Process validation of oral solid dosage form (tablet)

By:
Shoab Malek
Certified Quality
Auditor & Pharma
Consultant
Contact Details:
Email:
Shoab.malek@gmail.com
Mobile:
+91 9638069084
shoab.malek@gmail.com
1
PROCESS VALIDATION OF
ORAL SOLID DOSAGE FORM
(TABLET)

• US Food and Drug Administration, 1987
“Process Validation is establishing documented
evidence which provides a high degree of
assurance that a specified process will consistently
produce a product meeting its pre-determined
specifications and quality characteristics.”
 is the documented evidence that the process,
operated within established parameters, can
perform effectively and reproducibly to produce an
intermediate or API meeting pre-determined
specifications and quality attributes.”
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PROCESS
VALIDATION
RETROSPECTIV
E PROCESS
VALIDATION
PROSPECTIVE
PROCESS
VALIDATION
CONCRURREN
T PROCESS
VALIDATION

 PROSPECTIVE PROCESS VALIDATION
Prospective process validation shall be carried out before the
Process is commercialization. Minimum 3 consecutive batches
to be considered. The important requirement for the validation
is protocol preparation.
 RETROSPECTIVE PROCESS VALIDATION
“The retrospective process validation is an established
documented evidence that a process what it purports to do
Based on review and analysis of Historical data.”
 CONCURRENT VALIDATION
“Established documented evidence that a process does what it
purports to do based on information generated during actual
implementation of the process”
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 1. General information
 2. Objective
 3. Background/Prevalidation Activities Summary of
development and tech transfer (from R&D or another
site) activities to justify in-process testing and controls;
any previous validations.
 4. List of equipment and their qualification status
 5. Facilities qualification
 6. Process flow chart
 7. Manufacturing procedure narrative
 8. List of critical processing parameters and critical
excipients
 9. Sampling, tests and specifications
 10. Acceptance criteria
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Design or Development of Equipment, System, or Product
Installation Qualification
Operational Qualification
Process Performance Qualification
or Process Validation
Change Control

Revalidation
Validation Report and Sign-Off
Data Analysis
Protocol Execution
Validation Protocol- Review and Approval
Validation Protocol – Preparation
Pre-Validation Activities
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 Particle size of drug substance
 Bulk density of drug substance/excipients
 Powder load in granulator
 Amount and concentration of binder
 Mixer speed and mixing times
 Granulation moisture content
 Milling conditions
 Lubricant blending times
 Tablet hardness
 Coating solution spray rate
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Validation protocol for manufacturing of
tablets

Industrial Process overview of Solid dosage
form
•Steps & process parameter are following-
(1)Mixing or Blending-Material have similar
physical properties will be easier to form a uniform
mix or blend as compare to difference properties.
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.
10shoab.malek@gmail.com

(b)Mixing time-mixing time will be dependent
on the mixing technique & speed.
 If overmixed occured at the result demixing or
segregation of the material.
(c)Drug uniformity- handling of the material are 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 .
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 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.
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(2)Wet granulation- what type of wet granulation
technique will be used?
 Will it be of- low shear (hobart)
- high shear rate (diosna )or fluid bed (glatt)
 Wet granulation parameters to be processing during
development &validation are-
(a)Binder addition-should be added as a granulating
solution or dry like other excipients.
 Adding the binder dry avoids the need to determine
the optimal binder conc.
(b)Binder conc.- if the binder conc. are high they are
not ejected by spray nozzle then the binder needs to
be dilute enough so that it can be pumped through
the spray nozzle.
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(c)Amount of binder solution /granulating solvent-too
much binder or solvent solution will over wet the
material &prolong the drying time.
 Amount of binder solution is related to the binder
conc.
(d)Mixing time—
(e)Granulation end point –how is the granulation end
point determined? is it determined by granulation end
point equipment(eg-ammeter or wattmeter)
(3)wet milling does the wet granulation need to
be milled to break up the lumps & enhance drying of
the granulation
FACTORS-(a)Equipment size & capacity-mill should
be enough large to delump the entire batch within a
resonable time period to min.manufacturing time.
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(b)Screen size  screen needs to be small enough to
delump the material but not too small to cause
excesssive heating of the mill at the result drying of
granulation occurred.
(c)Mill speed sufficient speed without causing
staining the equipment.
(d)Feed rate of the wet granulation is interelated to
screen size ,mill size & speed
(4)Drying type of drying technique
(a)tray dryer
(b)fluid bed
(c) microwave
Changing dryer techniques could affect such tablet
properties such as hardness, disintegration
,dissolution & stability
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 High moisture content can result in-
(1)Tablet picking or sticking to tablet punch surfaces
2)Poor chemical properties as a result of hydrolysis .
 An over dried granulation could result in poor
hardness & fraibility.
Moisture content are analysed by following method –
(1)near I.R
(2)loss of drying
(3)karl fischer
FACTORS-(A)Inlet/outlet temp. The inlet temp. is
the temp. of the incoming air to dryer ,while the outlet
temp. is the temp. leaving the unit.
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 Inlet temp. should be set high enough to maximinise
drying without affecting the physical/chemical stability.
 The outlet temp. is an indicator is an of the
granulation temp. & will increase toward the inlet
temp. as the moisture content of the granulation
decreases (evaporization rate).
(B)Air flow insufficient air flow could prolong drying
&affect the chemical stability.
(C)Moisture uniformity moisture content could vary
within the granulation
 Drying is also affect the moisture in the granulation.
(D)Equipment capability/capacity
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(5)Milling milling operation will reduce the particle
size of the dried granulation.
 An optimal particle size/size distribution for the
formulation will need to determined .
FACTORS-
(a)Mill typewhat mill type should be used(impact or
screen)?
(b)Screen sizeA smaller screen size will produce a
small particle size & a greater number of fines.
(c)Mill speedwhat is the optimal mill speed?
 Higher speed will result in a smaller particle size &
possilbly a wider particle size distribution.
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(D)Feed rateis dependent on the mill capacity ,screen
size,mill speed
(6)Lubrication
(a) Selection of lubricantwhat kind of lubricant
should be used?
 Grade of lubricant used
 Compatibility with other ingredient.
(b)Amount of lubricanthow much amount lubricant
is required?
 Too much lubricant will form hyrophobic layer on the
tablet resulting dissolution problem.
(c)Mixing timehow much should the material is
mixed to ensure proper formation?
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 Should mixing stop after the addition of the lubricant
or should additional mixing be required ?
 If not mixed long enough from problems like chipping
,capping etc.
(7)Tablet compressionthe material should
readily flow from the hopper onto the feed frame &
into the dies.
 Inadequate flow can result in ‘RAT HOLING’in the
hopper.this can cause tablet weight &uniformity
problem.
FACTORS(A)Tolling The size ,shape &concavity
of the tooling should be examined based formulation
properties &commercial specification.
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(B)Compression speed range of compression speed to
determine the operating range of the compressor.
 The adequacy of the material’s flow into the dies will be
determined by examining the tablet weights.
 Is a force feeder required to ensure that sufficient
material feed into the dies.
(C)Compression or ejection force determined optimal
compression force to obtain the desired tablet hardness.
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 The following in-process tests should be examined
during the compression stage
 Appearance
 Hardness
 Tablet weight
 Friability
 Disintegration
 Weight uniformity
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 In process tests-
1. Moisture content of dried granulation
2. Granulation particle size distribution
3. Blend uniformity
4. Individual tablet/capsule weight
5. Tablet hardness
6. Tablet thickness
7. Disintegration
8. Impurity profile
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(8)Tablet coating tablet coating can occur by
different techniques(eg- sugar, film or compression)
 Key area to consider for tablet coating include the
following-
(a)Tablet properties –the tablet needs to be enough to
withstand the coating process.
 If tablet attrition occurs ,the tablets will have rough
surface appearance
 Round shape easily coated than multiple sides.
(b) Equipment type- coater will need to be selected.
 Conventional or perforated pan & fluid bed coaters are
potential.
(c)Coater load-what is the acceptance tablet load range of
the equipment?
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 Too high load at the result attrition occurred.
(d)Pan speed- what is the optimal pan speed?
 It is interelated to coating parameter such as inlet temp.
spray rate & flow rate.
(e)Spray guns- number & types of guns should be
determined in order to efficiently coat the tablet.
 Size of spray nozzle properly to ensure even distribution
over the tablet bed & to prevent clogging of the nozzles.
(f)Spray rate- spray rate should be determined .
 Spraying too fast will cause the tablets to become over
wet, resulting in clumping of the tablets & possible
dissolution of the tablet surface.
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 Spray too slowly will cause the coating material to prior to
adhesion to the tablets, result in rough & poor coating
efficiency.
(g)Tablet flow-flow of the tablets in the coater should be
examined to ensure proper flow.
 The addition of baffles may be required adequate
movement of the tablet for coating.
(h)inlet/outlet temp &air flow-parameter should be set to
ensure that the atomized coating solution reaches the
tablet surface & then is quickly dried.
(i)Coating solution-the conc. & viscosity of the coating
solution will need to be determined.
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 The stability of the coating solution should be
investigated to establish its shelf life.
(j)Coating weight-a min. & max. 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.
APPEARANCE TESTING FOR TABLET COATING-
 Cracking or peeling of the tablet
 Intagliation fill-in
 Color uniformity
 Coating efficiency should be determined for the coating
operation
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 Finished product tests-
1. Appearance
2. Assay
3. Content uniformity
4. Tablet hardness
5. Tablet friability
6. Impurity profile
7. Dissolution
 Process validation testing is generally done on the first
three batches of product made in production –size
equipment.
 Revalidation testing is only done when a significant
change has occured.
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Conclusion
 Tablet dosage form validation should be part of a
comprehensive validation program within an industry.
 The multidisciplinary validation team must identified the
product & process characteristics that must be studied &
incorporate specific validation tests to ensure that
product will meet all quality , manufacturing & regulatory
requirements.
 Continous awareness of validation will produce
reproducibility .
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THANK
YOU
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Process validation of oral solid dosage form (tablet)

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