validation of semisolids
TRANSCRIPT
VALIDATION OF
SEMISOLIDSGuided by: Dr. Tejal Mehta
Prepared by : Dhara Patel
14mph103
Validation of Semisolids
Semisolids:
A pharmaceutical dosage form category that includes ointments, cream emulsions, pastes, gels, and rigid foams. Their common property is the ability to cling to the surface of application for reasonable duration before they are washed or worn off. The adhesion is due to plastic rheologic behavior, which allows the semisolid to retain shape and cling as a film until acted upon by an outside force, in which case it will deform and flow.
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Validation Team: Production, QC,
QA, Engineer, Planner3
To prepare the validation protocol
Verify the calibration and maintenance
status of equipment
Verify change control
Schedule the validation activities
Training production operators
Conduct validation study
Monitor the critical steps in manufacturing
process
Assure that the approved testing
standard is being used
Evaluate all test results,
Prepare the validation report.
Pre-validation Requirements : Cleaning Validation
Preventive Maintenance for Facilities and Utilities
Calibration of Equipment
Equipment Qualification
Raw Materials/Components/Test Methods
Process Justification
Documentation
Change Control
Training operators
All must be proven suitable and reliable for the manufacturing process before the process can be validated
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Validation Protocol
A document stating how validation will be
conducted, including test parameters, product
characteristics, production equipment to be
used and decision points on what constitutes
acceptable test results.
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Validation Protocol should
contain: Title Page, Review/Approval Page
Purpose and Overview*
Equipment List
Ingredients and Component List
Process Flow Diagram and Description*
Equipment Critical Process Parameter
Process Validation Sampling Plan/Testing Requirements*
Acceptance Criteria*
Stability Requirements
Process for evaluation of any deviations occurring during validation
* Minimum requirements
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Equipment Critical Process Parameter:
Mixing Speed
Homogenizing Speed
Mixing Time
Heating / Cooling Time
Pumping Speed (Flow Rate)
Critical Manufacturing Step
Dissolving Step
Melting Step
Homogenizing Step
The commercial scale pre-validation trials may be evaluated for identification
of critical manufacturing steps, determination of critical process parameters
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Critical Parameters – Semi-
Solids
Critical Steps Critical Parameters
Mixing Mixing time
Mixing speed
Mixing volume (Batch Size)
Homogenizing Homogenizing Time
Homogenizing Speed
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Critical Processing Parameter
Mixing Speed
Mixing Time
Heating Time
Cooling Time
Pumping Speed
Homogenizing Speed
Homogenizing Time
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Preparing Internal and External phase
Mixing two phase together
Homogenizing
Final Mixing
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Final Mixing
Homogenizing
Mixing two phase together
Preparing internal and External phase Clear Solution
Homogeneity of product
Appearances, Texture
pH, Vicosmeter,
Appearance, Assay Content
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Equipment Critical Process
Parameter12
Mixing Speed
Homogenizing Speed
Mixing Time
Heating / Cooling Time
Pumping Speed (Flow Rate)
Vacuum
Critical Manufacturing Step13
Number of Validation Trials14
For New Product, Product Transfer
Generally at least three consecutive successful
batches at commercial scale are required
For Revalidation as a result of change control,
the number of trials to be determined by
validation team.
Product Testing15
Validation testing of bulk and F/G must be
based on testing standard release criteria and
in-process testing criteria
Routine QC release testing should be
performed on a routine sample. These
samples should be taken separately from the
validation samples
Validation Batch:16
New products and product transfer, Prospective validation is required
Manufacturing Process, Formula, Equipment and Batch Size have to be fixed during the validation trials.
Batch Size should be the same size as commercial production batch
The batch size must be fixed for production. However, it can be changed up to 10% with the on-going study by using the same equipment.
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Different lots but same manufacturer of active ingredients should be used during validation trials
At least 2 portions of this bulk quantity must be filled in to 2 batches of any size container. The portions should be from different bulk trials.
1 entire bulk should filled in to 1 batch of the smallest container size to demonstrate the largest filling run time.
The validation study should include the smallest and largest size of the same type of filled container.
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Raw materials, in-process product and finished product must pass all in process and testing standard release requirements.
Cleaning procedure for all relevant equipment must be evaluated for cleaning validation.
Product may not be released to the market until the validation report is approved and issued.
In-process Monitoring19
Record temperature of melted ingredients, mixtures, incoming liquids and final product, and rates of heating or cooling for comparison
against the product development batch information.
Record critical processing parameters for pumping, mixing, comminution and transfer of the product.
Check the product for foaming, presence of unusual lumps, or discoloration. Determine if there is any residue in the tanks after
emptying. Examine the filters and screens for unmixed or undissolved material.
Validation Batch: Bulk Sampling and
Testing20
Take 10 samples from the mixer, tank, or during product transfer to the storage/filling vessels. The samples must represent the top, middle and bottom of the vessel.
If sampling from the mixer/tank using an specific equipment, samples should be taken immediately adjacent to blades, baffles, and shafts where product movement during mixing may restricted.
The bottom of the tank and any potential dead spots should be sampled and examined for unmixed or undissolvedmaterial, if possible.
Qualification of Maximum Bulk Hold
Time21
The maximum period of time which the bulk can be held prior to fill
One full scale bulk batch should be held for most practical maximum time period prior to filling.
If there is not enough support information / qualification done. The period of 24 hours will be used.
Hold time qualification must simulate actual in-process conditions and handling.
The qualified hold time used in routine production must be specified in the manufacturing batch record.
Finish Product Testing22
• Perform testing on filled containers across the filling run.
• Perform testing per testing standard
Net Contents
• Samples from each of the beginning and end of the filling run and perform testing per Testing Standard
• Preservative Efficacy testing should be tested.
Microbiology
Content Uniformity
• Assay, pH, Viscosity, Preservative Content etc.
Other Testing
Sampling23
For single filling size
• Take a minimum of 3 fill containers from each of the beginning, middle and end of the filling run. The total number of samples must be not less than 10. All samples must be tested
Multiple filling size
• Take 3 samples each at the beginning and end of the filling size
Multiple Tanks and Multiple filling size
• Take 10 samples each at the beginning and end of the filling tank and take 10 samples each at the beginning and end of the filling size.
Other pattern
• Ten equidistant points across the filling run must be samples.
• The beginning and end of filling must be represented. Samples should be taken in triplicate
Samples must be representative of each filling nozzle
Filled Product: Content Uniformity
(Semi-Solids)24
Product
parameters
Acceptance Criteria
( n= 10)Sampling Plan
Content uniformity
UPL & LPL within 90 -
110% LA3 – 4 units from
beginning, middle and
end of filling cycles;
total = 10 unitsRSD ≤ 4.2%
The average result of 10 individual results must meet the release limit
for assay
Changes and Revalidation25
Change of any of the following
may need revalidation
Formula Composition
Raw material Source
Manufacturing Process
Manufacturing Location
Equipment
Batch Size
Changes26
Minor:
• It seems to have no impact on formulation
• It is not necessary to validate
Intermediate :
• It could have significant impact on formulation
• Depend on case-by-case (A minimum of 1 trial)
Major :
• It is likely to have significant impact on formulation
• Revalidation is required (A minimum of 3 trials)
1. Minor Change27
Delete or Decrease quantity of colorant, flavor
Qualitative inactive excepients change deemed minor by change control review
Process change deemed minor by change control review such as change in order of addition
Change in batch size of ≤ 10% using the same equipment
Manufacturing location change with in same building, same equipment, personnel, procedure and utilities are used
Equipment change but same design, configuration
2. Intermediate Changes28
Active ingredient source or synthesis change deemed intermediate by change control review
Qualitative inactive excepients change deemed intermediate by change control review
Change in formulation overage / excess (filling or stability)
Change in batch size 10% < batch size ≤ 100% using the same equipment
Manufacturing location change to a different building on the same site and same utilities, same equipment, personnel, and procedure are used
Process changes deemed intermediate by change control review, such as mixing times or operating ranges outside of previously validated capacity
Extension of the qualified in process hold time for intermediate or finished product prior to packaging
Equipment change deemed intermediate by change control review
3. Major Changes 29
Quantitative or qualitative formulation change deemed major by change control review
Inactive excipient or active ingredient source change deemed major by change control review
Transfer product from on site to another
Significant change in process
Change in batch size > 100%
Rework procedure
New dosage
Equipment change to a different design, configuration or operating principle.
Validation Report30
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.
Conclusion 31
Process must be continually monitored and
change control used to identify need for process
revalidation
Validation Protocol identifies critical process
parameters to be evaluated and predetermined
acceptance criteria
Production and QA have to review and approve
the validation result
Product must be held until the validation get
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