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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 validationPresentation of whole process and sub processesValidation protocol approval Installation and operational qualificationsQualification 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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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 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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Test parameters for emulsion and suspension

CONTINUOUSPHASE

WATERSURFACTANTS

OTHERHELPING AGENTS

PRESERVATIVES

MIXING

AQUEOUS SOLUTION

DISPERSE PHASE

FOR SUSPENSION FOR EMULSION

DRUG SOLUTIONIN OILMILLED DRUG

GRINDING OFDRUG &OTHER SOLIDS

DISSOLVED DRUG IN OIL

Manufacturing of Biphasic liquids:

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PRE – MIXOR

CRUDE DISPERSION

HOMOGENIZE

FINE DISPERSE DELIVERY SYSTEM

OTHER ADDITIVES(FLAVOURS, COLOURING AGENT)

VOLUME ADJUSTMENT

pH ADJUSTMENT

Disperse phase

Continuous phase

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Manufacturing of Monophasic liquids:

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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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.

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Process validation concerns to following operations:

Raw material validationMonitoring outputsFilling 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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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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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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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, :

AppearancepHViscositySpecific gravityMicrobial countContent uniformityDissolution 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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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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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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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 phaseParticle density of the internal phaseDensity of the external phaseViscosity 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 rateResuspendibilityParticle size & particle size distributionZeta potential measurement

Test parameters specific for solution

Clarity of solutionColor of solution

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 mainlyLeakage test for filled bottle

Cape sealing test

Fill volume determination

Water vapour permeability test

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Some precautions to be taken while filling and packagingProper 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 validationCommon similarities areParticle size distribution of the drug itselfHomogeneity of the drug throughout the external phaseReproducibility 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

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Limits of Process variables for factorial analysis

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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