pharmaceutical product validation

1. PRODUCT VALIDATION
SUBMITTED BY
V.SUHASINI
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2. 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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3. 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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4. • 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 operation
5. Examining test procedures themselves to ensure their
accuracy and reliability.
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5. 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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6. 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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7. VALIDATION OF EXCIPIENTS
Excipients 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 variability
Example :
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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8. 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 components
Repeatability:( 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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9. 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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10. Validation of finished product
• Organoleptic characteristic
• Physical characteristic
• Chemical characteristic
• Biological characteristic
• Microbiological characteristic
• Stability testing
• Storage condition
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11. Validation of tablets
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12. 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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13. 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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14. 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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15. Validation of capsules
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16. TEST
PHYSICAL TEST CHEMICAL TEST
 Disintegration test
 Weight variation
Dissolution test
Assay
Content uniformity
Stability testing
Moisture permeation test
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18. • 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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19. Major test parameters used for final product testing
Appearance
pH
Viscosity
Specific gravity
Microbial count
Leakage test for filled bottle (By plastic vacuum dessicator)
Check the cap sealing
Fill volume determination
Particulate matter testing
Water vapour permeability test
Stress test
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20. 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
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21. Semisolid
Dosage Form

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23. 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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24. • Evaluation of gel
Visual appearance
Drug content
Measurement of pH
Viscosity
Spreadability
Extrudability
Stability
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25. • Evaluation of paste
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Abrasiveness
Particle size
Cleansing property
Consistency
pH of the product
Foaming character
Limit test for arsenic and lead
Volatile matters and moisture

26. • Evaluation of Transdermal patches
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Physiochemical evaluation
Thickness of the patch
Folding endurance
Percentage of moisture absorbed
Percentage of moisture lost
Drug content uniformity
 skin irritation test
Stability test

27. • Evaluation of suppositories
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 Appearance
 Uniformity of weight test
 Melting rang test
 Breaking test
 Dissolution test

28. • Evaluation of Aerosols
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Leakage test
Internal pressure
Spray pattern
Discharge rate
Flammability
Particle size analysis
Moisture determination

29. 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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30. 1. Written documentation
2. Manufacturing parameters
3. Testing parameters
4. In process controls
5. 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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31. • Steam sterilization process summary sheet
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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 +0.50 c
Validation records stored archives A 105 - 11
Revalidation records stored in
archives
C314-70

32. • Evaluation of Ophthalmic product
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Sterility
Clarity test
Leakage test
pH
Viscosity
Irritancy test
Endotoxin test

33. • Evaluation of Parenteral product
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Leakage test
Content uniformity test
Color and clarity
Endotoxin test
Pyrogen test
Sterility test

34. Example of Process validation
protocol
 Contents
1. Protocol Approval
2. Objective
3. Scope
4. Validation Approach
5. Document Required
6. List of Equipments
7. Product Detailed
8. Parameter to be tested
9. Sampling plan
10. Acceptance Criteria
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35. 1. Protocol Approval
• Protocol effective date:
• 2. Objective
• 3. Scope
• 4. Validation approach
• Prepared by Checked by
Name Designation signature
Prepared by
Checked by
Rechecked by
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36. 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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37. 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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38. 8. Parameters to be tested
Process stage Process variable Validation response
1) Mixing a) Mixing time
b) Mixing rate
c) Mixing temp.
→By assay
→Consistency Test
2) Filling a) Filling rate
b) Speed
→Weight variation
→Sealing temp.
→Pressure, Crimping
→Coding.
Prepared by Checked by
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39. .
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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40. 10. Acceptance criteria
Prepared by Checked by
Stage Tests Acceptance Criteria
1) Mixing Assay of ingredients
Consistency test Spread smoothly &
homogeneously
2) Filling FOR 15 gm
Wt of empty tube
Wt of filled tube
Net content
Crimping
Coding
Sealing
Sealing temp.
Air trapping
Pressure
Assay of ingredients
Legible
Straight & Smooth
Complete & Leak proof
280°C – 300°C
Free from air bubble
3.5 – 4.0 Kg/cm2
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41. 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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