Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist: • Quality, safety, and efficacy are designed or built into the product. • Quality cannot be adequately assured merely by in-process and finished-product inspection or testing

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PROCESS VALIDATION
OF OINTMENT, CREAM
AND
LIQUID ORALS
PREPARED BY :-
BHASKAR DEWANGAN
B. Pharmacy
Institute Of Pharmacy
Pt. R. S. University, Raipur(C.G.)

2. PROCESS VALIDATION
2
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.

3. NEED OF VALIDATE
3
To conform Manufacturing to cGMP
regulations.
To avoid the possibility of rejected or recalled
batches.
To ensure the product uniformity and quality.

4. PROCESS VALIDATION PROTOCOL
4
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, conclusions, and
recommendations including the need for
requalification and revalidation
Certification and approval
Summary report of findings with conclusions

6. TYPES OF PROCESS VALIDATION
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Main four types of process validation:
1.Prospective validation
2.Retrospective validation
3.Concurrent validation
4. Revalidation

7. ORAL LIQUIDS
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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.

8. CLASSIFICATION OF LIQUID ORALS
8
Two main types:
1.Monophasic liquids: 2. Biphasic liquids:
Solutions Suspensions
Elixirs Emulsions
Syrup
Liquid drops …etc

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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
Test parameters for emulsion and suspension

10. CONTINUOUS
PHASE
WATER
SURFACTANTS
OTHER
HELPING
AGENTS
PRESERVATIVES
MIXING
AQUEOUS SOLUTION
DISPERSE PHASE
FOR SUSPENSION FOR EMULSION
DRUG SOLUTION
IN OILMILLED DRUG
GRINDING OF
DRUG &
OTHER SOLIDS
DISSOLVED
DRUG IN OIL
Manufacturing of Biphasic liquids
10

11. PRE – MIX
OR
CRUDE DISPERSION
HOMOGENIZE
FINE DISPERSE DELIVERY SYSTEM
OTHER ADDITIVES
(FLAVOURS,
COLOURING AGENT)
VOLUME ADJUSTMENT
pH ADJUSTMENT
Disperse
phase
Continuous
phase
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12. 12
Manufacturing of Monophasic liquids

13. Process Variables
13
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.

14. 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.
14

15. 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.
15

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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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Continue…
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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Continue….
 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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Continue….
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.

23. 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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Continue….
 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.

27. 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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Continue….
Preservative system used in the formulation-
The use of small amounts of propylene glycol(5-
15%) 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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Continue….
 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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Continue…
 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

34. Type of emulsion determination by
Dilution test
Conductivity test
Dye solubility test
COCl2 filter paper
Fluorescence test
34

35. 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
35

36. Continue….
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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37. Practical approach for managing
validation of emulsion and suspension
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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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Continue…
 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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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
Limits of Process variables for factorial analysis

40. 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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