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.
Using the data taken at the Pierre Auger Observatory between December 2004 and December 2012, we have examined the implications of the distributions of depths of atmospheric shower maximum (X ...sub(max)), using a hybrid technique, for composition and hadronic interaction models. We do this by fitting the distributions with predictions from a variety of hadronic interaction models for variations in the composition of the primary cosmic rays and examining the quality of the fit. Regardless of what interaction model is assumed, we find that our data are not well described by a mix of protons and iron nuclei over most of the energy range. Acceptable fits can be obtained when intermediate masses are included, and when this is done consistent results for the proton and iron-nuclei contributions can be found using the available models. We observe a strong energy dependence of the resulting proton fractions, and find no support from any of the models for a significant contribution from iron nuclei. However, we also observe a significant disagreement between the models with respect to the relative contributions of the intermediate components.
•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.
The Pierre Auger collaboration reports new results bearing on the composition of cosmic rays. The muon number of air showers, created by cosmic rays and measured by the collaboration, is intriguingly ...at odds with all theoretical models, posing a challenge to our current understanding of the mass composition of cosmic rays. We present the first hybrid measurement of the average muon number in air showers at ultrahigh energies, initiated by cosmic rays with zenith angles between 62degrees and 80degrees. The measurement is based on 174 hybrid events recorded simultaneously with the surface detector array and the fluorescence detector of the Pierre Auger Observatory. The muon number for each shower is derived by scaling a simulated reference profile of the lateral muon density distribution at the ground until it fits the data. A 10 super(19) eV shower with a zenith angle of 67degrees, which arrives at the surface detector array at an altitude of 1450 m above sea level, contains on average (2.68 + or - 0.04 + or - 0.48(sys)) x 10 super(7) muons with energies larger than 0.3 GeV. The logarithmic gain d ln N sub( mu )/d ln E of muons with increasing energy between 4 X 10 super(18) eV and 5 x 10 super(19) eV is measured to be (1.029 + or - 0.024 + or - 0.030(sys)).
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.
The surface detector array of the Pierre Auger Observatory provides information about the longitudinal development of the muonic component of extensive air showers. Using the timing information from ...the flash analog-to-digital converter traces of surface detectors far from the shower core, it is possible to reconstruct a muon production depth distribution. We characterize the goodness of this reconstruction for zenith angles around 60degrees and different energies of the primary particle. From these distributions, we define X super( mu ) sub(max) as the depth along the shower axis where the production of muons reaches maximum. We explore the potentiality of X super( mu ) sub(max) as a useful observable to infer the mass composition of ultrahigh-energy cosmic rays. Likewise, we assess its ability to constrain hadronic interaction models.
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.
A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) ...resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.
•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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