Transcript Verification of applicability of the validated/compendial API

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
Guidelines
ICH Q2A
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Validation of Analytical Methods: Definitions and
Terminology (CPMP/ICH/381/95)
ICH Q2B
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Validation of Analytical Procedures: Methodology
(CPMP/ICH/281/95)
ICH Q6A
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Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug
Products: Chemical Substances
(CPMP/ICH/367/96 corr)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
API
Assay
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Validation with respect to:
Specificity, linearity/range, accuracy, precision,
robustness
Impurities
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Validation with respect to:
Specificity, linearity/range, accuracy, precision,
limit of detection (LOD), limit of quantitation (LOQ),
robustness
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
FPP
New situation arising from the formulation
of the drug product
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Presence of further APIs
Presence of excipients (individual formulation)
Presence of known impurities/degradants of
all APIs and potential new degradants or
incompatibility products
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Requirements
Capability of the analytical method(s):
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Revalidation I
Revalidation of analytical methods with respect to:
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Specificity
presence of new API(s) and impurities/degradants/formulation
components
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Range
test concentrations of API(s) versus FPP
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Accuracy
influence of formulation components
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Precision
influence of formulation and sample preparation
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LOD/LOQ
test concentrations of API(s) versus FPP)
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Robustness
change of column material, column parameters, solvents)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Revalidation II
Revalidation reflected by ICH Q2A:
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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
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(e.g. robustness)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity
Identification
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity II
Assay and impurities
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Chromatographic procedures
Representative chromatograms with appropriate
labelling of individual components
Investigation at an appropriate level
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity III
Assay and impurities/degradants
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Discrimination of analytes where
impurities/degradants are available
Assay
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity IV
Assay and impurities/degradants
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Discrimination of analytes where
impurities/degradants are available
Impurities/Degradants
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity V
Assay and impurities/degradants
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Discrimination of analytes where
impurities/degradants are not available
Comparison of the test procedure to a second
well-characterized (independent) procedure
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Samples
Test samples containing impurities/degradants
Test samples stored under relevant stress conditions
(potential degradants arising during shelf life)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity VI
Assay and impurities/degradants
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Discrimination of analytes where
impurities/degradants are not available
Assay
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Comparison of test results by the two independent
procedures
Impurities/Degradants
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Comparison of impurity profiles
Peak purity assessment
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Demonstration that the analyte peak is attributable to
only one component
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Example
FDC (artesunate and amodiaquine)
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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
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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)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Range
Minimum specified ranges
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Assay
80 – 120% of the test concentration
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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)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Accuracy
Assay
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Accuracy II
Impurities/Degradants
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Precision
Assay and impurities/degradants
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Repeatability
9 determinations (3 x 3) covering the specified range
or
6 determinations at 100% of the test concentration
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Intermediate precision
Effects of random events on the precision of the procedure,
e.g.
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Days
Analysts
Equipment
To be performed with a test solution prepared
from the drug product
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Detection Limit
Determination based on
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Visual evaluation (non-instrumental and instrumental
methods)
Signal to Noise (baseline noise)
Standard deviation of response (s) and
slope (S)
DL=3.3s/S
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Quantitation Limit
Determination based on
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Visual evaluation (non-instrumental and instrumental
methods)
Signal to Noise (baseline noise)
Standard deviation of response (s) and
slope (S)
QL=10s/S
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Robustness I
Reliability of an analysis with respect to
deliberate variations in method parameters
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Susceptibility to variations in analytical
conditions?
control of analytical conditions
or
precautionary statement
establishment of system suitability parameters
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Robustness II
Examples of variations
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Stability of analytical solutions
Extraction time
In the case of liquid chromatography
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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
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Influence of columns (different lots and/or suppliers)
Influence of temperature
Influence of flow rate
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Dissolution
Applicability of the analytical method used for
assay and impurities/degradants
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Sample preparation
Range
Applicability of the dissolution method
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Appropriateness of drug release acceptance criteria
Solubility criteria of the APIs
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Appropriateness of test conditions and acceptance
criteria
Dissolution affecting bioavailability
Changes in formulation or manufacturing variables affecting
dissolution
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Dissolution II
Applicability of the analytical method used
for assay and impurities/degradants
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Potential parameters for revalidation
Sample preparation
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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?
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Test concentration of prepared dissolution sample versus
test concentration of FPP sample
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Dissolution III
Applicability of the dissolution method
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Appropriateness of drug release acceptance criteria
Solubility of the APIs (ICH Q6A Definitions)
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Dissolution IV
Appropriateness of drug release acceptance
criteria
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Solubility of the APIs
Problem with low solubility drugs:
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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
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Extending the dissolution volume beyond the time-limiting
volume
Validation of the dissolution procedure with extended volume
(applicability of the pharmacopoeial procedure)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Dissolution V
Applicability of the dissolution method
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Appropriateness of test conditions and acceptance
criteria (ICH Q6A)
Dissolution significantly affecting bioavailability
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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
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Control of these changes by another procedure and
acceptance criterion
or
Development of test conditions and acceptance criteria which
can distinguish these changes
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Deficiencies from prequalification
Validation of precision
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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)
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Deficiencies from prequalification II
Assay of API and impurities/degradants
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Deficiencies from prequalification III
Dissolution
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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
Guilin, January, 9 – 13, 2006
Dr. Birgit Schmauser, BfArM, Bonn