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Lecomte F.,University of Liege | Hubert C.,University of Liege | Demarche S.,University of Liege | De Bleye C.,University of Liege | And 6 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2012

Method validation is essential to ensure that an analytical method is fit for its intended purpose. Additionally, it is advisable to estimate measurement uncertainty in order to allow a correct interpretation of the results generated by analytical methods. Measurement uncertainty can be efficiently estimated during method validation as a top-down approach. However, method validation predictions of the quantitative performances of the assay and estimations of measurement uncertainty may be far away from the real performances obtained during the routine application of this assay. In this work, the predictions of the quantitative performances and measurement uncertainty estimations obtained from a method validation are compared to those obtained during routine applications of a bioanalytical method.For that purpose, a new hydrophilic interaction chromatography (HILIC) method was used. This method was developed for the determination of cidofovir, an antiviral drug, in human plasma. Cidofovir (CDV) is a highly polar molecule presenting three ionizable functions. Therefore, it is an interesting candidate for determination by HILIC mode. CDV is an acyclic cytidine monophosphate analog that has a broad antiviral spectrum and is currently undergoing evaluation in clinical trials as a topical agent for treatment of papillomavirus infections. The analytical conditions were optimized by means of design of experiments approach in order to obtain robust analytical conditions. These ones were absolutely necessary to enable the comparisons mentioned above. After a sample clean-up by means of solid phase extraction, the chromatographic analysis was performed on bare silica stationary phase using a mixture of acetonitrile-ammonium hydrogen carbonate (pH 7.0; 20. mM) (72:28, v/v) as mobile phase. This newly developed bioanalytical method was then fully validated according to FDA (Food and Drug Administration) requirements using a total error approach that guaranteed that each future result will fall within acceptance limits of ±30% with a probability of 95% over a concentration range of 92.7-1020. ng/mL. A routine application of the cidofovir determination in two pre-clinical trials demonstrated that the prediction made during the pre-study validation was consistent by retrospective analysis of the quality control (QC) samples. Finally, comparison of the measurement uncertainty estimations calculated from the method validation with those obtained from the routine application of the method was performed, stressing that the estimations obtained during method validation underestimated those obtained from routine applications and that the magnitude of this underestimation was function of the cidofovir concentration. Finally, this new HILIC method is reliable, easily applicable to routine analysis and transposable at low cost in other laboratories. © 2011 Elsevier B.V. Source

Debrus B.,University of Liege | Lebrun P.,University of Liege | Kindenge J.M.,University of Liege | Kindenge J.M.,University of Kinshasa | And 7 more authors.
Journal of Chromatography A | Year: 2011

An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE-ICA-DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE-ICA-DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE-ICA-DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study. © 2011 Elsevier B.V. Source

Debrus B.,University of Liege | Lebrun P.,University of Liege | Ceccato A.,Odyssea Pharma | Rozet E.,University of Liege | And 7 more authors.
Analytica Chimica Acta | Year: 2011

HPLC separations of an unknown sample mixture and a pharmaceutical formulation have been optimized using a recently developed chemometric methodology proposed by W. Dewé et al. in 2004 and improved by P. Lebrun et al. in 2008. This methodology is based on experimental designs which are used to model retention times of compounds of interest. Then, the prediction accuracy and the optimal separation robustness, including the uncertainty study, were evaluated. Finally, the design space (ICH Q8(R1) guideline) was computed as the probability for a criterion to lie in a selected range of acceptance. Furthermore, the chromatograms were automatically read. Peak detection and peak matching were carried out with a previously developed methodology using independent component analysis published by B. Debrus et al. in 2009. The present successful applications strengthen the high potential of these methodologies for the automated development of chromatographic methods. © 2011 Elsevier B.V. Source

Mantanus J.,University of Liege | Rozet E.,University of Liege | Van Butsele K.,Odyssea Pharma | De Bleye C.,University of Liege | And 4 more authors.
Analytica Chimica Acta | Year: 2011

Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below ±5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy. © 2011 Elsevier B.V. Source

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