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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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 Continue.

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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 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: 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 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 of agitation system, Viscosity of pH,
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 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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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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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

Clarityof 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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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 Upper control
limit(LCL) limit(UCL)

Moisture content 5% 15%

Processing 50 degree Celsius 70degree Celsius

temperature

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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