validation of solid oral dosage form, tablet 1

Submitted to:-

Dr. Sanjula Baboota

F/O Pharmacy

Jamia Hamdard

Prepared by :-Abdul MuheemM.Pharm 1st Year(Pharmaceutics)JAMIA HAMDARD

Sunday, February 24, 2013 1

PROCESS VALIDATION OF ORAL SOLID DOSAGE FORM (TABLET)

Process Validation of oral solid dosage form (Tablet)

DEFINITION

• US Food and Drug Administration, 1987“Process Validation is establishing documented

evidence which provides a high degree of assurancethat a specified process will consistently produce aproduct meeting its pre-determined specificationsand quality characteristics.”

is the documented evidence that the process,operated within established parameters, canperform effectively and reproducibly to produce anintermediate or API meeting pre-determinedspecifications and quality attributes.”

Sunday, February 24, 2013 2Process Validation of oral solid dosage

form (Tablet)

Types of process validation


PROCESS VALIDATION

RETROSPECTIVE PROCESS

VALIDATION

PROSPECTIVE PROCESS

VALIDATION

CONCRURRENT PROCESS

VALIDATION


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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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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Qualification And Process Validation


Design or Development of Equipment, System, or Product

Installation Qualification

Operational Qualification

Process Performance Qualificationor Process Validation

Change Control


Validation Process flow chart

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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Some Common Variables In The Manufacture Of Tablet Products

Particle size of drug substanceBulk density of drug substance/excipientsPowder load in granulator Amount and concentration of binderMixer speed and mixing timesGranulation moisture content Milling conditionsLubricant blending timesTablet hardnessCoating solution spray rate


form (Tablet)

Validation protocol for manufacturing of tablets


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Industrial Process overview of Solid dosage form

•Steps & process parameter are following-

(1)Mixing or Blending-Material have similar physicalproperties will be easier to form a uniform mix orblend as compare to difference properties.

Techniques-1-diffusion(tumble)

2-convection(planetary or high intensityor fluid bed.

Mixing or blending depending on various factor-

(a)Mixing speed-mixing the drug & excipient willrequire more intense mixing than adding thelubricant to the final blend.


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(b)Mixing time-mixing time will be dependent onthe mixing technique & speed.

• If overmixed occured at the result demixing or segregationof the material.

(c)Drug uniformity- handling of the material are key inobtaining valid content uniformity results .

• Segregation of the sample can occur by handling resultinginaccurate results.

• Sample should be equivalent to the weight of a singletablet.

(d)Excipient uniformity-excipient need to be uniform inthe granulation.Two keys excipient are-

(A)-LUBRICANT- lubricant needs to be distributeduniformly in the mixture/granulation for high speedcompression 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 tabletshave a uniform appreance (color,hue & intensity)

• Uniform dispersed in the blend prior to compression toavoid shading(molting).

(e)Equipment capacity/load-the bulk density ofmaterial will affect the capacity of the equipment .

• Undercharging or overcharging a blender can result inpoor drug or tablet lubricant distribution.


form (Tablet)

(2)Wet granulation- what type of wet granulationtechnique will be used?

• Will it be of- low shear (hobart)

- high shear rate (diosna )or fluid bed (glatt)

• Wet granulation parameters to be processing duringdevelopment &validation are-

(a)Binder addition-should be added as a granulating solutionor dry like other excipients.

• Adding the binder dry avoids the need to determine theoptimal binder conc.

(b)Binder conc.- if the binder conc. are high they are notejected by spray nozzle then the binder needs to be diluteenough so that it can be pumped through the spraynozzle.


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(c)Amount of binder solution /granulating solvent-too muchbinder 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 pointdetermined? is it determined by granulation end pointequipment(eg-ammeter or wattmeter)

(3)wet milling does the wet granulation need to bemilled to break up the lumps & enhance drying of thegranulation

FACTORS-(a)Equipment size & capacity-mill should beenough large to delump the entire batch within aresonable time period to min.manufacturing time.


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15Sunday, February 24, 2013Process Validation of oral solid dosage

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(b)Screen sizescreen needs to be small enough to delumpthe material but not too small to cause excesssive heatingof the mill at the result drying of granulation occurred.

(c)Mill speedsufficient speed without causing staining theequipment.

(d)Feed rateof the wet granulation is interelated to screensize ,mill size & speed

(4)Dryingtype of drying technique

(a)tray dryer

(b)fluid bed

(c) microwave

Changing dryer techniques could affect such tabletproperties such as hardness, disintegration ,dissolution &stability


form (Tablet)

• 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 thetemp.of the incoming air to dryer ,while the outlet temp.isthe temp.leaving the unit.


form (Tablet)

• Inlet temp.should be set high enough to maximinisedrying without affecting the physical/chemical stability.

• The outlet temp.is an indicator is an of the granulationtemp.&will increase toward the inlet temp.as the moisturecontent of the granulation decreases (evaporization rate).

(B)Air flowinsufficient air flow could prolong drying&affect the chemical stability.

(C)Moisture uniformitymoisture content could vary withinthe 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 theformulation will need to determined .

FACTORS-

(a)Mill typewhat mill type should be used(impact orscreen)?

(b)Screen sizeA smaller screen size will produce a smallparticle size & a greater number of fines.

(c)Mill speedwhat 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 rateis dependent on the mill capacity ,screensize,mill speed

(6)Lubrication(a) Selection of lubricantwhat kind of lubricant should be

used?

• Grade of lubricant used

• Compatibility with other ingredient.

(b)Amount of lubricanthow much amount lubricant isrequired?

• Too much lubricant will form hyrophobic layer on thetablet resulting dissolution problem.

(c)Mixing timehow much should the material is mixed toensure proper formation?


form (Tablet)

• Should mixing stop after the addition of the lubricant orshould additional mixing be required ?

• If not mixed long enough from problems like chipping,capping etc.

(7)Tablet compressionthe material should readily flowfrom the hopper onto the feed frame & into the dies.

• Inadequate flow can result in ‘RAT HOLING’in thehopper.this can cause tablet weight &uniformity problem.

FACTORS(A)TollingThe size ,shape &concavity of thetooling should be examined based formulation properties&commercial specification.


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(B)Compression speedrange of compression speed todetermine the operating range of the compressor.

• The adequacy of the material’sflow into the dies will bedetermined by examining the tablet weights.

• Is a force feeder required to ensure that sufficient materialfeed into the dies.

(C)Compression or ejection forcedetermined optimalcompression force to obtain the desired tablet hardness.

Sunday, February 24, 2013Process Validation of oral solid dosage

form (Tablet)23

• The following in-process tests should be examined duringthe compression stage

• Appearance

• Hardness

• Tablet weight

• Friability

• Disintegration

• Weight uniformity


form (Tablet)24


form (Tablet)

• 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


form (Tablet)26

(8)Tablet coatingtablet coating can occur by differenttechniques(eg-sugar,film or compression)

• Key area to consider for tablet coating include the following-

(a)Tablet properties –the tablet needs to be enough towithstand the coating process.

• If tablet attrition occurs ,the tablets will have rough surfaceappearance

• Round shape easily coated than multiple sides.

(b) Equipment type- coater will need to be selected.

• Conventional or perforated pan & fluid bed coaters arepotential.

(c)Coater load-what is the acceptance tablet load range of theequipment?


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• Too high load at the result attrition occurred.

(d)Pan speedwhat is the optimal pan speed?

• It is interelated to coating parameter such as inlet temp.,sprayrate & flow rate.

(e)Spray guns- number & types of guns should be determined inorder to efficiently coat the tablet.

• Size of spray nozzle properly to ensure even distribution overthe 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 overwet,resulting in clumping of the tablets & possible dissolutionof the tablet surface.


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• Spray too slowly will cause the coating material to prior toadhesion to the tablets,result in rough & poor coatingefficiency.

(g)Tablet flow-flow of the tablets in the coater should beexamined to ensure proper flow.

• The addition of baffles may be required adequate movementof the tablet for coating.

(h)inlet/outlet temp &air flow-parameter should be set toensure that the atomized coating solution reaches the tabletsurface & then is quickly dried.

(i)Coating solution-the conc. & viscosity of the coating solutionwill need to be determined.


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• The stability of the coating solution should be investigated toestablish its shelf life.

(j)Coating weight-a min. & max. coating weight should beestablished 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 coatingoperation


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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 threebatches of product made in production –size equipment.

• Revalidation testing is only done when a significant changehas occured.


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Conclusion

• Tablet dosage form validation should be part of acomprehensive validation program within an industry.

• The multidisciplinary validation team must identified theproduct & process characteristics that must be studied &incorporate specific validation tests to ensure that productwill meet all quality , manufacturing & regulatoryrequirements.

• Continous awareness of validation will producereproducibility .


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THANK

YOU


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validation of solid oral dosage form, tablet 1

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