validation of analytical procedure USFDA Guidline
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The document discusses the validation of analytical procedures as outlined by regulatory agencies like the USFDA. It defines key terms like accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. For each term, it provides the definition and recommendations on how to determine the characteristic during the validation process, such as testing a minimum number of samples over a specified range and concentration levels. The overall purpose of the validation is to establish that the analytical procedure is suitable for its intended use.
validation of analytical procedure USFDA Guidline
- 1. VALIDATION OF ANALYTICAL PROCEDURE (USFDA) By Achana Chavhan M.Pharm (QA) RSCP, Buldana
- 2. • Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications • Typical analytical performance characteristics that should be considered in the validation of the types of procedures described in this document are listed in Table 1.
- 3. Typical Analytical Characteristics Used in Method Validation Accuracy Precision Specificity Detection Limit Quantification Limit Linearity Range Robustness
- 4. Accuracy • The accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value. • The accuracy of an analytical procedure should be established across its range.
- 5. • Determination: • In the case of the assay of a drug substance, accuracy may be determined by application of the analytical procedure to an analyte of known purity (e.g., a Reference Standard) or by comparison of the results of the procedure with those of a second, well- characterized procedure, the accuracy of which has been stated or defined. • The ICH documents recommend that accuracy should be assessed using a minimum of nine determinations over a minimum of three concentration levels, covering the specified range
- 6. Precision • The precision of an analytical procedure is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of a homogeneous sample. • The precision of an analytical procedure is usually expressed as the standard deviation or relative standard deviation (coefficient of variation) of a series of measurements.
- 7. • Determination: • The precision of an analytical procedure is determined by assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically valid estimates of standard deviation or relative standard deviation(coefficient of variation). • The ICH documents recommend that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentrations and three replicates of each concentration) or using a minimum of six determinations at 100% of the test concentration.
- 8. Specificity • The ICH documents define specificity as the ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities, degradation products, and matrix components.
- 9. • Determination: • In the case of qualitative analyses (identification tests), the ability to select between compounds of closely related structure that are likely to be present should be demonstrated. • This should be confirmed by obtaining positive results (perhaps by comparison to a known reference material) from samples containing the analyte. • For validation of specificity for qualitative and quantitative determinations by spectroscopic methods, chapters related to topics such as near- infrared spectrophotometry, Raman spectroscopy, and X-ray powder diffraction should be consulted.
- 10. Detection Limit • The detection limit is a characteristic of limit tests. It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. • The detection limit is usually expressed as the concentration of analyte (e.g., percentage or parts per billion) in the sample.
- 11. • Determination: • For noninstrumental procedures, the detection limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected. • In the case of instrumental analytical procedures that exhibit background noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be detected is established
- 12. Quantitation Limit • The quantitation limit is a characteristic of quantitative assays for low levels of compounds in sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. • The quantitation limit is expressed as the concentration of analyte (e.g., percentage or parts per billion) in the sample.
- 13. • Determination: • For noninstrumental procedures, the quantitation limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable Accuracy and Precision. • For instrumental procedures, the same approach may be used as for noninstrumental procedures. In the case of procedures submitted for consideration as official compendial procedures, it is almost never necessary to determine the actual quantitation limit.
- 14. Linearity & Range • The linearity of an analytical procedure is its ability to elicit test results that are directly, or by a well-defined mathematical transformation, proportional to the concentration of analyte in samples within a given range. • The range of an analytical procedure is the interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity using the procedure as written. The range is normally expressed in the same units as test results (e.g., percent or parts per million) obtained by the analytical procedure.
- 15. • Determination: • Linearity should be established across the range of the analytical procedure. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. • The range of the procedure is validated by verifying that the analytical procedure provides acceptable precision, accuracy, and linearity when applied to samples containing analyte at the extremes of the range as well as within the range.
- 16. • It is also recommended that the following minimum specified ranges should be considered: • Assay of a drug substance (or a finished product): From 80% to 120% of the test concentration • Determination of an impurity: From 50% to 120% of the acceptance criterion • For content uniformity: A minimum of 70%– 130% of the test concentration, • For dissolution testing: ±20% over the specified range
- 17. Robustness • The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in procedural parameters • Robustness may be determined during development of the analytical procedure.