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Verification of applicability of the validated/compendial API analytical method for the final formulation. Assay, dissolution test and degradants. Guidelines. ICH Q2A Validation of Analytical Methods: Definitions and Terminology (CPMP/ICH/381/95) ICH Q2B

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slide1

Verification of applicability of the validated/compendialAPI analytical methodfor the final formulation

Assay, dissolution test and degradants

Dr. Birgit Schmauser, BfArM, Bonn

guidelines
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)

Dr. Birgit Schmauser, BfArM, Bonn

slide3
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

Dr. Birgit Schmauser, BfArM, Bonn

slide4
FPP
  • 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

Dr. Birgit Schmauser, BfArM, Bonn

requirements
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

Dr. Birgit Schmauser, BfArM, Bonn

revalidation i
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)

Dr. Birgit Schmauser, BfArM, Bonn

revalidation ii
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)

Dr. Birgit Schmauser, BfArM, Bonn

specificity
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

Dr. Birgit Schmauser, BfArM, Bonn

specificity ii
Specificity II
  • Assay and impurities
    • Chromatographic procedures
      • Representative chromatograms with appropriate labelling of individual components
      • Investigation at an appropriate level

Dr. Birgit Schmauser, BfArM, Bonn

specificity iii
Specificity III
  • Chromatogram with retention times and chemical structures of:
  • (1) arteannuin B
  • (2) artemisitene
  • (3) artemisinin
  • (4) artemisinic acid
  • (5) artemether (IS)
  • Analytical standard containing 1.2µg/ml of each analyte and 0.4 µg/ml IS

From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187

Dr. Birgit Schmauser, BfArM, Bonn

specificity iv
Specificity IV
  • 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:

- Injection of pure API

- Injection of API plus impurities/degradants

Dr. Birgit Schmauser, BfArM, Bonn

specificity v
Specificity V
  • 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:

Chromatographic profiles of API with and without impurities/degradants/excipients

Dr. Birgit Schmauser, BfArM, Bonn

specificity vi
Specificity VI
  • 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)

Dr. Birgit Schmauser, BfArM, Bonn

specificity vii
Specificity VII
  • 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

Dr. Birgit Schmauser, BfArM, Bonn

specificity viii
Specificity VIII

A

B

  • Peak purity
  • Overlapping peaks in HPLC (simulation)

C

D

From: Prof. Siegfried Ebel, University of Wuerzburg, in: Stavros Kromidas, Validierungin der Analytik, Wiley-VCH

Dr. Birgit Schmauser, BfArM, Bonn

specificity ix
Specificity IX

Fatty acids were reacted with

ethylene oxide and separatedby HPLC (Fractions 1-6)

  • Peak purity

Fraction 5 was analysedby MALDI

From: Dr. Michael Schmitt, Henkel KGaA, Düsseldorf, in: Stavros Kromidas, Validierungin der Analytik, Wiley-VCH

Dr. Birgit Schmauser, BfArM, Bonn

specificity with fdcs
Specificity with FDCs
  • FDC (e.g. artesunate and amodiaquine)
    • One analytical method for both APIs
      • Capability of one method to quantify both APIs and to separate/discriminate one API and its impurities/degradants and potential incompatibility products from the other API and its impurities/degradants/incompatibility products
        • 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)

Dr. Birgit Schmauser, BfArM, Bonn

range
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)

Dr. Birgit Schmauser, BfArM, Bonn

accuracy
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

Dr. Birgit Schmauser, BfArM, Bonn

accuracy ii
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

Dr. Birgit Schmauser, BfArM, Bonn

precision
Precision
  • Assay and impurities/degradants
    • Repeatability
      • 9 determinations (3 x 3) covering the specified rangeor
      • 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

Dr. Birgit Schmauser, BfArM, Bonn

detection limit
Detection Limit
  • Determination based on
    • Visual evaluation (non-instrumental and instrumental methods)
    • Signal to Noise (baseline noise)
    • Standard deviation of response (s) andslope (S)
      • DL=3.3s/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

Dr. Birgit Schmauser, BfArM, Bonn

quantitation limit
Quantitation Limit
  • Determination based on
    • Visual evaluation (non-instrumental and instrumental methods)
    • Signal to Noise (baseline noise)
    • Standard deviation of response (s) andslope (S)
      • QL=10s/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

Dr. Birgit Schmauser, BfArM, Bonn

robustness i
Robustness I
  • Reliability of an analysis with respect to deliberate variations in method parameters
    • Susceptibility to variations in analytical conditions?
      • control of analytical conditionsorprecautionary statement
      • establishment of system suitability parameters

Dr. Birgit Schmauser, BfArM, Bonn

robustness ii
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

Dr. Birgit Schmauser, BfArM, Bonn

robustness iii
Robustness III
  • Influence of pH of elution on separation of amino acids by RP-HPLC

From: Waters, in: Stavros Kromidas, Validierung in der Analytik, Wiley-VCH

Dr. Birgit Schmauser, BfArM, Bonn

robustness
Robustness
  • Electropherograms under identical conditions by different analytical equipment

From: Dr. Michael Krämer, NOVARTIS, Basel, in: Stavros Kromidas, Validierung in derAnalytik, Wiley-VCH

Dr. Birgit Schmauser, BfArM, Bonn

dissolution
Dissolution
  • Applicability of the analytical method used for assay and impurities/degradants
    • Sample preparation
    • Range
  • Applicability of the dissolution method
    • Appropriateness of drug releaseacceptance criteria
      • Solubility criteria of the APIs
    • Appropriateness of test conditionsandacceptance criteria
      • Dissolution affecting bioavailability
      • Changes in formulation or manufacturing variables affecting dissolution

Dr. Birgit Schmauser, BfArM, Bonn

dissolution ii
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

Dr. Birgit Schmauser, BfArM, Bonn

dissolution iii
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 than250 ml

Dr. Birgit Schmauser, BfArM, Bonn

dissolution iv
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

and

        • Validation of the dissolution procedure with extended volume (applicability of the pharmacopoeial procedure)

Dr. Birgit Schmauser, BfArM, Bonn

dissolution v
Dissolution V
  • Sink conditions
    • Ph. Eur 2.9.3: ..the material already in solution does not exert a significant modifying effect on the rate of dissolution of the remainder…
    • „Sink conditions normally occur in a volume of dissolution medium that isat least 3 to 10 times the saturation medium
    • Consequently: the amount of API contained in the dosage form should be soluble in NMT 300 ml of dissolution medium

Dr. Birgit Schmauser, BfArM, Bonn

dissolution v1
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 criterionor
        • Development of test conditions and acceptance criteria which can distinguish these changes

Dr. Birgit Schmauser, BfArM, Bonn

major problems
Major problems
  • Solubility of Artemisinins
    • Sink condition cannot be established
      • (+) Addition of solubilizers could help establish a (dis)solution test
      • (-) The test would disconnect dissolution and bioavalability and could only serve as parameter for batch to batch consistency
      • Disintegration could be considered as additional parameter
  • Stability of Artemisinins
    • Artesunate decomposes (to DHA) in buffers required for dissolution testing (e.g. pH 1.2, pH 4.5)
      • Dissolution could only be performed at a neutral pH (~ 7.0)

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from pq
Deficiencies from PQ
  • 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)

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from pq ii
Deficiencies from PQ 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

Dr. Birgit Schmauser, BfArM, Bonn

deficiencies from pq iii
Deficiencies from PQ 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

Dr. Birgit Schmauser, BfArM, Bonn

slide38
THANK

YOU

FOR

YOUR

ATTENTION

Dr. Birgit Schmauser, BfArM, Bonn