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See detailScreening study of SFC critical method parameters for the determination of pharmaceutical compounds
Dispas, Amandine ULg; Lebrun, Pierre ULg; Sacre, Pierre-Yves ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2016), 125

Nowadays, supercritical fluid chromatography is commonly presented as a promising alternative technique in the field of separation sciences. Nevertheless the selection of chromatographic conditions and ... [more ▼]

Nowadays, supercritical fluid chromatography is commonly presented as a promising alternative technique in the field of separation sciences. Nevertheless the selection of chromatographic conditions and sample preparation of pharmaceutical compounds remain a challenge and peak distortion was previously highlighted. The main objective of the present work was to evaluate the impact of different critical method parameters (CMPs), i.e. stationary phase, mobile phase composition and injection solvent nature. The experiments were performed considering two groups of antimalarial molecules: one group with neutral/apolar compounds and the other one with salt form of polar compounds. In this context, another objective was to propose a suitable sample solvent for quantitative analysis. The interest of new generation stationary phase to obtain good peak shape and the interest to tune the mobile phase composition were demonstrated. During this study, design of experiments and desirability function approach enabled to highlight optimal chromatographic conditions in order to maximise peak capacity and to get acceptable value of symmetry factor. Regarding sample injection solvent composition, some counterintuitive results were observed: solvents closer to the mobile phase polarity (i.e heptane or 2-propanol/heptane mixture) did not provide best results in terms of peak symmetry. In addition, acetonitrile and short aliphatic alcohols offered an interesting alternative as injection solvent: toxicity of solvents used is clearly reduced and better quantitative performances could be expected while keeping high peak capacity and symmetric sharp peaks. Finally, the quantitative performances were evaluated by the method validation for the quantitative determination of quinine sulfate in a pharmaceutical formulation. These better understandings on critical method parameters led SFC to be an even more promising technique in the field of the analysis of pharmaceutical compounds. [less ▲]

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See detailImplementing principles of Quality by Design (QbD) in validation context
Hubert, Cédric ULg; Lebrun, Pierre ULg; Rozet, Eric et al

Conference (2016, May 10)

Analytical method performances have to be specified by the analyst trough the definition of the “Analytical Target Profile (ATP)”, as proposed by the regulatory bodies. In the specific context of the ... [more ▼]

Analytical method performances have to be specified by the analyst trough the definition of the “Analytical Target Profile (ATP)”, as proposed by the regulatory bodies. In the specific context of the pharmaceutical industry, regulatory authorities have recently imposed the assessment and management of risk throughout the entire product lifecycle. This includes the analytical procedure and consequently its own lifecycle. The development step of an analytical method is still largely addressed using a “Changing One Separate Factor a Time (COST)” approach (also known as the “Quality-by-Testing (QbT)” approach). This strategy can lead to a suitable method for assessing the risk of routine use, even where the experimental domain is not examined. However, in order to consider an experimental domain rather than a set of specific experimental conditions during the development phase, a multivariate approach must be considered: the “Quality-by-Design (QbD)” strategy. This strategy allows the definition of a “Design Space (DS)” by means of design of experiments (DoE). This DS, computed considering critical method parameters, allows the analyst to focus on the main objective of an analytical method: obtaining reliable results using a robust method. In the course of a specific case study, the benefits of the QbD strategy in terms of managing the qualitative part of the analytical process were highlighted. Working in the context of analytical procedure, the validation step is a major part of the analytical method lifecycle. Indeed, the objective of analytical method validation is to demonstrate that this method is suited for quantifying the target analytes with an established and suitable level of accuracy, as defined by the “ATP”. This is sometimes called the “fit-for-future-purpose” concept. The decision regarding the validity of a method based on prediction can be achieved by using the “β-expectation tolerance interval” (accuracy profile). The capability of this approach to manage the quantitative part of the analytical procedure is nowadays largely illustrated in scientific literatures. Considering the assessment and management of risk throughout the analytical lifecycle, a global strategy allowing the unification of the development and validation phases in a single step was considered. With this innovative approach, a strategy allowing the management of global analytical risk (i.e., for both qualitative and quantitative part of the analytical method) was proposed. Indeed, the developed strategy allows validating an entire experimental domain by means of the accuracy profile rather than a single set of specific experimental conditions. With this strategy, the DS is no longer simply the place where qualitative performances are obtained, but also the space where quantitative performances of the analytical procedure are assessed and managed. [less ▲]

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See detailValidation des méthodes analytiques: Approche basée sur l'erreur totale
Ziemons, Eric ULg; Hubert, Cédric ULg; Marini Djang'Eing'A, Roland ULg et al

Scientific conference (2015, May 12)

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See detailDesign Space for Analytical Methods: Why ? What ? How ?
Rozet, Eric ULg; Debrus, Benjamin ULg; Lebrun, Pierre ULg et al

Conference (2015, January 22)

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See detailFighting Poor Quality Medicines: Develop-ment, Transfer and Validation of Generic HPLC Methods for Analyzing two WHO Recommended Antimalarial Tablets
Mbinze Kindenge, Jérémie; Yemoa, Achille; Lebrun, Pierre ULg et al

in American Journal of Analytical Chemistry (2015), 6

As serious but neglected public health problems, poor quality medicines, i.e. for antimalarial medicines, urged to be fought. One of the approaches is to consider the analytical chemistry and separative ... [more ▼]

As serious but neglected public health problems, poor quality medicines, i.e. for antimalarial medicines, urged to be fought. One of the approaches is to consider the analytical chemistry and separative techniques. In this study, a generic liquid chromatographic method was firstly devel-oped for the purpose of screening 8 antimalarial active ingredients, namely amodiaquine (AQ), piperaquine (PPQ), sulfalene (SL), pyrimethamine (PM), lumefantrine (LF), artesunate (AS), artemether (AM) and dihydroartemisinine (DHA) by applying DoE/DS optimization strategy. Since the method was not totally satisfying in terms of peak separation, further experiments were undergone applying the same development strategy while splitting the 8 ingredients into five groups. Excellent prediction was observed prior to correlation between retention times of predicted and observed separation conditions. Then, a successful geometric transfer was realized to reduce the analysis time focusing on the simultaneous quantification of two WHO's recommended ACTs in anti-malarial fixed-dose combination (AM-LF and AS-AQ) in tablets. The optimal separation was achieved using an isocratic elution of methanol-ammonium formate buffer (pH 2.8; 10mM) (82.5: 17.5, v/v) at 0.6ml/min through a C18 column (100mm×3.5mm, 3.5 μm) thermostated at 25°C. After a successful validation stage based on the total error approach, the method was applied to determine the content of AM/LF or AS/AQ in seven brands of antimalarial tablets currently marketed in West, Central and East Africa. Satisfying results were obtained compared to the claimed contents. [less ▲]

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See detailTowards a full integration of optimization and validation phases: An Analytical-Quality-by-Design approach
Hubert, Cédric ULg; Houari, Sabah ULg; Rozet, Eric ULg et al

in Journal of Chromatography. A (2015)

When using an analytical method, defining an Analytical Target Profile (ATP) focused on quantitative performance represents a key input, and this will drive the method development process. In this context ... [more ▼]

When using an analytical method, defining an Analytical Target Profile (ATP) focused on quantitative performance represents a key input, and this will drive the method development process. In this context, two case studies were selected in order to demonstrate the potential of a Quality-by-Design (QbD) strategy when applied to two specific phases of the method lifecycle: the pre-validation study and the validation step. The first case study focused on the improvement of a Liquid Chromatography (LC) coupled to Mass Spectrometry (MS) stability-indicating method by the means of the QbD concept. The Design of Experiments (DoE) conducted during the optimization step (i.e. determination of the qualitative Design Space (DS)) was performed a posteriori. Additional experiments were performed in order to simultaneously conduct the pre-validation study to assist in defining the DoE to be conducted during the formal validation step. This predicted protocol was compared to the one used during the formal validation. A second case study based on the LC/MS-MS determination of glucosamine and galactosamine in human plasma was considered in order to illustrate an innovative strategy allowing the QbD methodology to be incorporated during the validation phase. An operational space, defined by the qualitative DS, was considered during the validation process rather than a specific set of working conditions as conventionally performed. Results of all the validation parameters conventionally studied were compared to those obtained with this innovative approach for glucosamine and galactosamine. Using this strategy, qualitative and quantitative information were obtained. Consequently, an analyst using this approach would be able to select with great confidence several working conditions within the operational space rather than a given condition for the routine use of the method. This innovative strategy combines both a learning process and a thorough assessment of the risk involved. [less ▲]

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See detailA quality by design approach for longitudinal quality attributes
Lebrun, Pierre ULg; Giacoletti, Katherine; Scherder, Tara et al

in Journal of Biopharmaceutical Statistics (2015), 25

The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior ... [more ▼]

The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior knowledge gathered during pharmaceutical development studies to provide a scientific rationale for the manufacturing process of a product and provide guarantee of future quality. This poses several challenges from a statistical standpoint and requires a shift in paradigm from traditional statistical practices. First, to provide “assurance of quality” of future lots implies the need to make predictions regarding the quality given past evidence and data. Second, the quality attributes described in the Q8 guidelines are not always a set of unique, independent measurements. In many cases, these criteria are com- plicated longitudinal data with successive acceptance criteria over a defined period of time. A common example is a dissolution profile for a modified or extended-release solid dosage form that must fall within acceptance limits at several time points. A Bayesian approach for longitudinal data obtained in various conditions of a design of experiment is provided to elegantly address the ICH-Q8 recommendation to provide assurance of quality and derive a scientifically sound design space. [less ▲]

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See detailAnalytical Procedure Validation and the Quality by Design Paradigm
Rozet, Eric ULg; Lebrun, Pierre ULg; Michiels, Jean-François et al

in Journal of Biopharmaceutical Statistics (2015), 25

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 procedure developments to follow a similar approach. While development and optimization of analytical procedure following QbD principles have been largely discussed and described, the place of analytical procedure validation in this framework has not been clarified. This article aims at showing that analytical procedure validation is fully integrated into the QbD paradigm and is an essential step in developing analytical procedures that are effectively fit for purpose. Adequate statistical methodologies have also their role to play: such as design of experiments, statistical modelling, and probabilistic statements. The outcome of analytical procedure validation is also an analytical procedure design space, and from it, control strategy can be set. [less ▲]

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See detailEvaluation of the quantitative performances of Supercritical Fluid Chromatography : from method development to validation
Dispas, Amandine ULg; Lebrun, Pierre ULg; Ziemons, Eric ULg et al

in Journal of Chromatography. A (2014), 1353(Method Validation), 78-88

Recently, the number of papers about SFC increased drastically but scientists did not truly focus their work on quantitative performances of this technique. In order to prove the potential of UHPSFC, the ... [more ▼]

Recently, the number of papers about SFC increased drastically but scientists did not truly focus their work on quantitative performances of this technique. In order to prove the potential of UHPSFC, the present work discussed about the different steps of the analytical life cycle of a method: from development to validation and application. Moreover, the UHPSFC quantitative performances were evaluated in comparison with UHPLC, which is the main technique used for quality control in the pharmaceutical industry and then could be considered as a reference. The methods were developed using Design Space strategy, leading to the optimization of robust method. In this context, when the Design Space optimization shows guarantee of quality, no more robustness study is required prior to the validation. Then, the methods were geometrically transferred in order to reduce the analysis time. The UHPSFC and UHPLC methods were validated based on the total error approach using accuracy profile. Even if UHPLC showed better precision and sensitivity, UHPSFC method is able to give accurate results in a dosing range larger than the 80–120% range required by the European Medicines Agency. Consequently, UHPSFC results are valid and could be used for the control of active substance in a finished pharmaceutical product. Finally, UHPSFC validated method was used to analyse real samples and gave similar results than the reference method (UHPLC). [less ▲]

Detailed reference viewed: 83 (27 ULg)