Method validation for drug substances and drug product _remodified_2014

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Method validation is the process of proving that an analytical method is acceptable for its intended purposes. METHOD VALIDATION = ERROR ASSESSMENT 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 drug substances and drug products Validation: Prior Considerations 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 and approved standard test procedure and proper approved protocol with pre-established acceptance criteria Compendial vs. Non-compendial Methods Compendial methods-Verification Regulatory analytical procedure in USP/NF Non- compendial methods-Validation Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure Chromatographic Methods Demonstrate Resolution Impurities/Degradants Available Spike with impurities/degradants Show resolution and a lack of interference Impurities/Degradants Not Available Stress SamplesFor assay, Stressed and Unstressed Samples should be compared. Ability of an analytical method to measure the analyte free from interference due to other components. Selectivity describes the ability of an analytical method to differentiate various substances in a sample Original term used in USP Also Preferred by IUPAC and AOAC Also used to characterize chromatographic columns Degree of Bias (Used in USP) The difference in assay results between the two groups the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients Selectivity: For impurity test, impurity profiles should be compared. Temperature (50-60℃) Humidity (70-80%) Acid Hydrolysis (0.1 N HCl) Base Hydrolysis (0.1 N NaOH) Oxidation (3-30%) Light (UV/Vis/Fl) Intent is to create 10 to 30 % Degradation Change in the analytical procedure, drug substance, drug product, the changes, may necessitate revalidation of the analytical procedures. “The degree of revalidation depends on the nature of the change.” “FDA intends to provide guidance in the future on post-approval changes in analytical procedures.” 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 > 0.999 Requires a minimum of 6 concentration levels Normally derived from Linearity studies. Established by confirming that the method provides acceptable degree of linearity, accuracy, and precision. Specific range dependent upon intended application of the procedure.

Text of Method validation for drug substances and drug product _remodified_2014

  • Validationof AnalyticalValidationof Analytical Method for DrugMethod for Drug Substances & DrugProductsSubstances & DrugProducts Dr. R.Badmanaban., M.Pharm., M.D(A.M).,PhD., Associate Professor, Head of Dept - Pharmacognosy Shri Sarvajanik Pharmacy college - Mehsana-384001 www.sspcmsn.org Email: badu1977@gmail.com
  • Definition: Method validation is the process of proving that an analytical method is acceptable for its intended purposes. METHOD VALIDATION = ERROR ASSESSMENT 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 drug substances and drug products
  • Analytical Method Body Full name Guidance on Eurachem Focus for Analytical Chemistry in Europe Method validation CITAC Cooperation of International Traceability in Analytical Chemistry Proficiency testing Quality Assurance EA European Cooperation for Accreditation Accreditation CEN European Committee for Normalization Standardization IUPAC International Union of Pure & Applied Chem. Method validation ISO International Standardization Organisation Standardisation AOAC ILAC Association of Official Analytical Chemists International Laboratory Accreditation Cooperat. Internal qual. Control Proficiency testing Accreditation FDA US Food and Drug Administration Method validation USP United States Pharmacopoeia Method validation ICH International Conference on Harmonization Method validation International regulatory bodies and their guidelines on different aspects of QA
  • Chromatography todayChromatography today More than sixty variants of the technique have been developed. HPLC, GC, SFC, and CE are the most frequently used. HPLC: almost universal wide range of equipment and columns is commercially available well-understood separation mechanisms sensitive, specific, selective, precise and robust, Rugged, accurate. easy to maintain instrumentation flexible in optimizing separations More efficient than some of the separation techniques July 21, 2014 Shri Sarvajanik Pharmacy 4
  • Liquid Chromatography (HPLC) instrumentLiquid Chromatography (HPLC) instrument July 21, 2014 Shri Sarvajanik Pharmacy 5
  • The ChromatographicThe Chromatographic Process TheoreticalProcess Theoretical ConsiderationsConsiderations July 21, 2014 Shri Sarvajanik Pharmacy 6
  • Elution in Column ChromatographyElution in Column Chromatography July 21, 2014 Shri Sarvajanik Pharmacy 7 MobileMobile phasephase StationaryStationary phasephase tt00 tt11 tt22 tt44tt33
  • Intermolecular InteractionsIntermolecular Interactions July 21, 2014 Shri Sarvajanik Pharmacy 8
  • ChromatogramChromatogram July 21, 2014 Shri Sarvajanik Pharmacy 9
  • Retention RelationshipsRetention Relationships July 21, 2014 Shri Sarvajanik Pharmacy 10
  • 11 Validation (4M) Man Machine Material Method
  • Why Method Validation is Important ? Analytical Method
  • Why Method Validation is Important? 1. Develops confidence in using the method & Proof that Method is suitable for its intended purpose, The purpose of analytical measurement is to get consistent, reliable and accurate data. Incorrect measurement results can lead to tremendous costs. 2.2. Regulatory requirementRegulatory requirement, Equal importance for those working in a regulated and in an accredited environment.
  • When to be validated ? Analytical Method
  • When to be validated? Partial validation after development of method. Complete validation after manufacturing formula is finalized. Which methods are to be validated ? Compendia: Pharmacopoeia method Verification of suitability of method Non compendia methods: Laboratory developed methods. Pharmacopoeias methods used outside its scope.
  • Validation: Prior Considerations 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 and approved standard test procedure and proper approved protocol with pre-established acceptance criteria
  • Validation Activity Including the Complete Analytical Procedure Sampling Sample Preparation Analysis Data Evaluation Reporting
  • Validation Step Define the application, purpose and scope of the method. Analytes? Concentration? Develop a analytical method. Develop a validation protocol. Qualification of instrument. Qualify/train operator
  • Qualification of material. Perform pre-validation experiments. Adjust method parameters and/or acceptance criteria if necessary. Perform full validation experiments. Develop Procedures for executing the method in routine analysis. Document validation experiments and results in the validation report. Validation Step
  • Verification vs. Validation Compendial vs. Non-compendial Methods Compendial methods-Verification Regulatory analytical procedure in USP/NF Non- compendial methods-Validation Alternative analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure
  • Method Validation Method Transfer Method Development Approved BACKGROUND-LAB METHOD FLOW
  • ICH/USP Validation Requirements Precision Repeatability Intermediate Precision Reproducibility Limit of Detection Limit of Quantitation Robustness Specificity System suitability Linearity Range Accuracy
  • Validation Parameters Impurities Specificity Linearity and Range Accuracy Precision Robustness LOD & LOQs Dissolution Specificity Linearity and Range Accuracy Precision Robustness Assay / CU Specificity Linearity and Range Accuracy Precision Robustness
  • Specificity/Selectivity Ability of an analytical method to measure the analyte free from interference due to other components. Selectivity Bias
  • Specificity: ICH/USP The ability to measure accurately and specifically the analyte in the presence of components that may be expected to be present in the matrix The degree of interference Active Ingredients Excipients Impurities (synthetic precursors, enantiomers) Degradation Products Placebo Ingredients
  • Analytical Method
  • Continue.... . Combination of 2 or more analytical procedures may be required to achieve necessary level of discrimination . Stability indicating analytical methods should always be specific. . Analysts should ascertain whether the peaks within a sample chromatogram are pure or consist of more than one compound. Therefore should know how many compounds are in the sample or use procedures to detect peak purity Analytical Method
  • Specificity: Impurities Assay Chromatographic Methods Demonstrate Resolution Impurities/Degradants Available Spike with impurities/degradants Show resolution and a lack of interference Impurities/Degradants Not Available Stress Samples For assay, Stressed and Unstressed Samples should be compared. 29 2009
  • Selectivity Ability of an analytical method to measure the analyte free from interference due to other components. Selectivity describes the ability of an analytical method to differentiate various substances in a sample Original term used in USP Also Preferred by IUPAC and AOAC Also used to characterize chromatographic columns Degree of Bias (Used in USP) The difference in assay results between the two groups - the sample containing added impurities, degradation products, related chemical compounds, placebo ingredients Selectivity: For impurity test, impurity profiles should be compared. 30 2009
  • Analytical Method
  • Forced Degradation Studies Temperature (50-60) Humidity (70-80%) Acid Hydrolysis (0.1 N HCl) Base Hydrolysis (0.1 N NaOH) Oxidation (3-30%) Light (UV/Vis/Fl) Intent is to create 10 to 30 % Degradation 32 2009
  • Analytical Method
  • Linearity Ability of an assay to elicit a direct and proportional response to changes in analyte conc