Perspective Gagnon-Carignan, Lachance, Saint-Laurent, Gendron & Lévesque Key terms
Incurred samples reanalysis: Samples reanalyzed for the determination of bioanalytical method reproducibility where the two values for one sample are compared using the percent of difference formulae.
Deficiency letters: A query from a regulatory agency on potential issues noted during the review of a submission.
Labile metabolite: Metabolite that is considered to be unstable in different conditions or that can degrade into the parent drug. Lactones, glucuronide or N-oxide are considered labile metabolites.
Multi-analyte assay: A bioanalytical method that can analyze two or more analytes in the same assay. For instance, a method that can analyze the parent drug and its metabolite.
Ratio: The quantitative relation between the test formulation and the reference formulation.
• Metabolites back-conversion;
• Other ISR data obtained in the same laboratory; • Data from repeat analysis; • The obtained PK data in the study; • 90% confidence interval. In our experience, designing a justification accord-
ing to these five topics has a better chance of success. However, other types of data may be beneficial and thus, the justification should not be limited to the five points above if appropriate. For example, in our experi- ence, discussing the general study performance right from the beginning can quickly show the quality of the analyses.
The general study performances A good justification should remind the assessors of the overall quality of the study using the data that was already discussed in the study report. Detailing the calibrators and quality controls performance on both the precision and the accuracy (P&A) demonstrates that the assay did perform adequately during sample analysis. Moreover, the good performance of the rate of accepted bioanalytical runs and the number of analytical repeats can show that the analysis was well executed. In addition, going back to the results obtained in
validation and use those as a comparator for the study performance can strengthen the (P&A) demonstration mentioned above. Finally, showing that the study sam- ple analyses were carried within the validated stability parameters is one of the valuable arguments that can be used to show that no degradation or back-conversion
222 Bioanalysis (2015) 7(2)
has occurred during sample handling, storage and analysis.
The metabolites back-conversion Metabolites may interfere with the quantitation of an analyte, specifically when this metabolite is labile and may back-convert into the analyte of interest. Among the metabolites, special considerations must be taken with acidic, lactones, glucuronides and N-oxide metabolites, and more carefully if these are primary formation metabolites. The justification for the lack of ISR should include
an assessment of the extent of potential interference caused by labile metabolites. A thorough literature review is to be done in order to obtain as much infor- mation as possible on the product’s metabolism. The assessment should include a clear description of the metabolic pathway, when accessible (if this informa- tion is not available, this should be stated in the justifi- cation). Proportion of each metabolite should be taken into account with consideration of the absorption, distribution, metabolism and elimination of the prod- ucts. In the matrix of interest, metabolites at levels of 10% or more of that of the analyte of interest must be carefully studied. Metabolites with lower amount (less than 10%) are unlikely to interfere with the analyte quantitation. Moreover, if more than one metabolite is suscep-
tible to back-convert to the parent compound, each of these being less than 10% of the parent but collectively above 10%, all attempt is to be made in order to deter- mine if they are prone to back-convert at the same time or rate to the parent molecule. This is possible when PK profile or metabolites Tmax
are available. If this is
the case, the impact on the analyte concentration is to be evaluated attentively. In addition, each step of the bioanalysis must be
assessed for the degradation of the metabolites into the parent drug:
• Sample collection and handling; • Extraction and analysis of the analyte(s); • Stability in matrix. For studies performed before the recent regulations,
the extent of back-conversion has often not been stud- ied during method validation. In such cases, a theo- retical evaluation may be performed using scientific knowledge of the drug, its chemistry and metabolism. However, no matter how comprehensive the literature search and data are, this remains a theoretical evalua- tion. This is why a strong justification for the lack of
future science group
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