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It is the process of establishing, through
documented evidence, a high degree of
assurance that a specific process will
consistently produce a product that meets
its predetermined specifications and
quality characteristics.
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To conform Manufacturing to cGMP regulations.
To avoid the possibility of rejected or recalled
batches.
To ensure the product uniformity and quality.
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Following protocol is suggested:
 Purpose and prerequisites for validation
 Presentation of whole process and sub processes
 Validation protocol approval
 Installation and operational qualifications
 Qualification reports including methods, procedures,
release criteria, etc.
 Product qualification test data from prevalidation
batches
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 Test
data from formal validation batches
 Evaluation
of test data,
recommendations
including
requalification and revalidation
 Certification
 Summary
conclusions,
the
need
and
for
and approval
report of findings with conclusions
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Main four types of process validation:
1.
Prospective validation
2.
Retrospective validation
3.
Concurrent validation
4.
Revalidation
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
Oral Liquids are homogeneous liquid preparations,
usually consisting of a solution, an emulsion or a
suspension of one or more medicaments in a suitable
vehicle.
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Two main types:
1.Monophasic liquids:
Solutions
Elixirs
Syrup
Liquid drops …etc
2. Biphasic liquids:
Suspensions
Emulsions
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Test parameters for emulsion and suspension
Test parameter
Suspension
Emulsion
Appearance
yes
Specific gravity
yes
yes
Viscosity
yes
yes
PH
yes
yes
Content uniformity
yes
yes
Sedimentation
yes
No
Resuspendability
yes
No
Particle size
yes
yes
Release rate
yes
yes
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Manufacturing of Biphasic liquids:
WATER
SURFACTANTS
OTHER
HELPING
AGENTS
PRESERVATIVES
CONTINUOUS
PHASE
DISPERSE PHASE
FOR SUSPENSION
FOR EMULSION
MIXING
GRINDING OF
DRUG &
OTHER SOLIDS
DISSOLVED
DRUG IN OIL
AQUEOUS SOLUTION
MILLED DRUG
DRUG SOLUTION
IN OIL
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Continuous
phase
Disperse
phase
PRE – MIX
OR
CRUDE DISPERSION
pH ADJUSTMENT
OTHER ADDITIVES
(FLAVOURS,
COLOURING AGENT)
VOLUME ADJUSTMENT
HOMOGENIZE
FINE DISPERSE DELIVERY SYSTEM
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Manufacturing of Monophasic liquids:
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Process
Mixing
of
liquid
Equipment
Process variables
Properties
affected by
variables
Monitoring
output
Kettle &
Tank fitted
with agitator
Capacity of unit,
Shape & position
of agitation system,
Order of addition,
Rate of addition,
Fill volume,
Mixing speed of
agitator,
Temperature of
liquid,
Mixing time.
Appearance of
liquid,
Viscosity of
liquid.
Potency,
Appearance,
pH,
Viscosity,
Specific
gravity.
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Process
Mixing &
blending of
solids
Equipment
Blade
mixers &
tumblers.
Process variables
Properties
affected by
variables
Monitoring
Output
Capacity of unit,
Mixing speed of unit,
Shape of unit,
position of mixing
element within unit,
Product load.
Particle size
of solids,
Blending
uniformity.
Potency,
Particle size
analysis,
Content
uniformity of
active
component.
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Process
Equipment
Process variables
Properties
affected by
variables
Monitoring
output
Dispersing
Homogenizer,
Colloid mill,
ultrasonic
device/
Bore opening/
clearance of rotor
& stator/power
setting,
Pressure/rotor
speed/power
consumption,
Feed rate,
Temperature,
Dispersion time,
Order of mixing.
Particle size
of solids,
Viscosity of
liquid.
Potency,
Particle size
Distribution,
Viscosity,
Specific
gravity.
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Process validation
operations:
concerns
to
following
 Raw
material validation
 Monitoring outputs
 Filling and packaging validation
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Raw material validation:
It includes mainly following tests
 Particle size and size distribution
 Particle shape or morphology
 Microbial count
 Rheology of solvent or vehicle
 PH of the solvent or vehicle
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Raw materials are checked and validated for,
 Particle size and size distribution- Particle size
distribution range is 0.2-2microns for suspensions.
 Particle shape(Morphology)-It is also important to
consider because it affects the product appearance,
solubility, settling rates and drug stability.
 Microbial content-To prevent microbial growth on
the final product .
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





Rheology of solvent- It will determine how well
liquid will suspend the insoluble particles. Viscosity of
the External phase is generated by one or more of
following components:
Suspended solids
Blend of oils and waxes
presence of polyols and polyoxyethylene derivatives
High concentration of dispersed solids in water
Dispersed clays, gums, cellulosic, and/or polymers
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
PH of the solvent-Solubility of the drug in the
solvent or vehicle can be markedly influenced by
the PH of the solvent.PH of the solvent is
important
because
large
number
of
chemotherapeutic agents are either weak acids or
weak bases so their solubility markedly affected
by the PH of the solvent.
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Monitoring outputs
Some outputs to be monitored are as under,
:
Appearance
pH
Viscosity
Specific gravity
Microbial count
Content uniformity
Dissolution testing
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Appearance:


Appearance of the final product is checked and
validated because it indicates the signs of instability
and degradation. For e.g. settling of solid particles
in case of suspension and turbidity in case of
emulsion.
Time for mixing or agitation and temperature of
process can effect the appearance greatly.
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PH value
 PH
of aqueous oral formulations should be taken at a
given temperature and only after equilibrium has
been reached in order to minimize the PH drift.

Electrolytes , such as potassium chloride , may be
added to the aqueous external phase to stabilize their
PH drift.
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Viscosity:

Viscosity is defined as the study of fluid flow. or
It is a measurement of the applied stress per unit area
to maintain a certain flow rate.

The viscometer used for the measurement of
viscosity should be properly calibrated
at
equilibrium at a given temperature to establish
system reproducibility.
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Viscosity of the liquid oral dosage form is
important because it affects the settling rate of
suspended particles in suspension and of
globules of internal phase in emulsions and
also in case of oral solutions it affects the
overall appearance of the final product so it
must be measured and validated properly.
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Specific gravity:




Specific gravity is the weight of the product per unit
volume.
For most of the liquid oral products it is 1gm/cube
centimeter.
A decrease in specific gravity of the product like
suspensions indicates the presence of air within the
structure of the formulation.
Hydrometer is used to measure the specific gravity
of liquid orals at a given temperature using well
mixed uniform solution.
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Microbial count

Microbial count for the final product is essential to
validate because by performing microbial count we
can select the preservative for the final product
storage.

There are specifications for each liquid oral product
for the bioburden content.
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Preservative system used in the formulationThe use of small amounts of propylene glycol(515%) or disodium edetate(about 0.1%) or
decrease in the PH of the disperse system have
often been use to increase the efficiency of the
preservative system.
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Criteria for selection of preservatives:
 Must be effective against a broad spectrum of
microorganisms.
 Must be chemically, physically, and microbiologically
stable.
 It must be nontoxic, nonsensitizing, soluble and
compatible with other formulation components.

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Content uniformity:

In solution, suspensions and emulsions determination
of content uniformity affects the dose uniformity
in case of multidose formulations and also affects
the homogeneity of the drug within solvent system.
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Content uniformity of suspension is affected by
settling rate which is governed by following factors,
 Particle size of the internal phase
 Particle density of the internal phase
 Density of the external phase
 Viscosity and structure of the external phase

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Dissolution testing:

There is not any official method for dissolution
testing of dispersed system , but the best way to
perform dissolution of suspension like system is to
place a small amount of formulation inside a secure
Durapore (polyvinylidene fluoride) membrane pouch
of suitable viscosity and suspend it in a suitable
dissolution medium using a USP method 1 paddle
apparatus.
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Test parameters specific for suspension
 Sedimentation
rate
 Resuspendibility
 Particle size & particle size distribution
 Zeta potential measurement
Test parameters specific for solution
 Clarity
of solution
 Color of solution
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Type of emulsion determination by
Dilution test
Conductivity test
Dye solubility test
COCl2 filter paper
Fluorescence test
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Filling and packaging operation validation

Following tests are performed mainly
Leakage test for filled bottle
Cape sealing test
Fill volume determination
Water vapour permeability test
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Some precautions to be taken while filling and
packaging
Proper control of product temperature
Proper agitation in holding tanks and filling heads
Uniformity and homogeneity of active ingredient
Maintain stability in the primary container closure
system
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The
validation of suspension and emulsion can be
handled in the same way, because their similarities rather
than their differences are subjected to validation
 Common similarities are
 Particle size distribution of the drug itself
 Homogeneity of the drug throughout the external
phase
 Reproducibility and stability of the viscosity and/or
density in the final product
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
The primary focus of prospective validation is to
identify the critical unit operations, critical process
variables, and control limits for these variables in order
to establish in process control of the manufacturing
process. In this connection, fractional, factorial
designed experiments are used to determine the
critical process variables.
In retrospective validation the objective is to establish
and maintain process control by demonstration of
reproducibility of the various manufactured batches
primarily meeting their final product specifications.
This can be shown effectively by the use of quality
control charts.
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Limits of Process variables for factorial analysis
Processing variables
Lower control limit(LCL)
Upper control limit(UCL)
Moisture content
5%
15%
Processing temperature
50 degree Celsius
70degree Celsius
PH value
5.0
7.0
Processing time
2 hr
6 hr
Apparent viscosity
20,000cps
200,000cps
Blender speed
4,000rpm
20,000rpm
Avg. particle size
20 micron
40 micron
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References:
Lieberman H. A. , Rieger M. M. and Banker G. S.
“Pharmaceutical Dosage Forms: Disperse System” ,vol.3;
Second Edition,473-511
 R. A. Nash and A. H. Wachter “Pharmaceutical process
validation”; Third edition
 Agalloco James, Carleton J. Fredric
“Validation of
Pharmaceutical Processes”; Third edition,417-428
 The theory and practice of industrial pharmacy by Leon
Lachman, Herbert A. Liberman, Joseph L. Kanig; Third
edition

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THANK
YOU
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