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See detailValidation methodologies of near infrared spectroscopy methods in pharmaceutical applications
Chavez, Pierre-François ULg; De Bleye, Charlotte ULg; Sacre, Pierre-Yves ULg et al

in European Pharmaceutical Review (2013), 18(1), 3-6

As any analytical methods, a mandatory step at the end of the development of a near infrared spectroscopy (NIRS) method is the validation. This step enables to give enough guarantees that each future ... [more ▼]

As any analytical methods, a mandatory step at the end of the development of a near infrared spectroscopy (NIRS) method is the validation. This step enables to give enough guarantees that each future results coming from the application of the method in routine will be closed enough to the true value. However, from the literature, a minority of NIRS methods are thoroughly validated despite of the guidelines published by different group and regulatory authorities to help analyst to adequately decide if his method can be considered as valid. In this context, the aim of this review is to offer a critical overview of the different validation methodologies applied to assess the validity of quantitative methods using near infrared spectroscopy used in the field of pharmacy. [less ▲]

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See detailATR-IR and Raman spectroscopic study of interaction between major calixarene derivatives and oral anticoagulants
Tiuca, Ioana; Saponar, Alina; Bodoki, Andreea et al

in Farmacia (2013), 61(5), 874-882

In this study we analyzed by ATR-IR and Raman spectroscopy the interaction between six major calixarene derivatives and two anticoagulants: warfarin and acenocoumarol. The six calixarene derivatives were ... [more ▼]

In this study we analyzed by ATR-IR and Raman spectroscopy the interaction between six major calixarene derivatives and two anticoagulants: warfarin and acenocoumarol. The six calixarene derivatives were: p-tert-butyl-calix[4]arene (C4), p-tert- butyl-calix[6]arene (C6) and p-tert-butyl-calix[8]arene (C8) and their ethyl-ester- derivatives: tetraester-p-tert-butyl-calix[4]arene (C4Es4), hexaester-p-tert-butyl- calix[6]arene (C6Es6), octaester-p-tert-butyl-calix[8]arene (C8Es8). The results showed the most intense interaction in terms of complex formation for the C6-acenocoumarol couple and for the C6-warfarin couple, respectively. [less ▲]

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See detailPAT tools for the control of co-extrusion implants manufacturing process
Krier, Fabrice ULg; Mantanus, Jérome; Sacre, Pierre-Yves ULg et al

in International Journal of Pharmaceutics (2013), 458

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt ... [more ▼]

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively. These two different spectroscopic techniques provided comparable results. In fact, the RMSEC and RMSECV were very close in each PAT technique but NIR spectroscopy was easier to use and less sensitive to external changes. For the control of the homogeneity of API distribution and the thickness of the membrane, we used successfully Raman spectroscopy imaging. These PAT tools help reducing analysis time. [less ▲]

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See detailUsefulness of Information Criteria for the Selection of Calibration Curves
Rozet, Eric ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytical Chemistry (2013), 85

The reliability of analytical results obtained with quantitative analytical methods is highly dependant upon the selection of the adequate model used as calibration curve. To select the adequate response ... [more ▼]

The reliability of analytical results obtained with quantitative analytical methods is highly dependant upon the selection of the adequate model used as calibration curve. To select the adequate response function or model the most used and known parameter is the determination coefficient R². However it is well known that it suffers many inconvenient, such as leading to overfitting the data. A solution proposed is to use the adjusted determination coefficient R²adj that aims at reducing this problem. However there is another family of criteria that exists to allow the selection of an adequate model: the information criteria AIC, AICc and BIC. These criteria have rarely been used in analytical chemistry to select the adequate calibration curve. This works aims at assessing the performance of the statistical information criteria as well as R² and R²adj for the selection of an adequate calibration curve. They are applied to several analytical methods covering liquid chromatographic methods as well as electrophoretic ones involved in the analysis of active substances in biological fluids or aimed at quantifying impurities in drug substances. In addition, Monte-Carlo simulations are performed to assess the efficacy of these statistical criteria to select the adequate calibration curve. [less ▲]

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See detailUse of Raman spectrometry in the pharmaceutical field
Michelet, Alexandre; Boiret, Mathieu; Lemhachheche, Fatima et al

in STP Pharma Pratiques (2013), 23(2), 97-117

This document sets out the theoretical and practical fundamentals to guide users in the imple- mentation of Raman spectroscopy in industry or the university-hospital sector. It describes the principle of ... [more ▼]

This document sets out the theoretical and practical fundamentals to guide users in the imple- mentation of Raman spectroscopy in industry or the university-hospital sector. It describes the principle of this technique and currently available instruments. Since Raman spectrometers are used in a regulated context, the methodology of instru- ment qualification is discussed. Different types of applications encountered in the pharmaceutical field are presented: process monitoring, searching for and detecting counterfeits, and identifying raw materials on receipt. [less ▲]

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See detailMethodology for the Validation of Analytical Methods involved in Uniformity of Dosage Units tests
Rozet, Eric ULg; Ziemons, Eric ULg; Marini Djang'Eing'A, Roland ULg et al

in Analytica Chimica Acta (2013), 760

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving ... [more ▼]

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving the quality of the end products starting from its early design stage. However, no regulatory guideline or none of the published methodologies to assess method validation propose decision methodologies that effectively take into account the final purpose of developed analytical methods. In this work a solution is proposed for the specific case of validating analytical methods involved in the assessment of the Content Uniformity or Uniformity of Dosage Units of a batch of pharmaceutical drug products as proposed in the European or US pharmacopoeias. This methodology uses statistical tolerance intervals as decision tools. Moreover it adequately defines the Analytical Target Profile of analytical methods in order to obtain analytical methods that allow to make correct decisions about Content Uniformity or Uniformity of Dosage Units with high probability. The applicability of the proposed methodology is further illustrated using an HPLC-UV assay as well as a Near Infra-Red Spectrophotometric method. [less ▲]

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See detailIntérêt de la microscopie vibrationnelle dans la recherche de nouvelles formulations pharma-ceutiques à haute valeur ajoutée.
Sacre, Pierre-Yves ULg; Marini Djang'Eing'A, Roland ULg; Ziemons, Eric ULg et al

Report (2012)

La grande majorité des nouvelles molécules actives présente une faible biodisponibilité dans des formulations pharmaceutiques simples contenant principalement un ou plusieurs constituants et l’actif ... [more ▼]

La grande majorité des nouvelles molécules actives présente une faible biodisponibilité dans des formulations pharmaceutiques simples contenant principalement un ou plusieurs constituants et l’actif faiblement soluble dans l’eau. Dès lors, il est primordial d’investir dans la recherche de nouvelles formulations « plus sophistiquées » (formulations de demain) favorisant la solubilité de l’actif. Cependant cette recherche est limitée par celle de nouveaux outils analytiques pointus permettant de les caractériser, d’étudier les interactions au sein des formulations pharmaceutiques, de comprendre les mécanismes liès à leur formation et in fine de contrôler et garantir leur conformité. Par ailleurs, la Technologie Analytique des Procédés (PAT) est un concept développé par l’Administration Américaine des Aliments et des Médicaments (FDA) et soutenu par l’Agence Européenne des Médicaments (EMA). Ce concept qui devient de plus en plus incontournable (au niveau des dossiers d’Autorisation de Mise sur le Marché). La rapidité de mesure et le caractère non destructif de la spectroscopie vibrationnelle dont fait partie la microscopie Raman la rendent particulièrement compatibles avec ce concept. De plus, les techniques vibrationnelles de part l’absence de préparation de l’échantillon et de l’utilisation de solvant organique rencontrent également le concept de Chimie Verte et donc s’incrivent parfaitement dans un contexte de développement durable et respectueux de l’environnement. L’objectif du présent projet est d’explorer les potentialités de la microscopie Raman dans l’étude pointue des matrices complexes afin d’en améliorer les connaissances tant au niveau de leur charactérisation, des intéractions analyte-matrice que des mécanismes liés à leur formation. L’obtention de ces informations nécéssiteront la recherche de nouvelles méthodologies, outils et règles de décision dédicacés aux aspects qualitatifs et plus encore aux aspects quantiftatifs où l’accès à de telles données est très marginal. L’ensemble de cette recherche sera réalisée sur un modèle complexe, une formulation à haute valeur ajoutée issue de l’industrie pharmaceutique. [less ▲]

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See detailInnovative green supercritical fluid chromatography development for the determination of polar compounds
Dispas, Amandine ULg; Lebrun, Pierre ULg; Sassiat, Patrick et al

in Journal of Chromatography. A (2012), 1256

In the context of green analytical chemistry, a supercritical fluid chromatography method was developed. In order to prove the potential of this technology, a worst case was selected, i.e. the separation ... [more ▼]

In the context of green analytical chemistry, a supercritical fluid chromatography method was developed. In order to prove the potential of this technology, a worst case was selected, i.e. the separation of very polar compounds. For that purpose, an innovative methodology based on design of experiments (DoE) and design space (DS) was previously developed and successfully tested on liquid chromatography. For the first time, this methodology was applied to a supercritical fluid chromatography (SFC) separation. First, a screening design was used to select the stationary phase and the nature of the mobile phase based on a maximization of the number of peaks eluted and a minimization of the number of co-eluted peaks. Then, a central composite design with orthogonal blocks defined a set of experiments used to model the retention times of each peak at the beginning, the apex, and the end. The gradient slope, the isocratic plateau before the gradient, the temperature, and the concentration of trifluoroacetic acid (TFA) in the mobile phase were the potentially influential factors. The critical quality attributes (CQAs), i.e. the separation (S) between peaks of the most critical pair, and the analysis time were the responses considered to assess the quality of the separation. The DS was computed as the multidimensional subspace where the probability for the separation and analysis time criteria to be within acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modeled responses to the quality criterion using Monte Carlo simulations. The optimal condition was predicted at a gradient slope of 3.8% min−1 to linearly modify the modifier proportion between 5 and 40%, an isocratic time of 3 minutes, a concentration of TFA of 25 mM, and a temperature of 60.5 °C. This optimal condition was experimentally tested to confirm the prediction. Furthermore, chromatographic conditions included in the DS and on the limits of the DS were experimentally tested to assess the robustness of the developed SFC method. [less ▲]

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See detailDevelopment of near infrared spectroscopic methods using desirability indexes: How to select the most appropriate calibration model
Ziemons, Eric ULg; De Bleye, Charlotte ULg; Chavez, Pierre-François ULg et al

Conference (2012, May 10)

In the last decade, considerable research and developments dealing with near infrared spectroscopy (NIRS) have taken place in industrial field, especially in pharmaceutical industry. This enthusiasm can ... [more ▼]

In the last decade, considerable research and developments dealing with near infrared spectroscopy (NIRS) have taken place in industrial field, especially in pharmaceutical industry. This enthusiasm can be explained by the fact that NIRS is regarded as promising and attractive tool in Process Analytical Technology (PAT) and Green Chemistry frameworks. Taking into account its non-invasive, non-destructive character, fast data acquisition and the use of probes in on-line, in-line and at-lines, this technique is expected to reach the aims of the latters. However, the development of a NIR quantitative method is not straightforward in comparison with conventional analytical techniques. Its development requires time-consuming reference methods, chemometrics and iterative heuristic approaches to build a model allowing the prediction of the analyte of interest according to the acceptance criteria consistent with the intended use of the method. Facing to the lack of objective decision rule of the traditional chemometric criteria such as R2, RMSEC, RMSECV and RMSEP, it is essential to develop innovative approaches for the selection of the most appropriate calibration model from a models plurality. In this context, a methodology using desirability indexes, such as the Fitting Model Index (FMI), based on tolerance intervals was developed in order to increase significantly the objectivity of the decision process. This latter allows to reduce dramatically the development and the validation steps and thus could ease the implementation of NIR spectroscopy in pharmaceutical industry. [less ▲]

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See detailUse of Near Infrared and Raman spectroscopy for the optimization of API layer of pharmaceutical tablet
Chavez, Pierre-François ULg; Mantanus, Jérôme; Cuypers, Serge et al

Poster (2012, May)

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See detailRELIABILITY OF ANALYTICAL METHODS’ RESULTS: A BAYESIAN APPROACH TO ANALYTICAL METHOD VALIDATION
Rozet, Eric ULg; Govaerts, B.; Lebrun, Pierre ULg et al

Conference (2012, March)

Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the ... [more ▼]

Methods validation is mandatory in order to assess the fitness of purpose of the developed analytical method. Of core importance at the end of the validation is the evaluation of the reliability of the individual results that will be generated during the routine application of the method. Regulatory guidelines provide a general framework to assess the validity of a method, but none address the issue of results reliability. In this study, a Bayesian approach is proposed to address this concern. Results reliability is defined here as “the probability ()π of an analytical method to provide analytical results within predefined acceptance limits ()X()λ± around their reference or conventional true concentration values ()Tμ over a defined concentration range and under given environmental and operating conditions.” By providing the minimum reliability probability (minπ needed for the subsequent routine application of the method, as well as specifications or acceptance limits ()λ±, the proposed Bayesian approach provides the effective probability of obtaining reliable future analytical results over the whole concentration range investigated. This is summarized in a single graph: the reliability profile. This Bayesian reliability profile is also compared to two frequentist approaches, the first one derived from the work of Dewé et al. [1] and the second proposed by Govaerts et al. [2]. Furthermore, the applicability of the Bayesian reliability profile is shown using as example the validation of a bioanalytical method dedicated to the determination of ketoglutaric acid (KG) and hydroxymethylfurfural (HMF) in human plasma by SPE-HPLC-UV. [1] Dewé W., Govaerts B., Boulanger B., Rozet E., Chiap P., Hubert Ph., Chemometr. Intell. Lab. Syst. 85 (2007) 262-268. [2] B. Govaerts, W. Dewé, M. Maumy, B. Boulanger, Qual. Reliab. Engng. Int. 24 (2008) 667-680. [less ▲]

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See detailSMALL SAMPLE SIZE CAPABILITY INDEX FOR ASSESSING VALIDITY OF ANALYTICAL METHODS
Rozet, Eric ULg; Boulanger, B.; Ziemons, Eric ULg et al

Poster (2012, March)

Analytical method’s 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 method’s 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 (tolCpk−π) is 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 is illustrated through several case studies. [less ▲]

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