Process Validation of Ointment & Cream

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This is for m.pharm 3rd sem students of quality assurance whome are belonging from GTU. It is combination of various presentation which was previously made by experts..


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Process Validation of ointment/cream:

Process Validation of ointment/cream Prepared By:- Sanket.Patel 3 rd Sem – Q.A


CONTENT Introduction What is ointment & Cream? Semisolid Manufacturing Consideration Number of Validation Trials Product Testing Validation Batch In-process Monitoring Bulk Sampling and Testing Finish Product Testing Sampling Monitoring Output Revalidation Validation report References

Process Validation:

Process Validation Documented evidence, a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specification and quality characteristics.

Types of process validation:

Types of process validation

Who does process validation:

Who does process validation Formulation development Process development Pharmaceutical manufacturing Engineering QA QC API operations Regulatory affairs IT operations

Types of documentation:

Types of documentation Validation Master Plan (VMP) Validation protocols (VP) Validation reports(VR) Standard Operating Procedures (SOPs)


ointment/cream OINTMENT:- Soft, semisolid preparation intended for application to skin and mucus membrane. Appearance: Opaque Type: Oleaginous bases Absorption bases Emulsion bases Water soluble bases CREAM :- Viscous emulsion of semisolid consistency intended for application to skin and mucus membrane. Appearance: Translucent Type: oil-in-water(o/w) water-in-oil(w/o)

Semisolid Manufacturing Consideration:

Semisolid Manufacturing Consideration Flow diagram Unit Operation for semisolid System Mixing of liquid Mixing of solid Mixing of semisolid Dispersing Milling and size reduction of solid and semisolid Filling and Packaging Operation

A. Flow diagram:

A. Flow diagram Combine water soluble ingredient in auxiliary kettle. Heat to critical temperature Transfer water phase by pump Combine oil soluble ingredient in main kettle. Heat to critical temperature. Counter sweep agitation Homogenize or pass thru colloid mill while warm. Cool slowly with counter sweep agitator Transfer finished product by pump into drum or tank Filling and packaging operation

B. Unit Operation for semisolid System:

B. Unit Operation for semisolid System

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Mixing of Liquids :- Equipment: - Kettle and tank fitted with agitator

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Mixing and Blending of Solid Equipment: Blade mixture and tumbler

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3. Mixing and Blending of semisolid Equipment : Blade mixture and knider

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4. Dispersing Equipment: Homogenizers, Colloid mill, or ultrasonic device Homogenizer

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5. Size Reduction of Solid and Semisolid Equipment: end-runner mill, hammer mill, ball mill, colloid mill, micronizer

C. Filling and Packaging Operation:

C. Filling and Packaging Operation The following critical aspects must be evaluated and controlled during large-scale validation and manufacturing runs Proper control of product temperature to aid product flow and maintain product consistency before and during filling and packaging operations 2. Proper agitation in holding tanks and filling heads in order to main product uniformity and homogeneity during filling and packaging operation The use of air pressure and inert atmosphere to achieve product performance and stability in the primary container.

Number of Validation Trials:

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

Product Testing:

Product Testing Validation testing of bulk and Finish product 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 sampling and testing typically is 3 to 6 time the usual QC sampling.

Validation Batch:

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. Different lots but same manufacturer of active ingredients should be used during validation trials

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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. Raw materials, in-process product and finished product must pass all in process and testing standard release requirements

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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:

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.

Bulk Sampling and Testing:

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.

Finish Product Testing:

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.


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.

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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

Monitoring Output:

Monitoring Output Particle size Consideration Viscosity Content Uniformity Preservative effectiveness Dissolution Testing

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1. Particle size Consideration:- Control of particle morphology and particle size are important parameters to attain high quality drug product manufacture and control procedure. Particle size distribution for most disperse system should be in the range of 0.2-20 microns.

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2. Viscosity The Viscometer- Calibrated to measure the apparent viscosity of the disperse system at equilibrium at a given temperature to establish system reproducibility.

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3. Content Uniformity:- Most important parameter governing product stability and process control of the disperse system. In ointment/cream formulation are more dependent on particle size , shear rate , and mixing efficiency in order to attain and maintain uniformity of the active drug component(usually the internal phase).

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4. Preservative effectiveness:- Incorporating a USP antimicrobial preservative testing procedure or microbial limit test into formal validation of aqueous dispersion. Determination of bio burden for validation and production batches can also be used to establish appropriate validated cleaning procedure for the facilities and equipment used in manufacture of disperse system.

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5. Dissolution Testing :- It is primary used as a quality control procedure to determine product uniformity. s econdary as a means of assessing the in vivo absorption of the drug in terms of a possible in vitro/vivo correlation. For cream/ointments, the Franz in vitro flow through diffusion cell has been modified by using silicon rubber membrane barrie r to stimulate percutaneous dissolution unit for testing purpose.


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

Validation report:

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.

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STANDARD FORMAT Executive summary Discussion Conclusions & recommendation List of attachment Topic should be presented in the order in which they appear in the protocol. Protocol deviation are fully explained & justified. The report is signed & dated by designated representatives of each unit involved in water system validation.


REFERENCES R. A. Nash and A. H. Wachter “ Pharmaceutical process validation ”; Third edition Agalloco James, Carleton J. Fredric “Validation of Pharmaceutical Processes” ; Third edition,417-428 Process Validation of Semisolids By Weerayut Chirarutsami .

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