References of "Rozet, Eric"
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See detailCritical Review of Near-Infrared Spectroscopic Methods Validations in Pharmaceutical Applications
De Bleye, Charlotte ULg; Chavez, Pierre-François ULg; Mantanus, Jérôme ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2012), 69

Based on the large number of publications reported over the past five years, near-infrared spectroscopy (NIRS) is more and more considered an attractive and promising analytical tool regarding Process ... [more ▼]

Based on the large number of publications reported over the past five years, near-infrared spectroscopy (NIRS) is more and more considered an attractive and promising analytical tool regarding Process Analytical Technology and Green Chemistry. From the reviewed literature, few of these publications present a thoroughly validated NIRS method even if some guidelines have been published by different groups and regulatory authorities. However, as any analytical method, the validation of NIRS method is a mandatory step at the end of the development in order to give enough guarantees that each of the future results during routine use will be close enough to the true value. Besides the introduction of PAT concepts in the revised document of the European Pharmacopoeia (2.2.40) dealing with near-infrared spectroscopy recently published in Pharmeuropa, it agrees very well with this mandatory step. Indeed, the latter suggests to use similar analytical performance characteristics than those required for any analytical procedure based on acceptance criteria consistent with the intended use of the method. In this context, this review gives a comprehensive and critical overview of the methodologies applied to assess the validity of quantitative NIRS methods used in pharmaceutical applications. [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 detailUsefulness of capability indices in the framework of analytical methods validation
Bouabidi, Abderrahim ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytica Chimica Acta (2012), 714

Analytical methods capability evaluation can be a useful methodology to assess the fitness of purpose of these methods for their future routine application. However, care on how to compute the capability ... [more ▼]

Analytical methods capability evaluation can be a useful methodology to assess the fitness of purpose of these methods for their future routine application. However, care on how to compute the capability indices has to be made. Indeed, the commonly used formulas to compute capability indices such as Cpk, will highly overestimate the true capability of the methods. Especially during methods validation or transfer, there are only few experiments performed and, using in these situations the commonly applied capability indices to declare a method as valid or as transferable to a receiving laboratory will conduct to inadequate decisions. In this work, an improved capability index, namely Cpk-tol and the corresponding estimator of proportion of non conforming results ( ) has been proposed. Through Monte-Carlo simulations, they have been shown to greatly increase the estimation of analytical methods capability in particular in low sample size situations as encountered during methods validation or transfer. Additionally, the usefulness of this capability index has been illustrated through several case studies covering applications commonly encountered in the pharmaceutical industry. Finally a methodology to determine the optimal sample size required to validate analytical methods is also given using the proposed capability metric. [less ▲]

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See detailQuality by design compliant analytical method validation
Rozet, Eric ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytical Chemistry (2012), 84

The concept of quality by design (QbD) has recently been adopted for the development of pharmaceutical processes to ensure a predefined product quality. Focus on applying the QbD concept to analytical ... [more ▼]

The concept of quality by design (QbD) has recently been adopted for the development of pharmaceutical processes to ensure a predefined product quality. Focus on applying the QbD concept to analytical methods has increased as it is fully integrated within pharmaceutical processes and especially in the process control strategy. In addition, there is the need to switch from the traditional checklist implementation of method validation requirements to a method validation approach that should provide a high level of assurance of method reliability in order to adequately measure the Critical Quality Attributes (CQAs) of the drug product. The intended purpose of analytical methods is directly related to the final decision that will be made with the results generated by these methods under study. The final aim for quantitative impurity assays is to correctly declare a substance or a product as compliant with respect to the corresponding product specifications. For content assays, the aim is similar: making the correct decision about product compliance with respect to their specification limits. It is for these reasons that the fitness of these methods should be defined, as they are key elements of the Analytical Target Profile (ATP). Therefore, validation criteria, corresponding acceptance limits and method validation decision approaches should be settled in accordance with the final use of these analytical procedures. This work proposes a general methodology to achieve this in order to align method validation within the QbD framework and philosophy. β-expectation tolerance intervals are implemented to decide about the validity of analytical methods. The proposed methodology is also applied to the validation of analytical procedures dedicated to the quantification of impurities or active product ingredients (API) in drug substances or drug products and its applicability is illustrated with two case studies. [less ▲]

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See detailDesign Space ou Espace de Conception
Boulanger, B.; Lebrun, Pierre ULg; Rozet, Eric ULg et al

Scientific conference (2011, November 29)

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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 detailNEW TRENDS IN VALIDATION OF ANALYTICAL METHODS
Rozet, Eric ULg; Hubert, Philippe ULg

Conference (2011, September 08)

Analytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will ... [more ▼]

Analytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them. Even if several guidelines exist to help perform analytical method validations (ICH Q2R1 [1], USP <1225> [2], …) there is still the need to clarify the meaning and interpretation of analytical method validation criteria and methodology. Indeed, actually method validation is mostly realised as the traditional check list implementation of e.g. the ICH Q2R1 or USP <1225> method validation requirements. However, within the trend of Quality by Design [3], there is the need to switch from this traditional vision to an analytical method validation really adding value and providing a high level of assurance of analytical methods results reliability. Yet, different interpretations can be made of the validation guidelines as well as for the definitions of the validation criteria. This will lead to diverse experimental designs implemented to try fulfilling these criteria. Finally, different decision methodologies can also be interpreted from these guidelines. Therefore, the risk that a validated analytical method may be unfit for its future purpose will depend on a personal interpretation of these guidelines. The objective of this presentation is thus to show that analytical method validation should be planned and performed by first starting with the end in mind: what is the objective of the analytical methods under study? In such a way analytical method validation is coherent with the actual Quality by Design regulatory expectations. The risk of having validated an analytical method unfit for its purpose is strongly reduced as well as the risk of generating Out of Specification (OOS) results due to an unfit method. References [1] International Conference on Harmonisation (ICH) of Technical Requirements for registration of Pharmaceuticals for Human Use, Topic Q2 (R1): Validation of Analytical Procedures: Text and Methodology, Geneva, 2005. [2] USP 33 NF 28 S1, U.S. Pharmacopeia, 2007. USP–NF General Chapter <1225>. [3] 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 detailA RAPID UHPLC-DAD-ESI-MSn METHOD FOR ANTHOCYANINS QUANTIFICATION FROM Euterpe oleracea FRUITS HARVESTED AT DIFFERENT TIMES
Dias, A.; Chataigné, G.; Rozet, Eric ULg et al

Poster (2011, June 09)

Euterpe oleracea is a palm tree widely distributed in northern South America. Its greatest occurrence and economic importance happens in the floodplains of the Amazonian delta. The fruits called açai are ... [more ▼]

Euterpe oleracea is a palm tree widely distributed in northern South America. Its greatest occurrence and economic importance happens in the floodplains of the Amazonian delta. The fruits called açai are an interesting source of different anthocyanins. Lately they have gained popularity in North America and in the European countries in the food industry and in the health sector due to their extremely high antioxidant capacity and potential anti-inflammatory activities [1]. Some studies have characterized chemically açaí pulps and have reported anthocyanin profiles which differ both qualitatively and quantitatively. Among other reasons, these differences may be associated with the stages of ripening of the fruits, since açai fruits are generally harvested in different maturation stages. The evaluation of the anthocyanin profile of açai fruits during different maturation stages is thus important for the post-harvest industry. In addition a rapid separation by UHPLC and an unambiguous identification by MSn are very useful for an effective quality control of the fruits. Thus, the aim of this study was to characterize the anthocyanin profiles of açai fruits at different stages of maturity. The fruits were harvested during the peak harvesting season, between July and October 2009, in the floodplains of the eastern Amazonian region (State of Pará, Brazil). A protocol of solid-liquid extraction of phenolic compounds was developed. Characterisation of the anthocyanins present in the fruits of Euterpe oleracea was conducted by UHPLC–DAD–ESI–MSn analysis, in positive ionization mode. All identified compounds was separated in 10 minutes of a total run time of 21 min instead of 55 min in the previously developed HPLC method. Six anthocyanins were identified in the extracts namely: cyaniding-3-glucoside, cyaniding-3-rutinoside, pelargonidin-3-glucoside, peonidin-3-glucoside, peonidin-3-rutinoside and cyanidin. The first two compounds were the major constituents in all maturity stages, with similar proportions, except for the first maturity stage for which the anthocyanins were under the limit of quantification. However, in the last maturity stage, cyanidin-3-glucoside became less abundant than cyanidin-3-rutinoside. On the other hand, cyanidin decreased with maturation. For the other compounds, proportions were similar along maturation. Hence, this work was important as it provides valid information on variation of anthocyanin profiles of açai fruits during maturation. This may contribute to the selection of an optimal maturity stage for harvesting as well as it will allow a rapid quality control of the fruits. [1]: Heinrich, M., et al., Açai (Euterpe oleracea Mart.)- A phytochemical and pharmacological assessment of the species’ health claims. Phytochem. Lett. (2010), doi: 10.1016/j.phytol.2010.11.005 [less ▲]

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See detailComment adéquatement déclarer valide ou non valide une méthode analytique ?
Rozet, Eric ULg; Hubert, Philippe ULg

Conference (2011, April 04)

Vu le rôle central que jouent les méthodes d’analyse dans l’ensemble des activités tant de l’industrie (bio)pharmaceutique, agro-alimentaire, chimique ou dans l’environnement, il est essentiel de les ... [more ▼]

Vu le rôle central que jouent les méthodes d’analyse dans l’ensemble des activités tant de l’industrie (bio)pharmaceutique, agro-alimentaire, chimique ou dans l’environnement, il est essentiel de les valider. Les critères de validation ne sont pas une finalité et il est nécessaire de rappeler l’objectif d’une méthode analytique et de sa validation afin de planifier adéquatement cette étape de validation. Par ailleurs, les approches de décision habituelles qui se basent seulement sur des estimateurs ponctuelles ne répondent pas à l’objectif de la validation. Une stratégie alternative pour décider de la validité des méthodes est proposée utilisant les intervalles de tolérance : "ß-expectation tolerance interval". [less ▲]

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See detailPerformance of three HIV-1 DNA real-time PCRs for early diagnosis in infants and adults
Iserentant, G.; Masquelier, C.; Lambert, C. et al

Poster (2011, March)

Background Early pediatric HIV-1 diagnosis is a challenge in resource limited countries to identify HIV-infected newborns to provide early ART treatment. HIV DNA PCR testing is an accurate method for ... [more ▼]

Background Early pediatric HIV-1 diagnosis is a challenge in resource limited countries to identify HIV-infected newborns to provide early ART treatment. HIV DNA PCR testing is an accurate method for diagnosis in newborns and could be valuable for monitoring HIV infection in adults. We have evaluated the analytical, clinical performances and genotype inclusivity of 3 real-time Taqman PCRs targeting the ltr, int and env genes. Material and methods Total DNA was extracted from whole blood and Dried Blood Spots (DBS) using the NucleoSpin Blood kit (Macherey Nagel) and the Chelex resin. DNA amplification was performed using the Qiagen Multiplex PCR kit and detected on a 7300 Real time PCR system (Applied Biosystems). Method validation was realized as required by ISO 15189 standard. The accuracy profile methodology was applied. HIV-1 DNA of ACH2 cells (0, 25, 50, 100, 1000 and 5000 copies/PCR) mixed in whole blood were measured in 4 different series (2 PCR kits and 2 operators) of 5 independent DNA extraction of each standard. Linear and quadratic weighted and non weighted regression models were tested. Trueness, precision, limit of quantifications of the method and accuracy of the results were obtained for each model and compared. 93 whole blood samples of ART treated-patients with undetectable or low viraemia of 16 B and 77 non-B subtypes were assessed. Clinical evaluation of the assay was performed on 26 whole blood samples and 238 DBS from infants of Guinea Conakry determined HIV+ using the rapid Bioline HIV test Results The calibration model providing the most accurate results was the linear regression with an r² equal to 0.92 for ltr, 0.88 for int and 0.95 for env. Trueness, precision and accuracy were highly acceptable for the 3 sets of primers/probe not exceeding -0.23 log(copies/PCR) for bias and 0.5 log(copies) for intermediate precision standard deviation, respectively. The estimated lower limit of quantification was 41, 475 and 25 copies/PCR for ltr, int and env respectively. The accuracy profile of each gene showed that each future measurement using this assay has 80% probability to be within a limit of 0.5 log (copies/PCR) around the reference or true value of copies of each gene. 52/93 whole blood samples of ART-treated patients had 3 positive genes (Ct<40 cycles), 38/93 had two positive genes and 4/93 had only one positive gene (ltr). Among these patients, 3 were assigned as long term progressors and one was a subtype C strain. Clinical evaluation of the assay identified 1 HIV-1 infected newborn and 3 adults (at least 2 positive genes) for which HIV-1 infection was confirmed either by serology or viral load techniques as well as 96 HIV-1 infected infants using DBS. Conclusions This assay is suitable for detection of proviral HIV-1 DNA in infants and adults on whole blood and DBS samples. Despite an estimated lower limit of quantification higher than ltr and env, the int PCR was required to achieve a good genotype inclusivity. The method was fully validated as required by ISO 15189 and showed to provide sufficiently reliable results. [less ▲]

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