Validation of different liquid dosage forms

1. “Validation of liquids”“Validation of liquids”

2.  DEFINATION OF VALIDATION:-
-According to WHO validation is defied as-
“It is a documented program which provides a high degree of
assurance that a specific process will consistently produce a
product, meeting its pre-determined specifications and quality
attributes”.attributes”.
-The predominant use of this term is with reference to
manufacturing operations and direct supporting systems
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3. -Validation of manufacturing
processes for liquids refers as
Process validation which begins
with the batching of approved raw
materials to the storage and
shipping of the packed material.
-Process validation starts only after
the complete qualification
program (D.Q., I.Q., O.Q., and P.Q.)
of facilities and equipment is over.
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4. Why Process Validation?
1)To conform Manufacturing to cGMP
regulations.
2)To avoid the possibility of rejected2)To avoid the possibility of rejected
or recalled batches.
3)To ensure the product uniformity and
quality.
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5. Types of Process Validation
expected or expecting to be existing, happening, or
the specified thing in future done at the same time
Prospective Concurrent
repetition of a validation process looking back on or dealing with
the past situations
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Revalidation Retrospective

6. Objectives for Process Validation
1)Assurance of quality of the product.
2) Reduces variation between various batches.
3) Improve employee awareness for processes.
4) Easier maintenance of equipment.
5) Easier scale-up from development work.
6)More rapid and reliable start-up of new
equipment.
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7. 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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8. -Liquid dosage form can be administered,
1)Topically 2)Orally
3)Parentrally
Validation of Liquids 8

9. Classification of liquid orals
Monophasic Biphasic
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Solutions
Lectures
Elixir
Syrups
Liquid drops
ASSuspension
Emulsion

10. Process Description for liquid
ProductionProduction
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11. Manufacturing of Monophasic Liquids
Process Flow
Addition of Raw
materials & active
Ingredients
Control
Variables
Mixing time
Measured
Responses
Clarity
4/9/2018 Validation of Liquids 11
Mixing
Filtration
Filling
Mixing time
RPM
Temperature
Final Volume
Mesh size &
Filter
integrity
Filling
Machine
speed
Clarity
Viscosity
Assay
Clarity
Volume

12. Manufacturing of Biphasic system
Continuous
PhaseWater
Preservative
Surfactant Dispersed Phase
For
Suspension
For
Emulsion
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Mixing
Aqueous
Solution
Suspension Emulsion
Milled
Drug
Drug
solution in
Oil

13. Continuous
Phase
Dispersed
Phase
Crude Dispersion
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Fine Dispersion
pH
adjustment
Other
additives
Homogenization
and Volume
adjustment

14. Validation of Liquids
1. Equipment
2. Raw materials
3. Compounding
4. Microbiological quality4. Microbiological quality
5. Oral suspension uniformity
6. Product specifications
7. Stability
8. Packaging
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15. Qualification of Process EquipmentQualification of Process Equipment
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16. 1) Syrup & Suspension Manufacturing Vessel
Perform Installation qualification
Perform general operational controls verification test
Operate system throughout the range of operating design
specifications of mixing speed, temperature, and vacuum or the
range of intendedrange of intended
Verify weather all the safety devices of vessel are
operating as specified in manual
Verify that all recommended lubricants are being used during
the operation or not
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17. Verify that all the lubricants(like Oil and Grease) are kept in
clean, sealed containers so that moisture and dust can not
penetrate
Perform controller safety challenges to verify that the parameters
can not be altered without appropriate supervisory control
Assay the final mixture to check content uniformity of product
as per SOPs
Perform Particle size distribution & ReSuspendibility test for
final blend as per SOP[ For Suspensions]
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18. Acceptance Criteria:-
1)System should be installed as per the design specifications
2)General controls and alarms must operate with design
specifications
3)System should operate in accordance with design specification
throughout the operating range.
4)Recommended lubricants must be used as specified
5)Storage of lubricants must be according to manufacturer5)Storage of lubricants must be according to manufacturer
recommendation
6)Unauthorized changes to cycle parameters must not be allowed
without supervisory control or password.
7)Assay result must meet specifications
8)ReSuspendibility and particle size distribution must meet
specifications[For suspensions]
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19. 2) Mixer
Perform Installation Qualification
Perform general operational controls verification test
Operate system throughout the range of mixing speed or
range of intended userange of intended use
Verify weather all safety devices of mixture are operating as
specified in the manual
Verify that all recommended lubricants are being used during
operation or not
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20. Verify that all lubricants such as oil and grease are kept in clean,
sealed containers so that dust and moisture cant penetrate
Perform controller security challenges to verify that specified
parameters can not be altered without appropriate supervisory
controlcontrol
Assay the mixed blend to check content uniformity of product as
per SOPs
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21. Acceptance Criteria:-
1)System should be installed as per the design specifications
2) Instruments are calibrated, Identified and entered into
calibration program.
3)General controls and alarms must operate with design
specifications
4)System should operate in accordance with design4)System should operate in accordance with design
specification throughout the operating range.
5)Recommended lubricants must be used as specified
6)Storage of lubricants must be according to manufacturer
recommendation
7)Unauthorized changes to cycle parameters must not be allowed
without supervisory control or password.
8)Assay result must meet specifications
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22. 3) Emulsifying Mixture
Perform Installation Qualification
Verify equipment identification, required documents, utilities,
components materials, drawings and manuals
Perform general operational controls verification testPerform general operational controls verification test
Operate system throughout the range of operating design
specifications or range of intended use at fixed speed.
Verify the switches and push pull buttons, rotator direction and
motor variable speed
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23. Verify weather all safety devices of emulsifying mixture are
operating as specified in the manual
Verify that all recommended lubricants are being used during
operation or not
Verify that all lubricants such as oil and grease are kept in clean,
sealed containers so that dust and moisture cant penetratesealed containers so that dust and moisture cant penetrate
Perform controller security challenges to verify that specified
parameters can not be altered without appropriate supervisory
control
Perform globule size assay to check the uniformity of
emulsification of product as per SOPs
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24. Acceptance Criteria:-
1)System should be installed as per the design specifications
2) Instruments are calibrated, Identified and entered into
calibration program.
3)General controls and alarms must operate with design
specifications
4)System should operate in accordance with design
specification throughout the operating range.specification throughout the operating range.
5)Recommended lubricants must be used as specified
6)Storage of lubricants must be according to manufacturer
recommendation
7)Unauthorized changes to cycle parameters must not be allowed
without supervisory control or password.
8)Assay result must meet specifications
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25. 4) Filter Press
Perform Installation Qualification
Perform general operational controls verification test
Operate system throughout the range of mixing speed or
range of intended userange of intended use
Verify weather all safety devices of filter press are
operating as specified in the manual
Verify that all recommended lubricants are being used
during operation or not
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26. Verify that all lubricants such as oil and grease are kept in clean,
sealed containers so that dust and moisture cant penetrate
Perform controller security challenges to verify that specified
parameters can not be altered without appropriate supervisory
control
Perform visual inspection under magnification to check the
clarity of each product as per SOP
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27. Acceptance Criteria:-
1)System should be installed as per the design specifications
2) Instruments are calibrated, Identified and entered into
calibration program.
3)General controls and alarms must operate with design
specifications
4)System should operate in accordance with design4)System should operate in accordance with design
specification throughout the operating range.
5)Recommended lubricants must be used as specified
6)Storage of lubricants must be according to manufacturer
recommendation
7)Unauthorized changes to cycle parameters must not be allowed
without supervisory control or password.
8)Visual Inspection results must meet product specifications
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28. 5) Syrup and Suspension filling Machine
Perform Installation Qualification
Perform general operational controls verification test
Operate system throughout the range of mixing speed
or range of intended useor range of intended use
Verify weather all safety devices of vessel are operating as
specified in the manual
Verify that all recommended lubricants are being used
during operation or not
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29. Verify that all lubricants such as oil and grease are kept in clean,
sealed containers so that dust and moisture cant penetrate
Perform controller security challenges to verify that specified
parameters can not be altered without appropriate supervisory
control
Perform capability studies to check the volume of variation on
each size of product as per SOP
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30. Acceptance Criteria:-
1)System should be installed as per the design specifications
2) Instruments are calibrated, Identified and entered into
calibration program.
3)General controls and alarms must operate with design
specifications
4)System should operate in accordance with design
specification throughout the operating range.specification throughout the operating range.
5)Recommended lubricants must be used as specified
6)Storage of lubricants must be according to manufacturer
recommendation
7)Unauthorized changes to cycle parameters must not be allowed
without supervisory control or password.
8)The machine must be in stastical control as per capability study
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31. 6)Labelling Machine
Perform Installation qualification
Perform general operational controls verification test
Operate system throughout the range of operating design
specifications of mixing speed, temperature, and vacuumspecifications of mixing speed, temperature, and vacuum
or the range of intended
Verify weather all the safety devices of labeling machine
are operating as specified in manual
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32. Perform controller safety challenges to verify that the
parameters can not be altered without appropriate
supervisory control
Perform Inspection to check labeling on each product
as per SOPas per SOP
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33. Acceptance Criteria:-
1)System should be installed as per the design specifications
2)General controls and alarms must operate with design
specifications
3)System should operate in accordance with design3)System should operate in accordance with design
specification throughout the operating range.
4)Unauthorized changes to cycle parameters must not be
allowed without supervisory control or password.
5)The labeling is performed in accordance with the acceptance
criteria
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34. Number of Validation Trials
-For New Product, Product Transfer or
Having Major Changes generally at least
three consecutive successful batches are
required:
1) One Right = Accident
2) Two Right = Coincidence2) Two Right = Coincidence
3) Three Right = Validated
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35. Sampling for Validation
 For Solution, take at least 2 samples at
top and bottom of the bulk
 For Suspension, take at least 2 samples
at top, Middle and Bottom of the bulk
 Finished Product Testing (Net content,
Microbiology, Content Uniformity)
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36. Operations in Process Validation
I)Raw material validation
1.Particle size and size distribution
2.Particle shape or morphology
3.Microbial count
4.pH of the solvent or vehicle
II)Monitoring outputs
1.Appearance
2.pH value and Viscosity
3.Microbial count
4.Content uniformity
5.Dissolution testing
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37. III)Filling and Packaging Operation Validation
1. Leakage test for filled bottle
2. Cap sealing test
3. Fill volume determination
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38. Critical Parameters
Equipment Mixing Speed
Homogenizing Speed
Mixing Time
Heating/cooling time
Flow Rate
Manufacturing Dissolving step
Melting step
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Melting step
Homogenizing Step
Processing Mixing speed
Mixing Time
Cooling Time
Homogenizing Speed
Homogenizing Time

39. Acceptance Criteria
Dissolved Active Ingredients Clear solution
Filtration No residue on paper
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pH adjustment pH within specifications
Final Mixing pH, viscometer, appearance,
assay content

40. TEST PARAMETERS FOR SUSPENSIONS AND
EMULSIONS
Test Parameters Suspension Emulsion
Appearance √ √
Viscosity √ √
pH √ √
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pH √ √
Content uniformity √ √
Sedimentation Volume √ ˟
ReSuspendibility √ ˟
Particle Size √ √

41. VALIDATION REPORT
-Validation Team must prepare the report
-Report must be reviewed and approved by QA.
-Written Notification or either successful completion or failure of-Written Notification or either successful completion or failure of
the process validation must be issued to top management.
-In case of failure, an investigation must be completed and
documented prior to repeat the validation study.
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42. Changes and Revalidation
-Change of any of the following may need revalidation
1. Formula Composition
2. Raw Material Source
3. Manufacturing Process
4. Manufacturing Location
5. Equipments5. Equipments
6. Batch Size
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43. Applications Of Validation
1) Manufacturing process control (raw material)
2) Pre-formulation evaluation
3) Stability studies3) Stability studies
4) Environmental control/checks
5) Cleaning controls (contamination)
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44. References…
1) Pharmaceutical Master Validation Plan-The ultimate guide to
FDA,GMP and GLP compliance by syed Imtiaz Haidar, First Indian
reprinted Edition-2006
2) Validation in Pharmaceutical Industry-concepts, approaches &
guidelines by P.P.Sharma, First edition-2007,Vandana
Publications; Delhi.
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