Verification

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Verification of applicability of the validated/compendial API analytical method for the final formulation (assay, dissolution test and degradants):

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Verification of applicability of the validated/compendial API analytical method for the final formulation (assay, dissolution test and degradants)

Guidelines:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Guidelines ICH Q2A Validation of Analytical Methods: Definitions and Terminology (CPMP/ICH/381/95) ICH Q2B Validation of Analytical Procedures: Methodology (CPMP/ICH/281/95) ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96 corr)

API:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn API Assay Validation with respect to: Specificity, linearity/range, accuracy, precision, robustness Impurities Validation with respect to: Specificity, linearity/range, accuracy, precision, limit of detection (LOD), limit of quantitation (LOQ) , robustness

FPP:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn FPP New situation arising from the formulation of the drug product Presence of further APIs Presence of excipients (individual formulation) Presence of known impurities/degradants of all APIs and potential new degradants or incompatibility products

Requirements:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Requirements Capability of the analytical method(s): Assay of each API in the presence of the other APIs and all impurities/degradants Assay of each degradant in the presence of all APIs and all other degradants/impurities Influence of formulation components should be excluded/controlled

Revalidation I:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Revalidation I Revalidation of analytical methods with respect to: Specificity presence of new API(s) and impurities/degradants/formulation components Range test concentrations of API(s) versus FPP Accuracy influence of formulation components Precision influence of formulation and sample preparation LOD/LOQ test concentrations of API(s) versus FPP) Robustness change of column material, column parameters, solvents)

Revalidation II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Revalidation II Revalidation reflected by ICH Q2A: Revalidation may be necessary in the following circumstances: Changes in the synthesis of the drug substance Changes in the composition of the finished product Changes in the analytical procedure (e.g. robustness)

Specificity:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity Identification Discrimination between compounds of closely related structures positive results (from samples containing the analyte) negative results (from samples that do not contain the analyte) components structurally similar to the analyte do not give positive results

Specificity II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity II Assay and impurities Chromatographic procedures Representative chromatograms with appropriate labelling of individual components Investigation at an appropriate level

Specificity III:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity III Assay and impurities/degradants Discrimination of analytes where impurities/degradants are available Assay Demonstration of discrimination of the analyte in the presence of all impurities/degradants and/or excipients f. ex. assay result unaffected by presence of spiked impurities/degradants

Specificity IV:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity IV Assay and impurities/degradants Discrimination of analytes where impurities/degradants are available Impurities/Degradants Demonstration of separation of impurities/degradants individually and/or from excipients f. ex. spiking of API with appropriate levels of impurities/degradants and/or excipients

Specificity V:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity V Assay and impurities/degradants Discrimination of analytes where impurities/degradants are not available Comparison of the test procedure to a second well-characterized (independent) procedure Samples Test samples containing impurities/degradants Test samples stored under relevant stress conditions (potential degradants arising during shelf life)

Specificity VI:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Specificity VI Assay and impurities/degradants Discrimination of analytes where impurities/degradants are not available Assay Comparison of test results by the two independent procedures Impurities/Degradants Comparison of impurity profiles Peak purity assessment Demonstration that the analyte peak is attributable to only one component

Example:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Example FDC (artesunate and amodiaquine) One analytical method for both APIs Capability of one method to quantify both APIs and to separate/discriminate the other API and its impurities/degradants and potential incompatibility products from the existing API and its impurities/degradants Some reference material for impurities/degradants will be available (spiking experiments applicable) Other degradants are not available as reference material (stress testing necessary to generate in situ degradants)

Range:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Range Minimum specified ranges Assay 80 – 120% of the test concentration Content uniformity 70 – 130% of the test concentration Dissolution Q-20% - 120% Impurities/Degradants Reporting level to 120% of specification limit Revalidation is necessary, if the ranges covered during validation of the API-methods are different from those of the FPP-methods (different test concentrations)

Accuracy:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Accuracy Assay Application of the analytical procedure to synthetic mixtures of the product components (placebo mixture) to which known quantities of the analyte have been added In case certain product components are unavailable: Application of the analytical procedure to the product to which known quantities of the analyte have been added Comparison of results obtained by a second (independent) procedure with defined accuracy

Accuracy II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Accuracy II Impurities/Degradants Assessment of samples spiked with known amounts of impurities/degradants In case certain impurities/degradation products are unavailable Comparison of results obtained by a second (independent) procedure with defined accuracy

Precision:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Precision Assay and impurities/degradants Repeatability 9 determinations (3 x 3) covering the specified range or 6 determinations at 100% of the test concentration Intermediate precision Effects of random events on the precision of the procedure, e.g. Days Analysts Equipment To be performed with a test solution prepared from the drug product

Detection Limit:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Detection Limit Determination based on Visual evaluation (non-instrumental and instrumental methods) Signal to Noise ( baseline noise ) Standard deviation of response ( s ) and slope (S) DL=3.3 s /S Estimation of S from the calibration curve of the analyte Estimation of s from the standard deviation of the blank from the standard deviation (regression line or y-intercept) of a calibration curve in the range of the DL

Quantitation Limit:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Quantitation Limit Determination based on Visual evaluation (non-instrumental and instrumental methods) Signal to Noise ( baseline noise ) Standard deviation of response ( s ) and slope (S) QL=10 s /S Estimation of S from the calibration curve of the analyte Estimation of s from the standard deviation of the blank from the standard deviation (regression line or y-intercept) of a calibration curve in the range of the QL

Robustness I:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Robustness I Reliability of an analysis with respect to deliberate variations in method parameters Susceptibility to variations in analytical conditions? control of analytical conditions or precautionary statement establishment of system suitability parameters

Robustness II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Robustness II Examples of variations Stability of analytical solutions Extraction time In the case of liquid chromatography Influence of variations of pH in a mobile phase Influence of variations in mobile phase composition Influence of columns (different lots and/or suppliers) Influence of temperature Influence of flow rate In the case of gas chromatography Influence of columns (different lots and/or suppliers) Influence of temperature Influence of flow rate

Dissolution:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Dissolution Applicability of the analytical method used for assay and impurities/degradants Sample preparation Range Applicability of the dissolution method Appropriateness of drug release acceptance criteria Solubility criteria of the APIs Appropriateness of test conditions and acceptance criteria Dissolution affecting bioavailability Changes in formulation or manufacturing variables affecting dissolution

Dissolution II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Dissolution II Applicability of the analytical method used for assay and impurities/degradants Potential parameters for revalidation Sample preparation Stability of analytes in the dissolution medium? Preparation of an injectable sample volume according to the analytical method? Precision of analysis of the prepared dissolution sample? Range of test concentrations of API / impurities / degradants according to the validated ranges? Test concentration of prepared dissolution sample versus test concentration of FPP sample

Dissolution III:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Dissolution III Applicability of the dissolution method Appropriateness of drug release acceptance criteria Solubility of the APIs (ICH Q6A Definitions) Rapidly dissolving products Not less than 80% of the label amount of the drug substance dissolves within 15 minutes in each of the following media: pH 1.2, pH 4.0, pH 6.8 Highly water soluble drugs Drugs with a dose/solubility volume of less than or equal to 250 ml over a pH range of 1.2 to 6.8 Low solubility drugs Drugs with a dose/solubility volume of more than 250 ml

Dissolution IV:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Dissolution IV Appropriateness of drug release acceptance criteria Solubility of the APIs Problem with low solubility drugs: Solution of the drugs may become a time-limiting step Dissolution also dependent on the strength of the drug product Dissolution test cannot reflect batch to batch consistency Possible solution of the problem Extending the dissolution volume beyond the time-limiting volume Validation of the dissolution procedure with extended volume (applicability of the pharmacopoeial procedure)

Dissolution V:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Dissolution V Applicability of the dissolution method Appropriateness of test conditions and acceptance criteria ( ICH Q6A ) Dissolution significantly affecting bioavailability Have relevant developmental batches exhibited unacceptable bioavailability? Development of test conditions and acceptance criteria which can distinguish batches with unacceptable bioavailability Changes in formulation or manufacturing variables affecting dissolution Control of these changes by another procedure and acceptance criterion or Development of test conditions and acceptance criteria which can distinguish these changes

Deficiencies from prequalification:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from prequalification Validation of precision Precision of the drug substance solution lower than precision of the drug product solution Acceptance criteria for precision of the drug substance solution wider than for precision of the drug product solution Acceptance criteria much wider than real values assessed Acceptance criteria of assay specifications and precision do not match (3 x RSD outside the specification range)

Deficiencies from prequalification II:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from prequalification II Assay of API and impurities/degradants No acceptable mass balance found between assay of API and impurities/degradants Quantitation limit of impurities too high ICH requirement on threshold for identification and qualification of unknown impurities cannot be fulfilled

Deficiencies from prequalification III:

Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from prequalification III Dissolution Necessary information on development of dissolution test not presented Dissolution method (pharmacopoeial) not presented along with development of dissolution test and/or validation of applicability of analytical methods Test conditions and acceptance criteria of the dissolution test not justified