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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