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PROCESS VALIDATIONOF 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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CONTINUOUSPHASE

CONTINUOUSPHASE

WATERWATERSURFACTANTSSURFACTANTS

OTHERHELPING AGENTS

OTHERHELPING AGENTS

PRESERVATIVESPRESERVATIVES

MIXINGMIXING

AQUEOUS SOLUTIONAQUEOUS SOLUTION

DISPERSE PHASE

FOR SUSPENSIONFOR SUSPENSION FOR EMULSIONFOR EMULSION

DRUG SOLUTIONIN OIL

DRUG SOLUTIONIN OILMILLED DRUGMILLED DRUG

GRINDING OFDRUG &OTHER SOLIDS

DISSOLVED DRUG IN OIL

Manufacturing of Biphasic liquids:

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PRE – MIXOR

CRUDE DISPERSION

PRE – MIXOR

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 VariablesProcess 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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Process Equipment Process variables Properties affected

by variables

Monitoring 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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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 testsParticle size and size distributionParticle shape or morphologyMicrobial countRheology of solvent or vehiclePH 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 yes17

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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Thank YouSarika Kadam