Validation by Vilegave Kailash, Shivajirao S. Jondhle college of Pharmacy Asangaon.

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General aspects
Validation of parenterals
Validation of tablets
component of validation,function of different departments,reasons for validation,shivajirao s jondhle college of pharmacy asangaon,validation of parenterals,validation of tablets,validation priority,vilegave kailash

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Validation by Vilegave Kailash, Shivajirao S. Jondhle college of Pharmacy Asangaon.

  1. 1. PRESENTED BY……. Mr. Kailash Vilegave Department Of PharmaceuticsShivajirao S .Jondhle college of pharmacy Asangaon 421601 1
  2. 2. Contents Introduction General aspects Validation of parenterals Validation of tablets References 2
  3. 3. DEFINITION Validation is attaining & documentation of sufficient evidence to give reasonable assurance, stating that equipment or process does & will do what it purports to do. According to US FDA “validation is establishing documented evidence which provides a higher degree of assurance that a specific process , equipment or facility meets its pre determined specifications & quality characteristics & will consistently produce a product of standard quality” 3
  4. 4. Objective :to manufacture product of requisite quality with low cost Govt regulation Assurance of quality Cost reduction 4
  5. 5. WHEN VALIDATION BEGINS Validation should begin in the designing stage for new facility & pre formulation stage for a new dosage form. WHO DOES In order to have a valid & qualified system it must be designed by qualified individuals only. As it is complex process, it is performed by individuals with necessary training & experience & who are themselves previously qualified. 5
  6. 6. Validation team Q.AENGINERING Q.C TASK FORCE LEADERMAINTENANCE R&D MFG 6
  7. 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, process and strictly follow SOP. Follow the validation protocol developQ.C by Q.A & validate the incoming stock ,in process critical system &final product. Establish approvable validationQ.A protocols &conduct process validation by monitoring ,sampling ,challenging the process & equipment. 7
  8. 8. 1. Large volume parenteral.2. Small volume parenteral.3. Ophthalmic, other sterile products & medical devices. 8
  9. 9.  Analytical test procedures Instrument calibration Critical support system Operators Raw materials Packaging materials Equipment validation Facilities Manufacturing process Product design Utilities & services Records & reports 9
  10. 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. 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. 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. 13.  This method includes in process monitoring of critical process steps & end product testing of current production along with documentation . This shows that the manufacturing is in state of control The same parameter of retrospective validation are evaluated with more stress on critical parameters affecting the process . Revalidation This method involves validation of facility which is previously validated 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 specifications 13
  14. 14.  Design & validation of facility There are four basic steps in validation of facility1. Planning2. Documentation3. Construction4. Testing 14
  15. 15. 1. Planning Site selection Design staff Material flow path Room layout 15
  16. 16. Material flow path Receiving stores Component preparation Aseptic filling capping inspection labeling quarantine Release shipping 16
  17. 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. 18. 3. Construction Steps involved are:1. Ground2. Shell3. Rooms4. sewers5. Ductwork6. Landscaping 18
  19. 19.  Its done for1. Sensitivity2. Accuracy3. precision 19
  20. 20. Air system Validation is performed mainly in four phases1. Pre construction phase - - design &engineer air system2. Construction phase - - all steps of planning are in place3. Post Construction phase - - rest phase4. Post Construction phase - -same test are performed with machines HVAC systemPurpose-To provide a specific set of environmental conditions required for manufacturing process. 20
  21. 21. HVAC AIR FILTRATION CONTROL SYSTEMAIR HANDLING AIR DISTRIBUTION 21
  22. 22.  Class-100 room: particle count limit 100/cubic foot of 0.5 µm or larger in size. Class- 10,000 room : particle count limit 10,0000/cubic foot of 0.5 µm or larger in sizeArea Absolute Intermediate Pre-filterpreparation optional recommended recommendedwashing optional recommended recommendedfilling required optional recommendedpackaging not required not recommended recommended 22
  23. 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. 24.  Different classes of waterCLASS MINERAL MICROBE T.M.REM PYROGE QUALITY S OVAL NWELL + + - + IWATERPOTABLE + CONTRO - + II LPURIFIE - CONTRO - + IIID LW.F.RINS - CONTRO + NIL IVE LW.F.I - NIL + NIL V 24
  25. 25. SAMPLE POINT TEST FREQUENCYRAW WATER MICROBIAL, cl DAILY RESIDUAL, TDS,PHFILTERS MICROBIAL, cl DAILY RESIDUALDISTILLATION /R.O MICROBIAL ,pH CONTINUOUSEQUIPEMENTSTORAGE TANK MICROBIAL, p H, MULTIPLE TIME IN PYROGEN, CYCLE CHEMICALS USP.DISTRIBUTION MICROBIAL DAIILY/USAGE POINT PYROGEN , pH 25
  26. 26. 1.VALIDATION OF GASES : nitrogen, carbon dioxide, compressed air. VALIDATION OF GASES INCLUDES 3 STEPS Supply of gas (adequate purity & quality) Storage conditions Distribution network 26
  27. 27. 2. Validation of steam system validation of steam generator Efficiency. Pressure. Analysis of condensate. Distribution network.3. Validation of electrical system main objective is to meet : Qualitative specifications. (frequency, voltage, stability ). Quantitative specifications ( load demand). Back up system are validated . 27
  28. 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. 29.  D-value: time required to reduce the microbial content by 90%i.e.one logarithmic reduction F-value: time required to destroyed all spores of suspension when using 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 of microbial population. 29
  30. 30.  Biological indicator E.g. for steam sterilization-Bacillus stearothermophillus for dry heat sterilization- Bacillus subtilis var. niger for ethylene oxide- Bacillus subtilis var. globigli for ionizing radiation- bacillus pumilis 30
  31. 31.  Operation condition are 121ºc, 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 + 2.5ºc5. Heat penetration studies By container mapping studies- in which thermocouples are introduced at different heights in the container. 31
  32. 32.  Its done for Batch oven & tunnel oven validation mainly includes1. Qualification & calibration2. Selection & calibration of thermocouples3. Selection & calibration of B.I4. Air balance determination5. Heat distribution studies 1. cool spot is find out 2. temp dif should not be more than + 2.5ºc6. Heat penetration studies 32
  33. 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 of radiation is released every time. Normal dose for over kill approach is 2.5 Mrad. 33
  34. 34.  Sources for 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 something other thsn hepa filters i.e. SANITIZERDef- it is defined as a chemical agent that kills microbial contamination in the vegetative form only.E.g.; Hypochlorite , phenol ,surfactant etc. 34
  35. 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. 36.  a) INTEGRITY OF RUBBER :1. Quality2. Penetratability3. Fragmentation4. Water extractive5. Self-seal ability b) INTEGRITY OF GLASS : There are mainly 4 types of glass TYPE 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. 37. 1. Chemical composition2. Leaching3. Powder glass test4. Water attack test C) Leaking tests: There are mainly two types of leak test:1. Vacuum dye leak test.2. Autoclave dye test. 37
  38. 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. 39.  Key elements that form the basis of a prospective process validation program1.Definition of the desirable attributes of drug product or components thereof as well as those characteristics that are not desired2. Establishment of limitation or constraints for these attributes3. Determination of the controls or testing parameters that will be measured or tested.4. Initiation of studies to establish control or boundary limits for those attributes that influence the product, process ,quality & performance. 39
  40. 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 uptake compressibility ,lubricant efficiencyeg;1) Mg sterate (lubricant). Its action depends on particle size. 2) dyes (color) variation in material occur depending up on ….a) Method of transportation chosen,b) Exposure of material to undesirable conditions (heat and humidity) 40
  41. 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. 42.  Once the samples of raw materials have been selected it should be used to manufacture a batch of final dosage form it may be appropriate to manufacture to several lots of final product with raw material at the low &high ends of the specifications limit . The final step of raw material should involve an on –site inspection of the supplier to review the vendors manufacturing operations and control procedures 42
  43. 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. 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 parameter E.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. 45.  General tests in process validation are1. Moisture content2. Content uniformity3. Hardness4. Disintegration & dissolution5. Friability6. Weight variation7. Granulation particle size distribution 45
  46. 46. A. Tablet composition: Normal properties Density Particle size distribution Surface area Flow properties Moisture content solubility 46
  47. 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. 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 / application 48
  49. 49. D. Equipment evaluation Blending equipment Granulating equipment Tablet equipment Tablet coating. 49
  50. 50. ReferencesPharmaceutical dosage forms: parenterals medications vol III LACHMANLEBERMANNPHARMACEUTICAL PROCESS VALIDATION BERRY & NASHValidation of aseptic pharmaceutical process J.P.AGALLOCCOCARLETONWWW.GOOGLE.CO.IN. 50
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