VALIDATION OF

SEMISOLIDS
Guided by: Dr. Tejal Mehta
Prepared by : Dhara Patel
14mph103
 Validation of Semisolids
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 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 Team: Production, QC,
QA, Engineer, Planner
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Verify the
To prepare the calibration and Schedule the
Verify change
validation maintenance validation
control
protocol status of activities
equipment

Monitor the Assure that the

Training
Conduct critical steps in approved testing
production
validation study manufacturing standard is
operators
process being used

Evaluate all test Prepare the

results, validation report.
 Pre-validation Requirements :
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 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 Protocol
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 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.
 Validation Protocol should
contain:
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 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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The commercial scale pre-validation trials may be evaluated for identification

of critical manufacturing steps, determination of critical process parameters

Equipment Critical Critical Manufacturing

Process Parameter: Step
Mixing Speed
Dissolving Step
Homogenizing Speed
Mixing Time Melting Step
Heating / Cooling Time
Homogenizing Step
Pumping Speed (Flow Rate)
 Critical Parameters – Semi-
Solids
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Critical Steps Critical Parameters

Mixing Mixing time

Mixing speed

Mixing volume (Batch Size)

Homogenizing Homogenizing Time

Homogenizing Speed
 Critical Processing Parameter
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 Mixing
Speed
 Mixing Time
 Heating
Time
 Cooling  Homogenizing
Time Speed
 Pumping  Homogenizing
Speed Time
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Preparing Internal and External phase

Mixing two phase together

Homogenizing

Final Mixing
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Preparing internal and External phase Clear Solution

Mixing two phase together Homogeneity of product

Homogenizing Appearances, Texture

Final Mixing pH, Vicosmeter,

Appearance, Assay
Content
 Equipment Critical Process
Parameter
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Mixing Speed

Homogenizing Speed

Mixing Time

Heating / Cooling Time

Pumping Speed (Flow Rate)

Vacuum
 Critical Manufacturing Step
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 Number of Validation Trials
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 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 Testing
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 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:
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 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 Monitoring
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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
Testing
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 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.
 Qualification of Maximum Bulk Hold
Time
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 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 Testing
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Net 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 Uniformity

Other Testing
• Assay, pH, Viscosity, Preservative Content etc.
 Sampling
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Samples must be representative of each filling nozzle

For single filling Multiple Tanks and

Multiple filling size Other pattern
size Multiple filling size

• Take a minimum • Ten equidistant

of 3 fill containers • Take 10 samples points across the
from each of the each at the filling run must be
beginning, middle • Take 3 samples beginning and samples.
and end of the each at the end of the filling • The beginning
filling run. The beginning and tank and take 10 and end of filling
total number of end of the filling samples each at must be
samples must be size the beginning and represented.
not less than 10. end of the filling Samples should
All samples must size. be taken in
be tested triplicate
 Filled Product: Content Uniformity
(Semi-Solids)
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Product Acceptance Criteria

Sampling Plan
parameters ( n= 10)

UPL & LPL within 90 - 3 – 4 units from

110% LA beginning, middle and
Content uniformity
end of filling cycles;
total = 10 units
RSD ≤ 4.2%

The average result of 10 individual results must meet the release limit
for assay
 Changes and Revalidation
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Formula
Composition

Raw material
Batch Size
Source
Change of any
of the following
may need
revalidation Manufacturing
Equipment
Process

Manufacturing
Location
 Changes
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Minor: Intermediate : Major :

• It seems to have • It could have • It is likely to

no impact on significant have significant
formulation impact on impact on
• It is not formulation formulation
necessary to • Depend on • Revalidation is
validate case-by-case (A required (A
minimum of 1 minimum of 3
trial) trials)
 1. Minor Change
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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 Changes
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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
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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 Report
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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
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 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
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