Process validation of liquid orals (pharmaceutical process validation)

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PROCESS VALIDATION
OF LIQUID ORALS
Sarika Kadam

WHAT ARE ORAL LIQUIDS?
Oral Liquids are homogeneous liquid
preparations, usually consisting of a solution, an
emulsion or a suspension of one or more active
ingredients in a suitable vehicle.
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CLASSIFICATION OF LIQUID ORALS
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Manufacturing of Monophasic liquids
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CONTINUOUS
PHASE
CONTINUOUS
PHASE
WATERWATER
SURFACTANTSSURFACTANTS
OTHER
HELPING
AGENTS
OTHER
HELPING
AGENTS
PRESERVATIVESPRESERVATIVES
MIXINGMIXING
AQUEOUS SOLUTIONAQUEOUS SOLUTION
DISPERSE PHASE
FOR SUSPENSIONFOR SUSPENSION FOR EMULSIONFOR EMULSION
DRUG SOLUTION
IN OIL
DRUG SOLUTION
IN OILMILLED DRUGMILLED DRUG
GRINDING OF
DRUG &
OTHER SOLIDS
DISSOLVED
DRUG IN OIL
Manufacturing of Biphasic liquids:
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PRE – MIX
OR
CRUDE DISPERSION
PRE – MIX
OR
CRUDE DISPERSION
HOMOGENIZE
FINE DISPERSE DELIVERY SYSTEMFINE DISPERSE DELIVERY SYSTEM
OTHER ADDITIVES
(FLAVOURS,
COLOURING AGENT)
VOLUME ADJUSTMENT
pH ADJUSTMENT
Disperse
phase
Disperse
phase
Continuous
phase
Continuous
phase
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Process Variables
Process Equipment Process
variables
Properties
affected by
variables
Monitoring
output
Mixing
of
liquid
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 Equipment Process
variables
Properties
affected
by
variables
Monitoring
Output
Mixing &
blending of
solids
Blade mixers
& tumblers.
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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Sarika Kadam

Process Equipment Process variables Properties
affected
by
variables
Monitorin
g output
Dispersing Homogenizer,
Colloid mill,
ultrasonic
device/
Bore opening/
clearance of rotor &
stator,
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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Sarika Kadam

Process validation concerns to following
operations:
• 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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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 of the final product 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.
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.
Viscosity affects the settling rate of suspended particles in
suspension and coalescence 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: A decrease in specific gravity of the
product like suspensions indicates the presence of air
within the structure of the formulation.
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.
 Content uniformity affects the dose uniformity in case of
multidose formulations and also affects the homogeneity
of the drug within solvent system.
 Dissolution testing: no official method for dissolution
testing of dispersed system
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Test parameters for suspension
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Test parameters for Emulsions
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Test parameter Suspension Emulsion
Appearance yes 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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Test parameters for emulsion and suspension
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Filling and packaging operation validation:
Tests performed:
• Leakage test for filled bottle
• Cap sealing test
• Fill volume determination
• Water vapour permeability test
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Sarika Kadam

Process validation of liquid orals (pharmaceutical process validation)

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