VALIDATION

1. PROCESS VALIDATION OF ORAL
SOLID DOSAGE FORM (TABLET)
Submitted to:- Prepared by :-
Dr. Sanjula Baboota Abdul Muheem
M.Pharm 1st Year
F/O Pharmacy
(Pharmaceutics)
Jamia Hamdard JAMIA HAMDARD
Process Validation of oral solid dosage
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2. DEFINITION
• 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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3. Types of process validation
PROCESS
VALIDATION
RETROSPECTIVE CONCRURRENT
PROCESS PROCESS
VALIDATION VALIDATION
PROSPECTIVE
PROCESS
VALIDATION
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4. DEFINITIONS
 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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5. Validation Protocol
• 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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6. Qualification And Process Validation
Design or Development of Equipment, System, or Product
Installation Qualification
Operational Qualification
Process Performance Qualification
or Process Validation
Change Control
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7. Validation Process flow chart
Pre-Validation Activities
Validation Protocol – Preparation
Validation Protocol- Review and Approval
Protocol Execution
Data Analysis
Validation Report and Sign-Off
Revalidation
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8. Some Common Variables In The
Manufacture Of Tablet Products
 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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9. Validation protocol for manufacturing of tablets
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10. 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.
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11. (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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12. • 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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13. (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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14. (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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15. Process Validation of oral solid dosage
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16. (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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17. • 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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18. • 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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19. Process Validation of oral solid dosage
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20. (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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21. (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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22. • 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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23. (B)Compression speedrange of compression speed to
determine the operating range of the compressor.
• The adequacy of the material’sflow 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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24. • The following in-process tests should be examined during
the compression stage
• Appearance
• Hardness
• Tablet weight
• Friability
• Disintegration
• Weight uniformity
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25. Process Validation of oral solid dosage
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26. • 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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27. (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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28. • 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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29. • 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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30. • 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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31. • 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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32. 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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33. THANK
YOU
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