Seminar on,

PILOT PLANT SCALE-UP TECHNIQUES

CONTENTS
Introduction.
Objectives of pilot plant.
Importance of pilot plant.
General considerations.
Pilot plant scale up techniques for injections.
Operations involved in the production of
injections.

PILOT PLANT:

Pilot plant can be defined as a part of the

pharmaceutical industry where a lab scale formula is
transformed into a viable product by development of
liable practical procedure for manufacture.

R&D

PRODUCTION

PILOT PLANT
Pilot plant is an intermediate sized.
It is a small scale model of the larger chemical
plant.

SCALE-UP:
The art of designing of prototype using the
data obtained from the pilot plant model.

The process of increasing the batch size.

OBJECTIVES:
Find mistakes on small scale and make profit on
large scale.
To produce physically and chemically stable
therapeutic dosage forms.

 Close examination of the formula.

Review of the processing equipment.
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula.
To train the personnel.

IMPORTANCE OF PILOT PLANT:

The ability of the lab scale formula.
The capability of the product being processed
and packed on large scale.
The specifications of the raw materials.
Production rates.
The physical space required.
Personnel.
STEPS IN PILOT PLANT SCALE-UP TECHNIQUES:

1)

Laboratory Batch:
Selection of suitable preliminary formula.

 The work is performed in the development

laboratory.
(1X) Batch.
-3 to 5 kg of solid or semisolid.
-3 to 5 ltrs of liquids.
-3000 to 5000 units of tablet/capsules.
2)

Laboratory Pilot Batch:

(10X) Batch.
-30 to 50 kg of solid or semisolid.
-30 to 50 ltrs of liquids.
-30,000 to 50,000 units of tablet/capsules.
The size may vary depending upon the,
-Equipment availability.
-Active drug substance availability.
-Cost of raw materials.
-Inventory

requirements

clinical

and

nonclinical studies.
3)

Pilot Production:
Development

laboratory

and

manufacturing unit will combine to do work.

 Represents a full production batch in

standard production equipment.
(100x) Batch.
-300 to 500 kg of solid or semisolid.
-300 to 500 ltrs of liquids.
-300,000 to 500,000 units of tablet/capsules.

Separate pilot plant function,

DEVELOPMENT LAB

PILOT PLANT

PRODUCTION

 Joint pilot plant function,

DEVELOPMENT LAB

PILOT BATCH

PILOT BATCH

COMPLETION

REQUEST

REPORT

PRODUCTION

GENERAL CONSIDERATIONS:

1. REPORTING RESPONSIBILITIES:
Pilot plant may be separate or joint.

 There should be good relationship.

2. PERSONNEL REQUIREMENT:
Qualification.
Experience of working.
Ability to communicate with each other.
Should have some engineering knowledge.

3. SPACE REQUIREMENT:
A pilot plant for should have following types of
space requirements,
Administration and Information Processing.
Physical Testing area.
Standard Pilot Plant Equipment Floor.
Storage Area.

4) REVIEW OF THE FORMULA:

A thorough review of each aspect of the
formulation.
Each ingredient.

5) RAW MATERIALS:
Approval and validation.
Larger scale ingredients may change in,
- Particle size.
- Shape.
- Morphology.
- Bulk density.
- Static charge.
- Rate of solubility.
- Flow properties.
- Color.
This may result in,
Different handling procedures.

6) RELEVANT PROCESSING EQUIPMENT:

Most economical.-The simplest.

 The most efficient.

The most capable of consistently producing the
product.
Should not be too large or too small.
Ease of cleaning.
7) PRODUCTION RATES:
Depends upon,
Availability of the API and raw materials.
Availability of the equipment.
Size and efficiency of the equipment.
Number of personnel working.
Number of batches that will need to be tested
for release.
Product loss during the manufacture.
The time required to clean the equipment
between batches.
The immediate and future market requirement.

8) PROCESS EVALUATION:

 Evaluated critically and the process is optimized

based on the evaluation.
Parameters that should be examined include,

Water for injection or the vehicle used for

preparation.
Washing and sterilization.
Order of addition of components.
Mixing speed.
Mixing time.
Heating and cooling rates.
Maintenance of aseptic environment in the
filling and sealing area.
Filtration.
Sterilization techniques.
Product evaluation.
9) PREPARATION OF MASTER MANUFACTURING
PROCEDURES:
All minute details and the parameters.
Chemicals required in a batch.
Order in which they will be used.

 Order of addition of ingredients.

Temperature.
pH maintained and buffer used.
Preservatives used.
Sterilization specifications,
Temperature and pressure maintained.
Time required.
Concentration of the antibacterial used.
Maintenance of environment,

Humidity level.

Air flow.

Air conditioning.

Testing procedures,
Content uniformity.
Clarity test.
Leakage test.
Sterility test.
Pyrogen test

10) GMP CONSIDERATIONS:

Checklist includes,

 Equipment qualification.
Process validation.
Regularly scheduled preventive maintenance.
Regular process review and validation.

Relevant

written

standard

operating

procedures.
The use of competent, technically qualified
personnel.
Adequate provisions for training of personnel.
A well defined technology transfer system.
Validated cleaning procedures.
An orderly arrangement of equipment.

11) TRANSFER OF ANALYTICAL METHODS TO

QUALITY ASSURANCE:
Analytical testing methods transformed to the
quality assurance department.
The quality assurance staff should review the
process.
PARENTERAL DRUG SCALE-UP:

 One of the most important processes is mixing.

One substance (solute) achieves uniform conc.
In another substance (solvent).
Small scale- Molecular diffusion.
Large scale- Bulk diffusion.
In small scale mixing depends on shear.
In large scale mixing depends on flow within the
vessel.

THE METHODS TO ACHIEVE APPROPRIATE

SCALE-UP OF MIXING:

I)

GEOMETRIC SIMILARITY:

Involves geometric parameters of the vessel.

The scale up parameters include,
D/T and Z/T

 Similar ratios are compared for both small and

large scale equipment,
R= D1/T1 = D2/T2
R is geometric scaling factor.
After determination of R, rotational speed of the
larger equipment can be calculated,
N2 = N1 (1/R)n
n is the power law exponent.

Physical Interpretation

Equal blend time

1/2

Equal surface motion

2/3

Equal mass transfer rates

3/4

Equal solid suspension

Equal solid motion (equal average fluid velocity)

In most designs the D/T will be between 0.15 to

0.60 and Z/T will be between 0.30 to 1.50

II)

DIMENSIONLESS NUMBER METHOD:

Reynolds Number;
NRe = d2n/
Where,
N- shaft speed (sec-1)

D- propeller blade diameter (cm)

- density of solution dispersion (g/cm3)
-

viscosity

of

solution

dispersion

(g/cm.sec-1)

Froude Number;
NFr = DN2/g
Where,
g- acceleration due to gravity cm/sec
Power number;
NP = Pgc /N3D5
Where,
P- power
gc- gravitational conversion factor

III) SCALE OF AGITATION APPROACH:

 Developed in the mid 1970s.

The basis is a geometric scale up with the power
law exponent n=1.
The analysis proceeds as follows,
Determine the D/T ratio of the tank.
Note the rpm and horsepower of the mixer.
Determine the density and viscosity of the
product.
Calculate the impeller Reynolds number
and it should be greater than 2000.
Obtain

the

terminal

pumping

number

using,
NQ = 1.1283- 1.07118(D/T)

Determine the cross sectional area of

the pilot size tank using,
A = T2/4 cm2

 Calculate the effective pumping capacity of

the pilot size mixer using,
Q = NQND3 cm3/sec
The value for bulk fluid velocity around

largest impeller of the system is obtained

using,
Vb = Q/A cm/sec.
The Vb can be used to determine the

level of agitation achieved in the original

R&D batch.
THIS

CAN

BE

ILLUSTRATED

BY

THE

FOLLOWING EXAMPLE:

Scale up of injectable solution from

378 liter batch to 3780 liter production size
batch.

Known parameters,

 Density of the liquid- 1.018 g/cm3

Viscosity of the liquid- 0.0588 g/
(cm/sec)
Diameter of the tank- 74.6 cm
Cross sectional area of the tank4371 cm2
Diameter of the impeller- 40.64 cm
rpm- 90 rpm or 1.5/sec

From

the

above

known

parameters

the

following results are obtained for 378 liter

batch,
D/T= 0.54
NRe = 44449

 Q = 55375 cm3/sec
Vb = 12.6 cm/sec

Now the appropriate shaft speed for scaled up

production equipment can be calculated,
Known parameters are,
The tank capacity is 3780 liters.
Shaft speed range is 20 to 58 rpm.
Diameter of the tank is 167 cm.
Diameter of the impeller is 87 cm.

From the above parameters and the results

obtained in the 378 liter production batch the
following are determined,
Cross sectional area, A = 21,904 cm2

 Effective pumping capacity in larger

vessel, Q = 275,990 cm3/sec
Pumping number, NQ = 0.57
Finally the shaft speed, N = 0.73/sec
or 44 rpm
The

Typical

Operations

Involved

In

The

Production Of Injections:

1)

CLEANING EQUIPMENT AND CONTAINERS:

Must be clean and sterile.

Cleaning new containers:
Rinsing procedure.
First with clean steam.
With filtered WFI.
Finally a blast of clean air to blow out
remaining water.
The cleaned containers must be protected
from dust and other particulates.

Sterilization in SS boxes under the protection

of HEPA-filtered laminar air flow.

Cleaning rubber and plastic components:

Hot detergent solution.
0.5% sod.pyrophosphate.
Followed by thorough water rinse.
Final rinse with WFI.

2)

STERILIZATION OF EQUIPMENT:
Equipment, containers, closures and all other
components should be sterilized.

3)

COMPOUNDING OF THE PRODUCT:

Under the clean, aseptic environment.
Attention is given to achieve the homogeneity.

4)

FILTRATION:
The primary objectives are clarification or
sterilization.
Must

be

protected

contamination.

from

environmental

5)

FILLING PROCEDURE:
This should be done in completely aseptic
area.

6)

SEALING:
Done immediately after filling operation in
aseptic area.
For ampoules tip sealing or pull sealing is
followed.
Rubber closures are inserted to the bottles
and vials by hand using sterile forceps or by
machines.
Aluminum caps are used.

7)

STERILIZATION:
The product must be sterilized.

8)

PACKAGING:
Extremely an important part of the product.

References:

Lachman and Lieberman, The Theory

and Practice of Industrial Pharmacy

Drug and Pharmaceutical Sciences, Vol-

118,

Pharmaceutical Process Scale Up,

Marcel-Dekker