Quality assurance in research: incorporating ISO9001:2000 into a GMP quality management system in a pharmaceutical R+D+I center

There is currently no universal or standardized quality system for the recognition of excellence of a research center. Knowledge and competence may not be enough in the current rapidly changing world in which high productivity and continuous improvement are essential. The purpose of this study was to assess the impacts of implementing the ISO9001:2000:2000 standard in an academic research center dedicated to R+D+I (research, development and innovation) in the pharmaceutical industry. The article describes the stages we followed to implement the ISO9001:2000 system, which was achieved by integrating it into the previous regulatory system of GMP (Good Manufacturing Practices). As a result of implementing ISO9001:2000, the center has seen distinct improvements, such as fewer errors in project documentation, improved assessment of customer satisfaction, and the effective implementation of periodic plans, e.g., in calibration, preventive maintenance, and investments. Overall, ISO9001:2000 implementation has been beneficial for the organization and could be applied to other research centers.     

Direct Injection of Plasma Samples and Micellar Chromatography of Procainamide and Its Metabolite N-Acetylprocainamide

Micellar liquid chromatography was employed for the monitoring of procainamide and its metabolite N-acetylprocainamide using a C18 column. Sodium dodecyl sulphate (SDS) and modifier concentrations were optimised in order to obtain minimum analysis time, maximum sensitivity and good resolution. The optimum chromatographic conditions were as follows: flow rate 1 mL min^?1, injection volume 20 μL, temperature at 25 °C, respectively. The mobile phase consisted of 0.05 M SDS-1% (v/v) butanol–phosphate buffer (10 mM, pH 7, 0.9%, w/v) NaCl using a detection wavelength at 280 nm. Validation studies were carried out according to the ICH guideline and included the determination of calibration curves (r ² > 0.999), intra- and inter-day precisions (CV < 3.9%), robustness and interference studies, respectively. The recoveries in spiked serum samples were adjusted. Finally, the optimized method was applied to serum samples of patients treated with antiarrhythmics, and the results were compared with those given by a reference method where a good correlation was obtained.     

A note on congruences of semilattices with sectionally finite height

We present a bijective correspondence between congruences of semilattices with sectionally finite height (i.e., meet-semilattices whose principal downsets have finite length) and certain special subsets of their universes. We characterize these subsets from a purely order-theoretic point of view and prove that the bijection coincides with the Leibniz operator of abstract algebraic logic.     

Short-chain reactive probes as tools to unravel the Pseudomonas aeruginosa quorum sensing regulon

In recent years, the world has seen a troubling increase in antibiotic resistance among bacterial pathogens. In order to provide alternative strategies to combat bacterial infections, it is crucial deepen our understanding into the mechanisms that pathogens use to thrive in complex environments. Most bacteria use sophisticated chemical communication systems to sense their population density and coordinate gene expression in a collective manner, a process that is termed “quorum sensing” (QS). The human pathogen Pseudomonas aeruginosa uses several small molecules to regulate QS, and one of them is N-butyryl-l-homoserine lactone (C₄-HSL). Using an activity-based protein profiling (ABPP) strategy, we designed biomimetic probes with a photoreactive group and a ‘click’ tag as an analytical handle. Using these probes, we have identified previously uncharacterized proteins that are part of the P. aeruginosa QS network, and we uncovered an additional role for this natural autoinducer in the virulence regulon of P. aeruginosa, through its interaction with PhzB1/2 that results in inhibition of pyocyanin production.

Short-chain reactive probes can be used as tools to shed new light on virulence mechanisms in bacterial pathogens.     

The ortho‐Substituent Effect on the Ag‐Catalysed Decarboxylation of Benzoic Acids

A combined experimental and computational investigation on the Ag‐catalysed decarboxylation of benzoic acids is reported herein. The present study demonstrates that a substituent at the ortho position exerts dual effects in the decarboxylation event. On one hand, ortho‐substituted benzoic acids are inherently destabilised starting materials compared to their meta‐ and para‐substituted counterparts. On the other hand, the presence of an ortho‐electron‐withdrawing group results in an additional stabilisation of the transition state. The combination of both effects results in an overall reduction of the activation energy barrier associated with the decarboxylation event. Furthermore, the Fujita–Nishioka linear free energy relationship model indicates that steric bulk of the substituent can also exert a negative effect by destabilising the transition state of decarboxylation.     

Synthetic Haptens and Monoclonal Antibodies to the Cyanotoxin Anatoxin‐a

Early warning systems for monitoring toxic events may benefit from the availability of monoclonal antibodies enabling the sensitive and specific detection of anatoxin‐a, a cyanotoxin involved in numerous cases of animal poisoning resulting from toxic algal blooms in freshwaters. Through the synthesis of three functionalized derivatives of anatoxin‐a, we have succeeded in generating the first‐ever reported immunoreagents (bioconjugates and antibodies) suitable for the development of immunoanalytical approaches aimed at rapid and onsite detection of this harmful cyanotoxin.     

A multicommutated flow system for determination of bismuth in milk shakes by hydride generation atomic fluorescence spectrometry incorporating on-line neutralization of waste effluent

A highly sensitive method was developed for determination of bismuth in milk shakes by multicommutation hydride generation atomic fluorescence spectrometry (HG-AFS) based on off-line sonication for 10 min with aqua regia 8% (v/v) and on-line waste treatment. The instrumentation and chemistry variables were studied in order to provide the best performance. The limit of detection in the original samples, established for a probability level of 99.6% (k = 3), was 1.67 ng/g Bi. The method provides a fast alternative in control analysis with a sampling throughput of 72 h as compared with 31 h obtained by the classical continuous measurement. Additionally, multicommutation reduces waste generation by a factor of 2.6. The consumption of sample, reductant, and blank, as compared with continuous mode HG-AFS, was reduced 9.6, 4.5, and 13.3 times, respectively. To confirm the accuracy of the method, recovery studies were performed, and excellent agreement between multicommutation and continuous measurement-based values was obtained. Application of the developed methodology for bismuth determination in milk shake samples from the Spanish market provided concentrations ranging from 4.2 to 15.0 ng/mL, and good comparability with data obtained by continuous measurements after microwave-assisted total digestion of samples for a 95% probability level and 12 degrees of freedom was found.     

Design and performance of BOREAS,the beamline for resonant X‐ray absorption and scattering experiments at the ALBA synchrotron light source

The optical design of the BOREAS beamline operating at the ALBA synchrotron radiation facility is described. BOREAS is dedicated to resonant X‐ray absorption and scattering experiments using soft X‐rays, in an unusually extended photon energy range from 80 to above 4000 eV, and with full polarization control. Its optical scheme includes a fixed‐included‐angle, variable‐line‐spacing grating monochromator and a pair of refocusing mirrors, equipped with benders, in a Kirkpatrick–Baez arrangement. It is equipped with two end‐stations, one for X‐ray magnetic circular dichroism and the other for resonant magnetic scattering. The commissioning results show that the expected beamline performance is achieved both in terms of energy resolution and of photon flux at the sample position.     

Electronic Structure of Rh(2)(&mgr;-CO)(CO)(2)(H(2)PCH(2)PH(2))(2). An Example of a Non-A-Frame Structure

Calculations based on density functional theory (DFT) and Hartree-Fock configuration interaction (HF-CI) methodology have been carried out to investigate the rhodium-rhodium coupling in Rh(2)(CO)(2)(dppm)(2), 1 (dppm = Ph(2)PCH(2)PPh(2)) and in Rh(2)(&mgr;-CO)(CO)(2)(dppm)(2), 2. DFT geometries, obtained with the Dgauss program, are in good agreement with those determined from X-ray, but HF geometries, calculated using the same basis sets, yield bond distances systematically too long. Calculations indicate that the rhodium atoms in 1 are linked by a single bond. The insertion of a semibridging carbonyl between the two metal atoms leads to a shortening of the rhodium-rhodium distance and also to a noticeable weakening of the metal-metal interaction. Both effects, and also the stabilization of the HOMO of 2, are related to an observed change from square planar to tetrahedral of the ligand environment of the Rh atom proximal to the inserted CO. Both MO analysis and bond characterization from the topology of the charge density confirm the existence of a bonding interaction between the semibridging carbonyl and the distal rhodium atom. The electronic structures of the dicationic complex [Rh(2)(CO)(3)(dppm)(2)](2+) and of the A-frame-like, isoelectronic system Rh(2)Br(2)(&mgr;-CO) (dppm)(2) are also discussed. The electron deformation density is derived from 2 by means of several methodological approaches, namely, HF, HF-CI, DFT, and DFT + gradient corrections. The HF deformation density obtained in the plane containing the metals and the three CO ligands is discussed, as well as the "correlation density" obtained from the difference maps DFT - HF and CI - HF.     

Nickel‐Catalyzed Enantioselective C?C Bond Formation through C?O Cleavage in Aryl Esters

We report the first enantioselective C C bond formation through C O bond cleavage using aryl ester counterparts. This method is characterized by its wide substrate scope and results in the formation of quaternary stereogenic centers with high yields and asymmetric induction.