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.
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,
Equipment validation steps
1) Check extra paddle, choppers provided
2) Verify paddle is mounted to shaft properly.
3) Granulation end point detection system.
4) Options to introduce the granulating fluid (e.g. dump, meter, spray)
5) Verify automated charging of discharging system.
1) Cabinet with heater.
2) Check position of heaters.
3) Check fans provided.
4) Exhausting system.
5) Verify air handle.
6) Verify inlet or outlet system.
7) Explosion relief duct to avoid explosion.
1) Extra hammers, stationery knives are provided.
2) Verify the location and size of screen in mills.
3) Feeding and discharging system.
2) Installation qualification
1) Verify approved purchase order
2) Manufacturer and supplier.
3) Model and serial number.
4) Physical damage.
5) Confirm location and installation required per recommendation of manufacturer.
6) Required utilities.
7) Installation as per instruction provided in manual.
8)Ensure that all relevant documents are received
- User manual
- Maintenance manual & List of changed parts.
1) Perform calibration requirements.
2) Operate the equipment at low, medium and high-speed rate.
3) Verify all that switches and push buttons are functioning properly.
4) Establish procedure for operation, maintenance, and calibration.
5) Training program for staff.
6) Measure mixing time at low, medium and high speed. Compare the average and deviation from the average of the single measurement with supplier's specifications.
1) Run three batches of each product and analyze for
-Active ingredient uniformity
-Particle size distribution
Based on these data fixing a drying end point of process.
(E.g. moisture content)
1) Run the mills at high, low, medium speed and determine
-Particle size distribution
-Range of units
From this data set the time and speed of mills.
Carry out operations for different samples and each product shall meet its predetermined characteristics
Carry out operations for different samples and determine drying temperature and time and characteristics of product.
Determine milling time and speed for different products.
- Particle size distribution of each sample at different time and speed.
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
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
-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
- To break up the lumps and aggregates and enhance drying of granules
Factors to be considered-
Equipment size and capacity
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
> 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.
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.
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.
Mr.Sohan S.Chitlange, Mr. Ajay S. Pawar, Mr.Hemant I. Pawar, Mr.Santosh S. Bhujbal, Mr.Amol A. Kulkarni
Asst. Professor , Dept.of Pharm.Chemistry , Padm.dr.D.Y.patil institute of Pharma.Science &Resreach, Pimpri, Pune. email@example.com
Mr. Ajay S. Pawar
M. Pharm. (QA)
Mr.Hemant I. Pawar
Mr.Santosh S. Bhujbal
Asst.Professor, Dept.of Pharmacognosy
Mr.Amol A. Kulkarni
Lecturer, Dept.of Pharm.Chemistry