmail.com
avengersagar16@gmail.com
2015-016
2015-016
Department of Pharmacy (Pharmaceutics) | Sagar savale
2. Content
Definitions
Introduction
Objectives
Reason for building of pilot plant
Why conduct pilot plant study ?
Steps in scale-up
Scientific scale -up
General considerations
GMP considerations
SUPAC
Significance
Uses
Advantages
Disadvantages
Pilot Plant design for Tablets
References
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3. Plant :- It is a place were the 5 M’s like money, material, man,
method and machine are brought together for the
manufacturing of the products.
Definitions
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4. 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 and practical procedure of manufacture.
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5. Scale-up :- The art for designing of prototype using the data
obtained from the pilot plant model.
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6. Introduction
Last 25-30 year pharmaceutical research are going on very
fast speed.
Have witnessed amazing invention and innovation in
pharmaceutical field.
NDA and ANDA are all time high.
Researcher are motivated to adopt new processes and
technology.
Scale up batches are essential for ensuring success in the
clinical testing and bioequivalence study.
Pilot plant scale up is one of the most imp stage in the product
development.
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7. Objective
To try the process on a model of proposed plant before
committing large sum of money on a production unit.
Examination of the formula to determine it’s ability to withstand
Batch-scale and process modification.
Evaluation and Validation for process and equipments
To identify the critical features of the process
Guidelines for production and process controls.
To provide master manufacturing formula with instructions for
manufacturing procedure.
To avoid the scale-up problems.
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8. Reasons for building a pilot plant
To evaluate on process of
large change in scale up
operation.
To find and examine all by-
products or waste .
To produce a trail lot of
quantities of material.
Clinical studies, analytical
development, process dev-
elopment, stability testing.
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9. 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 scale processing plant from
laboratory data alone with any degree of success.
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11. Development process for formulation
Development batches / laboratory scale batch
Pre-exhibit batch / process qualification batch
Exhibit batch / pivotal batch
Production scale batch
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Scale up
batches
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12. Laboratory scale batch
• Early development at laboratory stage.
• It is generally 100-1000 times less than production batch.
• It is 1X (3-10 kg or 3-10 liters or 3000-10000 unit) batch.
Uses
• To support formulation.
• For packaging development.
• For preclinical trial.
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13. Pre-exhibit batch
• It is 1st
step in scale up.
• It generally 70 % of the size of the exhibit batch.
• It prepaid with the complete process documentation and fully
validated analytical methodology.
Uses
• To detect any problem arise in manufacture of exhibit batch .
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14. Exhibit batch
It is demonstration batch.
It contains the mfg. documentation, product specification,
accelerated stability data submitted to FDA.
It generally 10 % of the production scale batch.
It is 10X (30-100 kg or 30-100 liters or 30000-100000 unit)
batch .
It is manufactured under GMP.
Exhibit batch also called as :-
NDA or ANDA batch
Regulatory reference batch
Bioequivalence batch
Fully GMP batch
Stability tested batch
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15. Production batch
It is produced during the routine marketing of product.
It is 100X batch means :- 300-1000 kg or
300-1000 liters or
300000-1000000 unit
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16. Scientific scale up
Should done in incremental manner.
Process being validated for each new scale.
The equipment should possess following similarity
1) Geometric similarity
2) Kinematic similarity
3) Dynamic similarity
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17. Geometric similarity
Dimensions of equipment in all scale up should have same
ratio such as like,
Vessel diameter
Impeller diameter
Baffle widths
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18. Kinematic similarity
This requires all corresponding
point in each system to have the
same ratio.
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Dynamic similarity
This requires equal force ratio at corresponding point of
the system like,
Gravitation
Surface tension
Viscosity
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19. 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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20. 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.
2. Personnel Requirement:-
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22. Administration and information process:
Adequate office and desk space should be provided for both
scientist and technicians.
The space should be adjacent to the working area.
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23. Physical testing area:-
This area should provide permanent bench top space for
routinely used physical- testing equipment.
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24. Standard pilot-plant equipment floor space:-
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.
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25. It should have two areas divided
as approved and unapproved area
for active ingredient as well as
excipient.
Different areas should provided
for the storage of the in-process
materials, finished bulk products
from the pilot-plant & materials
from the experimental scale-up
batches made in the production.
Storage area for the packing
material should also be provided.
Storage Area:-
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26. 4. 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.
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27. 5. Raw materials:-
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
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Why?
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28. 6. 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.
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29. 7. Production Rates:-
The immediate as well as the future market trends/requirements are
considered while determining the production rates.
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30. 8. Process Evaluation:-
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
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31. Why to carry out process evaluation????
The knowledge of the effects of various process parameters
as few mentioned above form the basis for process
optimization and validation.
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32. 9. Master Manufacturing Procedures:-
The three important aspects
Weight sheet Processing
directions
Manufacturing
procedure
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33. The weight sheet should clearly identify the chemicals required
In a batch. To prevent confusion the names and identifying nos.
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. 33
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34. 10. 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.
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35. Scale-up and post approval changes
(SUPAC)
FDA and American Association of Pharmaceutical Scientists
(AAPS) provided the scientific foundation for the scale up and
post approval changes required for immediate release product
Called as SUPAC.
It provide guideline for post approval changes in the following
Component
Composition
Site of mfg
Process and equipment
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IR Tablet
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36. GMP consideration
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
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37. Significance of pilot plant
Examination of formulae.
Review of range of relevant processing equipments.
production rate adjustment.
Idea about physical space required.
Appropriate records and reports to support GMP.
Identification of critical features to maintain quality.
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38. 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-life and storage stability studies.
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.
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39. 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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40. Disadvantages
The frequency of direct interaction of the formulator with the
production personnel in the manufacturing area will be
reduced.
Any problem in manufacturing will be directed towards it’s
own pilot-plant personnel's.
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42. 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.
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43. Extraneous and microbiological contamination must be guarded
against by incorporating the following features in the pilot plant
design:
1.Fluorescent lighting fixtures should be the ceiling flush type.
2.The various operating areas should have floor drains to simplify
cleaning.
3.The area should be air-conditioned and humidity controlled.
4.High -density concrete floors should be installed.
5.The walls in the processing and packaging areas should be
enamel cement finish on concrete.
6.Equipment in the pharmaceutical pilot plant should be similar to
that used by production division- manufacture of tablets.
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51. Wet granulation can
also be prepared using
tumble blenders
equipped with high-
speed chopper blades.
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52. 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
Fluidized bed dryers are an
attractive alternative to the
circulating hot air ovens.
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60. References
1. “The theory and practice of industrial pharmacy” by Leon
Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third
edition. Varghese publishing house. Page no. 681-703.
2. “Pharmaceutical dosage forms: Tablets” Volume 3. second
edition by Leon Lachman, Herbert A. Lieberman, Joseph B.
Schwartz. Page no. 303-365.
3. “Pharmaceutical process scale –up” by Michael Levin marcel
dekker inc volume-157, 2003.
4. “Pharmaceutical process validation” by Robert A. Nash and
Alfred H Wachter marcel dekker inc volume-129, 2003 .
Page no. 17-21.
5. “Text book of industrial pharmacy” by Shobha Rani R.
Hircmath, orient longman pvt ltd Chennai . 60
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