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See detailA BAYESIAN PROBABILITY CRITERION TO ASSESS ANALYTICAL RESULTS RELIABILITY
Rozet, Eric ULg; Lebrun, Pierre ULg; Boulanger, B et al

Conference (2013, May 21)

In pharmaceutical and biomedical industries, quantitative analytical methods such as HPLC play a key role. Indeed, the analytical results obtained from them are used to make crucial decisions such as the ... [more ▼]

In pharmaceutical and biomedical industries, quantitative analytical methods such as HPLC play a key role. Indeed, the analytical results obtained from them are used to make crucial decisions such as the release of batches of drugs, the evaluation of safety and efficacy of new drug candidates or the monitoring of patients health. Prior to their routine use, analytical methods are submitted to a stringent validation study [1] where they have to demonstrate that they are fit for their final purpose, i.e. providing accurate results: where is the analytical result, is the theoretical unknown true concentration of analyte in the sample analyzed and a regulatory acceptance limit. Typically this demonstration is made by either providing point estimates of systematic error (bias) and random error (variance) or sometimes by providing interval estimates of these statistical parameters at several well defined concentration levels of the target analyte [2]. They are then compared to maximum acceptable levels. More recently, tolerance intervals approaches have been proposed that are evaluated in a similar way at these key concentration levels [3]. However none of these decision approaches allow knowing the probability to obtain accurate results over the whole concentration range of interest: is a vector of parameters and Pmin is a minimum reliability probability. Frequentist approximations have been proposed to estimate this probability but only at the concentration levels experimentally tested [4,5]. In this work, a linear hierarchical Bayesian approach is proposed. It takes into account the potential random characteristic of the slope and intercept observed from one analytical run to the other, but it also integrates the possible covariance between the parameters. Additionally, heteroscedasticity of the residual variance over the concentration range investigated is taken into account. A situation regularly observed in practice. Finally a reliability profile for the whole concentration range studied is obtained using MCMC sampling. This profile provides the probability (Prel) to obtain accurate results over the full concentration range investigated. This profile is then compared to a minimum reliability probability (Pmin) that will define the valid concentration range of the analytical method. The usefulness of this approach is illustrated through the validation of a bioanalytical method and also compared with one concentration level at a time frequentist approaches [4,5]. [1] International Conference on Harmonization (ICH) of Technical Requirements for registration of Pharmaceuticals for Human Use Topic Q2 (R1): Validation of Analytical Procedures: Text and Methodology, Geneva, 2005. [2] A. Bouabidi and al., J. Chromatogr. A, 1217 (2010) 3180. [3] Ph. Hubert and al., J. Pharm. Biomed. Anal., 36 (2004) 579. [4] W. Dewé and al., Chemometr. Intell. Lab. Syst. 85 (2007) 262. [5] B. Govaerts and al., Qual. Reliab. Engng. Int. 24 (2008) 667. [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 detailBlood lead, urinary lead, urinary δ-aminolevulinic acid and urinary porphyrins levels among people living in kinshasa, D.R. Congo : a pilot biomonitoring study
Mputu Malolo, Corneille-Liévin; Ndelo di Phanzu, Josaphat; Marini Djang'Eing'A, Roland ULg et al

in Acta Clinica Belgica (2013), 68(6), 475

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See detailImplementation of a Design Space Approach for Enantiomeric Separations in Polar Organic Solvent Chromatography
Nistor, Iolanda; Lebrun, Pierre ULg; Ceccato, Attilio ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 74

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 ... [more ▼]

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures. Good correlations were found between the observed data obtained after using a central composite design and the expected chromatographic behaviours predicted by applying the design of experiments-design space (DoE-DS) methodology. The critical quality attribute represented here by the separation criterion (Scrit) allowed assessing the quality of the enantioseparation. Baseline separation for the compounds of interest in an analysis time of less than 20 minutes was possible due to the original and powerful tools applied which facilitated an enhanced method comprehension. Finally, the advantage of the DoE-DS approach resides in granting the possibility to concurrently assess robustness and identify the optimal conditions which are compound dependent. [less ▲]

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See detailModèles statistiques Bayésiens et méthodologies pour calculer le Design Space (OPTIMAL-DS)
Marini Djang'Eing'A, Roland ULg; Lebrun, Pierre ULg; Hubert, Philippe ULg

Report (2012)

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de ... [more ▼]

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de conduites initiées par la FDA ou d'autres organismes de contrôles. Notamment, le document ICH Q8 introduit les notions de "Process Analytical Technology", de "Quality by Design" et de "Design Space", ayant attraits à la qualité des procédés industriels, des procédés d'analyse ainsi qu'à la qualité des produits finis. Cependant, si les lignes de conduites pour ces exigences sont expliquées, aucune méthodologie pour les atteindre n'est donnée. Or, un nombre considérable de nouvelles entités chimiques sont synthétisées par les laboratoires pharmaceutiques, biotechnologiques ou agroalimentaires. Les producteurs de matières premières et/ou d’excipients (secteur chimique) ont également besoin de disposer rapidement de méthodes analytiques de contrôle qui leur permettront de s’assurer de la qualité de leurs produits. On comprend aisément la nécessité pour ces secteurs de disposer rapidement de résultats fiables puisque les activités de recherches mais aussi des investissements, souvent importants, sont orientés ou stoppés sur base de données chiffrées, produits par les méthodes analytiques. La production de résultats fiables et la démonstration de cette fiabilité sont donc économiquement fondamentales. Ce projet vise la mise au point de stratégies et de modèles génériques de développement automatisé de nouvelles méthodes analytiques séparatives, en se basant sur la modélisation des temps de rétention, la planification expérimentale, et le concept de Design Space. L’objectif connexe est d’appliquer cette méthodologie à l’optimisation de n’importe quel procédé. Le fait de pouvoir disposer d’une méthodologie de mise au point automatique de méthodes analytiques ou de tous procédés analytiques aura un impact significatif. Cette nouvelle technologie permettra de réduire de façon drastique le temps d’optimisation des méthodes et procédés, permettant une production plus efficiente de produits (pharmaceutique, cosmétique, agro-alimentaire ou biotechnologique) répondant aux spécifications du client. [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 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 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 detailBayesian Design Space applied to Pharmaceutical Development
Lebrun, Pierre ULg

Doctoral thesis (2012)

Given the guidelines such as the Q8 document published by the International Conference on Harmonization (ICH), that describe the “Quality by Design” paradigm for the Pharmaceutical Development, the aim of ... [more ▼]

Given the guidelines such as the Q8 document published by the International Conference on Harmonization (ICH), that describe the “Quality by Design” paradigm for the Pharmaceutical Development, the aim of this work is to provide a complete methodology addressing this problematic. As a result, various Design Spaces were obtained for different analytical methods and a manufacturing process. In Q8, Design Space has been defined as the “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” for the analytical outputs or processes involved in Pharmaceutical Development. Q8 is thus clearly devoted to optimization strategies and robustness studies. In the beginning of this work, it was noted that existing statistical methodolo- gies in optimization context were limited as the predictive framework is based on mean response predictions. In such situations, the data and model uncertainties are generally completely ignored. This often leads to increase the risks of taking wrong decision or obtaining unreliable manufactured product. The reasons why it happens are also unidentified. The “assurance of quality” is clearly not addressed in this case. To improve the predictive nature of statistical models, the Bayesian statistical framework was used to facilitate the identification of the predictive distribution of new outputs, using numerical simulations or mathematical derivations when possi- ble. By use of the improved models in a risk-based environment, separation analytical methods such as the high performance liquid chromatography were studied. First, optimal solutions of separation of several compounds in mixtures were identified. Second, the robustness of the methods was simultaneously assessed thanks to the risk-based Design Space identification. The usefulness of the methodology was also demonstrated in the optimization of the separation of subsets of relevant compounds, without additional experiments. The high guarantee of quality of the optimized methods allowed easing their use for their very purpose, i.e., the tracing of compounds and their quantification. Transfer of robust methods to high-end equipments was also simplified. In parallel, one sub-objective was the total automation of analytical method de- velopment and validation. Some data treatments including the Independent Com- ponent Analysis and clustering methodologies were found more than promising to provide accurate automated results. Next, the Design Space methodology was applied to a small-scale spray-dryer manufacturing process. It also allowed the expression of guarantees about the quality of the obtained powder. Finally, other predictive models including mixed-effects models were used for the validation of analytical and bio-analytical quantitative methods. [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 detailModèles statistiques Bayésiens et méthodologies pour calculer le Design Space (OPTIMAL-DS)
Marini Djang'Eing'A, Roland ULg; Lebrun, Pierre ULg; Rozet, Eric ULg et al

Report (2012)

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de ... [more ▼]

La compréhension des procédés technologiques et industriels dans les secteurs (bio)pharmaceutiques, biotechnologiques, agroalimentaires et environnementaux doit permettre de se conformer aux lignes de conduites initiées par la FDA ou d'autres organismes de contrôles. Notamment, le document ICH Q8 introduit les notions de "Process Analytical Technology", de "Quality by Design" et de "Design Space", ayant attraits à la qualité des procédés industriels, des procédés d'analyse ainsi qu'à la qualité des produits finis. Cependant, si les lignes de conduites pour ces exigences sont expliquées, aucune méthodologie pour les atteindre n'est donnée. Or, un nombre considérable de nouvelles entités chimiques sont synthétisées par les laboratoires pharmaceutiques, biotechnologiques ou agroalimentaires. Les producteurs de matières premières et/ou d’excipients (secteur chimique) ont également besoin de disposer rapidement de méthodes analytiques de contrôle qui leur permettront de s’assurer de la qualité de leurs produits. On comprend aisément la nécessité pour ces secteurs de disposer rapidement de résultats fiables puisque les activités de recherches mais aussi des investissements, souvent importants, sont orientés ou stoppés sur base de données chiffrées, produits par les méthodes analytiques. La production de résultats fiables et la démonstration de cette fiabilité sont donc économiquement fondamentales. Ce projet vise la mise au point de stratégies et de modèles génériques de développement automatisé de nouvelles méthodes analytiques séparatives, en se basant sur la modélisation des temps de rétention, la planification expérimentale, et le concept de Design Space. L’objectif connexe est d’appliquer cette méthodologie à l’optimisation de n’importe quel procédé. Le fait de pouvoir disposer d’une méthodologie de mise au point automatique de méthodes analytiques ou de tous procédés analytiques aura un impact significatif. Cette nouvelle technologie permettra de réduire de façon drastique le temps d’optimisation des méthodes et procédés, permettant une production plus efficiente de produits (pharmaceutique, cosmétique, agro-alimentaire ou biotechnologique) répondant aux spécifications du client. [less ▲]

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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 detailAN INNOVATIVE APPROACH TO SELECT THE PREDICTION MODEL IN THE DEVELOPMENT OF NIR SPECTROSCOPIC METHODS
Ziemons, Eric ULg; Mantanus, Jérôme ULg; Rozet, Eric ULg et al

Poster (2012, March)

Taking into account its non-invasive, non-destructive character and fast data acquisition, near infrared spectroscopy is more and more integrated in production processes to acquire analytical results ... [more ▼]

Taking into account its non-invasive, non-destructive character and fast data acquisition, near infrared spectroscopy is more and more integrated in production processes to acquire analytical results. Implementation of a NIR quantitative method is performed using an iterative heuristic approach that will ultimately build a model allowing the prediction of the concentration of the analyte of interest. In this context, the aim of the present study was to develop an innovative approach based on statistical tolerance intervals and the desirability index FMI (Fitting Model Index) to select the most appropriate prediction model from a list of candidate models instead of using conventional criteria such as R², RMSEC, RMSECV and RMSEP [1-2] without objective decision rules. This new approach is illustrated on different steps of a real pharmaceutical manufacturing process: water and Active Pharmaceutical Ingredient (API) determinations in pharmaceutical pellets. Variability sources such as production campaigns, batches, days and operators were introduced in the calibration and validation sets. Partial Least Square (PLS) regression on the calibration sets was performed to build prediction models of which the ability to quantify accurately was tested with the validation sets. Regarding the product specifications, the acceptance limits were set at 20% and 5%, for the moisture and API determination, respectively.As can be seen from Figure 1 and 2, this innovative approach based on the desirability index FMI of the accuracy profile enabled to build and select the most appropriate prediction model in full accordance with its very final goal, to quantify as accurately as possible the analytes of interest. [1] Hubert Ph. et al., J. Pharm. Biomed. Anal., 36, 2007, 579-586. [2] Rozet E. et al., Ana. Chim. Acta, 591, 2007, 239-247. [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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