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OBJECTIVE
PUBLISHED GUIDANCES
TYPES OF ANALYTICAL METHOD TO BE VALIDATED
CONSIDERATIONS PRIOR TO METHOD VALIDATION
TYPICAL ANALYTICAL PERFORMANCE
CHARACTERISTICS USED IN METHOD VALIDATION
REVALIDATION
POSSIBLE QUESTIONS
REFERENCES
PUBLISHED GUIDANCES
ICH-Q2A “Text on Validation of Analytical Procedure:(1994)
ICH-Q2B “Validation of Analytical Procedures: Methodology: (1995)
CDER “Reviewer Guidance: Validation of Chromatographic Method” (1994)
CDER “Submitting Samples and Analytical Data for Method Validations” (1987)
CDER Draft “Analytical Procedures and Method Validation” (2000)
CDER “Bioanalytical Method Validation for Human Studies” (1999)
USP<1225> “Validation of Compendial Methods” (current revision)
SUBMISSION TO THE COMPENDIARATIONALE
PROPOSED ANALYTICAL PROCEDURE
DATA ELEMENTS
TYPES OF ANALYTICAL PROCEDURES TO BE VALIDATEDIdentification tests.Quantitative tests for impurities' content.Limit tests for the control of impurities.Quantitative tests of the active moiety in
samples of drug.substance or drug product or other
selected component(s) in the drug product.
CONSIDERATIONS PRIOR TO METHOD VALIDATION
Suitability of InstrumentStatus of Qualification and Calibration
Suitability of MaterialsStatus of Reference Standards, Reagents, etc.
Suitability of AnalystStatus of Training and Qualification Records
Suitability of DocumentationWritten analytical procedure and proper approved protocol with pre-established acceptance criteria.
EXAMPLES OF METHODS THAT REQUIRE VALIDATION DOCUMENTATION
CHROMATOGRAPHIC METHODS
SPECTROPHOTOMETRIC METHODS
CAPILLARY ELECTROPHORESIS METHODS
PARTICLE SIZE ANALYSIS METHODS
DISSOLUTION METHODS
TITRATION METHODS
AUTOMATED ANALYTICAL METHODS
ANALYTICAL METHOD VALIDATION
Validation of an analytical method is the process by which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical applications.
TYPICAL ANALYTICAL PERFORMANCE CHARACTERISTICS USED IN METHOD VALIDATION
Specificity (Selectivity)LinearityRangeAccuracyPrecisionDetection LimitQuantitation LimitRobustnessSystem Suitability
Testing
SPECIFICITY
SPECIFICITY is the ability to assess unequivocally the analyte in presence of components which may be expected to be present.
DETERMINATION
IDENTIFICATION TESTS
ASSAY AND IMPURITY TEST(S) Impurities are available Impurities are not available
LINEARITYLINEARITY of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.
DETERMINATION- Linearity should be evaluated by visual inspection of a plot of signals as a function of analyte concentration or content.
NOTEFor the establishment of linearity, a minimum of five concentrations is recommended.
RANGE
RANGE of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
DETERMINATION-The specified range is normally derived from linearity studies and depends on the intended application of the procedure.
ACCURACYACCURACY of an analytical method is the closeness of
test results obtained by that method to the true value.
DETERMINATION-Accuracy should be established across
the specified range of the analytical procedure.ASSAY
Drug SubstanceDrug Product
IMPURITIES (QUANTITATION)
NOTE
Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3 concentration levels covering the specified range (i.e., three concentrations and three replicates of each).
PRECISION
PRECISION of an analytical method is the degree of agreement among
individual test results when the method is applied repeatedly to multiple
samplings of a homogenous sample.
DETERMINATION- A sufficient number of aliquots of a
homogeneous sample are assayed to be able to calculate statistically valid
estimates of standard deviation or relative standard deviation.
Repeatability
Intermediate precision
Reproducibilty
DETECTION LIMITDETECTION LIMIT of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated, under the stated experimental conditions.
DETERMINATION- Several approaches for determining the detection limit are possible, depending on whether the procedure is a non-instrumental or instrumental.
BASED ON VISUAL EXAMINATION
BASED ON SIGNAL TO NOISE RATIO
QUANTITATION LIMIT
QUANTITATION LIMIT of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.
DETERMINATION- Several approaches for determining the detection limit are possible, depending on whether the procedure is a non-instrumental or instrumental.
BASED ON VISUAL EXAMINATION
BASED ON SIGNAL TO NOISE RATIO
LOQ, LOD and SNRLimit of Quantitation Limit of DetectionSignal to Noise Ratio
noise
Peak ALOD
Peak BLOQ
Baseline
RUGGEDNESS
NOTEIncluded in
but not in
RUGGEDNESS of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of conditions, such as different laboratories different analyst, different instruments, different lots of reagent, different elapsed assay times, different assay temperatures, different days, etc.
ROBUSTNESSROBUSTNESS of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.
DETERMINATION- The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study.
SYSTEM SUITABILITY TESTINGSYSTEM SUITABILITY TESTING is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such.
Recommended Validation Characteristics of the Various Types of Tests
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;The degree of revalidation required depends on the nature of the changes. Certain other changes may require validation as well.
The United State Pharmacopoeia 24; The National
Formulary 19; 2000: [1225] VALIDATION OF
COMPENDIAL METHODS.
www.labcompliance.com/methods/meth_va
htm#introduction
http://www.fda.gov/cder/guidance/2396dft.htm
www.fda.gov/ohrms/dockets/
ac/02/slides/3841s1_07_lachman.PPT
http://www.fda.gov/cder/guidance/ameth.htm
http://www.ich.orghttp://www.fda.gov/cder/guidance/4252fnl.htmhttp://www.pharmtech.com/pharmtech/
dat a/articlestandard/pharmtech/102003/48314/article.pdfhttp://www.ivstandards.com/tech/
reliability/part17.asphttp://www.aoac.org/