New WHO Guidance on Analytical Method Validation
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This document summarizes guidelines for analytical method validation from a presentation by the non-profit organization "Drug Regulations". Key points include: analytical methods must be validated for their intended use; validation should demonstrate accuracy, precision, specificity, linearity, range and robustness; changes may require revalidation; and transfer between labs requires verification to ensure equivalent performance.
New WHO Guidance on Analytical Method Validation
- 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.
- 2. This presentation is compiled from freely available resource like the website of WHO specifically WHO Draft Guidance Titled GUIDELINES ON VALIDATION – APPENDIX 4 ANALYTICAL METHOD VALIDATION “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit Our Website GMP Training for latest information from the world of Pharmaceuticals. 04-09-2016 2 Visit Our WEBSITE GMP Training http://fdagmp.blogspot.in/
- 3. This presentation is based on WHO Draft Guidance titled GUIDELINES ON VALIDATION – APPENDIX 4 ANALYTICAL METHOD VALIDATION 04-09-2016 3Visit Our Website GMP Training
- 4. The need for revision of earlier Supplementary guidelines on good manufacturing practices: validation was identified by the Prequalification of Medicines Programme A draft document was circulated for comment in early 2013. 04-09-2016 4Visit Our Website GMP Training
- 5. The focus of the revision was the Appendix on non- sterile process validation (Appendix 7), which had been revised and was adopted by the Committee at its forty- ninth meeting in October 2014. ◦ See our presentation here Modified Appendix 4 on Analytical Method Validation is now published in working document QAS/16.671. 04-09-2016 5Visit Our Website GMP Training
- 6. This guidance covers following ◦ Principle ◦ General ◦ Pharmacopoeial Methods ◦ Non Pharmacopoeial Methods ◦ Method Validation ◦ Method Verification ◦ Method Transfer ◦ Revalidation ◦ Characteristics of Analytical Methods 04-09-2016 6Visit Our Website GMP Training
- 7. This guidance presents information on the characteristics that should be considered during Analytical method Validation. 04-09-2016 7Visit Our Website GMP Training
- 8. Approaches other than that specified in this guidance can be adopted. Manufacturers should choose validation protocols and and procedures most suitable for testing their products. 04-09-2016 8Visit Our Website GMP Training
- 9. It is essential to demonstrate that the Analytical Procedure is suitable for intended use. All analytical methods should be validated. ◦ Whether they are stability indicating or not 04-09-2016 9Visit Our Website GMP Training
- 10. Validation of Analytical method should be performed by the R & D There after the method can be transferred to Quality Control. Follow recommendations provided in Good Laboratory practices guidance Also follow the recommendations given in Transfer of Technology Guidance. 04-09-2016 10Visit Our Website GMP Training
- 11. Have specifications for both materials and products. The tests to be performed should be described in the documentation on Standard Test Methods. 04-09-2016 11Visit Our Website GMP Training
- 12. Pharmacopeial or Non Pharmacopeial Methods May be Used. Well Characterized reference materials with documented purity should be used in analysis. 04-09-2016 12Visit Our Website GMP Training
- 13. Most common Analytical procedures Include ◦ Identification Tests ◦ Assay of Drug Substance ◦ Assay of Pharmaceutical Products ◦ Quantitative tests for content of Uniformities ◦ Limit Test for Impurities ◦ Dissolution Testing ◦ Determination of Particle Size. 04-09-2016 13Visit Our Website GMP Training
- 14. The Results of Analytical Procedures should be ◦ Legible ◦ Contemporaneous ◦ Original ◦ Reliable ◦ Reproducible All Results should be archived for an appropriate period of time. They should be in compliance with NRA requirements 04-09-2016 14Visit Our Website GMP Training
- 15. The procedure should become part of a continuous verification procedure Demonstrate that it meets predefined criteria over the life of the procedure. 04-09-2016 15Visit Our Website GMP Training
- 16. Perform following at intervals to ensure that the method is appropriate for its intended use. ◦ Trend Analysis ◦ Risk Assessment 04-09-2016 16Visit Our Website GMP Training
- 17. Manage changes to methods as per COC procedure Consider following when methods are transferred from one lab to another or when major pieces of analytical equipment are changed: ◦ Variability of Reference materials. ◦ Changes in process of synthesis ◦ Changes in composition of the finished product ◦ Changes in Analytical Procedure 04-09-2016 17Visit Our Website GMP Training
- 18. The changes referred earlier should be ◦ Understood ◦ Controlled ◦ Where possible reduced. Consider Verification or Revalidation 04-09-2016 18Visit Our Website GMP Training
- 19. Perform risk assessment for such changes Scope of verification & degree of revalidation depend on ◦ Nature of changes ◦ Out come of risk assessment 04-09-2016 19Visit Our Website GMP Training
- 20. Analyst should be appropriately qualified. Qualification should be documented For certain tests conduct “Analyst Proficiency” Data for method validation and verification should be covered by GxP Follow good data and record management. Associated metadata should also be retained and be subjected to good data and record management practices. 04-09-2016 20Visit Our Website GMP Training
- 21. Use of computerized systems should comply with the principles given in Guidance for Computerized Systems Validation. Pay Adequate attention to sample preparation. This step should be described in as much detail as possible. 04-09-2016 21Visit Our Website GMP Training
- 22. Attention should be paid to factors such as : ◦ Sonification Time ◦ Sonification Bath Temperature ◦ Mixing ◦ Demixing where such is known to happen 04-09-2016 22Visit Our Website GMP Training
- 23. Document & report all failures during method validation. Also document how these failures were overcome It is not acceptable to give only passing results. This will give biased information about reliability of the method. 04-09-2016 23Visit Our Website GMP Training
- 24. When such method are used there should be evidence that such methods are suitable for routine laboratory use. i.e. The methods should be verified. When such methods are used for determination of content or impurities , the specificity of the methods should be demonstrated. i.e. Specificity with respect to the substance under consideration – no placebo interference. 04-09-2016 24Visit Our Website GMP Training
- 25. All Non Pharmacopoeial Methods should be appropriately validated. 04-09-2016 25Visit Our Website GMP Training
- 26. Perform validation as per a protocol. Protocol should include procedure and acceptance criteria for all characteristics. Results should be documented in the validation report. Justification should be provided if Non Pharmacopoeial methods are used when Pharmacopoeial are available. Justification should include data for comparison with Pharmacopoeil and other methods. 04-09-2016 26Visit Our Website GMP Training
- 27. Standard Test methods should be described in details. They should provide sufficient information to allow a properly trained analyst to perform analysis in reliable manner. As a minimum, the description should include chromatographic conditions, reagent needed, reference standards, formulae for calculation of results and system suitability tests. 04-09-2016 27Visit Our Website GMP Training
- 28. Method verification consists of partial velidation. It should be performed for a validated method under following conditions: ◦ When an already validated method is used on a product for the first time. Change of active ingredient supplier, change in method of synthesis, reformulation of a drug product ◦ When an already validated method is used in a laboratory for the first time. In some cases method transfer may be preferred. 04-09-2016 28Visit Our Website GMP Training
- 29. May include only the validation characteristics of relevance to the particular change. ◦ In case of change in API supplier the expected change would be impurity profile or solubility of the API. ◦ Therefore for an Related substances method there should be an appropriate verification that the method is able to detect and quantitate all potential impurities including the late eluting ones. ◦ Specificity should be amongst the tests considered. 04-09-2016 29Visit Our Website GMP Training
- 30. Method Verification is suitable in lieu of method validation for Pharmacopoeial methods. 04-09-2016 30Visit Our Website GMP Training
- 31. Methods should be maintained in validated state over the life of the method. Perform Revalidation when there are following changes: ◦ Changes to the Mobile Phase( Refer Pharmacopoeias for acceptance limits beyond which revalidation must be performed. ◦ Changes to the column ◦ Changes to the temperature of the column ◦ Changes to the concentration/composition of the sample and standards 04-09-2016 31Visit Our Website GMP Training
- 32. Perform Revalidation when there are following changes: ◦ Changes to the detector Change in detector type Wavelength of detection 04-09-2016 32Visit Our Website GMP Training
- 33. Perform Revalidation when there are following changes: ◦ In cases of repeated system suitability failures ◦ In case of doubtful results ◦ In such cases perform an investigation to determine root cause. ◦ Then make appropriate changes and revalidate the methods 04-09-2016 33Visit Our Website GMP Training
- 34. Perform revalidation according to a period that is scientifically justifiable. It is acceptable to include only the validation characteristics of relevance to the particular change and methods 04-09-2016 34Visit Our Website GMP Training
- 35. Establish Documented evidence that ◦ a method has equivalence performance when used in a laboratory different from that where it was originally validated. 04-09-2016 35Visit Our Website GMP Training
- 36. Generally it should be performed ◦ By comparing a set of results obtained by an analyst in one laboratory ◦ to that obtained by another analyst at the laboratory to which the method is being transferred. 04-09-2016 36Visit Our Website GMP Training
- 37. Two set of results should be statistically compared The differences between the two sets of test results should be within an acceptable range. 04-09-2016 37Visit Our Website GMP Training
- 38. Method transfer should be performed before testing of samples for obtaining critical data. ◦ For Dossier ◦ Process Validation ◦ Stability Studies ◦ For Routine use 04-09-2016 38Visit Our Website GMP Training
- 39. Follow a predetermined protocol which should include: ◦ A title ◦ Objective ◦ Scope ◦ Responsibilities of the sending unit & the receiving unit ◦ A specification of materials and methods ◦ Experimental design ◦ Acceptance criteria 04-09-2016 39Visit Our Website GMP Training
- 40. Follow a predetermined protocol which should include: ◦ Documentation: Information to be supplied with results, forms etc. ◦ Deviation handling procedure ◦ References ◦ Details of Reference samples, starting materials, intermediates and finished products Protocol should be authorized and dated 04-09-2016 40Visit Our Website GMP Training
- 41. Independent Testing by a separate entity: National Quality Control Testing Laboratory. This may not be considered an obligation. This may be considered an optional step when encountering difficulties in applying a particular method. ◦ Refer WHO Guidance on technology Transfer (See our Presentation) 04-09-2016 41Visit Our Website GMP Training
- 42. Consider following Characteristics while validation: ◦ Specificity ◦ Linearity ◦ Range ◦ Accuracy ◦ Precision ◦ Detection Limit ◦ Quantitation Limit ◦ Robustness 04-09-2016 42Visit Our Website GMP Training
- 43. Accuracy ◦ Degree of agreement of Test Results with the True Value ◦ Closeness of the results obtained by the procedure to the true value. ◦ Generally established on samples of the material to be examined that have been prepared to quantitative accuracy. ◦ Should be established across the range specified for the analytical procedure. 04-09-2016 43Visit Our Website GMP Training
- 44. Accuracy ◦ Acceptable to use a spiked placebo where a known quantity or concentration of a reference material is used. 04-09-2016 44Visit Our Website GMP Training
- 45. Precision ◦ Degree of agreement among individual results. ◦ Apply complete procedure repeatedly to separate identical samples drawn from the same homogenous batch of materials. ◦ Measured by the scatter of individual results from the mean. ◦ Expressed as the Relative Standard Deviation-RSD 04-09-2016 45Visit Our Website GMP Training
- 46. Repeatability ◦ Determine using a minimum of nine determinations covering the specified range for the procedure. ◦ Three concentration/three replicates each or ◦ A minimum of six determinations at 100 % of the test concentrations. 04-09-2016 46Visit Our Website GMP Training
- 47. Intermediate Precision ◦ This expresses within laboratory variations Different days Different analysts Different equipment ◦ If reproducibility is assessed , a measure of intermediate precision is not required. 04-09-2016 47Visit Our Website GMP Training
- 48. Reproducibility ◦ Expresses precision between laboratories 04-09-2016 48Visit Our Website GMP Training
- 49. Robustness( or Ruggedness) ◦ Ability of the procedure to provide analytical results of acceptable accuracy and precision under a variety of conditions. 04-09-2016 49Visit Our Website GMP Training
- 50. Robustness( or Ruggedness) ◦ Results from separate samples are influenced by changes in the operational or environmental conditions. ◦ Robustness should be considered during the development phase ◦ Should show the reliability of an analysis when deliberate variations are made in method parameters. 04-09-2016 50Visit Our Website GMP Training
- 51. Robustness( or Ruggedness) ◦ Verification of stability of analytical solutions is of importance. ◦ Other characteristics of robustness should include extraction time. ◦ In case of Liquid chromatography robustness testing may also include Verification of the impact of changes in pH, temperature and flow rate. 04-09-2016 51Visit Our Website GMP Training
- 52. ◦ Factors that can have an effect on robustness when performing chromatographic analysis include: Stability of standard & test solutions Reagents Different columns-different lots/suppliers Extraction time Variations of pH of mobile phase Variations in mobile phase compositions Temperature Flow Rate 04-09-2016 52Visit Our Website GMP Training
- 53. Linearity ◦ Indicates ability to produce results that are directly proportional to the concentration of the solution. ◦ Use samples in which the analyte concentrations span the claimed range of the procedure. ◦ In case of a linear relationship use appropriate statistical test to show linearity. ◦ A minimum of 5 concentrations should be used. 04-09-2016 53Visit Our Website GMP Training
- 54. Range ◦ Expression of the lowest and highest level of analyte that have been demonstrated to determinable for the product. ◦ Specified range is normally derived form linearity study. 04-09-2016 54Visit Our Website GMP Training
- 55. Specificity ( selectivity) ◦ Ability to measure unequivocally the desired analyte in the presence of components such as excipients and impurities that may also be expected to be present. ◦ An investigation of specificity should be performed during the validation of identification tests, the determination of impurities and assay. 04-09-2016 55Visit Our Website GMP Training
- 56. Detection Limit ( Limit of Detection) ◦ Smallest quantity of analyte that can be detected and not necessarily determined in a quantitative fashion. ◦ Approaches may include instrumental or non-instrumental procedures ◦ Could include those based on Visual evaluation Signal to noise Standard deviation of the response and the slope Standard deviation of the blank Calibration curve 04-09-2016 56Visit Our Website GMP Training
- 57. Quantitation Limit ( Limit of Quantitation) ◦ Lowest concentration in a sample that may be determined with acceptable accuracy and precision. ◦ Approaches may include instrumental or non instrumental procedures ◦ Could include those based on Visual evaluation Signal to noise Standard deviation of the response and the slope Standard deviation of the blank Calibration curve 04-09-2016 57Visit Our Website GMP Training
- 58. 04-09-2016 58Visit Our Website GMP Training
- 59. Use appropriate statistical analysis to evaluate validation characteristic against predetermined acceptance criteria. Use appropriately validated software Consider appropriate number of samples to provide adequate statistical power and range. 04-09-2016 59Visit Our Website GMP Training
- 60. Integral part of analytical testing procedure. Tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such. 04-09-2016 60Visit Our Website GMP Training
- 61. SS parameters that need to be established for a particular procedure depend on the ◦ Type of procedure being evaluated 04-09-2016 61Visit Our Website GMP Training
- 62. Suitability of the entire system should be confirmed prior to and during method validation tests. Similarly this should be done during sample analysis. 04-09-2016 62Visit Our Website GMP Training
- 63. SS runs should include only established standards or reference material of known concentrations. This provides appropriate comparator for the potential variability of the instrument. 04-09-2016 63Visit Our Website GMP Training
- 64. When a sample is used for system suitability written procedures should be established. Results of all such trial runs should be included in the results and data review process. 04-09-2016 64Visit Our Website GMP Training
- 65. A sample can be used only if it is well characterized material. Characterization in such cases should be performed prior to the use of this sample as part of SS testing. 04-09-2016 65Visit Our Website GMP Training
- 66. The sample material or product under test should not be used for trial run purposes or to evaluate the SS. Refer WHO guidelines on data and record management. ◦ See our presentation here. 04-09-2016 66Visit Our Website GMP Training
- 67. This presentation is compiled from freely available resource like the website of WHO specifically WHO Draft Guidance Titled GUIDELINES ON VALIDATION – APPENDIX 4 ANALYTICAL METHOD VALIDATION “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit Our Website GMP Training for latest information from the world of Pharmaceuticals. 04-09-2016 67 Visit Our WEBSITE GMP Training http://fdagmp.blogspot.in/