Implementation of a Design Space Approach for Enantiomeric Separations in Polar Organic Solvent Chromatography

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 ▲]

Comparison of the quantitative performances and measurement uncertainty estimates obtained during method validation versus routine applications of a novel hydrophilic interaction chromatography method for the determination of cidofovir in human plasma

in Journal of Pharmaceutical & Biomedical Analysis (2012), 57

BUILDING THE QUALITY INTO THE POLYMERIC SOLID DOSAGE FORM MANUFACTURING LINE - CRITICAL QUALITY ATTRIBUTES EVALUATION WITH NIR AND RAMAN PAT TOOLS

Poster (2011, September)

Innovative high-performance liquid chromatography method development for the screening of 19 antimalarial drugs based on a generic approach, using design of experiments, independent component analysis and design space

in Journal of Chromatography. A (2011), 1218

An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 ... [more ▼]

An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE–ICA–DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE–ICA–DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE–ICA–DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study. [less ▲]

Implementation of a design space approach for enatiomeric separations in polar organic solvent chromatography

Poster (2011)

Validation of a HILIC method for the determination of cidofovir in plasma

Poster (2010, September)

NIR Real-time monitoring of a silicone-based drug reservoir crosslinking process

Poster (2010, May 05)

Critical analysis of several analytical method validation strategies in the framework of the fit for purpose concept.

in Journal of Chromatography. A (2010), 1217

Analytical method validation is a mandatory step at the end of the development in all analytical laboratories. It is a highly regulated step of the life cycle of a quantitative analytical method. However ... [more ▼]

Analytical method validation is a mandatory step at the end of the development in all analytical laboratories. It is a highly regulated step of the life cycle of a quantitative analytical method. However, even if some documents have been published there is a lack of clear guidance for the methodology to follow to adequately decide when a method can be considered as valid. This situation has led to the availability of several methodological approaches and it is therefore the responsibility of the analyst to choose the best one. The classical decision processes encountered during method validation evaluation are compared, namely the descriptive, difference and equivalence approaches. Furthermore a validation approach using accuracy profile computed by means of beta-expectation tolerance interval and total measurement error is also available. In the present paper all of these different validation approaches were applied to the validation of two analytical methods. The evaluation of the producer and consumer risks by Monte Carlo simulations were also made in order to compare the appropriateness of these various approaches. The classical methodologies give rise to inadequate and contradictory conclusions which do not allow them to answer adequately the objective of method validation, i.e. to give enough guarantees that each of the future results that will be generated by the method during routine use will be close enough to the true value. It is found that the validation methodology which gives the most guarantees with regards to the reliability or adequacy of the decision to consider a method as valid is the one based on the use of the accuracy profile. [less ▲]

A new statistical method for the automated detection of peaks in UV-DAD chromatograms of a sample mixture

in Talanta (2009), 79

One of the major issues within the context of the fully automated development of chromatographic methods consists of the automated detection and identification of peaks coming from complex samples such as ... [more ▼]

One of the major issues within the context of the fully automated development of chromatographic methods consists of the automated detection and identification of peaks coming from complex samples such as multi-component pharmaceutical formulations or stability studies of these formulations. The same problem can also occur with plant materials or biological matrices. This step is thus critical and time-consuming, especially when a Design of Experiments (DOE) approach is used to generate chromatograms. The use of DOE will often maximize the changes of the analytical conditions in order to explore an experimental domain. Unfortunately, this generally provides very different and “unpredictable” chromatograms which can be difficult to interpret, thus complicating peak detection and peak tracking (i.e. matching peaks among all the chromatograms). In this context, Independent Components Analysis (ICA), a new statistically based signal processing methods was investigated to solve this problem. The ICA principle assumes that the observed signal is the resultant of several phenomena (known as sources) and that all these sources are statistically independent. Under those assumptions, ICA is able to recover the sources which will have a high probability of representing the constitutive components of a chromatogram. In the present study, ICA was successfully applied for the first time to HPLC–UVDAD chromatograms and it was shown that ICA allows differentiation of noise and artifact components from those of interest by applying clustering methods based on high-order statistics computed on these components. Furthermore, on the basis of the described numerical strategy, itwas also possible to reconstruct a cleaned chromatogram with minimum influence of noise and baseline artifacts. This can present a significant advance towards the objective of providing helpful tools for the automated development of liquid chromatography (LC) methods. It seems that analytical investigations could be shortened when using this type of methodologies. [less ▲]

Utilisation de la spectroscopie proche infrarouge dans la cadre de la fabrication d'un dispositif intra-utérin

Report (2009)