Process Validation of Liquid Orals
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Transcript of Process Validation of Liquid Orals
PROCESS VALIDATION OF LIQUID ORALS Presented By:
Aasawaree Jeevan YadavF.Y.M. Pharmacy (Pharmaceutics)
Guided By:Dr. (Mrs.) Snehalatha Boddu
VALIDATION
Documented program
Pre-determined specifications and quality attributes
WHO - Validation is documented act of providing that any procedure,
process, equipment, material, activity or system actually leads to the
expected results
Aasawaree Jeevan Yadav
SCOPE OF VALIDATION1. Instrument calibration
2. Process utility services (support services)
3. Raw materials and Packaging materials (Stage 1 & 2)
4. Equipment
5. Manufacturing
6. Product design
7. Cleaning
8. Operators (knowledge, skills, attitude)
9. Analytical test methods
i. Accuracyii. Precision
a. Repeatabilityb. Reproducibilityc. Intermediate precision
iii. Linearityiv. Rangev. Limit of detection (LOD)vi. Limit of quantification
(LOQ)vii. Ruggednessviii. Robustness
knowledge
attitude
skills
Aasawaree Jeevan Yadav
1. Manufacturing process control (raw material)2. Pre-formulation evaluation3. Stability studies4. Environmental control/checks5. Cleaning controls (contamination)
APPLICATIONS OF VALIDATION
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PROCESS VALIDATION
Aasawaree Jeevan Yadav
USFDA - establishing documented evidence which provides a
high degree of assurance that a specific process (such as the
manufacture of pharmaceutical dosage forms) will
consistently produce a product meeting its predetermined
specifications and quality characteristics.
Aasawaree Jeevan Yadav
OBJECTIVE OF PROCESS VALIDATION1. Reduces variation between various batches.2. Assurance of quality of the product. 3. Decreases the risk of regulatory noncompliance.4. Ensure the consistency of the manufacturing operation and reproducibility of the process.5. Ensure the existence of all necessary quality assurance system within
organization.6. More rapid and reliable start-up of new equipment.7. Easier scale-up from development work.8. Easier maintenance of equipment.9. Improve employee awareness for processes.
Aasawaree Jeevan Yadav
REASONS FOR PROCESS VALIDATIONChanges in:1. New product or existing products as per
SUPAC (Scale-Up and Post Approval Changes)
2. Site of manufacturing.3. Batch size.4. Equipment.5. Process existing products.6. Composition or components.7. Critical control parameters.8. Vendor of API or critical excipient.
Aasawaree Jeevan Yadav
ADVANTAGES OF PROCESS VALIDATION
1. Simple process 2. Moisture sensitive and heat sensitive products 3. Consistent through output.4. Reduction in rejections and reworks.5. Fewer complaints about process related failure.6. Reduced testing in process and finished goods.7. Easier scale-up from development work.8. Easier maintenance of equipment.9. More rapid and accurate investigations process deviation.10. Increased confidence about process reproducibility and product
quality.11. Improve employee awareness of processes.
Aasawaree Jeevan Yadav
STRATEGY FOR VALIDATION METHODS1. Define the application purpose
and scope of the method2. Define the performance
parameters and acceptance criteria
3. Define validation experiments4. Develop SOPs for executing the
method routinely5. Define criteria for revalidation6. Document validation
experiments and results in the validation report
Aasawaree Jeevan Yadav
STAGES OF PROCESS VALIDATION
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PHASES OF PROCESS VALIDATION
1. Pre-validation Qualification
2. Process Validation
3. Validation Maintenance
Aasawaree Jeevan Yadav
expected or expecting to be thespecified thing in the future
existing, happening, or done at the same time
looking back on or dealing with past events or situations
repetition of a validation process
TYPES OF PROCESS VALIDATION
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PRINCIPLES OF VALIDATION Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)
CRITICAL FACTORS OF PROCESS VALIDATION
1. All the critical point of the process should be clearly identified.2. The process should run using the extremes of the system at the
critical points.3. The quality system should support the validation effort by way of
document control, preventive maintenance, calibration, etc.4. Adequate data are required to provide statistical support to
demonstrate product consistency. Aasawaree Jeevan Yadav
1. Validation Master Plan (VMP)
2. Validation Protocol (VP)
3. Validation Reports (VR)
4. Standard Operating Processes (SOPs)
DOCUMENTATION IN VALIDATION PROCESS
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LIQUID ORALS
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LIQUID DOSAGE FORMS CAN BE ADMINISTERED
1. Topically
2. Orally (per oral)
3. Parenterally (S.C., I.M., I.V.)
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Liquid orals
MonophasicSolutionsLinctuses
ElixirsSyrups
Liquid drops
Biphasic
SuspensionEmulsion
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LIQUID DOSAGE FORMS CAN BE PREPARED1. By dissolving the active drug substance(s) in an aqueous or
nonaqueous (e.g. alcohol, ether, glycerin) solvent
2. By suspending the drug in appropriate medium
3. By incorporating the drug substance into an oil or water phases
Aasawaree Jeevan Yadav
MANUFACTURING OF MONOPHASIC LIQUIDS Process Flow
Mixing
Addition of Raw MaterialsActiveExcipients
Mixing timeRPMTemperatureFinal volume
Measured ResponsesControl Variables
ClarityViscosityAssay
ClarityMesh sizeFilter integrity
Filtration
VolumeFilling machine speedFillingAasawaree Jeevan Yadav
MANUFACTURING OF BIPHASIC LIQUIDS
Water
Continuous Phase
Other helping agents
Mixing
Aqueous solution
Dispersed Phase
For suspension
Preservatives
Surfactants
Drug solution in oil
Grinding of Drug and
other solids
Dissolved drug in oil
For emulsion
Milled drug
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Continuous Phase
Dispersed Phase
Pre-mix or crude Dispersion
Fine Dispersed Delivery System
pH adjustment
Other additives (flavors and coloring agents)
Volume adjustment
Homogenize
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VALIDATION OF
LIQUID ORALSAasawaree Jeevan Yadav
OBJECTIVES OF PROCESS VALIDATION FOR LIQUIDS
To do the process
systematically to assure the
quality of the product
Ensures that the product meet
the predetermined
specifications
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VALIDATION OF LIQUID ORALS1. Equipment
2. Raw materials
3. Compounding
4. Microbiological quality
5. Oral suspension uniformity
6. Product specifications
7. Stability
8. Packaging
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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 = Accident2. Two Right = Coincidence3. Three Right = Validated
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)Aasawaree Jeevan Yadav
CRITICAL PARAMETERS
Equipment
Mixing speedHomogenizing speed
Mixing timeHeating/ cooling time
Flow rate
ManufacturingDissolving step
Melting stepHomogenizing step
Processing
Mixing speedMixing timeCooling time
Homogenizing speedHomogenizing timeAasawaree Jeevan Yadav
ACCEPTANCE CRITERIADissolved
active ingredient
Clear solution
Filtration No residue on filter
pH adjustment pH within specification
Final mixingpH, viscometer,
appearance, assay content
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TEST PARAMETERS FOR SUSPENSIONS AND EMULSIONS
TEST PARAMETER SUSPENSION EMULSION
Appearance √ √
Viscosity √ √
pH √ √
Content uniformity √ √
Sedimentation √ ˟Re-suspendability √ ˟
Particle size √ √
Release rate √ √Aasawaree Jeevan Yadav
OPERATIONS IN PROCESS VALIDATION Raw material validation
1. Particle size and size distribution2. Particle shape or morphology3. Microbial count4. pH of the solvent or vehicle
Monitoring outputs1. Appearance2. pH value and Viscosity3. Microbial count4. Content uniformity5. Dissolution testing
Aasawaree Jeevan Yadav
OPERATIONS IN PROCESS VALIDATION Filling and Packaging
Operation Validation
1. Leakage test for filled
bottle
2. Cap sealing test
3. Fill volume
determination
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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 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.
Aasawaree Jeevan Yadav
CHANGES AND REVALIDATION Change of any of the following may need revalidation
1. Formula Composition2. Raw Material Source3. Manufacturing Process4. Manufacturing Location5. Equipments6. Batch Size
1. Minor2. Intermediate3. Major
CHANGES
Aasawaree Jeevan Yadav
accurate and reliable method of
estimation
quality, identity, strength, purity,
stability, effectiveness and safety
better acceptability of the drug
Aasawaree Jeevan Yadav
Aasawaree Jeevan Yadav