Process Validation

of
Semisolids

By

Weerayut Chirarutsami

23/8/2006
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
Validation of Semisolids

Validation Team: Production, QC, QA, Engineer,Planner

# 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.
Validation of Semisolids
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
Validation 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
what constitutes acceptable test results
 Validation 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 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
 Critical Parameters Semi-Solids

Critical Steps Critical Parameters

Mixing time
Mixing speed
Mixing
Mixing volume (batch
size)
Homogenizing time
Homogenizing
Homogenizing speed
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

Mixing two phase together

Homogenizing

Final Mixing
Acceptance Criteria

Prepare Internal & External Phase Clear Solution

Mixing Homogeneity of product

Homogenizing Appearances, Texture

Final Mixing pH, Vicosmeter,

Appearance, Assay
Content
Equipment Critical Process Parameter:
Mixing Speed
Homogenizing Speed
Mixing Time
Heating / Cooling Time
Pumping Speed (Flow Rate)
Vacuum
Critical Manufacturing Step
Dissolving Step
Melting Step
Homogenizing Step
Vacuum Step
Validation of Semisolids

Number of Validation Trials

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
 Validation 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 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 Semisolids

Validation Batch:Continued
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
Validation 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 Semisolids

In-process Monitoring
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 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 &
Acceptance Criteria
 Establishing Bulk Homogeneity
Acceptance Criteria: Semi-Solids

Product Acceptance
Sampling Plan
Parameters Criteria
UPL & LPL within
Take samples from
90 110% LA *
2 3 levels to get 6
Bulk
RSD 3.6% 10 samples
Homogeneity
(n=6) or 4.2% depending on batch
(n=10) size/mixer design
For bulk in mixing, storage or holding tank; * Prod Specs =
90 110 % LA; LPL & UPL = Lower & Upper Prediction
Limits
RSD Limits for Bulk Samples
(Semi-Solids)
RSD Limits for Bulk Samples
(Semi-Solids)
Validation 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
 Validation of Semisolids

Finish Product Testing

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.
Validation 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 filling
size.
Validation 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 Uniformity
(Semi-Solids)

Acceptance
Product Criteria Sampling Plan
Parameters
(n = 10)
UPL & LPL within 90
3 4 units from
110% LA *
beginning,
Content
middle and end
Uniformity
RSD 4.2% of filling cycle;
total = 10 units

The average result of 10 individual results must meet the

release limit for assay
Validation 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 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 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 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 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 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 Semisolids

Major Change
Rework procedure

New dosage

Equipment change to a different design, configuration or

operating principle.
Validation 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 Semisolids
Conclusion
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
approval