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Product validation

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pharmaceutical product validation

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Product validation

  2. 2. DEFINITION- Validation is a key process for effective quality assurance. “Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.” or Defined as the verification, by data and analysis that the design objectives of a given facility, system, apparatus or procedures are reliably fulfilled in routine operation 2
  3. 3. The major reasons for validation are: • Quality assurance: Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch. • Economics: Due to successful validation, there is a decrease in sampling and testing procedures and there are less number of product rejections and retesting. This leads to cost-saving benefits. 3
  4. 4. • Compliance: For compliance to current good manufacturing practices, validation is essential. Validation involves in the steps: 1. Choosing the desired attributes of the product. 2. Determining specifications for those attributes. 3. Selecting appropriate processes and equipment. 4. Monitoring and testing processes, equipment and personnel while in operation 5. Examining test procedures themselves to ensure their accuracy and reliability. 4
  5. 5. PRODUCT VALIDATION Product validation is associated with validation of the full-scale manufacture of numerous earlier aspects of product development that are critical to the subsequent phases of the process. Product validation involves following steps: • validation of raw materials • validation of excipients. • validation of analytical methods • validation of finished product 5
  6. 6. VALIDATION OF RAW MATERIALS • Validation of raw materials is one of the major causes of product variation or deviation from specification. The API may represent the most uncontrollable component in the complete product . • The validation process of dosage form begins with the validation of raw materials ,both API and excipients. • Preformulation is one of the critical step to be validated in product validation • Physical characters such as drug and particle size can affect material flow and blend uniformity. • Chemical characters like impurities can effect stability of drug. The hygroscopic nature is important in both handling and reproducibility of the manufacturing process. 6
  7. 7. VALIDATION OF EXCIPIENTS Excipients can represent less then 1% of a tablet formula Factors to be aware of are • The grade and source of the excipients • Particle size and shape characteristics and • Lot-to-lot variability Example : Microcrystalline cellulose(MCC) used as diluents shows significant changes in the chemical composition, crystalinity, particle size between different lots. Differences in particle size of MCC can affect wet granulation/blend uniformity of tablet formulation. In direct compression formulations differences in particle size distribution between lots can result in • Non uniformity in initial mix • Materials segregate during compression. 7
  8. 8. VALIDATION OF ANALYTICAL METHODS Accuracy of method: • Ability of a method to measure the true value of a sample. Specificity: • Ability to accurately measure the analyte in the presence of other components Repeatability:( in day /out of day variation ) • Does the precision and accuracy of the method change when conducted numerous times on the same day and repeated on a subsequent day? 8
  9. 9. Reproducibility:( between operator variation ) • Repeat the precision and accuracy studies within the same lab using the same instrument but different analysts to challenge the reproducibility of the method. Precision: (between instrument variation ) • How will different instruments within the same lab run by the same analyst affect the accuracy and precision of the method. Ruggedness:( between laboratory variation) • Will the precision and accuracy of the method be same between the development and quality control lab? 9
  10. 10. Validation of finished product • Organoleptic characteristic • Physical characteristic • Chemical characteristic • Biological characteristic • Microbiological characteristic • Stability testing • Storage condition 10
  11. 11. Validation of tablets 11
  12. 12. TABLET COMPRESSION The following in-process tests should be examined during the compression stage- • Appearance • Hardness- 4 -8 kg/cm • Tablet weight-90-110% • Friability-0.5-1% • Disintegration-15-30 min • Weight uniformity 12
  13. 13. TEST FOR TABLET COATING • cracking or peeling of the tablet • color uniformity • coating efficiency should be determined for the coating operation 13
  14. 14. TEST IN- PROCESS TEST Finished product • Moisture content of dried granulation- usually less then 2% • Granulation particle size distribution • Appearance • Individual tablet weight • Tablet hardness • Tablet thickness • friability • Disintegration • stabilty • Appearance • Assay • content uniformity • Tablet hardness • Tablet thickness • Impurity profile • dissolution 14
  15. 15. Validation of capsules 15
  16. 16. TEST PHYSICAL TEST CHEMICAL TEST  Disintegration test  Weight variation Dissolution test Assay Content uniformity Stability testing Moisture permeation test 16
  17. 17. 17
  18. 18. • ORAL LIQUID DOSAGE FORMS – Monophasic • Simple solutions • Draughts • Drops • Linctuses • Syrups • Elixirs – Biphasic • Suspensions (solid in liquid) • Emulsions (liquid in liquid) 18
  19. 19. Major test parameters used for final product testing Appearance pH Viscosity Specific gravity Microbial count Leakage test for filled bottle (By plastic vacuum dessicator) Check the cap sealing Fill volume determination Particulate matter testing Water vapour permeability test Stress test 19
  20. 20. Test parameters specific for suspension • Sedimentation rate • Resuspendibility • Particle size & particle size distribution • Zeta potential measurement Type of emulsion determination by • Dilution test • Conductivity test • Dye solubility test • COCl2 filter paper • Fluorescence test • Direction of creaming Test parameters specific for solution • Clarity of solution • Color of solution 20
  21. 21. Semisolid Dosage Form
  22. 22. 22
  23. 23. Evaluation of Ointments Evaluation of creams Content uniformity of drug  Penetration Rate of release of medicament Absorption of medicament in blood stream Irritant effect: Rheology Sensitivity 23
  24. 24. • Evaluation of gel Visual appearance Drug content Measurement of pH Viscosity Spreadability Extrudability Stability 24
  25. 25. • Evaluation of paste 25 Abrasiveness Particle size Cleansing property Consistency pH of the product Foaming character Limit test for arsenic and lead Volatile matters and moisture
  26. 26. • Evaluation of Transdermal patches 26 Physiochemical evaluation Thickness of the patch Folding endurance Percentage of moisture absorbed Percentage of moisture lost Drug content uniformity  skin irritation test Stability test
  27. 27. • Evaluation of suppositories 27  Appearance  Uniformity of weight test  Melting rang test  Breaking test  Dissolution test
  28. 28. • Evaluation of Aerosols 28 Leakage test Internal pressure Spray pattern Discharge rate Flammability Particle size analysis Moisture determination
  29. 29. Steam sterilization process • Sterile product have several unique dosage from properties such as freedom from micro organism , freedom from pyrogens, freedom from particulates and extremely high standards of purity and quality • However, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination Basic principle in the validation of sterile product • The theoretical approaches to validation the performance of the actual validation experiments and the analysis and documentation of the validation data Theoretical approaches • Generally five basic step are necessary to validate manufacturing process 29
  30. 30. 1. Written documentation 2. Manufacturing parameters 3. Testing parameters 4. In process controls 5. Final product testing Each validation process should have a documented protocol of the steps to follow and the data to collect during the experimentation example : Steam sterilization process 30
  31. 31. • Steam sterilization process summary sheet 31 Autoclave identification number or latter P6037 Location Building 22, floor 1 Tag no 896101 Validation date 10-14-99 Revalidation date 4-14-00 Description of process validation Load containing filling equipment & accessories not to exceed 102 kg Temperature set point for validation 121.0 0 c Cycle validated +0.50 c Validation records stored archives A 105 - 11 Revalidation records stored in archives C314-70
  32. 32. • Evaluation of Ophthalmic product 32 Sterility Clarity test Leakage test pH Viscosity Irritancy test Endotoxin test
  33. 33. • Evaluation of Parenteral product 33 Leakage test Content uniformity test Color and clarity Endotoxin test Pyrogen test Sterility test
  34. 34. Example of Process validation protocol  Contents 1. Protocol Approval 2. Objective 3. Scope 4. Validation Approach 5. Document Required 6. List of Equipments 7. Product Detailed 8. Parameter to be tested 9. Sampling plan 10. Acceptance Criteria 34
  35. 35. 1. Protocol Approval • Protocol effective date: • 2. Objective • 3. Scope • 4. Validation approach • Prepared by Checked by Name Designation signature Prepared by Checked by Rechecked by 35
  36. 36. 5. Document required 6. List of equipments Prepared by Checked by Document Effective Date Ref. No. BMR BPR Test data sheet 36
  37. 37. 7.Product detailed • Generic name: • Brand name: • Product description: • Dosage form: • Labeled claim: • Category: • Composition with specification: Prepared by Checked by 37
  38. 38. 8. Parameters to be tested Process stage Process variable Validation response 1) Mixing a) Mixing time b) Mixing rate c) Mixing temp. →By assay →Consistency Test 2) Filling a) Filling rate b) Speed →Weight variation →Sealing temp. →Pressure, Crimping →Coding. Prepared by Checked by 38
  39. 39. . 9. Sampling plan Prepared by Checked by Process Stage No. of sample taken Qty Test 1) Mixing 2 30 gm from each location Qty of sample taken Test 2) Filling Equivalent to no of filling station 39
  40. 40. 10. Acceptance criteria Prepared by Checked by Stage Tests Acceptance Criteria 1) Mixing Assay of ingredients Consistency test Spread smoothly & homogeneously 2) Filling FOR 15 gm Wt of empty tube Wt of filled tube Net content Crimping Coding Sealing Sealing temp. Air trapping Pressure Assay of ingredients Legible Straight & Smooth Complete & Leak proof 280°C – 300°C Free from air bubble 3.5 – 4.0 Kg/cm2 40
  41. 41. REFERENCE- • http//www.pharmainfo.net/reviews/guidelines-general- principles-validation-solid-dosage. • Pharmaceutical process validation ( In International third edition ) edited by Robert A. NASH Printed and bound by Replika press pvt.Ltd.india • Validation of pharmaceutical process (third edition ) edited by James Agallow ,2008 by informa health care USA INC • Apps.who.int./print/en/p/docf/WHO Pharmacopoeia • www.ncbi.nlm.nih.gov/pmc/articules/pmc 35355108 • www.usp.org/site/defeult/files/usp-pdf/topical and transdermal .pdf 41
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