1. PRESENTED BY.Mr. Kailash Vilegave Department Of PharmaceuticsShivajirao S .Jondhle college ofpharmacy Asangaon 421601 1

2. Contents Introduction Generalaspects Validation of parenterals Validation of tablets References2 3. DEFINITION Validation is attaining & documentation of sufficientevidence to give reasonable assurance, stating thatequipment or process does & will do what it purports todo.According to US FDA validation is establishing documented evidence whichprovides a higher degree of assurance that a specificprocess , equipment or facility meets its pre determinedspecifications & quality characteristics & will consistentlyproduce a product of standard quality 3 4. Objective :to manufacture product of requisitequality with low cost Govt regulation Assurance of quality Cost reduction 4 5. WHEN VALIDATION BEGINS Validation should begin in the designing stage for newfacility & pre formulation stage for a new dosage form. WHO DOES In order to have a valid & qualified system it must bedesigned by qualified individuals only. As it is complex process, it is performed by individualswith necessary training & experience & who arethemselves previously qualified. 5 6. Validation team Q.AENGINERING Q.CTASK FORCELEADERMAINTENANCER&D MFG 6 7. Install, qualify & certify plant facility,Engineering equipment &support systems.Design, optimize, qualifyR&D manufacturing process with limits &specifications.Operate & maintain plant facilities,Manufacturing equipments ,support systems, processand strictly follow SOP.Follow the validation protocol developQ.C by Q.A & validate the incoming stock,in process critical system &finalproduct.Establish approvable validationQ.A protocols &conduct process validationby monitoring ,sampling ,challengingthe process & equipment. 7 8. 1. Large volume parenteral.2. Small volume parenteral.3. Ophthalmic, other sterile products & medical devices. 8 9. Analytical test procedures Instrument calibration Critical support system Operators Raw materials Packaging materials Equipment validation Facilities Manufacturing process Product design Utilities & services Records & reports9 10. 1. Prospective validation.2. Retrospective validation.3. Concurrent validation.4. revalidation. Prospective validation This is validation program executed before commercialization of a new drug/ formulation, to make sure that there are no potential hazards in full scale manufacture of product. 10 11. It is a program chosen for established products whose manufacturing process are considered stable (i.e. long history of state control operation).This method involves statistical analysis of numerical data obtained from different batches & then justify whether the system is qualified or not.The data includesa) MFR,BFR.b) b) assay values.c) End product test results.d) In process data.11 12. Different parameters checked in parenteral. pH value. Viscosity. Density. Color & clarity. Potency. Sterilization parameters.Different statistical methods are Basic statistics (mean , standard deviation, tolerance limit ) . Analysis of variance (ANOVA) . Regression analysis. Cumulative sum analysis. Control charting most advance & useful. 12 13. This method includes in process monitoring of critical processsteps & end product testing of current production along withdocumentation . This shows that the manufacturing is in state of control The same parameter of retrospective validation are evaluated withmore stress on critical parameters affecting the process . Revalidation This method involves validation of facility which is previouslyvalidated when1 Change in critical component .2 Change in critical piece of equipment.3 Change in facility / plant (design / location ).4 Significant increased / decease in batch size.5 Sequential batches fail to meet product / process specifications13 14. Design & validation of facility There are four basic steps in validation of facility1. Planning2. Documentation3. Construction4. Testing 14 15. 1. PlanningSite selectionDesign staffMaterial flow pathRoom layout15 16. Material flow pathReceiving stores Component preparation Aseptic fillingcapping inspectionlabelingquarantine Release shipping 16 17. Typical room layout: Salient feature Double door with interlock system Positive pressure in sterile area. Separate entry for material &personal. Clean room or class-100 room in the filling area. Entry is done only after gowning 17 18. 3. ConstructionSteps involved are:1. Ground2. Shell3. Rooms4. sewers5. Ductwork6. Landscaping 18 19. Its done for1. Sensitivity2. Accuracy3. precision19 20. Air system Validation is performed mainly in four phases1.Pre construction phase - - design &engineer air system2.Construction phase - - all steps of planning are inplace3.Post Construction phase - - rest phase4.Post Construction phase - -same test are performedwith machines HVAC systemPurpose-To provide a specific set of environmentalconditions required for manufacturing process. 20 21. HVACAIR FILTRATION CONTROL SYSTEMAIR HANDLING AIR DISTRIBUTION21 22. Class-100 room: particle count limit 100/cubic foot of 0.5 mor larger in size. Class- 10,000 room : particle count limit 10,0000/cubic footof 0.5 m or larger in sizeAreaAbsolute Intermediate Pre-filterpreparation optional recommendedrecommendedwashing optional recommendedrecommendedfilling required optional recommendedpackaging not required notrecommended recommended22 23. Hepa filter leak test . Temperature control test. Humidity control test. Air flow uniformity test. Pressure control test. Particle count test. Induction leak test. Airborne microbial sampling. 23 24. Different classes of waterCLASSMINERAL MICROBE T.M.REM PYROGE QUALITY S OVALNWELL+ +-+IWATERPOTABLE +CONTRO-+II LPURIFIE -CONTRO-+IIIDLW.F.RINS-CONTRO+NILIVELW.F.I - NIL+NILV 24 25. SAMPLE POINTTEST FREQUENCYRAW WATER MICROBIAL, clDAILYRESIDUAL, TDS,PHFILTERS MICROBIAL, clDAILYRESIDUALDISTILLATION /R.O MICROBIAL ,pHCONTINUOUSEQUIPEMENTSTORAGE TANKMICROBIAL, p H,MULTIPLE TIME INPYROGEN, CYCLECHEMICALS USP.DISTRIBUTIONMICROBIALDAIILY/USAGE POINTPYROGEN , pH25 26. 1.VALIDATION OF GASES : nitrogen, carbondioxide, compressed air.VALIDATION OF GASES INCLUDES 3 STEPSSupply of gas (adequate purity & quality)Storage conditionsDistribution network 26 27. 2. Validation of steam system validation of steam generator Efficiency. Pressure. Analysis of condensate. Distribution network.3. Validation of electrical systemmain objective is to meet : Qualitative specifications. (frequency, voltage,stability ). Quantitative specifications ( load demand). Back up system are validated . 27 28. VALIDATION OF FILLINGParenterals are checked for1. Fill volume2. Syringe able volume3. Sterile fillingMonitoring of viable &non viable particles: Particle counter Strip test Reuter centrifugal sample (RCS)28 29. D-value: time required to reduce the microbial content by90%i.e.one logarithmic reduction F-value: time required to destroyed all spores of suspension whenusing a suspension at 121 c Z-value: the no of degree required for 1 log reduction in D-value N0 value: No of living organism / defined unit of surface Log reduction value: ability of filter in terms of log reduction ofmicrobial population.29 30. Biological indicator E.g. for steam sterilization-Bacillus stearothermophillusfor dry heat sterilization- Bacillus subtilis var. nigerfor ethylene oxide- Bacillus subtilis var. globiglifor ionizing radiation- bacillus pumilis30 31. Operation condition are 121c, 15Psig, for 20 min1. Qualification & calibration:Checking, upgrading the unit2. Selection & calibration of thermocouples3. Selection & calibration of B.I4. Heat distribution studies 1. cool spot is find out 2. temp dif should not be more than + 2.5c5. Heat penetration studiesBy container mapping studies- in which thermocouples are introduced at different heights in the container.31 32. Its done forBatch oven & tunnel oven validation mainly includes1.Qualification & calibration2.Selection & calibration of thermocouples3.Selection & calibration of B.I4.Air balance determination5. Heat distribution studies1. cool spot is find out2. temp dif should not be more than + 2.5c6. Heat penetration studies32 33. Validation of radiation sterilization Major source are cobalt 60, ceasium136 . Determine D-values using biological indicator. First calculation of dose based on bio burden. Calibration of equipment so that same amount ofradiation is released every time. Normal dose for over kill approach is 2.5 Mrad.33 34. Sourcesfor contamination are Skin &hair fragments. Droplets from mucous membrane. Material deposition due to personal. Fibers released from person &equipment. Packaging material. so to maintain aseptic conditions we need somethingother thsn hepa filters i.e. SANITIZERDef- it is defined as a chemical agent that kills microbialcontamination in the vegetative form only.E.g.; Hypochlorite , phenol ,surfactant etc.34 35. Membrane filters are cartridges & plates Physical integrity of filter media is checked by1. Bubble point test.2. Bacterial challenge test.3. Flow rate.4. Longevity of filter.35 36. a) INTEGRITY OF RUBBER :1. Quality2. Penetratability3. Fragmentation4. Water extractive5. Self-seal abilityb) INTEGRITY OF GLASS : There are mainly 4 types of glassTYPE I (borosilicate glass ). For (parenterals)TYPE II ( treated soda lime glass). (for dry powders)TYPE III (soda lime glass).TYPE IV (non parenteral glass) 36 37. 1. Chemical composition2. Leaching3. Powder glass test4. Water attack testC) Leaking tests: There are mainly two types of leak test:1. Vacuum dye leak test.2. Autoclave dye test.37 38. Validationis a systematic approach to identifying, measuring, evaluating ,documenting,& reevaluating a series of critical steps in manufacturing process that require control to ensure are producible final product.38 39. Keyelements that form the basis of a prospective process validation program1.Definition of the desirable attributes of drug product orcomponents thereof as well as those characteristics thatare not desired2. Establishment of limitation or constraints for theseattributes3. Determination of the controls or testing parameters thatwill be measured or tested.4. Initiation of studies to establish control or boundary limitsfor those attributes that influence the product, process,quality & performance. 39 40. It includes validation of both active ingredients& excipients.Characteristicsparticle size, surface area, color, density.Chemical characteristics- water content residue on ignition &heavy metals.Variables: Flow, blend uniformity, granulation solution/binder uptakecompressibility ,lubricant efficiencyeg;1) Mg sterate (lubricant). Its action depends on particlesize. 2) dyes (color) variation in material occur depending up on .a) Method of transportation chosen,b) Exposure of material to undesirable conditions (heat andhumidity) 40 41. Steps involved in validation of raw materials1. Each raw material should be validated by performing checks on several batches, preferably 3,from the primary supplier as well as the alternate supplier .the batches chosen should be selected to represent the range of acceptable specifications both high and low2. Depending on susceptibility of the raw material to ageing ,either physical , chemical or microbial stability assessed . 41 42. Once the samples of raw materials have been selected it shouldbe used to manufacture a batch of final dosage form it may beappropriate to manufacture to several lots of final product withraw material at the low &high ends of the specifications limit . The final step of raw material should involve an on siteinspection of the supplier to review the vendors manufacturingoperations and control procedures 42 43. Analytical criteria must be assessed .1. Accuracy of method2. Precision of method3. In day /out of-day variation4. Operator variation.5. Instrument variation6. Laboratory variation 43 44. process validation can be defined as means of challenging a process during development to determine which variables must be controlled to ensure consistent production of a product or intermediate.Steps in development of validation program :1. Obtaining test data to determine the numerical range of each parameterE.g.: assess the tablet hardness over a series of batches .2. Establishing specification limits from the test data derived for a given parameter.3. Determining how well the specification limit indicates that the process is under control4. Certify the equipment operating conditions Eg: rpm , temp, are within specification limits.44 45. General tests in process validation are1. Moisture content2. Content uniformity3. Hardness4. Disintegration & dissolution5. Friability6. Weight variation7. Granulation particle size distribution 45 46. A. Tablet composition: Normal properties Density Particle size distribution Surface area Flow properties Moisture content solubility46 47. B. Process evaluation & selection: Blending operation Determine time of un mixing Characteristics of blend bulk density Particle size distribution Color uniformityC. Wet granulation1.Evaluation of binder Binder concentration Solubility in granulating solution2.Evalution of mixed granulation3.Evalution of drying 47 48. 4. Tablet compression Appearance Color quality Power flow Speed of tablet machine5.Tablet coating Evaluate coating procedure in different size pans Coating speed Amount of material required / application48 49. D. Equipment evaluation Blending equipment Granulating equipment Tablet equipment Tablet coating.49 50. ReferencesPharmaceutical dosage forms: parenterals medications vol III LACHMANLEBERMANNPHARMACEUTICAL PROCESS VALIDATION BERRY & NASHValidation of aseptic pharmaceutical process J.P.AGALLOCCOCARLETONWWW.GOOGLE.CO.IN. 50 51. 51