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 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 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 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


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


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


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 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 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 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


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 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)


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.



• 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.


• 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


• Changes and Revalidation– Change of any of the following may need

revalidation

• Formula Composition

• Raw material Source

• Manufacturing Process

• Manufacturing Location

• Equipment

• Batch Size


• 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)


• 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


• 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


• 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


• 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%


• 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.


• 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

2.pv semisolid fda

Documents

manufacturing process

validation activities

validation report

stability requirements

semisolidsvalidation

e t e s t r e s u

production equipment

t c o n s t i t u t