Design Spaces for analytical methods Rozet, E.; Lebrun, P.; Hubert, P. ...
TrAC, Trends in analytical chemistry (Regular ed.),
January 2013, 2013, 2013-01-00, Letnik:
42
Journal Article, Web Resource
Recenzirano
► Design of Experiments is useful to define Design Spaces for analytical methods. ► Mean response surfaces are not sufficient for Design Spaces for analytical methods. ► Design Spaces for analytical ...methods require probability evaluation. ► Bayesian statistics allows correct definition of Design Spaces for analytical methods. ► Critical review of published Design Spaces for analytical methods.
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 (DS) of analytical methods where assurance of quality is provided. Several DSs for analytical methods have been published, stressing the importance of this concept.
This article aims to explain what an analytical method DS is, why it is useful for the robust development and optimization of analytical methods and how to build such a DS. We distinguish the usual mean response surface approach, overlapping mean response surfaces and the desirability function as only they correctly define a DS. We also review and discuss recent publications assessing the DS of analytical methods.
•An enhanced quality-by-design strategy throughout the analytical method lifecycle.•Quantitative design space: an innovative approach for development of analytical methods.•Integrated approaches for ...optimization and validation phases.•Full validation of an operational space.
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.
First discovered as inhibitors of cytokine signalling, the suppressor of cytokine signalling (SOCS) proteins have appeared, over recent years, as potent repressors of other signalling pathways ...including the one induced by insulin. SOCS-1 and SOCS-3 have been extensively studied both in vitro and in vivo in the context of insulin action. It has been shown that these two SOCS members are able to inhibit the insulin signalling pathway by three different mechanisms: (1) inhibition of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins because of competition at the docking site on the insulin receptor (IR), (2) induction of the proteasomal degradation of the IRS and (3) inhibition of the IR kinase. A key feature of the SOCS proteins is that they are induced regulators. Indeed, expression of SOCS proteins is virtually absent in basal conditions, but is rapidly and robustly induced in response to several stimuli such as hormones, cytokines and growth factors. A significant correlation between SOCS-3 expression and insulin resistance has been demonstrated in vivo. Interestingly, the level of SOCS-3 expression is strikingly enhanced in insulin-sensitive tissues from both patients and animal models with type 2 diabetes and insulin resistance. While it remains to be established whether the increased expression of SOCS is a cause or a consequence of insulin resistance, a large body of observations supports a role for SOCS proteins in the disease process found in states with insulin resistance.
ABSTRACT We analyze the distribution of arrival directions of ultra-high-energy cosmic rays recorded at the Pierre Auger Observatory in 10 years of operation. The data set, about three times larger ...than that used in earlier studies, includes arrival directions with zenith angles up to 80°, thus covering from to in declination. After updating the fraction of events correlating with the active galactic nuclei (AGNs) in the Véron-Cetty and Véron catalog, we subject the arrival directions of the data with energies in excess of 40 EeV to different tests for anisotropy. We search for localized excess fluxes, self-clustering of event directions at angular scales up to 30°, and different threshold energies between 40 and 80 EeV. We then look for correlations of cosmic rays with celestial structures both in the Galaxy (the Galactic Center and Galactic Plane) and in the local universe (the Super-Galactic Plane). We also examine their correlation with different populations of nearby extragalactic objects: galaxies in the 2MRS catalog, AGNs detected by Swift-BAT, radio galaxies with jets, and the Centaurus A (Cen A) galaxy. None of the tests show statistically significant evidence of anisotropy. The strongest departures from isotropy (post-trial probability %) are obtained for cosmic rays with EeV in rather large windows around Swift AGNs closer than 130 Mpc and brighter than 1044 erg s−1 (18° radius), and around the direction of Cen A (15° radius).
We report a first measurement for ultrahigh energy cosmic rays of the correlation between the depth of shower maximum and the signal in the water Cherenkov stations of air-showers registered ...simultaneously by the fluorescence and the surface detectors of the Pierre Auger Observatory. Such a correlation measurement is a unique feature of a hybrid air-shower observatory with sensitivity to both the electromagnetic and muonic components. It allows an accurate determination of the spread of primary masses in the cosmic-ray flux. Up till now, constraints on the spread of primary masses have been dominated by systematic uncertainties. The present correlation measurement is not affected by systematics in the measurement of the depth of shower maximum or the signal in the water Cherenkov stations. The analysis relies on general characteristics of air showers and is thus robust also with respect to uncertainties in hadronic event generators. The observed correlation in the energy range around the ‘ankle’ at lg(E/eV)=18.5–19.0 differs significantly from expectations for pure primary cosmic-ray compositions. A light composition made up of proton and helium only is equally inconsistent with observations. The data are explained well by a mixed composition including nuclei with mass A>4. Scenarios such as the proton dip model, with almost pure compositions, are thus disfavored as the sole explanation of the ultrahigh-energy cosmic-ray flux at Earth.
•Quality-by-Design approach: the understanding of a stability-indicating method.•Comparison between Quality-by-Testing and Quality-by-Design strategy.•Steps of the method development based on ...acquired knowledge: a learning process.•Quality-by-Design and Design Space concepts as adaptive optimization tool.
The understanding of the method is a major concern when developing a stability-indicating method and even more so when dealing with impurity assays from complex matrices. In the presented case study, a Quality-by-Design approach was applied in order to optimize a routinely used method. An analytical issue occurring at the last stage of a long-term stability study involving unexpected impurities perturbing the monitoring of characterized impurities needed to be resolved. A compliant Quality-by-Design (QbD) methodology based on a Design of Experiments (DoE) approach was evaluated within the framework of a Liquid Chromatography (LC) method. This approach allows the investigation of Critical Process Parameters (CPPs), which have an impact on Critical Quality Attributes (CQAs) and, consequently, on LC selectivity. Using polynomial regression response modeling as well as Monte Carlo simulations for error propagation, Design Space (DS) was computed in order to determine robust working conditions for the developed stability-indicating method. This QbD compliant development was conducted in two phases allowing the use of the Design Space knowledge acquired during the first phase to define the experimental domain of the second phase, which constitutes a learning process. The selected working condition was then fully validated using accuracy profiles based on statistical tolerance intervals in order to evaluate the reliability of the results generated by this LC/ESI-MS stability-indicating method.
A comparison was made between the traditional Quality-by-Testing (QbT) approach and the QbD strategy, highlighting the benefit of this QbD strategy in the case of an unexpected impurities issue. On this basis, the advantages of a systematic use of the QbD methodology were discussed.
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