Department of Pharmacy (Pharmaceutics) | Sagar savale

PILOT PLANT
SCALE-UP TECHNIQUES

Mr.Sagar Kishor Savale

Department of Pharmaceutics
avengersagar16@gmail.com
2015-016
1
 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
04/21/16 Sagar Kishor Savale 2
 Definitions
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.

04/21/16 Sagar Kishor Savale 3

 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.

04/21/16 Sagar Kishor Savale 4

 Scale-up :- The art for designing of prototype using the data
obtained from the pilot plant model.

04/21/16 Sagar Kishor Savale 5

 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.

04/21/16 Sagar Kishor Savale 6

 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.

04/21/16 Sagar Kishor Savale 7

 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.

04/21/16 Sagar Kishor Savale 8

 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.

04/21/16 Sagar Kishor Savale 9

 STEPS IN SCALE UP

04/21/16 Sagar Kishor Savale 10

 Development process for formulation

Development batches / laboratory scale batch

Pre-exhibit batch / process qualification batch

Scale up
Exhibit batch / pivotal batch
batches

Production scale batch

04/21/16 Sagar Kishor Savale 11

 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.

04/21/16 Sagar Kishor Savale 12

 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 .

04/21/16 Sagar Kishor Savale 13

 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
04/21/16 Sagar Kishor Savale 14
 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

04/21/16 Sagar Kishor Savale 15

 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

04/21/16 Sagar Kishor Savale 16

 Geometric similarity
Dimensions of equipment in all scale up should have same
ratio such as like,
Vessel diameter
Impeller diameter
Baffle widths

04/21/16 Sagar Kishor Savale 17

 Kinematic similarity
This requires all corresponding
point in each system to have the
same ratio.

Dynamic similarity
 This requires equal force ratio at corresponding point of
the system like,
Gravitation
Surface tension
Viscosity

04/21/16 Sagar Kishor Savale 18

 General considerations
1. Reporting Responsibility

R & D group with The formulator who developed the

separate staffing product can take into the
production and can provide support
even after transition into
production has been completed.

04/21/16 Sagar Kishor Savale 19

 2. Personnel Requirement:-
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.
04/21/16 Sagar Kishor Savale 20
 3.Space Requirements

Administration Standard Storage

Physical
and information equipment area
testing area
processing floor space

04/21/16 Sagar Kishor Savale 21

  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.

04/21/16 Sagar Kishor Savale 22

 Physical testing area:-

This area should provide permanent bench top space for

routinely used physical- testing equipment.

04/21/16 Sagar Kishor Savale 23

 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.

04/21/16 Sagar Kishor Savale 24
 Storage Area:-
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.

04/21/16 Sagar Kishor Savale 25

 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.

04/21/16 Sagar Kishor Savale 26

5. 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

04/21/16 Sagar Kishor Savale 27

 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.

04/21/16 Sagar Kishor Savale 28

 7. Production Rates:-
The immediate as well as the future market trends/requirements are
considered while determining the production rates.

04/21/16 Sagar Kishor Savale 29

 8. Process Evaluation:-

Order of mixing of
Drying temp. components Mixing
And drying time speed

Mixing
Screen size PARAMETERS time
(solids)

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

04/21/16 Sagar Kishor Savale 30

  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.

04/21/16 Sagar Kishor Savale 31

 9. Master Manufacturing Procedures:-

The three important aspects

Weight sheet Processing Manufacturing

directions procedure

04/21/16 Sagar Kishor Savale 32

 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.
04/21/16 33
Sagar Kishor Savale
 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.

04/21/16 Sagar Kishor Savale 34

 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

04/21/16 Sagar Kishor Savale

IR Tablet 35
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
04/21/16 Sagar Kishor Savale 36
 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.

04/21/16 Sagar Kishor Savale 37

 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.
04/21/16 Sagar Kishor Savale 38
 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.

04/21/16 Sagar Kishor Savale 39
 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.

04/21/16 Sagar Kishor Savale 40

 Pilot Plant design for Tablets

04/21/16 Sagar Kishor Savale 41

 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.
04/21/16 Sagar Kishor Savale 42
 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.

04/21/16 Sagar Kishor Savale 43

04/21/16 Sagar Kishor Savale 44
04/21/16 Sagar Kishor Savale 45
 Material handling system

Vacuum loading machine

04/21/16 Sagar Kishor Savale 46

 Dry Blending
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.
04/21/16 Sagar Kishor Savale 47
 V – cone blender Double cone blender
04/21/16 Sagar Kishor Savale 48
 Ribbon blender
04/21/16 Sagar Kishor Savale 49
 Granulation

Sigma blade mixer Planetary mixer

04/21/16 Sagar Kishor Savale 50
 Wet granulation can
also be prepared using
tumble blenders
equipped with high-
speed chopper blades.

04/21/16 Sagar Kishor Savale 51

 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.

04/21/16 Sagar Kishor Savale 52

 Reduction of Particle size

Oscillating type granulator Hammer mill

04/21/16 Sagar Kishor Savale 53
 Blending
Equipments used for mixing
Sigma blade mixer.
Planetary mixer.
Twin shell blender.
High shear mixer

04/21/16 Sagar Kishor Savale 54

 Compression

DIFFERENT PUNCHES &DIES

04/21/16 Sagar Kishor Savale 55

 HIGH SPEED ROTARY
MULTI ROTARY MACHINE
MACHINE

04/21/16 Sagar Kishor Savale 56

 DOUBLE ROTARY UPPER PUNCH AND
MACHINE LOWER PUNCH

04/21/16 Sagar Kishor Savale 57

 SINGLE ROTARY MACHINE

04/21/16 Sagar Kishor Savale 58

 Tablet Coating

04/21/16 Sagar Kishor Savale 59

 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.
04/21/16
Hircmath, orient longman pvt ltd Chennai .
Sagar Kishor Savale 60
 www.google.com

• htpp://en.wikipedia.org/pilotplantscaleup

• www.Pilotplanstzeton.com

• www.sciencedirect.com

04/21/16 Sagar Kishor Savale 61

04/21/16 Sagar Kishor Savale 62