More Related Content

Similar to Ich guidelines for validation final(20)


Recently uploaded(20)


Ich guidelines for validation final

  4.  METHOD VALIDATION : Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the substances in products.  Method validation is primarily concerned with: Identification of the sources of potential errors Quantification of the potential errors in the method An method validation describes in mathematical and quantifiable t e r ms t h e p e rf o rma n c e c h a ra c t e ri s t i cs of an a s sa y 4
  5. Examples of Methods That Require Validation Documentation  Chromatographic Methods - HPLC, GC, TLC, GC/MS, etc. Pharmaceutical Analysis - In support of CMC. Bioanalytical Analysis - In support of PK/PD/Clinical Studies.  Spectrophotometric Methods – UV/VIS, IR, AAS, XRD, ICP-MS, AAS, XRF, etc  Particle Size Analysis Methods - Laser, Microscopic, Sieving, SEC, etc.  Automated Analytical Methods - Robots, AutomatedAnalysis.
  6. Considerations Prior to Method Validation  Suitability of Instrument  Status of Qualification and Calibration  Suitability of Materials  Status of Reference Standards, Reagents, Placebo Lots  Suitability of Analyst  Status of Training and Qualification Records  Suitability of Documentation  Written analytical procedure and proper approved protocol  with pre-established acceptance criteria
  7. Purpose of Method Validation  Identification of Sources and Quantitation of Potential errors  Determination if Method is Acceptable for IntendedUse  Establish Proof that a Method Can be Used for DecisionMaking  Satisfy Requirements
  8. Published Validation Guidelines  1978 Current Good Manufacturing Practices (cGMPs)  1987 FDA Validation Guideline  1989 Supplement 9 to USP XXI  1994 CDER Reviewer Guidance: Validation of Chromatographic Method  1995 ICH Validation Definitions: Q2A, Text on Validation of Analytical procedures  1997 ICH Validation Methodology: Q2B, Validation of Analytical Procedures: Methodology  1999 Supplement 10 to USP 23 <1225>: Validation of Compendial Methods  1999 CDER “Bioanalytical Method Validation for Human Studies”  2000 CDER Draft “Analytical Procedures and Method Validation”
  9. Today’s Validation Requirements ICH/USP GMPs (legal) FDA
  10. ICH/USP Validation Requirements & Parameters ICH  Specificity  Linearity  Range  Accuracy  Precision  Repeatability  Intermediate Precision  Reproducibility  Limit of Detection  Limit of Quantitation USP  Specificity  Linearity and Range  Accuracy  Precision  Limit of Detection  Limit of Quantitation  Ruggedness  Robustness
  11. Specificity/Selectivity  Ability of an analytical method to measure the analyte freefrom interference due to other components. Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc. Assay (content or potency): to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.  Selectivity describes the ability of an analytical method todifferentiate various substances in a sample
  12. Linearity 12  Ability of an assay to elicit a direct and proportional response to changes in analyte concentration.
  13. Linearity Should be Evaluated  By Visual Inspection of plot of signals vs. analyte concentration  By Appropriate statistical methods  Linear Regression (y = mx + b)  Correlation Coefficient, y-intercept (b), slope(m)  Acceptance criteria: Linear regression r2 >0.95 Requires a minimum of 5 concentration levels
  14. Range  The specified range is normally derived from linearity studies and depends on the intended application of the procedure. It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure.  Acceptable range having linearity, accuracy, precision.  For Drug Substance & Drug product Assay  80 to 120% of test Concentration  For Content Uniformity Assay  70 to 130% of test Concentration  For Dissolution Test Method  +/- 20% over entire Specification Range  For Impurity  From MDL to 100% of Impurity Specification Limit
  15. Accuracy  Closeness of the test results obtained by the method to the true value.  Should be established across specified range of analytical procedure.  Should be assessed using a minimum of 3 concentration levels, each in triplicate (total of 9 determinations)  Should be reported as:  Percent recovery of known amount added or  The difference between the mean assay result and the accepted value.
  16. Precision  The closeness of agreement (degree of scatter) between a series of measurements obtained from multiple samplings of the same homogeneous sample.  Should be investigated using homogeneous, authentic samples. Precision Considered at 3 Levels :  Repeatability  Intermediate Precision  Reproducibility
  17. Repeatability  Express the precision under the same operating conditions over a short interval of time.  Also referred to as Intra-assay precision Should be assessed using minimum of 9 determinations (3 concentrations/ 3 replicates) or Minimum of 6 determinations at the 100% level.
  18. Reproducibility  Definition: Ability reproduce data within the predefined precision  Determination: SD, RSD and confidence interval  Repeatability test at two different labs.
  19. Detection Limit (LOD)/ Quantitation Limit (LOQ)  LOD Lowest amount of analyte in a sample that can be detected but not necessarily quantitated. Estimated by Signal to Noise Ratio of 3:1. LOQ Lowest amount of analyte in a sample that canbe quantified with suitable accuracy and precision. Estimated by Signal to Noise Ratio of 10:1.
  20.  Definition: Capacity to remain unaffected by small butdeliberate variations in method parameters  Determination: Comparison results under differingconditions with precision under normal conditions  Examples of typical variations in LC  Influence of variations of pH in a mobile phase  Influence of variations in mobile phase composition  Different columns (different lots and/or suppliers)  Temperature  Flow rate Robustness