Adaptive combination of SSB and SUB equipment to master complexity in clinical manufacturing in the clinical supply center

Today’s clinical manufacturing of complex monoclonal antibodies under GMP conditions needs to be highly adaptive in order to face the requirements of constant acceleration of processes. The main challenge of the clinical supply center (CSC) in Penzberg (Germany) is to successfully master the complexity of producing different products in different phases (clinical phase I – III) with different process versions. New products for clinical phase I have different requirements than older products, as well as products in later phases or resupplies. In addition, the actual change to more intensified processes will increase the complexity even more. The CSC is equipped with a variety of bioreactors in different sizes and types. Stainless steel as well as single use bioreactors, which were installed over the past 25 years. In order to face the main challenge, it is mandatory to create a framework that allows the adaptive combination of standard (SSB) and new technologies (SUB). To realize that, SUBs and SSBs are treated equally. SUBs have the advantage to be used more flexible than SSBs because of less preparation time and an easier adaption to intensified processes (like perfusion modules in the N-1 bioreactor). Furthermore, SUBs can be easily connected to every existing bioreactor type (SSB as well) via hose connections. This all offers the chance to utilize existing bioreactor racks more efficient with less slack time. An adaptive combination is also faster and more favorable than just replacing existing with new equipment. The poster shows the successful implementation of the adaptive combination in the CSC, by adding SUBs with increasing volume to the facility (starting with 250L and ending with 2000L production volume) and apply them for existing and new processes. The intensified usage of SUB equipment shortens the upgrade time to adapt to future needs (e.g. switch to perfusion technology). With this flexible setup the multi-product-GMP facility in Penzberg is perfectly prepared for actual and upcoming challenges

Production-Grid: Task-Farming in D-Grid

Die D-Grid Initiative stellt Bundesweit derzeit >30.000 Rechencores insgesamt 36 Community-Projekten zur Verfügung. Insgesamt wurden bisher in 3 „Calls“ und mehreren Infrastruktursonderinvestitionen ca. 134 Millionen Euro investiert. Auf den Resourcen laufen mehrere sogenannte Middlewares. Die Auslastung der Ressourcen die mithilfe der Middleware Globus benutzt werden (~70% der total installierten Leistung) beträgt praktisch mittlerweile 100%. Im wesentlichen nutzen zwei Usecases diese Resourcen zu ca. 98%: Im astrophysikalischen Bereich sind dies Gravitationswellenanalysen mittels der einstein@home-Jobs vom Max-Planck-Institut für Gravitationsphysik Albert-Einstein-Institut (AEI) und sowie Genomanalysen der Biophysikalischen Genomik, BioQuant/DKFZ. Beide nehmen derzeit mehr als 150.000 CPU-Stunden auf den Globus-Ressourcen im D-Grid auf. Vom wissenschaftlichen Standpunkt sind diese Rechnungen und Analysen von großer Bedeutung wie sich an der ansteigenden Zahl an Publikationen zeigt. Hinter den zwei hierbei verwendeten Nutzerkennungen verbergen sich dabei mehrere Nutzer die durch A. Beck-Ratzka und T. A. Knoch in Kooperationsprojekten gebündelt sind, die entweder einzelne Applikationen und/oder ganze Pipelinesysteme benutzen. Dazu gehören auch Nutzer die u.a. in nationalen, europäischen bzw. internationalen Konsortien für den Informatikpart zuständig sind. Im astrophysikalischen Fall handelt es sich dabei um 10 Nutzer/Projekte, im biomedizinischen Fall sind dies international mittlerweile ca. 200 Nutzer/Projekte (180 hierbei durch die Nutzung einer sog. Assoziation Pipeline, die von äußerst wichtiger diagnostischer Relevanz ist). Die Stärkung des Standorts Deutschland durch die erfolgreiche Nutzung im Produktionsbetrieb hat einerseits die Machbarkeit einer funktionierenden Grid-Infrastruktur für die Globus Ressourcen-Betreiber gezeigt und andererseits durch die Schaffung wissenschaftlich hoch-relevanter Ergebnisse zu einer damit verbundenen forschungspolitischen Stärkung geführt. Beides kann nicht hoch genug eingeschätzt werden, da beide Usecases vor allem auch im internationalen Vergleich eine herausragende Stellung einehmen – faktisch gehören sie mittlerweile zu den größten Nutzern von Rechenzeit weltweit. Der große Erfolg der zwei Usecases Gravitationswellenanalyse und Genomanalyse hat die Ressourcen bezüglich der Globus basierten Infrastruktur zu nahezu 100% ausgeschöpft Er basiert auf unabhängig voneinander entwickelten Komponenten, welche die Middleware in eine produktive Umgebung integrieren, und damit ein Produktionsgrid erst ermöglichen. Dies ist einzigartig im D-Grid-Umfeld. Die Personalkapatzität von A. Beck-Ratzka und T. A. Knoch sind aufgrund der Unterstützungsanforderungen von weiteren/neuen Nutzern zu 100% ausgereizt. Folglich stoßen wir in Bezug auf i) Rechenzeit für unsere eigenen Projekte sowie die neuer Nutzer, ii) die Unterstützung und Anwerbung neuer Nutzer, sowie iii) entsprechenden Unterstützung beim Management in Hinblick auf Daten Sicherheits/Vertraulichkeit, SLAs und Coaching, an die Grenze unserer bisher existierenden Möglichkeiten. Die entsprechende Projektanforderungen bezüglich Rechenleistung sind klar durch die entsprechenden Projekterfolge gegeben, d.h. dass über die Laufzeit der D-Grid Infrastruktur bis 2014 massive Anforderungen über den bisher für uns zugänglichen Rahmen hinaus bestehen. Anfragen von neuen Nutzer gibt es von 10 weiteren im astrophysikalischen (Berliner Raum) und 50-60 weiteren im biomedizinischen Bereich (Raum Heidelberg), die uns als verläßliche bzw. erfahrene Garanten für erfolgreiche Hoch-Durchsatz Gridnutzung ansehen, aber entsprechende Unterstützung brauchen. Zusätzlich gibt es auch Anfragen von mehreren nationalen und internationalen Verbünden, die genau solche Komponenten wie die unsrigen sofort benutzen würden. Darüberhinaus besteht in diesem Zusammenhang der Bedarf an weiteren Lösungen im Datensicherheits- und Vertraulichkeits-Bereich, die durch diese Bereiche konkret angefordert werden, was mit entsprechendem Coaching und Management einhergehen muss und immer wieder von uns eingefordert wird. Wir sind fest davon überzeugt, dass mit dem im folgenden beschriebenen Vorschlag nicht nur diese Flaschenhälse beseitigt werden können, sondern auch die Nachhaltigeit und damit der Erfolg des gesamten D-Grid Projektes massiv gestärkt werden kann! Ein weiterer Aspekt der produktiven Usecases ist, dass erst mit diesen die Grid-Ressourcen richtig für den Produktionsbetrieb getestet werden können. Die Problematik im DGUS-Ticket 853 beispielsweise ist ein Problem, dass erst durch produktive Usecases aufgedeckt wird Die Globus basierten Grid-Ressourcen im D-Grid sind durch die beiden produktiven Usecases Gravitationswellenanalyse und Genomanalyse stabiler geworden. Durch die in im Rahmen dieses Projektes geplante Erweiterung der Usecases auf gLite- und Unicore-Ressourcen würden auch die Betreiber dieser Ressourcen enorm profitieren, weil es damit auf diesen Ressourcen zu einem Produktionsbetrieb kommen würde

Convergence of the critical attractor of dissipative maps: Log-periodic oscillations, fractality and nonextensivity

For a family of logistic-like maps, we investigate the rate of convergence to the critical attractor when an ensemble of initial conditions is uniformly spread over the entire phase space. We found that the phase space volume occupied by the ensemble W(t) depicts a power-law decay with log-periodic oscillations reflecting the multifractal character of the critical attractor. We explore the parametric dependence of the power-law exponent and the amplitude of the log-periodic oscillations with the attractor's fractal dimension governed by the inflexion of the map near its extremal point. Further, we investigate the temporal evolution of W(t) for the circle map whose critical attractor is dense. In this case, we found W(t) to exhibit a rich pattern with a slow logarithmic decay of the lower bounds. These results are discussed in the context of nonextensive Tsallis entropies.Comment: 8 pages and 8 fig

Non-Equilibrium Electron Transport in Two-Dimensional Nano-Structures Modeled by Green's Functions and the Finite-Element Method

We use the effective-mass approximation and the density-functional theory with the local-density approximation for modeling two-dimensional nano-structures connected phase-coherently to two infinite leads. Using the non-equilibrium Green's function method the electron density and the current are calculated under a bias voltage. The problem of solving for the Green's functions numerically is formulated using the finite-element method (FEM). The Green's functions have non-reflecting open boundary conditions to take care of the infinite size of the system. We show how these boundary conditions are formulated in the FEM. The scheme is tested by calculating transmission probabilities for simple model potentials. The potential of the scheme is demonstrated by determining non-linear current-voltage behaviors of resonant tunneling structures.Comment: 13 pages,15 figure

Efficacy of language intervention in the early years

Background: Oral language skills in the preschool and early school years are critical to educational success and provide the foundations for the later development of reading comprehension. Methods: In a randomized controlled trial, 180 children from 15 UK nursery schools (n = 12 from each setting; Mage = 4;0) were randomly allocated to receive a 30-week oral language intervention or to a waiting control group. Children in the intervention group received 30 weeks of oral language intervention, beginning in nursery (preschool), in three group sessions per week, continuing with daily sessions on transition to Reception class (pre-Year 1). The intervention was delivered by nursery staff and teaching assistants trained and supported by the research team. Following screening, children were assessed preintervention, following completion of the intervention and after a 6-month delay. Results: Children in the intervention group showed significantly better performance on measures of oral language and spoken narrative skills than children in the waiting control group immediately after the 30 week intervention and after a 6 month delay. Gains in word-level literacy skills were weaker, though clear improvements were observed on measures of phonological awareness. Importantly, improvements in oral language skills generalized to a standardized measure of reading comprehension at maintenance test. Conclusions: Early intervention for children with oral language difficulties is effective and can successfully support the skills, which underpin reading comprehensio

Simulations of galactic dynamos

We review our current understanding of galactic dynamo theory, paying particular attention to numerical simulations both of the mean-field equations and the original three-dimensional equations relevant to describing the magnetic field evolution for a turbulent flow. We emphasize the theoretical difficulties in explaining non-axisymmetric magnetic fields in galaxies and discuss the observational basis for such results in terms of rotation measure analysis. Next, we discuss nonlinear theory, the role of magnetic helicity conservation and magnetic helicity fluxes. This leads to the possibility that galactic magnetic fields may be bi-helical, with opposite signs of helicity and large and small length scales. We discuss their observational signatures and close by discussing the possibilities of explaining the origin of primordial magnetic fields.Comment: 28 pages, 15 figure, to appear in Lecture Notes in Physics "Magnetic fields in diffuse media", Eds. E. de Gouveia Dal Pino and A. Lazaria

Processing of aluminum-graphite particulate metal matrix composites by advanced shear technology

Copyright @ 2009 ASM International. This paper was published in Journal of Materials Engineering and Performance 18(9) and is made available as an electronic reprint with the permission of ASM International. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplications of any material in this paper for a fee or for commercial purposes, or modification of the content of this paper are prohibited.To extend the possibilities of using aluminum/graphite composites as structural materials, a novel process is developed. The conventional methods often produce agglomerated structures exhibiting lower strength and ductility. To overcome the cohesive force of the agglomerates, a melt conditioned high-pressure die casting (MC-HPDC) process innovatively adapts the well-established, high-shear dispersive mixing action of a twin screw mechanism. The distribution of particles and properties of composites are quantitatively evaluated. The adopted rheo process significantly improved the distribution of the reinforcement in the matrix with a strong interfacial bond between the two. A good combination of improved ultimate tensile strength (UTS) and tensile elongation (e) is obtained compared with composites produced by conventional processes.EPSR

The G0 Experiment: Apparatus for Parity-Violating Electron Scattering Measurements at Forward and Backward Angles

In the G0 experiment, performed at Jefferson Lab, the parity-violating elastic scattering of electrons from protons and quasi-elastic scattering from deuterons is measured in order to determine the neutral weak currents of the nucleon. Asymmetries as small as 1 part per million in the scattering of a polarized electron beam are determined using a dedicated apparatus. It consists of specialized beam-monitoring and control systems, a cryogenic hydrogen (or deuterium) target, and a superconducting, toroidal magnetic spectrometer equipped with plastic scintillation and aerogel Cerenkov detectors, as well as fast readout electronics for the measurement of individual events. The overall design and performance of this experimental system is discussed.Comment: Submitted to Nuclear Instruments and Method

Magnetic Field Amplification in Galaxy Clusters and its Simulation

We review the present theoretical and numerical understanding of magnetic field amplification in cosmic large-scale structure, on length scales of galaxy clusters and beyond. Structure formation drives compression and turbulence, which amplify tiny magnetic seed fields to the microGauss values that are observed in the intracluster medium. This process is intimately connected to the properties of turbulence and the microphysics of the intra-cluster medium. Additional roles are played by merger induced shocks that sweep through the intra-cluster medium and motions induced by sloshing cool cores. The accurate simulation of magnetic field amplification in clusters still poses a serious challenge for simulations of cosmological structure formation. We review the current literature on cosmological simulations that include magnetic fields and outline theoretical as well as numerical challenges.Comment: 60 pages, 19 Figure

Neutrino Propagation in a Strongly Magnetized Medium

We derive general expressions at the one-loop level for the coefficients of the covariant structure of the neutrino self-energy in the presence of a constant magnetic field. The neutrino energy spectrum and index of refraction are obtained for neutral and charged media in the strong-field limit ($M_{W}\gg \sqrt{B}\gg m_{e},T,\mu ,| \mathbf{p}|$) using the lowest Landau level approximation. The results found within the lowest Landau level approximation are numerically validated, summing in all Landau levels, for strong $B\gg T^{2}$ and weakly-strong $B \gtrsim T^{2}$ fields. The neutrino energy in leading order of the Fermi coupling constant is expressed as the sum of three terms: a kinetic-energy term, a term of interaction between the magnetic field and an induced neutrino magnetic moment, and a rest-energy term. The leading radiative correction to the kinetic-energy term depends linearly on the magnetic field strength and is independent of the chemical potential. The other two terms are only present in a charged medium. For strong and weakly-strong fields, it is found that the field-dependent correction to the neutrino energy in a neutral medium is much larger than the thermal one. Possible applications to cosmology and astrophysics are considered.Comment: 23 pages, 4 figures. Corrected misprints in reference