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1. Process Validation of Tablets and Liquids
Prepared By:
Abdul Raheem. T
2nd Sem. M.pharm
Bapuji Pharmacy College, Davangere
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2. INTRODUCTION
By A.R.T 2
 PROCESS VALIDATION : Is establishing documented
evidence which provides a high degree of assurance that
a specific process will consistently produce a product
meeting its pre-determined specifications & quality
characteristics.
 WHY?
• Application of process validation results in fewer
product recalls & trouble shooting assignment in
manufacturing processes.
• To produce economically & technically sound products
& their manufacturing process.

3. Newly developed manufacturing procedure
Write & approve process procedure
Write and approve validation protocol
Equipment installation, trial runs & debugging
Modifications (if necessary ) to meet process
requirements
Selection of process equipment
Qualify equipment & personnel
Schematic diagram for VALIDATION
OF NEW PROCESS
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4. .
Modify procedure or
equipment
Validate process
Impact is
minor
Impact is
minor
Impact is
major
Impact is
major
Implement monitoring and
change control procedure
Successful Unsuccessful
Procedure
change
required
Equipment
change
required
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5. PROCESS VALIDATION OF
SOLID DOSAGE FORM : TABLETS
• A tablet is a most known solid pharmaceutical dosages form
and comprises of a mixture of active substances and suitable
excipients.
• The knowledge of stepwise manufacturing process of any
dosages form is a must for validating any process.
• It helps in determining the critical areas which need special
consideration in terms of causing problems during the
process.
By A.R.T 5

6. PROCESS EVALUATION AND SELECTION:
Mixing Or Blending :
Mixing is one of the most critical step and used at
various stages during manufacturing of tablets.
parameters to be considered in mixing process are:
a) Mixing Or Blending Technique: -
• The techniques like Diffusion (tumble), convection
(planetary or high intensity), or pneumatic (fluid bed) are
used to mix or blend materials.
• The choice of technique depends on whether the drug
and excipients are mixed for a direct compression
formulation or for granulation.
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7. b) Mixing or Blending Speed:-
• Mixing the drug and excipient requires more intense
mixing than adding the lubricant to the final blend.
c) Mixing or blending time: -
• It will be dependent on the mixing or blending
technique and speed.
d) Drug uniformity: -
• The test for content uniformity is usually performed to
estimate the uniformity of drug throughout the mix or
blend.
e) Excipient uniformity: -
• Two key excipients are: 1- Lubricant . 2- colorants
By A.R.T 7

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f) Equipment capacity/load: -
• The bulk density of materials or granules will affect the
capacity of the equipment. Undercharging or
overcharging a blender can result in poor drug or tablet
lubricant distribution.
Wet Granulation :
• Wet granulation parameters to be considered during
development and validation are:
a) Binder Addition: -
• Adding the binder dry avoids the need to determine the
optimal binder concentration and a separate manufacture
for the binder solution.

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b) Binder Concentration: -
• 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 dilute enough
so that it can be pumped through the spray nozzle. It
should also be sufficiently concentrated to form
granules without over wetting the materials.
c) Amount of Binder Solution/Granulating Solvent:-
• Too much binder or solvent solution will over wet the
materials and prolong the drying time. The amount of
binder solution is related to the binder concentration.

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d) Binder Solution/Granulating Solvent Addition Rate:
• The rate or rate range at which the binder solution or
granulating solvent can be added to the materials should
be defined properly.
e) Mixing Time:
• Granulations that are not mixed long enough can form
incomplete or weak granules. These granules may have
poor flow and compression properties. On the other
hand, over mixing the granulation can lead to harder
granules and a lower dissolution rate.

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Wet Milling :
Sometimes wet milling of granules is needed before
subjecting it for drying to efficiently dry them.
• Factors to consider are:
a) Equipment Size And Capacity:-
• The mill should be large enough to carry the entire
batch within a reasonable time period to minimize
manufacturing time and prevent the material from
drying during this operation.
b) Feed Rate:-
• The feed rate of the wet granulation is interrelated to
screen size, mill size and speed.

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c) Screen Size:-
• The screen needs to be small enough to carry the material,
but not too small to cause excessive heating of the mill,
resulting in drying of the granulation.
c) Mill Speed:-
• The speed should be sufficient to efficiently reduce size of
the material without straining the equipment.
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.

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• The optimal moisture content of the dried granulation
needs to be determined.
i. High moisture content can result in
a) Tablet picking or sticking to tablet punch
surfaces and
b) Poor chemical stability as a result of
hydrolysis.
ii. An over dried granulation could result in poor hardness
and friability.

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Parameters to consider are:
a) Inlet/Outlet Temperature: -
• The inlet temperature is the temperature of the incoming
air to the dryer, while the outlet temperature is the
temperature leaving the unit. The inlet temperature is
critical to the drying efficiency of the granulation and
should be set high enough to maximize drying without
affecting the chemical/physical stability of the
granulation. The outlet temperature is an indicator of the
granulation temperature and will increase toward the
inlet temperature as the moisture content of the
granulation decreases (evaporisation rate).

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b) Airflow:-
• There should be sufficient airflow to ensure removal of
moisture air from the wet granulation. Insufficient air
flow could prolong drying and affect the chemical
stability of the drug.
c) Moisture Uniformity:- The moisture content could vary
within the granulation
d) Equipment Capability/Capacity:- The load that can be
efficiently dried within the unit needs to be known.

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Dry Milling:
• The milling operation will reduce the particle size of the
dried granulation. The resultant particle size
distribution will affect such material properties as flow,
compressibility, disintegration, and dissolution. An
optimal particle size/size distribution for the
formulation will need to be determined. Factors to
consider in dry milling are same as that of wet milling.

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Lubrication:
Lubricants are added in order to remove the problem of
sticking and picking in the tablets.
a) Selection of Lubricant: -
• Grade of the lubricant used and compatibility with other
ingredients should be studied thoroughly and then the
appropriate one must be chosen.
b) Amount of Lubricant Added:-
• How much lubricant is required? Too much lubricant
will form hydrophobic layer on the tablet resulting in
dissolution problems.

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c) Mixing Time: -
• The optimum mixing time must be decided on proper
trial of batches because if not mixed long enough, form
problems like chipping, capping, etc.
Tablet Compression:
Compression is a critical step in the production of a
tablet dosage form. As for the compressibility properties
of the formulation, it should be examined on an
instrumented tablet press. Factors to consider during
compression are as follows:
a) Tooling:-
• The shape, size, and concavity of the tooling should be
examined based on the formulation properties and
commercial specifications.

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b) Compression speed: -
• The formulation should be compressed at a wide range of
compression speeds to determine the operating range of the
compressor.
c) Compression/ejection force: -
• The compression profile for the tablet formulation will need
to be determined to establish the optimal compression force
to obtain the desired tablet hardness.
The following in-process tests should be examined during
the compression stage:
I. Appearance
II. Hardness
III. Tablet weight
IV. Friability
V. Disintegration
VI. Weight uniformity
VII. Tablet Coating

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Tablet coating can occur by different techniques (e.g., sugar,
film, or compression):
• Film coating has been the most common technique over
recent years and will be the focus of this section.
Key areas to consider for tablet coating include the
following:
a. Tablet Properties:-
• Tablet properties such as hardness and shape are
important to obtain a good film-coated tablet. The tablet
needs to be hard enough to withstand the coating
process

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c) Coater Load:-
• A large pan load can cause attrition of the tablets
because of the overall tablet weight in the coater.
• In the case of a fluid bed coater, there may not be
sufficient airflow to fluidize the tablets.
d) Pan Speed:-
• This will be interrelated to other coating parameters,
such as inlet temperature, spray rate and flow rate.
e) Spray Guns:-
• The number and types of guns should be determined in
order to efficiently coat the tablets.

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f) Application/Spray Rate:-
• The optimal application/spray rate should be
determined. Spraying too fast will cause the tablets to
become over wet, resulting in clumping of tablets and
possible dissolution of the tablet surface. Spraying too
slowly will cause the coating materials to dry prior to
adhesion to the tablets. This will result a rough tablet
surface and poor coating efficiency.
g) Tablet Flow:-
• The flow or movement of the tablets in the coater
should be examined to ensure proper flow. The addition
of baffles may be required to provide adequate
movement of tablets for tablet coating.

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h) Inlet/Outlet Temperature and Airflow:-
• These parameters are interrelated and should be set to
ensure that the atomized coating solution reaches the
tablet surface and then is quickly dried.
i) Coating Solution:-
• The concentration and viscosity of the coating solution
will need to be determined. The solution will need to be
sufficiently diluted in order to spray the material on the
tablets.

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j) Coating Weight:-
• A minimum and maximum coating weight should be
established for the tablet.
k) Residual Solvent Level:-
• If solvents are used for tablet coating, the residual
solvent level will need to be determined

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Summary table including steps, control variable and
critical parameters to be checked in manufacturing of
tablets.

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Process Validation Of Liquids
• They are liquid preparation in which the drugs are
dissolved, suspended or disperse in a suitable vehicle and
generally several doses are contained in the bottle.
• Types Of Oral Liquids
1. Syrups
2. Solutions
3. Suspension
4. Eye drops
5. Nasal drops etc

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Validation Includes Mainly Following Tests :
a. Particle size and size distribution
b. Particle shape or morphology
c. Microbial count
d. Rheology of solvent or vehicle
e. PH of the solvent or vehicle

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Monitoring outputs :
Some outputs to be monitored are
a. Appearance
b. pH
c. Viscosity
d. Specific gravity
e. Microbial count
f. Content uniformity
g. Dissolution testing

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• Appearance of the final product indicates the signs of
instability and degradation. For e.g. settling of solid
particles in case of suspension and turbidity in case of
emulsion.
• Time for mixing or agitation and temperature of process
can affect the appearance greatly.

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• Viscosity affects the settling rate of suspended particles
in suspension and coalescence of globules of internal
phase in emulsions and also in case of oral solutions it
affects the overall appearance of the final product so it
must be measured and validated properly.
• A decrease in specific gravity of the product like
suspensions indicates the presence of air within the
structure of the formulation.

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• Microbial count for the final product is essential to
validate because by performing microbial count we can
select the preservative for the final product storage.
• Content uniformity affects the dose uniformity in case
of multi dose formulations and also affects the
homogeneity of the drug within solvent system

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• PH of aqueous oral formulations should be taken at a
given temperature and only after equilibrium has been
reached in order to minimize the PH drift.
• Microbial count for the final product is essential to
validate because by performing microbial count we can
select the preservative for the final product storage.
There are specifications for each liquid oral product for
the bio burden content.

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Summary table for validation of liquid dosages form

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References :
• Ira RB, Robert AN, Pharmaceutical process validation.
2nd ed. Newyork: Marcel dekker; 1993. p.167-88.
• Frederick JC, James PA, Validation of pharmaceutical
processes. Newyork: Marcel dekker; 1999. p.703-20.
• Nitish M, Saroj J, Satish S. Process validation of liquid
lyophillized formulation: a review. J Adv Pharm Edu
Res 2013; 3(2): 46-58.
• Warkad PR, Joshi AM, Wagdarikar M, Kakad S,
Nadendla S. Process validation of sterile product. Int J
Pharmac Res Sch 2014; 3(3): 369-86.

35. By A.R.T 35
• Sindhur N, Gouthami B, Madhuri L, Lavanya RV,
Krishnaveni N, Meyyanathan SN et al. The concept of
process validation in tablet manufacturing:Review. J
Pharm Res 2012;5(2): 1264-67.
• Lakshmana PS, Suriyaprakash TNK, Ruckmani K,
Thirumurugan R. Concepts of process validation in
solid dosage form [tablet] – an overview. SAJ Pharm
Pharmacol 2014; 1(1): 1-12.
• Sharma C, Rana AC, Bala R, Seth N. An overview of
industrial process validation of tablets. J Drug Delv
Therapeu 2013; 3(3): 175-183.
• Goyal A, Priyambada P.Process Validation of
pharmaceutical dosages form: a review. Biomed J Sci &
Tech Res 2017;1(5):1-9.

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THANK YOU…