Root cause analysis during process development using Joint-Y PLS

The original purpose of the JYPLS model was to aid product transfer and scale-up. This work demonstrates that the JYPLS model is also well suited to analyze data from a process in development where the number and type of sensors and sensor locations are also being decided. The specific application in this case was to determine the root cause for a bias found during the development of a multivariate calibration model for a Near Infrared (NIR) instrument. The calibration model was built in parallel with the development of the manufacturing process itself. Each time the calibration model was tested with data from a new batch run, a non-explained bias was observed. Laboratory results on samples gathered from the process show that the NIR signal itself was biased and not the actual concentration of the constituent. Data on the processing conditions were collected for all the batches and included in the JYPLS model along with NIR and lab results. The loadings and scores from the JYPLS model were interpreted to isolate the root cause of the observed drift in the calibration model. This work discusses the general approach and presents the sequence of diagnostics used to analyze the different campaigns during process development. This should be applicable to other scenarios in process development where the data has the same architecture.     

On the efficient computation of robust regression estimators

The problem of providing efficient and reliable robust regression algorithms is considered. The impact of global optimization methods, such as stopping conditions and clustering techniques, in the calculation of robust regression estimators is investigated. The use of stopping conditions permits us to devise new algorithms that perform as well as the existing algorithms in less time and with adaptive algorithm parameters. Clustering global optimization is shown to be a general framework encompassing many of the existing algorithms.     

Centralized Modular Diagnosis and the Phenomenon of Coupling

This paper studies modular decomposition as an approach for failure diagnosis based on Discrete Event Systems. This paper also analyses the problem of coupling produced in the implementation of centralized modular diagnosers, as coupled diagnosers cannot carry out their own diagnosis task, when there is a failure in another subsystem sharing a common energy or material flow. In addition, we propose a method to avoid diagnoser coupling, by means of decoupling functions using non-local information with respect to the coupled diagnoser and generated in the diagnoser where the failure has been isolated.     

The influence of chemical treatment and suture on the elastic behavior of calf pericardium utilized in the construction of cardiac bioprostheses

Poor mechanical properties of biological tissue are known to cause wear, leading to the failure of cardiac bioprostheses made of calf pericardium. Different chemical agents such as sodium dodecyl sulfate (SDS) are presently being tested as possible inhibitors of the calcification process. The objective of this report was to determine the mechanical behavior of calf pericardium treated with SDS for 24 h and the influence of the suture on the mechanical properties of the tissue. Forty-eight samples were tested: 24 subjected to a standard treatment with glutaraldehyde (12 sewn with 4/0 silk suture thread) and 24 incubated with SDS for 24 h (12 sewn with the same suture thread). Each sutured and non-sutured sample was cut into two strips to yield paired samples. All were subjected to tensile stress to breaking point. The mean stress at breaking point in the non-sutured series treated with glutaraldehyde alone was 16.42 and 13.85 MPa depending on the region of the pericardium, while in the sutured samples subjected to glutaraldehyde the mean stress was 7.50 and 7.63 MPa, respectively, differences which were statistically significant (p = 0.03 and p = 0.003, respectively) when the means for non-sutured samples from equivalent regions treated with glutaraldehyde were compared. The stress at breaking point was lower in the SDS-treated series, ranging between 2.60 and 3.56 MPa. The mathematical functions that govern the stress/strain or deformation were obtained. In the series of pericardium treated with SDS, deformations of 10% were produced with stresses of under 0.4 MPa, an outcome that is intolerable from the constructive point of view. We established a regression model that enabled us to determine the mechanical behavior of a sutured sample by testing a contiguous piece of tissue, with a high correlation coefficient (r > 0.99). We consider this finding to be of interest in the selection of pericardium for use in the construction of leaflets for cardiac bioprostheses.     

Using Structural Equation Modeling (SEM) for the Study of Impurity Profiles of Drug Substances

The impurity profile is one of the most important quality characteristics of a drug substance. Although it is always desirable to determine the chemical structure of all impurities forming the impurity profile, unfortunately this is not always economically and technically feasible because of the extremely low concentrations at which some impurities may be found in the drug substance. Therefore, alternative approaches to the chemical analysis are needed for trying to determine the origin of the unidentified impurities.

In a previous study conducted by our group, based on exploratory (principal component and hierarchical cluster) analysis, we were able to suggest a hypothesis for explaining the origin of the unidentified impurities of a drug substance. However, there was still a concern that alternative hypotheses might explain the same phenomenon equally well. This article explores the application of recent developments in structural equation modeling for the systematic generation and selection of hypotheses (models) worthy of being confirmed by chemical research.     

Examination of the kinetics of herpes simplex virus glycoprotein D binding to the herpesvirus entry mediator, using surface plasmon resonance

Previously, we showed that truncated soluble forms of herpes simplex virus (HSV) glycoprotein D (gDt) bound directly to a truncated soluble form of the herpesvirus entry mediator (HveAt, formerly HVEMt), a cellular receptor for HSV. The purpose of the present study was to determine the affinity of gDt for HveAt by surface plasmon resonance and to compare and contrast the kinetics of an expanded panel of gDt variants in binding to HveAt in an effort to better understand the mechanism of receptor binding and virus entry. Both HveAt and gDt are dimers in solution and interact with a 2:1 stoichiometry. With HveAt, gD1(306t) (from the KOS strain of HSV-1) had a dissociation constant (KD) of 3.2 x 10(-6) M and gD2(306t) had a KD of 1.5 x 10(-6) M. The interaction between gDt and HveAt fits a 1:1 Langmuir binding model, i.e., two dimers of HveAt may act as one binding unit to interact with one dimer of gDt as the second binding unit. A gD variant lacking all signals for N-linked oligosaccharides had an affinity for HveAt similar to that of gD1(306t). A variant lacking the bond from cysteine 1 to cysteine 5 had an affinity for HveAt that did not differ from that of the wild type. However, variants with double cysteine mutations that eliminated either of the other two disulfide bonds showed decreased affinity for HveAt. This result suggests that two of the three disulfide bonds of gD are important for receptor binding. Four nonfunctional gDt variants, each representing one functional domain of gD, were also studied. Mutations in functional regions I and II drastically decreased the affinity of gDt for HveAt. Surprisingly, a variant with an insertion in functional region III had a wild-type level of affinity for HveAt, suggesting that this domain may function in virus entry at a step other than receptor binding. A variant with a deletion in functional region IV [gD1(Delta290-299t)] exhibited a 100-fold enhancement in affinity for HveAt (KD = 3.3 x 10(-8) M) due mainly to a 40-fold increase in its kinetic on rate. This agrees with the results of other studies showing the enhanced ability of gD1(Delta290-299t) to block infection. Interestingly, all the variants with decreased affinities for HveAt exhibited decreased kinetic on rates but only minor changes in their kinetic off rates. The results suggest that once the complex between gDt and HveAt forms, its stability is unaffected by a variety of changes in gD.     

Emerging gallium nitride based devices

Wide bandgap GaN has long been sought for its applications to blue and UV emitters and high temperature/high power electronic devices. Recent introduction of commercial blue and blue-green LED's have led to a plethora of activity in all three continents into the heterostructures based on GaN and its alloys with AlN and InN. In this review, the status and future prospects of emerging wide bandgap gallium nitride semiconductor devices are discussed. Recent successes in p-doping of GaN and its alloys with InN and AlN, and in n-doping with much reduced background concentrations have paved the way for the design, fabrication, and characterization of devices such as MESFET's, MISFET's, HBT's, LED's, and optically pumped lasers. We discuss the electrical properties of these devices and their drawbacks followed by future prospects. After a short elucidation of materials characteristics of the nitrides, we explore their electrical transport properties in detail. Recent progress in processing such as formation of low-resistance ohmic contacts and etching is also presented. The promising features of quarternaries and double heterostructures in relation to possible current injection lasers, LED's, and photodetectors are also elaborated on     

Influence of fermentation oxygen partial pressure on semicontinuous acetification for wine vinegar production

This paper describes semicontinuous acetic acid fermentations for wine vinegar production carried out with different aerating gas compositions ranging from 21% (air) to 63% oxygen content and using low aeration (3.7 h^–1, vvm), in order to study the influence of the oxygen partial pressure on the aerating gas supplied to the reactor in this industrial biotransformation process. The acetification process was conducted in 6- to 100-l reactors. The overall acetic acid productivity increased from 0.72 g l^–1 h^–1 with air to 1.35 g l^–1 h^–1 when oxygen-rich (36%) air was used. The same behaviour was observed for the maximum acetification rate, and therefore the total process time was reduced in proportion to the increase in productivity, from 65 h using air to 35 h using an aerating gas mixture containing 36% oxygen. The yield of the process was high, 96–99%; the final concentration of acetic acid reached was 116–118 g l^–1; and the substrate yield coefficient based on ethanol metabolised was higher using oxygen-rich air than with air. It was not feasible to carry out semicontinuous acetification cycles with an oxygen content higher than 40%, and when the oxygen content was 63%, the process stopped during the first cycle with very little acetic acid production. Moreover, an inverse relationship between the acetic acid formation rate profile in the course of the acetification process and the amount of dissolved acetaldehyde in the fermentation broth formed by the acetic bacteria was observed.     

A wavelet-based ECG delineator: evaluation on standard databases

In this paper, we developed and evaluated a robust single-lead electrocardiogram (ECG) delineation system based on the wavelet transform (WT). In a first step, QRS complexes are detected. Then, each QRS is delineated by detecting and identifying the peaks of the individual waves, as well as the complex onset and end. Finally, the determination of P and T wave peaks, onsets and ends is performed. We evaluated the algorithm on several manually annotated databases, such as MIT-BIH Arrhythmia, QT, European ST-T and CSE databases, developed for validation purposes. The QRS detector obtained a sensitivity of Se = 99.66% and a positive predictivity of P+ = 99.56% over the first lead of the validation databases (more than 980,000 beats), while for the well-known MIT-BIH Arrhythmia Database, Se and P+ over 99.8% were attained. As for the delineation of the ECG waves, the mean and standard deviation of the differences between the automatic and manual annotations were computed. The mean error obtained with the WT approach was found not to exceed one sampling interval, while the standard deviations were around the accepted tolerances between expert physicians, outperforming the results of other well known algorithms, especially in determining the end of T wave.