PROCESS VALIDATION OF ORAL    SOLID DOSAGE FORM (TABLET)Submitted to:-                                    Prepared by :-Dr...
DEFINITION       • US Food and Drug Administration, 1987       “Process Validation is establishing documented         evid...
Types of process validation                                      PROCESS                                     VALIDATION   ...
DEFINITIONS PROSPECTIVE PROCESS VALIDATION  Prospective process validation shall be carried out before  the Process is co...
Validation Protocol• 1. General information• 2. Objective• 3. Background/Prevalidation Activities Summary of development  ...
Qualification And Process Validation                Design or Development of Equipment, System, or Product                ...
Validation Process flow chart                                    Pre-Validation Activities                               V...
Some Common Variables In The                     Manufacture Of Tablet Products        Particle size of drug substance   ...
Validation protocol for manufacturing of tablets                            Process Validation of oral solid dosageSunday,...
Industrial Process overview of Solid dosage                              form    •Steps & process parameter are following-...
(b)Mixing time-mixing time will be dependent on         the mixing technique & speed.       • If overmixed occured at the ...
• Uneven distribution of the lubricant can result in picking &         sticking problem during compresion.       (B)Color-...
(2)Wet granulation- what type of wet granulation          technique will be used?       • Will it be of- low shear (hobart...
(c)Amount of binder solution /granulating solvent-too much          binder or solvent solution will over wet the material ...
Process Validation of oral solid dosageSunday, February 24, 2013                                             15           ...
(b)Screen size screen needs to be small enough to delump          the material but not too small to cause excesssive heat...
• High moisture content can result in-       (1)Tablet picking or sticking to tablet punch surfaces       2)Poor chemical ...
• Inlet temp.should be set high enough to maximinise          drying without affecting the physical/chemical stability.   ...
Process Validation of oral solid dosageSunday, February 24, 2013                                             19           ...
(5)Milling milling operation will reduce the particle size         of the dried granulation.       • An optimal particle ...
(D)Feed rateis dependent on the mill capacity ,screen          size,mill speed       (6)Lubrication        (a) Selection...
• Should mixing stop after the addition of the lubricant or         should additional mixing be required ?       • If not ...
(B)Compression speedrange of compression speed to   determine the operating range of the compressor.• The adequacy of the...
• The following in-process tests should be examined during  the compression stage• Appearance• Hardness• Tablet weight• F...
Process Validation of oral solid dosageSunday, February 24, 2013                                             25           ...
• In process tests-1.     Moisture content of dried granulation2.     Granulation particle size distribution3.     Blend u...
(8)Tablet coatingtablet coating can occur by different   techniques(eg-sugar,film or compression)• Key area to consider f...
• Too high load at the result attrition occurred.(d)Pan speed- what is the optimal pan speed?• It is interelated to coatin...
• Spray too slowly will cause the coating material to prior to   adhesion to the tablets,result in rough & poor coating   ...
• The stability of the coating solution should be investigated to   establish its shelf life.(j)Coating weight-a min. & ma...
• Finished product tests-1.     Appearance2.     Assay3.     Content uniformity4.     Tablet hardness5.     Tablet friabil...
Conclusion• Tablet dosage form validation should be part of a  comprehensive validation program within an industry.• The m...
THANK                                YOU                            Process Validation of oral solid dosageSunday, Februar...
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Validation of solid oral dosage form, tablet 1

  1. 1. PROCESS VALIDATION OF ORAL SOLID DOSAGE FORM (TABLET)Submitted to:- Prepared by :-Dr. Sanjula Baboota Abdul Muheem M.Pharm 1st YearF/O Pharmacy (Pharmaceutics)Jamia Hamdard JAMIA HAMDARD Process Validation of oral solid dosageSunday, February 24, 2013 1 form (Tablet)
  2. 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.” Process Validation of oral solid dosageSunday, February 24, 2013 2 form (Tablet)
  3. 3. Types of process validation PROCESS VALIDATION RETROSPECTIVE CONCRURRENT PROCESS PROCESS VALIDATION VALIDATION PROSPECTIVE PROCESS VALIDATION Process Validation of oral solid dosageSunday, February 24, 2013 3 form (Tablet)
  4. 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” Process Validation of oral solid dosageSunday, February 24, 2013 4 form (Tablet)
  5. 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 Process Validation of oral solid dosageSunday, February 24, 2013 5 form (Tablet)
  6. 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 Process Validation of oral solid dosageSunday, February 24, 2013 6 form (Tablet)
  7. 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 Process Validation of oral solid dosageSunday, February 24, 2013 7 form (Tablet)
  8. 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 Process Validation of oral solid dosageSunday, February 24, 2013 8 form (Tablet)
  9. 9. Validation protocol for manufacturing of tablets Process Validation of oral solid dosageSunday, February 24, 2013 9 form (Tablet)
  10. 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. Process Validation of oral solid dosageSunday, February 24, 2013 10 form (Tablet)
  11. 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 . Process Validation of oral solid dosageSunday, February 24, 2013 11 form (Tablet)
  12. 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. Process Validation of oral solid dosageSunday, February 24, 2013 12 form (Tablet)
  13. 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. Process Validation of oral solid dosageSunday, February 24, 2013 13 form (Tablet)
  14. 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. Process Validation of oral solid dosageSunday, February 24, 2013 14 form (Tablet)
  15. 15. Process Validation of oral solid dosageSunday, February 24, 2013 15 form (Tablet)
  16. 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 Process Validation of oral solid dosageSunday, February 24, 2013 16 form (Tablet)
  17. 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. Process Validation of oral solid dosageSunday, February 24, 2013 17 form (Tablet)
  18. 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 Process Validation of oral solid dosageSunday, February 24, 2013 18 form (Tablet)
  19. 19. Process Validation of oral solid dosageSunday, February 24, 2013 19 form (Tablet)
  20. 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. Process Validation of oral solid dosageSunday, February 24, 2013 20 form (Tablet)
  21. 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? Process Validation of oral solid dosageSunday, February 24, 2013 21 form (Tablet)
  22. 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. Process Validation of oral solid dosageSunday, February 24, 2013 22 form (Tablet)
  23. 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. Process Validation of oral solid dosageSunday, February 24, 2013 23 form (Tablet)
  24. 24. • The following in-process tests should be examined during the compression stage• Appearance• Hardness• Tablet weight• Friability• Disintegration• Weight uniformity Process Validation of oral solid dosageSunday, February 24, 2013 24 form (Tablet)
  25. 25. Process Validation of oral solid dosageSunday, February 24, 2013 25 form (Tablet)
  26. 26. • In process tests-1. Moisture content of dried granulation2. Granulation particle size distribution3. Blend uniformity4. Individual tablet/capsule weight5. Tablet hardness6. Tablet thickness7. Disintegration8. Impurity profile Process Validation of oral solid dosageSunday, February 24, 2013 26 form (Tablet)
  27. 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? Process Validation of oral solid dosageSunday, February 24, 2013 27 form (Tablet)
  28. 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. Process Validation of oral solid dosageSunday, February 24, 2013 28 form (Tablet)
  29. 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. Process Validation of oral solid dosageSunday, February 24, 2013 29 form (Tablet)
  30. 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 Process Validation of oral solid dosageSunday, February 24, 2013 30 form (Tablet)
  31. 31. • Finished product tests-1. Appearance2. Assay3. Content uniformity4. Tablet hardness5. Tablet friability6. Impurity profile7. 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. Process Validation of oral solid dosageSunday, February 24, 2013 31 form (Tablet)
  32. 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 . Process Validation of oral solid dosageSunday, February 24, 2013 32 form (Tablet)
  33. 33. THANK YOU Process Validation of oral solid dosageSunday, February 24, 2013 33 form (Tablet)
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