References of "Debrus, Benjamin"
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See detailA New Method for Quality by Design Robust Optimization in Liquid Chromatography
Debrus, Benjamin ULg; Lebrun, Pierre ULg; Rozet, Eric ULg et al

in LC-GC Europe (2013), -(-), -

A new method to optimize liquid chromatography (LC) methods using a Quality by Design (QbD) approach is presented. This method is based on the use of design of experiments (DOE) and independent component ... [more ▼]

A new method to optimize liquid chromatography (LC) methods using a Quality by Design (QbD) approach is presented. This method is based on the use of design of experiments (DOE) and independent component analysis (ICA) to accurately estimate the modelled responses (that is, the retention times at the beginning, the apex, and the end) of each peak, even for coeluted peaks. The modelling of these responses usesmultiple linear regressions, while the propagation of the error affecting the responses and coming from the models is carried out by Monte Carlo simulation. The design space is determined as the region of assay factors where the probability to reach baseline-resolved peaks is higher than the desired level of quality. This method was applied to the optimization of the separation of nine compounds in a mixture, yielding the design space and the demonstration of robustness of the method. Finally, the method was validated. [less ▲]

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See detailA Bayesian Design Space for analytical methods based on multivariate models and predictions
Lebrun, Pierre ULg; Boulanger, Bruno ULg; Debrus, Benjamin ULg et al

in Journal of Biopharmaceutical Statistics (2013), 23

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of ... [more ▼]

The International Conference for Harmonization (ICH) has released regulatory guidelines for Pharmaceutical Development. In the document ICH Q8, The Design Space of a process is presented as the set of factor settings providing satisfactory results. However, ICH Q8 does not propose any practical methodology to define, derive and compute Design Space. In parallel, in the last decades, it has been observed that the diversity and the quality of analytical methods have evolved exponentially allowing substantial gains in selectivity and sensitivity. However, there is still a lack for a rationale towards the development of robust separation methods in a systematic way. Applying ICH Q8 to analytical methods provides a methodology for predicting a region of the space of factors in which results will be reliable. Combining design of experiments and Bayesian standard multivariate regression, an identified form of the predictive distribution of a new response vector has been identified and used, under non-informative as well as informative prior distributions of the parameters. From the responses and their predictive distribution, various critical quality attributes can be easily derived. This Bayesian framework was then extended to the multi-criteria setting to estimate the predictive probability that several critical quality attributes will be jointly achieved in the future use of an analytical method. An example based on a high-performance liquid chromatography (HPLC) method is given. For this example, a constrained sampling scheme was applied to ensure the modeled responses have desirable properties. [less ▲]

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See detailDesign Spaces for Analytical Methods
Rozet, Eric ULg; Lebrun, Pierre ULg; Debrus, Benjamin ULg et al

in Trends in Analytical Chemistry [=TRAC] (2013), 42

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a Quality by Design (QbD) approach, there have been many discussions on the opportunity for ... [more ▼]

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a Quality by Design (QbD) approach, there have been many discussions on the opportunity for analytical method developments to follow a similar approach. A key component of the QbD paradigm is the definition of the Design Space of analytical methods where assurance of quality is provided. Several Design Spaces for analytical methods have been published, stressing the importance of this concept. This paper aims at explaining what is an analytical method Design Space, why it is useful for the robust development and optimization of analytical methods and how to build such a Design Space. A strong emphasis is made by distinguishing the usual mean response surface approach, overlapping mean response surfaces and the desirability function one to other probabilistic approaches as only these last ones correctly define a Design Space. In addition, recent publications assessing the Design Space of analytical methods are reviewed and discussed. [less ▲]

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See detailAPPLICATION OF AN INNOVATIVE DESIGN SPACE OPTIMIZATION STRATEGY TO THE DEVELOPMENT OF LC METHODS TO COMBAT POTENTIALLY COUNTERFEIT NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Mbinze Kindenge, Jérémie ULg; Lebrun, Pierre ULg; Debrus, Benjamin ULg et al

in Journal of Chromatography. A (2012), 1263

In the context of the battle against counterfeit medicines, an innovative methodology has been used to develop rapid and specific high performance liquid chromatographic methods to detect and determine 18 ... [more ▼]

In the context of the battle against counterfeit medicines, an innovative methodology has been used to develop rapid and specific high performance liquid chromatographic methods to detect and determine 18 non-steroidal anti-inflammatory drugs, 5 pharmaceutical conservatives, paracetamol, chlorzoxazone, caffeine and salicylic acid. These molecules are commonly encountered alone or in combination on the market. Regrettably, a significant proportion of these consumed medicines are counterfeit or substandard, with a strong negative impact in countries of Central Africa. In this context, an innovative design space optimization strategy was successfully applied to the development of LC screening methods allowing the detection of substandard or counterfeit medicines. Using the results of a unique experimental design, the design spaces of 5 potentially relevant HPLC methods have been developed, and transferred to an ultra high performance liquid chromatographic system to evaluate the robustness of the predicted DS while providing rapid methods of analysis. Moreover, one of the methods has been fully validated using the accuracy profile as decision tool, and was then used for the quantitative determination of three active ingredients and one impurity in a common and widely used pharmaceutical formulation. The method was applied to 5 pharmaceuticals sold in the Democratic Republic of Congo. None of these pharmaceuticals was found compliant to the European Medicines Agency specifications [less ▲]

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See detailDevelopment of a generic micellar electrokinetic chromatography method for the separation of 15 antimalarial drugs as a tool to detect medicine counterfeiting
Lamalle, Caroline ULg; Marini Djang'Eing'A, Roland ULg; Debrus, Benjamin ULg et al

in Electrophoresis (2012), 33

Since antimalarial drugs counterfeiting is dramatically present on the African market, the development of simple analytical methods for their quality control is of great importance. This work consists in ... [more ▼]

Since antimalarial drugs counterfeiting is dramatically present on the African market, the development of simple analytical methods for their quality control is of great importance. This work consists in the CE analysis of 15 antimalarials (artesunate, artemether, amodiaquine, chloroquine, piperaquine, primaquine, quinine, cinchonine, mefloquine, halofantrine, sulfadoxine, sulfalen, atovaquone, proguanil, and pyrimethamine). Since all these molecules cannot be ionized at the same pH, MEKC was preferred because it also allows separation of neutral compounds. Preliminary experiments were first carried out to select the most crucial factors affecting the antimalarials separation. Several conditions were tested and four parameters as well as their investigation domain were chosen: pH (5–10), SDS concentration (20–90 mM), ACN proportion (10–40%), and temperature (20–35°C). Then, the experimental design methodology was used and a central composite design was selected. Mathematical modeling of the migration times allowed the prediction of optimal conditions (29°C, pH 6.6, 29 mM SDS, 36% ACN) regarding analyte separation. The prediction at this optimum was verified experimentally and led to the separation of 13 compounds within 8 min. Finally, the method was successfully applied to the quality control of African antimalarial medicines for their qualitative and quantitative content. [less ▲]

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See detailCOMBINATION OF INDEPENDENT COMPONENT ANALYSIS, DESIGN OF EXPERIMENTS AND DESIGN SPACE FOR A NOVEL METHODOLOGY TO DEVELOP CHROMATOGRAPHIC METHODS
Rozet, Eric ULg; Debrus, Benjamin ULg; Lebrun, Pierre ULg et al

Poster (2012, February)

As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process ... [more ▼]

As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management”. A risk–based QbD–compliant approach is proposed for the robust development of analytical methods. This methodology based on Design of Experiments (DoE) to study the experimental domain models the retention times at the beginning, the apex and the end of each peak corresponding to the compounds of a mixture and uses the separation criterion (S) rather than the resolution (RS) as a Critical Quality Attribute. Stepwise multiple linear regressions are used to create the models. The estimated error is propagated from the modelled responses to the separation criterion (S) using Monte Carlo simulations in order to estimate the predictive distribution of the separation criterion (S) over the whole experimental domain. This allows finding ranges of operating conditions that will guarantee a satisfactory quality of the method in its future use. These ranges define the Design Space (DS) of the method. In chromatographic terms, the chromatograms processed at operating conditions within the DS will assuredly show high quality, with well separated peaks and short run time, for instance. This Design Space can thus be defined as the subspace, necessarily encompassed in the experimental domain (i.e. the knowledge space), within which the probability for the criterion to be higher than an advisedly selected threshold is higher than a minimum quality level. Precisely, the DS is defined as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” [1]. Therefore, this DS defines a region of operating conditions that provide prediction of assurance of quality rather than only quality as obtained with traditional mean response surface optimisation strategies. For instance, in the liquid chromatography there is a great difference in e.g. predicting a resolution (RS) higher than 1.5 vs. predicting that the probability for RS to be higher than 1.5 (i.e. P(RS> 1.5)) is high. The presentation of this global methodology will be illustrated for the robust optimisation and DS definition of several liquid chromatographic methods dedicated to the separation of different mixtures: pharmaceutical formulations, API and impurities/degradation products, plant extracts, separation of enantiomers, … References [1] International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q8(R2): Pharmaceutical development, Geneva, 2009. [less ▲]

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See detailChapter 3 Method Transfer Between Conventional HPLC and UHPLC
Debrus, Benjamin ULg; Rozet, Eric ULg; Hubert, Philippe ULg et al

in Guillarme, Davy; Veuthey, jean-Luc (Eds.) UHPLC in Life Sciences (2012)

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See detailAPPLICATION OF DESIGN OF EXPERIMENTS AND DESIGN SPACE METHODOLOGY FOR THE HPLC-UV SEPARATION OPTIMIZATION OF APORPHINE ALKALOIDS FROM LEAVES OF Spirospermum penduliflorum THOUARS
Rafamantanana, Mamy; Debrus, Benjamin ULg; Raoelison, Guy et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 62

Spirospermum penduliflorum Thouars (Menispermaceae) is an endemic species of Madagascar traditionally used as vasorelaxant. Recently, two aporphine alkaloids known to possess antihypertensive activity ... [more ▼]

Spirospermum penduliflorum Thouars (Menispermaceae) is an endemic species of Madagascar traditionally used as vasorelaxant. Recently, two aporphine alkaloids known to possess antihypertensive activity (dicentrine and neolitsine) were isolated and identified from the leaves of this plant. In the present study, a HPLC-UV method allowing the separation of all alkaloids and the quantification of dicentrine in the alkaloidic extract of leaves was developed using design of experiments and design space methodology. Three common chromatographic parameters (i.e. the mobile phase pH, the initial proportion of methanol and the gradient slope) were selected to construct a full factorial design of 36 experimental conditions. The times at the beginning, the apex (i.e. the retention time) and the end of each peak were recorded and modelled by multiple linear equations. The corresponding residuals were normally distributed which confirmed that the models can be used for the prediction of the retention times and to optimize the separation. The optimal separation was predicted at pH 3, with a gradient starting at 32% of methanol and a gradient slope of 0.42%/min. Good agreement was obtained between predicted and experimental chromatograms. The method was also validated using total error concept. Using the accuracy profile approach, validation results gave a LOD and LOQ for dicentrine of 3 µg/ml and 10 µg/ml, respectively. A relative standard deviation for intermediate precision lower than 10% was obtained. This method was found to provide accurate results in the concentration range of 10 µg/ml to 75 µg/ml of dicentrine and is suitable for routine analysis. [less ▲]

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See detailNew Methodology for the Development of Chromatographic Methods
Rozet, Eric ULg; Debrus, Benjamin ULg; Lebrun, Pierre ULg et al

Conference (2011, September 08)

As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process ... [more ▼]

As defined by ICH [1] and FDA, Quality by Design (QbD) stands for “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management”. A risk–based QbD–compliant approach is proposed for the robust development of analytical methods. This methodology based on Design of Experiments (DoE) to study the experimental domain models the retention times at the beginning, the apex and the end of each peak corresponding to the compounds of a mixture and uses the separation criterion (S) rather than the resolution (RS) as a Critical Quality Attribute. Stepwise multiple linear regressions are used to create the models. The estimated error is propagated from the modelled responses to the separation criterion (S) using Monte Carlo simulations in order to estimate the predictive distribution of the separation criterion (S) over the whole experimental domain. This allows finding ranges of operating conditions that will guarantee a satisfactory quality of the method in its future use. These ranges define the Design Space (DS) of the method. In chromatographic terms, the chromatograms processed at operating conditions within the DS will assuredly show high quality, with well separated peaks and short run time, for instance. This Design Space can thus be defined as the subspace, necessarily encompassed in the experimental domain (i.e. the knowledge space), within which the probability for the criterion to be higher than an advisedly selected threshold is higher than a minimum quality level. Precisely, the DS is defined as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” [1]. Therefore, this DS defines a region of operating conditions that provide prediction of assurance of quality rather than only quality as obtained with traditional mean response surface optimisation strategies. For instance, in the liquid chromatography there is a great difference in e.g. predicting a resolution (RS) higher than 1.5 vs. predicting that the probability for RS to be higher than 1.5 (i.e. P(RS> 1.5)) is high. The presentation of this global methodology will be illustrated for the robust optimisation and DS definition of several liquid chromatographic methods dedicated to the separation of different mixtures: pharmaceutical formulations, API and impurities/degradation products, plant extracts, separation of enantiomers, … References [1] International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q8(R2): Pharmaceutical development, Geneva, 2009. Acknowledgements A research grant from the Belgium National Fund for Scientific Research (F.R.S-FNRS) to E. Rozet is gratefully acknowledged. [less ▲]

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See detailDesign Space and desirability index. A Bayesian predictive risk-based approach to flexibly achieve multi-criteria decision methods.
Lebrun, Pierre ULg; Boulanger, Bruno; Hubert, Philippe ULg et al

Conference (2011, March 02)

The Design Space (DS) is defined as the set of factors settings (input conditions) that will provide results at least better than pre-defined acceptance limits. The proposed methodology aims at ... [more ▼]

The Design Space (DS) is defined as the set of factors settings (input conditions) that will provide results at least better than pre-defined acceptance limits. The proposed methodology aims at identifying a region in the space of factors that will likely provide satisfactory results during the future use of an analytical method or process in routine, through an optimization process. In a Bayesian framework, the responses are modelled using a multivariate multiple regression model allowing deriving their joint predictive posterior distribution. On the basis of this consequent distribution, a multi-criteria risk-based decision is taken with respect to the pre-defined acceptance limits. This aims to identify the DS. In this context, desirability methodologies are also applied to take the risk-based decision in a more flexible way. An example based on high-performance liquid chromatography illustrates the applicability of the methodology with highly correlated and constrained responses. [less ▲]

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See detailInnovative methodology to transfer conventional GC-MS heroin profiling to UHPLC-MS/MS
Debrus, Benjamin ULg; Broséus, Julian; Guillarme, Davy et al

in Analytical and Bioanalytical Chemistry (2011), 399(8), 2719-2730

Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good ... [more ▼]

Nowadays, in forensic laboratories, heroin profiling is frequently carried out by gas chromatography coupled with mass spectrometry (GC-MS). This analytical technique is well established, provides good sensitivity and reproducibility, and allows the use of large databases. Despite those benefits, recently introduced analytical techniques, such as ultra-high-pressure liquid chromatography (UHPLC), could offer better chromatographic performance, which needs to be considered to increase the analysis throughput for heroin profiling. With the latter, chromatographic conditions were optimized through commercial modeling software and two atmospheric pressure ionization sources were evaluated. Data obtained from UHPLC–MS/MS were thus transferred, thanks to mathematical models to mimic GC-MS data. A calibration and a validation set of representative heroin samples were selected among the database to establish a transfer methodology and assess the models’ abilities to transfer using principal component analysis and hierarchical classification analysis. These abilities were evaluated by computing the frequency of successful classification of UHPLC–MS/MS data among GC-MS database. Seven mathematical models were tested to adjust UHPLC–MS/MS data to GC-MS data. A simplified mathematical model was finally selected and offered a frequency of successful transfer equal to 95%. [less ▲]

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See detailValidation, transfer and measurement uncertainty estimation of an HPLC-UV method for the quantification of artemisinin in hydro alcoholic extracts of Artemisia annua L.
ZIME DIAWARA, H.; GBAGUIDI, F.; Evrard, Brigitte ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2011), 56

Malaria is the world’s most important parasitic infection with 500 millions cases annually and almost 2 millions death per year. This disease is more present in Sub-Saharan Africa where 90% of the ... [more ▼]

Malaria is the world’s most important parasitic infection with 500 millions cases annually and almost 2 millions death per year. This disease is more present in Sub-Saharan Africa where 90% of the infections are found. Artemisinin and its semi synthetic derivatives (artemether, artesunate) have actually the most powerful activity on malaria, even in its complicated forms and resistance cases. Various methods have been proposed for detection and quantification of artemisinin in Artemisia annua L. by HPLC-UV, but the plant extracts used for this quantification were extracts obtained with organic solvents (toluene, petroleum ether, hexane …). To be able to use crude A. annua extracts prepared at low cost to formulate antipaludic drugs, we chose the use of a mixture of water and ethanol as solvent of extraction, but no adequate analytical method for this kind of extracts is published. The main objectives of this work were first to develop an analytical method for artemisinin quantification in hydro alcoholic extracts of A. annua. Second, this method had to be thoroughly validated by the research and development laboratory and, third, the transfer of this method to the routine laboratory had to be demonstrated. The final aim was to compare the estimation of measurement uncertainty obtained during the method validation with validation standards to measurement uncertainty estimates obtained during the method transfer study with real samples. The method was validated following the accuracy profile methodology and was found to be accurate in the concentration range of 10.0 to 54.0 µg/ml with CV <8%. Limit of detection and of quantification were 2.73 and 10.0 µg/ml, respectively. The method was then successfully transferred to a laboratory in Benin by showing that the quality of the results that it will generate during routine application of the method is sufficient. Finally, the measurement uncertainty of the method was estimated from the validation experiments as well as from the transfer study with authentic unspiked samples of A. annua. The comparison of these measurement uncertainty estimations showed that they were coherent. It confirmed thus that the estimation of measurement uncertainty from validation experiments predicts well the measurement uncertainty of real routine samples. This analytical method was thus shown to be convenient for routine analysis of hydro alcoholic extracts of A. annua in Benin. [less ▲]

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