Mr.Sohan S.Chitlange

Validation is establishing documented evidence, which provides high degree assurance that a specific process will consistently produce a product meeting its predetermined specification and quality characteristics.

But validation itself does not improve process but assures that the process has been properly developed and is under control.

Types of validation: ¹

1. Prospective validation:

Validation conducted prior to the distribution of either a new product or product made under a revised manufacturing process.

2. Retrospective validation:

Validation of a process for a product already in distribution based upon accumulated production, testing and control data.

3. Concurrent validation:

In process monitoring of critical processing steps and end product testing of current production is involved in concurrent validation

Validation of granulation process: ^2,3

There are two methods of granulation,

1. Wet Granulation,

2. Dry Granulation

Validation of Granulation process involves ¹

1. Equipment validation

2. Process validation

3. Final product (granule) validation

1) Equipment Validation: ¹

Different types of equipments are utilized in granulation process depending upon the method of granulation and final product specification. Following are some of the equipments used in both granulation processes.

1. Mixer

2. Dryer

3. Blender

4. Mills

5. Sieves

In an ideal situation the equipment used to manufacture dosage forms would be selected based upon such factors as formulation, safety requirements, handling or production efficiencies and commercial demands.

Steps Involved in Equipment validation: ⁴

1. Design Qualification

2. Installation Qualification

3. Operational Qualification

4. Performance Qualification

Various equipment utilized in granulation process are,

1) Mixer/Granulation

2) Dryer

3) Blender

4) Mills

5) Sieves

2) Granulation process

ss validation: ¹

Validating a granulation process involves identification of critical parameters, which must be controlled to ensure the consistent production of granulation.

Various operations carried out in granulation process are

1) Mixing /Blending

2) Wet Granulation

3) Drying

4) Milling

I) Mixing/Blending:

Physical properties drugs and excipients like

- Bulk density

- Particle shape

- Particle size distribution

- Surface area

Factors in creating uniform blending:

-Mixing or blending technique

-Mixing/ Blending speed

-Mixing time

-Drug uniformity

-Excipients uniformity.

-Equipment capacity or load.

II) wet granulation:

Parameters considered in wet granulation process are

I) Binder addition

II) Binder concentration

III) Amount of binder solution or granulating solvent

IV) Binder solution or granulating solvent addition rate

V) Mixing time

VI) Granulation end point

III) milling:

- To break up the lumps and aggregates and enhance drying of granules

Factors to be considered-

Equipment size and capacity

Screen size

Milling speed

Feed rate

IV) drying:

Type of drying technique (Tray, Fluid, and Microwave) required for formulation needs to be determined and justified depending on drug formulation properties and equipment availability.

Optimal moisture content of dried granules needs to be determined. High moisture contents can result in-

1) Final tablet picking and sticking to punch surface

2) Poor chemical stability due to hydrolysis.

Parameters to be considered in drying

1) Inlet and outlet temperature:

Inlet temperature is critical to drying efficiency of granules and should be set high enough to maximize drying without affecting chemical or physical stability of granules.

2) Air flow:

Sufficient to ensure removal of moisture from wet granules

3) Moisture uniformity:

Factors affecting moisture uniformity are

- Heat uniformity of the dryer

- Amount of granules per tray

- Incomplete fluidization of the bed.

4) Equipment capability or capacity:

Optimal load size needs to be determined to enhance drying process.

Larger load will require more moisture to be removed on drying and will affect the drying time

3) Final product (granuls) validation: ³

Parameters in final granules validation validated are

1) Granule flow

2) Bulk density

3) Moisture content

4) Particle size distribution (Sieve analysis)

5) Granule compressive or crushing strength

1) Granule flow:

Angle of repose is measured for determining the granule flow property.

It is the maximum angle obtained between the freestanding surface of a granule heap and the horizontal plane.

Angle of Repose Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

> 40 Very poor

2) Bulk density:

Depends on particle packing and charges as the granules are compressed.

Bulk Density = Mass of granules (M)

Bulk Volume (V _b )

3) Moisture conent of granules:

Karl fischer method:

Water is quantitatively measured by titration under anhydrous condition by the use of reagent containing iodine, sulfur dioxide, pyridine and methanol.

End point may be detected visually or preferably by the use of electrometric and automatic titration assembly.

4) Particle size distribution (sieve analysis):

- Mechanical sieve shaker is used. Granules are mechanically shaked through a series of successively smaller sieves and weighing of the sample retained on each sieve.

-Size of particle retained is taken as arithmetic or geometric mean of to sieves.

5) Granules compressive or crushing strength:

It may be expressed in terms of compressive, tensile, shear, bending, impact and abrasion test.

Compressive strength of granule has been investigated by placing individual granule between two plates and breaking them by application of a compressive load .

There is an optimum range of average granule crushing strength for a given size of granule. Below range tend to break down during mixing and handling.

Summary:

Process validation is a requirement of CGMP regulation for finished pharmaceutical products. It is a key element in assuring that the quality goals are met. Successfully validating a process may reduce the dependence upon intensive in process and finished product testing.

Validation of granulation process involves validation of equipments utilized in manufacturing of granulation and validation of operation carried out for granulation. It also validate final product for bulk density, moisture content, particle size distribution etc.

References:

1) Nash R A., Wachter A.H., Pharmaceutical process validation, 3 ^rd edition, Marcel Dekker publication, p.g. no-xxx-xxxiv, 173-182.

2) Lachman L., Liebberman H.A., Kania J.L., The theorty and practice of industrial pharmacy, 3 ^rd edition, Varghese publishing house, p.g.no. 318-320.

3) N. K. Jain & S. N. Sharma, A Text Book of Professional Pharmacy, Vallabh Prakashan, p.g.no. -295-297

4) Haider S.I., Validation Standard Operating Procedures St. Lucie Press Publishers, p.g. no. 345-353.

About Authors:

Mr.Sohan S.Chitlange, Mr. Ajay S. Pawar, Mr.Hemant I. Pawar, Mr.Santosh S. Bhujbal, Mr.Amol A. Kulkarni

Mr.Sohan S.Chitlange

Asst. Professor , Dept.of Pharm.Chemistry , Padm.dr.D.Y.patil institute of Pharma.Science &Resreach, Pimpri, Pune. sohanchitlange@rediffmail.com

Mr. Ajay S. Pawar

M. Pharm. (QA)

Mr.Hemant I. Pawar

M.Pharma. (Q.A.)

Mr.Santosh S. Bhujbal

Asst.Professor, Dept.of Pharmacognosy

Mr.Amol A. Kulkarni

Lecturer, Dept.of Pharm.Chemistry