Transcript Analytical Validation Finished Pharmaceutical Products

Verification of applicability
of the validated/compendial
API analytical method
for the final formulation
Assay, dissolution test and
degradants
Dar es Salaam, August, 21-25, 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)
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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)
Dar es Salaam, August, 21-25, 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)
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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)
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity VIII
• Peak purity
• Overlapping
peaks in HPLC
(simulation)
A
B
C
D
From: Prof. Siegfried Ebel, University of Wuerzburg, in: Stavros Kromidas, Validierung
in der Analytik, Wiley-VCH
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Specificity IX
• Peak purity
Fatty acids were reacted with
ethylene oxide and separated
by HPLC (Fractions 1-6)
Fraction 5 was analysed
by MALDI
From: Dr. Michael Schmitt, Henkel KGaA, Düsseldorf, in: Stavros Kromidas, Validierung
in der Analytik, Wiley-VCH
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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)
Dar es Salaam, August, 21-25, 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)
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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=3.3s/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
Dar es Salaam, August, 21-25, 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=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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
Robustness
• Electropherograms under identical conditions by
different analytical equipment
From: Dr. Michael Krämer, NOVARTIS, Basel, in: Stavros Kromidas, Validierung in der
Analytik, Wiley-VCH
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 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
and
– Validation of the dissolution procedure with extended volume
(applicability of the pharmacopoeial procedure)
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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 is at 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
Dar es Salaam, August, 21-25, 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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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)
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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)
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
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
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn
THANK
YOU
FOR
YOUR
ATTENTION
Dar es Salaam, August, 21-25, 2006
Dr. Birgit Schmauser, BfArM, Bonn