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Validation
- 4. Criteria For Analytical Test Validation PRECISION LIMITS ACCURACY LINEARITY RANGE SPECIFICITY REPEATABILITY QUANTIFICATION INTERMEDIATE PRECISION DETECTION
- 5. Table
- 7. Specificity Is this analytical procedure specific for the drug under test? Suppose we alter test conditions slightly?
- 20. Example (continued) Concentration of ketotifen fumarate Area detected Acceptance criteria mg/ml % 0.280 0.320 0.360 0.400 0.440 0.480 0.520 70 80 90 100 110 120 130 1473566 1677013 1904848 2091215 2293647 2518976 2670144 Regression: y = ax + b a = 5055766.964 b = 67608.786 r 2 = 0.9984 0.998 – 1.002
- 35. Example (continued): Conc. of ketotifen fumarate Area detected Recovery (%) Acceptance Criteria mg/ml % 0.280 0.320 0.360 0.380 0.400 0.420 0.440 0.480 0.520 70 80 90 95 100 105 110 120 130 1473566 1677013 1904848 1905862 2091215 2180374 2293647 2518976 2670144 99.32 99.48 100.94 100.51 100.06 100.03 100.07 101.01 98.99 Mean (recovery) : 100.04 Standard deviation : 0.699 Relative standard deviation (RSD) : 0.699 % 98.0–102.0 % < 2 %
- 43. Example (continued) Acceptance criteria: Relative standard deviation (RSD): not more than 2 % Sample no. Concentration (mg/ml) Area detected 1 2 3 4 5 6 7 0.4 0.4 0.4 0.4 0.4 0.4 0.4 1902803 1928083 1911457 1915897 1913312 1897702 1907019 Mean : 1910896 Standard deviation : 9841.78 Relative standard deviation (RSD) : 0.515 %
- 46. Quantitation limit How much of it is present??? How much of it is there?
- 74. Are the data concerning analytical validation satisfactory? YES/NO If NO, recommended questions to the applicant appear in …………………………………………………………………… (eg page number below , or draft letter to the company on page …… ) Evaluation of analytical validation data The objective of the analytical procedure The analytical technique Item Data provided by applicant (very briefly) Acceptable or not? (add comments if necessary, & reasons if unacceptable) Is a chromatogram, spectrum or similar provided? Specificity Linearity Range Accuracy Precision: Repeatability Precision: Intermediate Precision: Reproducibility Detection limit Quantitation limit Robustness System suitability (if necessary) Data on the reference standard Other evaluator comments:
Hinweis der Redaktion
- NB From perspective of an evalr, not from perspective of an analyst experienced in HPLC.
- Selectivity: Provide representative chromatograms with labelled peaks Suitable acceptance criteria might be: Capacity factor k’ > 1.0 Resolution >1.0 If ref imps not available, can prepare a suitable solution by forced degradation. If degradation >10%, may have to argue relevance. Diode array (suggested by ICH) may not be sensitive to low levels of imps, esp if chromophores similar When validating ID tests, remember to consider other actives on your site, as well as excipients
- Linearity: Normally submit plot of detector response vs concentration, plus regression analysis Normally also determine accuracy and precision at extremes of range TGAL usually test across range of 50-150%, especially when test is to be used for CU and/or dissolution testing
- Accuracy: When need to determine accuracy over a range of concentrations, normally 3 concentrations sufficient If mixture of excipients not available, may add known quantities of active and determine difference in results Care with reference substance. If a working standard (ie qualified wrt pharmacopoeial ref subst), bear in mind possibility that errors can accumulate. Care with hydration. Watch for time dependent variability, possibly associated with decomposition. If sample is filtered during preparation, specify type of filter and check for losses (soln of ref filtered vs not filtered)
- ‘ System’ repeatability: Aka repeatability between injections %CV can be of the order of 0.2%, particularly when automated FDA recommends min of 10 injections with %CV < 1.0% Many EP monographs prescribe %CV < 1% Acceptable %CV depends in part on the acceptance range for the assay in question Method repeatability: Aka repeatability of the complete method In practice, often estimated in conjunction with accuracy Means should be within + 2% of t/c Typically measured by: 6 replicates at 100% t/c OR 3 replicates of 3 concentrations %CV can be of the order of 0.4%, particularly when automated Acceptable %CV may be higher for: Impurities More complex matrices (such as creams) Microdose products
- Intermediate precision: FDA uses the term ‘ruggedness’ with same meaning Although slide states means preferably within 2%, criteria are not laid down Acceptability is assessed on case by case basis
- Reproducibility: Again: although slide states means preferably within 2%, criteria are not laid down Again: acceptability is assessed on case by case basis
- LOD: LOD especially important for imps Submit typical chromatograms at LOD Std dev may be estimated from: Std dev of blank samples Std dev of intercept Residual std dev from regression analysis of calibration plot
- LOQ: Again important for imps LOQ must be < acceptance criterion for the imp(s) !! Personally I would not want to rely on ‘visual’ evaluation for limit of quantitation. Submit typical chromatograms at LOQ As for LOD, std dev may be estimated from: Std dev of blank samples Std dev of intercept Residual std dev from regression analysis of calibration plot Confirm the LOQ by determining %CV at that value
- Dot point 1: - If difference in assay >2%, describe attempts to improve. If little improvement gained, insert warnings into write-up of method. Dot point 2: - Duration and conditions of storage should represent most stressful situation likely to occur, eg during a 24hour auto-sampling run.