Download - 2.Pv Semisolid FDA
Process ValidationProcess Validationof of
SemisolidsSemisolids
ByBy
Weerayut ChirarutsamiWeerayut Chirarutsami
23/8/2006
Validation of SemisolidsValidation 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
Validation of SemisolidsValidation of Semisolids
Validation Team: Production, QC, QA, Engineer,PlannerTo 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.
Validation of SemisolidsValidation of SemisolidsPre-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
Validation of SemisolidsValidation of Semisolids
Validation Protocol
A document stating how validation will be conducted,including test parameters, product characteristics,production equipment to be used and decision points on w h a t c o n s t i t u t e s a c c e p t a b l e t e s t r e s u l t s
Validation of SemisolidsValidation of Semisolids
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
Validation of SemisolidsValidation of Semisolids
The commercial scale pre-validation trials may be evaluated for identification of critical manufacturing steps, determination of critical process parameters
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
Homogenizing
Critical ParametersCritical Steps
Homogenizing speed
Homogenizing time
Mixing time
MixingMixing volume (batch size)
Mixing speed
Critical Parameters Critical Parameters –– SemiSemi--SolidsSolids
Critical Processing Parameter
•Mixing Speed
•Mixing Time
•Heating Time
•Cooling Time
•Pumping Speed
•Homogenizing Speed
•Homogenizing Time
Critical Processing Steps
Preparing Internal and External Phase
Homogenizing
Final Mixing
Mixing two phase together
Acceptance Criteria
Prepare Internal & External Phase
Homogenizing
Final Mixing
Mixing
Clear Solution
Homogeneity of product
Appearances, Texture
pH, Vicosmeter,Appearance, Assay Content
Equipment Critical Process ParameterEquipment Critical Process Parameter::Mixing SpeedHomogenizing SpeedMixing TimeHeating / Cooling TimePumping Speed (Flow Rate)Vacuum
Critical Manufacturing StepCritical Manufacturing StepDissolving StepMelting StepHomogenizing StepVacuum Step
Validation of SemisolidsValidation of Semisolids
Number of Validation Trials
For New Product, Product TransferGenerally 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
Validation of SemisolidsValidation of Semisolids
Product Testing
– 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 of SemisolidsValidation of Semisolids
Validation Batch:– 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.
Validation of SemisolidsValidation of Semisolids
Validation Batch:ContinuedDifferent 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 2batches 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
Validation of SemisolidsValidation of Semisolids
Validation Batch:(Continued)– 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
Validation of SemisolidsValidation of Semisolids
In-process MonitoringRecord 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 of SemisolidsValidation of Semisolids
Validation Batch: Bulk Sampling and Testing
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 undissolved material, if possible
Sampling Plan &Sampling Plan &Acceptance CriteriaAcceptance Criteria
For bulk in mixing, storage or holding tank; * Prod Specs = 90 – 110 % LA; LPL & UPL = Lower & Upper Prediction Limits
UPL & LPL within 90 – 110% LA *
RSD ≤ 3.6% (n=6) or 4.2% (n=10)
Take samples from 2 – 3 levels to get 6 – 10 samples depending on batch size/mixer design
Bulk Homogeneity
Sampling PlanAcceptance Criteria
Product Parameters
Establishing Bulk Homogeneity Establishing Bulk Homogeneity Acceptance Criteria: SemiAcceptance Criteria: Semi--SolidsSolids
RSD Limits for Bulk SamplesRSD Limits for Bulk Samples(Semi(Semi--Solids)Solids)
RSD Limits for Bulk SamplesRSD Limits for Bulk Samples(Semi(Semi--Solids)Solids)
Validation of SemisolidsValidation of Semisolids
Qualification of Maximum Bulk Hold Time– 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 TestingNet Contents
Perform testing on filled containers across the filling run. Perform testing per testing standard
Microbiology Samples from each of the beginning and end of the filling run and perform testing per Testing Standard Preservative Efficacy testing should be tested.
Content UniformityOther Testing
Assay, pH, Viscosity, Preservative Content etc.
Validation of SemisolidsValidation of Semisolids
Validation of SemisolidsValidation of Semisolids
• Sampling– Samples must be representative of each filling nozzle
• 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 fillingsize.
Validation of SemisolidsValidation of Semisolids
• Sampling
– 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
Filled Product: Content UniformityFilled Product: Content Uniformity(Semi(Semi--SolidsSolids))
•The average result of 10 individual results must meet the release limit for assay
UPL & LPL within 90 – 110% LA *
RSD ≤ 4.2%
3 – 4 units from beginning, middle and end of filling cycle; total = 10 units
Content Uniformity
Sampling PlanAcceptance
Criteria(n = 10)
Product Parameters
Validation of SemisolidsValidation of Semisolids
• Changes and Revalidation– Change of any of the following may need
revalidation
• Formula Composition
• Raw material Source
• Manufacturing Process
• Manufacturing Location
• Equipment
• Batch Size
Validation of SemisolidsValidation of Semisolids
• Changes– 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)
Validation of SemisolidsValidation of Semisolids
• Minor Change• Delete or Decrease quantity of colorant, flavor
• Qualitative inactive excipient 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
Validation of SemisolidsValidation of Semisolids
• Intermediate Changes• Active ingredient source or synthesis change deemed
intermediate by change control review
• Qualitative inactive excipient 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
Validation of SemisolidsValidation of Semisolids
• Intermediate Change• 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
Validation of SemisolidsValidation of Semisolids
• Major Changes• 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%
Validation of SemisolidsValidation of Semisolids
• Major Change• Rework procedure
• New dosage
• Equipment change to a different design, configuration or
operating principle.
Validation of SemisolidsValidation of Semisolids• 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.
Validation of SemisolidsValidation of Semisolids
• ConclusionProcess 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 approval