The document discusses validation of processing techniques for wet granulation. It outlines key parameters that must be considered and validated at each stage of wet granulation including blending, wet granulation, drying, and tablet compression. Parameters like mixing time and speed, binder concentration, granulation endpoint, drying temperature and moisture content, and compression force must be optimized and shown to consistently produce tablets meeting quality standards. Equipment used at each stage must also be validated to ensure it is suitable for the processing steps.

1. VALIDATION OF PROCESSING TECHNIQUES
By Ch.Sandhya

2. Steps for validation and acceptance criteria in wet granulation process

4. 1. Mixing or Blending ensures production of uniform
mixture of active pharmaceutical ingredients and
excipients that do not segregate post blending. So this
step is carefully scrutinized and validated.
• Parameters to consider:
Mixing or blending technique
Mixing or blending speed
Mixing or blending time:
Drug uniformity
Excipient uniformity
Equipment capacity/load .

5. 1. Mixing or Blending - Material have similar physical properties
will be easier to form a uniform mix or blend as compare to
difference in properties.
2. Techniques-
1- diffusion(tumble)
2- convection(planetary or high intensity or fluid bed.
Mixing or blending depending on various factor-
(a)Mixing speed - mixing the drug & excipient will require more
intense mixing than adding the lubricant to the final blend.
(b)Mixing time - mixing time will be dependent on the mixing
technique & speed.

6. • If over mixed occured at the result demixing or segregation
of the material.
(c)Drug uniformity - handling of the material is key in
obtaining valid content uniformity results .
• Segregation of the sample can occur by handling resulting
inaccurate results.
• Sample should be equivalent to the weight of a single tablet.
(d)Excipient uniformity - excipient need to be uniform in the
granulation. Two keys excipient are-
(A)-LUBRICANT- lubricant needs to be distributed uniformly
in the mixture/granulation for high speed compression
operation

7. Uneven distribution of the lubricant can result in picking &
sticking problem during compresion.
(B)Color-evenly distributed in the mixture so the tablets have
a uniform appreance (color,hue & intensity)
• Uniform dispersed in the blend prior to compression to avoid
shading(molting).
(e)Equipment capacity/load-the bulk density of material will
affect the capacity of the equipment . • Undercharging or
overcharging a blender can result in poor drug or tablet lubricant
distribution.

8. 2. Wet Granulation : Wet granulation parameters to be
considered during development and validation are:
Binder addition
Binder concentration
Amount of binder solution/granulating solvent
Binder solution/granulating solvent addition
Mixing time
Granulation end point

9. Wet granulation parameters to be considered during
development and validation are:
Binder concentration and addition: The optimal binder
concentration will need to be determined for the formulation. If
the binder is to be sprayed, the binder solution needs to be
diluted enough so that it can be pumped through the nozzle. It
should also be sufficiently concentrated to form granules
without overwetting the materials.
Amount of binder solution: how much binder or solvent solution
is required to granulate the materials?. Too much binder or
solvent solution will over wet the materials and prolong the
drying time.

10. Binder solution addition rate: Define the rate at which the
binder solution can be added to the material.
Mixing time: How long the material should be mixed to ensure
proper formation of granules. Over mixing the granulation can
lead to harder granules and a lower dissolution rate.
Granulation end point: How is the granulation end point
determined? Is it controlled by specifying critical processing
parameters?.
•EQUIPMENT VALIDATION:
•MIXER/GRANULATOR:
• a. What is the method of mixing (e.g., planetary, pneumatic)?

11. • b. Is the equipment capable of providing low and/or high
shear to the material?
•c. Can the mixing be varied (e.g., changing the rpm of the
impeller)?
• d. Does the mixer/granulator have a monitoring system (e.g.,
end point detection) or can it accommodate one?
e. What is the working load range and capacity of the
equipment? f. How is material charged and discharged from the
unit? Is it manual, semi-automated, or automated? g. Are there
options to introduce the granulating fluid (e.g., dump, meter, or
spray)?

12. 3. Drying
The type of drying technique (e.g., tray, fluid bed, and microwave)
required for the formulation needs to be determined and justified.
The type of technique may be dependent on such factors as drug
or formulation properties and equipment availability.
Changing dryer techniques could affect such tablet properties as
hardness, disintegration, dissolution, and stability.
The optimal moisture content of the dried granulation needs to be
determined. High moisture content can result in tablet picking or
sticking to tablet punch surfaces and poor chemical stability as a
result of hydrolysis.

13. An over dried granulation could result in poor hardness and
friability. Moisture content analysis can he performed using the
conventional loss-on-drying techniques or such state-of-the-art
techniques as near infrared (NIR) spectroscopy.
Factors to be considered are:
1. Inlet/outlet temperature
2. Airflow
3. Moisture uniformity
4. Equipment capability/capacity

14. (A) Inlet/outlet temp.
• Inlet temp.should be set high enough to maximinise drying
without affecting the physical/chemical stability.
• The outlet temp. is an indicator of the granulation temp. &
insufficient air flow could prolong drying will increase toward
the inlet temp.as the moisture content of the granulation
decreases (evaporization rate).
(B) Air flow & moisture content could vary within the
granulation
• Drying also affect the moisture in the granulation.

15. •EQUIPMENT EVALUATION
• DRYER
• a. What is the operating principle of the dryer (e.g., direct
heating—fluid bed, indirect conduction—tray, or indirect
radiant—microwave)?
• b. Will the wet material be static (e.g., tray) or fluid (e.g., fluid
bed)?
• c. What is the working load range and capacity of the
equipment?
• d. What is the heating range and airflow capabilities of the
equipment?
•

16. •e. What is the heat distribution of the unit? Are there any hot
and/ or cold spots?
• f. Can the unit pull a vacuum? What is the vacuum range of
the unit?
• g. Can the equipment handle different types of filter bags? For
example, can a filter bag be dedicated to a particular product?

17. 4. Tablet Compression
Compression is a critical step in the production of a tablet dosage
form. The materials being compressed will need to have adequate
flow and compression properties. The material should readily flow
from the hopper onto the feed frame and into the dies.
Inadequate flow can result in “rat holing” in the hopper and/or
segregation of the blend in the hopper/feed frame.
This can cause tablet weight and content uniformity problems.
Factors to consider during compression are as follows:
Tooling
Compression speed
Compression/ejection force

18. • Tooling: The shape, size and concavity of the tooling should
be examined.
• Compression speed and force: compression speed of the
tablet press is adjusted based on the flow rate of the
granulation, tablet weight required and tablet hardness
required.
• TABLET COMPRESSION MACHINE
• a.How many compression stations does the compressor
have?
• b. What is the operating range (rpm) of the unit?
• c. What is the output range of the compressor (e.g., tablets
per min)? Will the unit meet the demands (sales forecast)

19. •d. What kind of powder feeding capabilities does the
equipment have (e.g., gravity, power-assisted, or centrifugal)?
Can this capability be altered or controlled (e.g., open feed
frame, forced below feeder)?
• e. What is the compression force range of the equipment? f.
Is the equipment capable of monitoring compression and
ejection force? g. Does the unit have precompression
capabilities? h. How long can the equipment operate without
routine maintenance?