Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 1 | Prequalification programme: Priority essential medicines Training programme on pharmaceutical quality, good manufacture practice and bioequivalence with a focus on TB products. Jiaxing Peoples’ Republic of China 5 – 9 November 2007
Prequalification programme: Priority essential medicines. Training programme on pharmaceutical quality, good manufacture practice and bioequivalence with a focus on TB products. Jiaxing Peoples’ Republic of China 5 – 9 November 2007. - PowerPoint PPT Presentation
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Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 20071 |
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HistoryHistory
Development pharmacokinetics:
computers
separation technics
analytical methods
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HistoryHistory
chromatography
spectrometry
gas chromatrography
liquid chromatography
mass spectrometry
'30
‘50
‘60
‘70
‘90
mg/ml
μg/ml
ng/ml
pg/ml
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MethodsMethods
ANALYTICAL METHODS
immunological methods
LC-MS/MS
GLCHPLC
GC-MS
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PrinciplePrinciple
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GuidanceGuidance
FDA Guidance for Industry– Bioanalytical method validation, May 2001
ICH Guidance for industry– Validation of analytical methods: definitions and
terminology, June 1995 – Validation of analytical procedures: methodology,
November 1996
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GCP/GLPGCP/GLP
GCP/GLP compliance– Clinical studies have to be performed under
conditions complying with the principles of Good Clinical Practice, and for analytical methods and sample data handling conditions complying with the principles of Good Laboratory Practice are required.
– For older studies without statement of complinace with the above mentioned principles, the assessor should rely on the quality of the submitted report.
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Choices of methodsChoices of methods
LC-MS-MS
GC-MS
HPLC
GLC
Immunological methods
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Choices of methodsChoices of methods
Method used for the determination of drugs and/or metabolites should be:
SensitiveAccurateDiscriminativePrecise
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SensitivitySensitivity
Method should be able to quantify the drug in the sampled specimen at least 10 % of the maximum concentration reached after dosing.
Limit of Quantification (LOQ): 1/10 Cmax
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DiscriminativeDiscriminative
The method should be able to discriminate between the selected analyte and interfering compounds from the environment or from other compounds administered simultaneously
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AccuracyAccuracy
The method must be accurate enough to measure the true value (concentration) of the analyte in a relative small sample
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PrecisionPrecision
The analytical method should be presice enough to reveal identical results when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of the biological matrix
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ValidationValidation
To measure is to know!
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ValidationValidation
Specificity
Detection limit (LOD)
Quantification limit (LOQ)
Linearity
Range
Accuracy
Precision
Robustness
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Validation-specificityValidation-specificity
Investigation of specificity should be conducted during the validation phase of the assay
The procedures used to demonstrate specificity should be clearly reported
Must be applied with structurally similar materials
Choices base on scientific judgements
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Validation-specificityValidation-specificity
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Validation-LODValidation-LOD
Various methods possible
visual evaluation• minimum level at which the analyte can be
detected reliably
signal-to noise• 3:1 ratio is acceptable
standard deviation of the slope and response• LOD = 3.3 σ / S
– σ = standard deviation of the response– S = slope of the calibration curve
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Validation-LOQValidation-LOQ
Based on signal-to noise– Reliable quantification is a 10:1 ratio
Based on SD of the response and the slope – LOQ = 10 σ / S
• σ = standard deviation of the response• S = slope of the calibration curve
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Validation-LOD/LOQValidation-LOD/LOQ
Recommended data:
The LOD and LOQ and the method used for the LOQ should be presented
The limits should be validated by the analyses of a suitable number of samples prepared at the LOD and LOQ limits
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Validation-LODValidation-LOD
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LOQ, LOD and SNR
Limit of Quantitation
Limit of Detection
Signal to Noise Ratio
noise
Peak ALOD
Peak BLOQ
Baseline
Validation
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Validation-linearityValidation-linearity
Should be evaluated across the range of concentrations expected during the study
A minimum of five concentrations used in the range is recommended
The correlation coefficient, y-intercept slope of the regression and residual sum of squares should be submitted
Deviations from the regression line should be analysed for evaluating linearity
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Validation-linearityValidation-linearity
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Validation-rangeValidation-range
The specified range is derived from linearity studies and should cover the extremes of the concentrations probably reached during the study
The range should be justified in the report based on scientific information
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Validation-accuracyValidation-accuracy
Accuracy should be assessed on samples spiked with known amounts of the analyte
Accuracy should be assessed using determinations over a minimum of 3 concentration levels (low, medium and high)
Accuracy should be reported as percent recovery from the added amount and with confidence intervals
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Validation-accuracyValidation-accuracy
LQC
MQC
HQC
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Validation-precisionValidation-precision
Repeatability– concentrations covering the specified range
Intermediate precision– Like days, analysts, equipment
Reproducibility– Determined if analyses take place in separate periods
Recommended data– SD, Coefficient of variations, and confidence intervals
should be reported on each type of precision
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