Product validation

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PRODUCT VALIDATION

SUBMITTED BY V.SUHASINI

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DEFINITION- Validation is a key process for effective quality assurance.

 “Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.”

or Defined as the verification, by data and analysis that the

design objectives of a given facility, system, apparatus or procedures are reliably fulfilled in routine operation

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The major reasons for validation are:• Quality assurance:

Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.

• Economics: Due to successful validation, there is a decrease in sampling

and testing procedures and there are less number of product rejections and retesting. This leads to cost-saving benefits.

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• Compliance: For compliance to current good manufacturing practices,

validation is essential.

Validation involves in the steps:

1. Choosing the desired attributes of the product.2. Determining specifications for those attributes.3. Selecting appropriate processes and equipment.4. Monitoring and testing processes, equipment and personnel

while in operation5. Examining test procedures themselves to ensure their

accuracy and reliability.

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PRODUCT VALIDATION

Product validation is associated with validation of the full-scale manufacture of numerous earlier aspects of product development that are critical to the subsequent phases of the process.

Product validation involves following steps:• validation of raw materials • validation of excipients.• validation of analytical methods • validation of finished product

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VALIDATION OF RAW MATERIALS• Validation of raw materials is one of the major causes of product

variation or deviation from specification. The API may represent the most uncontrollable component in the complete product .

• The validation process of dosage form begins with the validation of raw materials ,both API and excipients.

• Preformulation is one of the critical step to be validated in product validation

• Physical characters such as drug and particle size can affect material flow and blend uniformity.

• Chemical characters like impurities can effect stability of drug. The hygroscopic nature is important in both handling and reproducibility of the manufacturing process.

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VALIDATION OF EXCIPIENTSExcipients can represent less then 1% of a tablet formula Factors to be aware of are • The grade and source of the excipients• Particle size and shape characteristics and• Lot-to-lot variabilityExample :

Microcrystalline cellulose(MCC) used as diluents shows significant changes in the chemical composition, crystalinity, particle size between different lots.

Differences in particle size of MCC can affect wet granulation/blend uniformity of tablet formulation.

In direct compression formulations differences in particle size distribution between lots can result in

• Non uniformity in initial mix• Materials segregate during compression.

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VALIDATION OF ANALYTICAL METHODS

Accuracy of method:• Ability of a method to measure the true value of a sample.Specificity:• Ability to accurately measure the analyte in the presence of

other componentsRepeatability:( in day /out of day variation )• Does the precision and accuracy of the method change when

conducted numerous times on the same day and repeated on a subsequent day?

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Reproducibility:( between operator variation )• Repeat the precision and accuracy studies within the same lab

using the same instrument but different analysts to challenge the reproducibility of the method.

Precision: (between instrument variation )• How will different instruments within the same lab run by the

same analyst affect the accuracy and precision of the method.Ruggedness:( between laboratory variation)• Will the precision and accuracy of the method be same

between the development and quality control lab?

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Validation of finished product • Organoleptic characteristic • Physical characteristic• Chemical characteristic• Biological characteristic• Microbiological characteristic• Stability testing • Storage condition

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Validation of tablets

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TABLET COMPRESSION

The following in-process tests should be examined during the compression stage-

• Appearance• Hardness- 4 -8 kg/cm • Tablet weight-90-110%• Friability-0.5-1%• Disintegration-15-30 min • Weight uniformity

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TEST FOR TABLET COATING

• cracking or peeling of the tablet• color uniformity• coating efficiency should be determined for

the coating operation

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TEST IN- PROCESS TEST Finished product

• Moisture content of dried granulation- usually less then 2%

• Granulation particle size distribution• Appearance • Individual tablet weight• Tablet hardness• Tablet thickness• friability• Disintegration • stabilty

• Appearance• Assay• content uniformity• Tablet hardness• Tablet thickness• Impurity profile• dissolution

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Validation of capsules

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TESTPHYSICAL TEST CHEMICAL TEST

Disintegration test

Weight variation

Dissolution testAssayContent uniformityStability testingMoisture permeation test

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ORAL LIQUID

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• ORAL LIQUID DOSAGE FORMS– Monophasic• Simple solutions• Draughts• Drops• Linctuses• Syrups• Elixirs

– Biphasic• Suspensions (solid in liquid)• Emulsions (liquid in liquid)

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Major test parameters used for final product testingAppearancepHViscositySpecific gravityMicrobial countLeakage test for filled bottle (By plastic vacuum dessicator)Check the cap sealingFill volume determinationParticulate matter testingWater vapour permeability testStress test

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Test parameters specific for suspension • Sedimentation rate• Resuspendibility• Particle size & particle size distribution• Zeta potential measurement

Type of emulsion determination by• Dilution test • Conductivity test• Dye solubility test• COCl2 filter paper• Fluorescence test• Direction of creaming

Test parameters specific for solution • Clarity of solution• Color of solution

Semisolid Dosage Form

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Evaluation of Ointments Evaluation of creams

Content uniformity of drug

Penetration

Rate of release of medicament

Absorption of medicament in blood stream

Irritant effect:

Rheology

Sensitivity

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• Evaluation of gel

Visual appearance Drug content Measurement of pHViscositySpreadabilityExtrudabilityStability

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• Evaluation of paste

AbrasivenessParticle sizeCleansing propertyConsistencypH of the productFoaming characterLimit test for arsenic and leadVolatile matters and moisture

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• Evaluation of Transdermal patches

Physiochemical evaluation Thickness of the patch Folding endurance Percentage of moisture absorbed Percentage of moisture lostDrug content uniformity skin irritation testStability test

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• Evaluation of suppositories

Appearance Uniformity of weight test Melting rang test Breaking test Dissolution test

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• Evaluation of Aerosols

Leakage testInternal pressureSpray pattern Discharge rate Flammability Particle size analysisMoisture determination

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Steam sterilization process

• Sterile product have several unique dosage from properties such as freedom from micro organism , freedom from pyrogens, freedom from particulates and extremely high standards of purity and quality

• However, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination

Basic principle in the validation of sterile product • The theoretical approaches to validation the performance of the

actual validation experiments and the analysis and documentation of the validation data

Theoretical approaches • Generally five basic step are necessary to validate manufacturing

process

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1. Written documentation 2. Manufacturing parameters 3. Testing parameters4. In process controls5. Final product testing Each validation process should have a documented

protocol of the steps to follow and the data to collect during the experimentation example : Steam sterilization process

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• Steam sterilization process summary sheet Autoclave identification number or latter

P6037

Location Building 22, floor 1

Tag no 896101

Validation date 10-14-99

Revalidation date 4-14-00

Description of process validation Load containing filling equipment & accessories not to exceed 102 kg

Temperature set point for validation 121.0 0 c

Cycle validated +0.5 0 c

Validation records stored archives A 105 - 11

Revalidation records stored in archives

C314-70

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• Evaluation of Ophthalmic product

Sterility Clarity testLeakage testpH ViscosityIrritancy test Endotoxin test

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• Evaluation of Parenteral product

Leakage test Content uniformity testColor and clarityEndotoxin testPyrogen test Sterility test

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Example of Process validation protocol

Contents

1. Protocol Approval2. Objective3. Scope4. Validation Approach5. Document Required 6. List of Equipments7. Product Detailed8. Parameter to be tested9. Sampling plan10. Acceptance Criteria

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1. Protocol Approval

• Protocol effective date:

• 2. Objective• 3. Scope• 4. Validation approach

• Prepared by Checked by

Name Designation signaturePrepared by

Checked by

Rechecked by

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5. Document required

6. List of equipments

Prepared by Checked by

Document Effective Date Ref. No.BMR

BPR

Test data sheet

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7.Product detailed• Generic name:• Brand name:• Product description:• Dosage form:• Labeled claim:• Category:• Composition with specification:

Prepared by Checked by

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8. Parameters to be tested

Process stage Process variable Validation response

1) Mixing a) Mixing timeb) Mixing ratec) Mixing temp.

→By assay→Consistency Test

2) Filling a) Filling rateb) Speed

→Weight variation→Sealing temp.→Pressure, Crimping→Coding.

Prepared by Checked by

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. 9. Sampling plan

Prepared by Checked by

Process Stage No. of sample taken

Qty Test

1) Mixing 2 30 gm from each location

Qty of sample taken

Test

2) Filling Equivalent to no of filling station

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10. Acceptance criteria

Prepared by Checked by

Stage Tests Acceptance Criteria1) Mixing Assay of ingredients

Consistency test Spread smoothly & homogeneously

2) Filling FOR 15 gmWt of empty tubeWt of filled tubeNet content

Crimping CodingSealing Sealing temp.Air trappingPressure Assay of ingredients

LegibleStraight & SmoothComplete & Leak proof280°C – 300°CFree from air bubble3.5 – 4.0 Kg/cm2

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REFERENCE-• http//www.pharmainfo.net/reviews/guidelines-general-

principles-validation-solid-dosage. • Pharmaceutical process validation ( In International third

edition ) edited by Robert A. NASH Printed and bound by Replika press pvt.Ltd.india • Validation of pharmaceutical process (third edition ) edited by James Agallow ,2008 by informa health care USA

INC • Apps.who.int./print/en/p/docf/WHO Pharmacopoeia • www.ncbi.nlm.nih.gov/pmc/articules/pmc 35355108• www.usp.org/site/defeult/files/usp-pdf/topical and transdermal

.pdf

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