PROCESS VALIDATION

OF OINTMENT, CREAM
AND
LIQUID ORALS

PREPARED BY :-
BHASKAR DEWANGAN
B. Pharmacy
Institute Of Pharmacy
Pt. R. S. University, Raipur(C.G.)
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 PROCESS VALIDATION
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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 NEED OF VALIDATE

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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 PROCESS VALIDATION PROTOCOL
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

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 TYPES OF PROCESS VALIDATION
Main four types of process validation:

1. Prospective validation

2. Retrospective validation

3. Concurrent validation

4. Revalidation

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 ORAL LIQUIDS

 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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 CLASSIFICATION OF LIQUID ORALS
Two main types:
[Link] liquids: 2. Biphasic liquids:
Solutions Suspensions
Elixirs Emulsions
Syrup
Liquid drops …etc

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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 PRESERVATIVES
HELPING CONTINUOUS DISPERSE PHASE
AGENTS PHASE

FOR SUSPENSION FOR EMULSION

MIXING
GRINDING OF DISSOLVED
DRUG & DRUG IN OIL
OTHER SOLIDS
AQUEOUS SOLUTION
DRUG SOLUTION
MILLED DRUG IN OIL
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 Continuous
phase

Disperse
phase PRE – MIX
OR
CRUDE DISPERSION

OTHER ADDITIVES
(FLAVOURS,
pH ADJUSTMENT COLOURING AGENT)

VOLUME ADJUSTMENT
HOMOGENIZE

FINE DISPERSE DELIVERY SYSTEM

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 Manufacturing of Monophasic liquids

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 Process Variables
Process Equipment Process variables Properties Monitoring
affected by output
variables

Mixing Kettle & Capacity of unit, Appearance of Potency,

of Tank fitted Shape & position liquid, Appearance,
liquid with agitator Viscosity of pH,
of agitation system,
liquid. Viscosity,
Order of addition,
Specific
Rate of addition, gravity.
Fill volume,
Mixing speed of
agitator,
Temperature of
liquid,
Mixing time.

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 Process Equipment Process variables Properties Monitoring
affected by Output
variables

Mixing & Blade Capacity of unit, Particle size Potency,

blending of mixers & Mixing speed of unit, of solids, Particle size
solids tumblers. Shape of unit, Blending analysis,
position of mixing uniformity. Content
element within unit, uniformity of
Product load. active
component.

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Process Equipment Process variables Properties Monitoring
affected by output
variables

Dispersing Homogenizer, Bore opening/ Particle size Potency,

Colloid mill, clearance of rotor of solids, Particle size
ultrasonic & stator/power Viscosity of Distribution,
device/ setting, liquid. Viscosity,
Pressure/rotor Specific
speed/power gravity.
consumption,
Feed rate,
Temperature,
Dispersion time,
Order of mixing.

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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 [Link] 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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 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.

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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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 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

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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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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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 Practical approach for managing
validation of emulsion and suspension
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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 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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