A mathematical approach to evaluate equivalence in E&L assessments of SUS

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Simplified Extractables and Leachables Assessment Using Prior Knowledge and IT solutions

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Microplastics profile along the Rhine River

Microplastics result from fragmentation of plastic debris or are released to the environment as pre-production pellets or components of consumer and industrial products. In the oceans, they contribute to the ‘great garbage patches’. They are ingested by many organisms, from protozoa to baleen whales, and pose a threat to the aquatic fauna. Although as much as 80% of marine debris originates from land, little attention was given to the role of rivers as debris pathways to the sea. Worldwide, not a single great river has yet been studied for the surface microplastics load over its length. We report the abundance and composition of microplastics at the surface of the Rhine, one of the largest European rivers. Measurements were made at 11 locations over a stretch of 820 km. Microplastics were found in all samples, with 892,777 particles km −2 on average. In the Rhine-Ruhr metropolitan area, a peak concentration of 3.9 million particles km −2 was measured. Microplastics concentrations were diverse along and across the river, reflecting various sources and sinks such as waste water treatment plants, tributaries and weirs. Measures should be implemented to avoid and reduce the pollution with anthropogenic litter in aquatic ecosystems

On the “Fate of Leachables” in biopharmaceutical up-stream and down- stream processes

Single use systems (SUS), based on polymeric materials, are widely used in the biopharmaceutical manufacturing. Compounds potentially migrating from the polymeric materials into the production process at various stages as leachables can either negatively influence the production process performance (e.g. inhibit cell growth) or can contribute to process related drug impurities, which may potentially have an effect on product quality and/or patient safety. Today, the concept of investigating leachables is mainly focused on the measurement of extractables under worst case- or simulation-conditions plus their assessment including an interpolation towards potential leachables. In particular, in the frame of this assessment of leachables, substance specific properties and the effective process conditions are not taken into account. To better understand the range, the load and the concentration of leachables within a dynamic process and finally in a drug product a paradigm change towards the “Fate of Leachables” concept is required. This “Fate of Leachables” concept is based on underlying physical-chemical principles rather than a sequence of worst-case experiments and conservatively adding up concentrations. Relevant levels of leachables can be quantitatively modeled and predicted based on the knowledge of potential extractables in the materials, their phys.-chem. properties and the effective process conditions (medium composition, volume, flow, surfaces, temperature), i.e. Leachables may reach equilibrium concentration in certain static process steps, whereas in dynamic process steps diffusion controlled leachables levels have to be anticipated and appropriately modeled. Adsorption and desorption processes significantly influence the levels of leachables in any biopharmaceutical manufacturing, e.g. in down-stream filtration, separation and purification steps. Ultrafiltration and diafiltration steps can influence the leachables load by diluting or removing them completely. For all these process steps illustrative examples from SSB research studies and based on existing published data will be discussed together with a quantitative description of the underlying physical-chemical processes to demonstrate the capability of the “Fate of Leachables” concept. To motivate the use of the “Fate of Leachables” concept, for a generic process stream, the level of leachables estimated via a worst case evaluation will be compared with the results based on the “Fate of Leachables” concept

The proper use of extractables data - aspects beyond extractables-measurment

Appropriate extraction techniques for SUS/SUT and methods for analysis of extractables have been intensively discussed over the last years. Today, several proposals for common methods are available and used to conduct extractables studies in the bio-pharmaceutical industry. Therefore it is expected that the number of available extractables data will significantly rise over the next years and it is worth to (re-)consider their proper use for materials and device qualification and risk assessment. While this exercise is straightforward for container closure systems (CCS), for SUS/SUT the situation is more complex. In CCS applications, a single drug product, in contact with a well-defined container system for long term storage is studied. In contrast to a CCS the number of materials, their dimensions and combinations are highly flexible in SUS/SUT applications. Additionally, SUS/SUT are used under dynamic process-conditions of variable solvents, dwell-times, temperatures, flow-rates etc. In our contribution we will discuss two major questions that persist and cannot be solved by means of analytics alone: How can we obtain extractables data for SUS/SUT devices of different sizes and for complex device combinations (assemblies)? This aspect is critical for the device industry, because a high number of different devices and combinations are requested by our customers. Further, assembled products from Configured to Order (CTO) or Engineered to Order (ETO) processes utilizing various compounds, even such from various suppliers can increase their amount and combinations nearly infinitely. It is easily conceivable that it is technically impossible to conduct individual extractables studies for each possible combination. Another aspect which has to be taken into account in the future, is the proper use of extractables data for extrapolations toward potential leachables required for quality risk-assessment. In this context a publication from Jenke & Rabinow (2017) has to be considered, where they showed that the validity of the “intuitive” approach to scale extractables data just by surface area is questionable. We will show how we can develop methods to overcome these - so far - unsolved problems. The proposed methods will be based on basic physical chemistry principles rather than “intuitive” worst-case assumptions. We will show illustrative examples on how extractables data, obtained by different protocols can be used heuristically in scaling and combination exercises. The limits of the conventional scaling by surface areas are discussed in terms of the influence of equilibrium versus diffusion controlled conditions in long versus short term contact. Furthermore, an example will be shown for a calculation of potential leachables solely built on physical chemistry considerations and avoiding any generic worst-case assumption. Jenke & Rabinow: Proper Accounting for Surface Area to Solution Volume Ratios in Exaggerated Extractions PDA J Pharm Sci and Tech (2017), 71 225-23

Structure elucidation and toxicological evaluation of cyclic Polyethersulfone oligomers present in extracts of membrane filters

Polyethersulfone (PES) is a widely used polymer in consumer and technical products. An important application is PES membranes used in the biopharmaceutical industry for sterilizing-grade filtration and for filtration of food and beverages. For both uses, detailed information about migrating compounds that can be extracted from the polymeric material into a liquid must be gathered. In the pharmaceutical industry, comprehensive extractables studies are required for contact materials, and the data is used in the qualification of the process equipment. PES is generated via polycondensation, which forms cyclic oligomers as a by-product of the reaction. However, no structural information is available for these cyclic oligomers so far. In this publication, we present the analytical determination of PES cyclic oligomers. Their presence in extracts of PES membrane filters is confirmed. The structure of the PES cyclic trimer is elucidated by X-ray and NMR investigation, obtained as crystals from the sublimation of the PES raw material. A strategy is shown to assess the toxicity of such cyclic oligomers and to derive a permitted daily exposure (PDE). The data will reduce the levels of unknowns in extractables and leachables screenings and supports the risk assessment of PES sterile filters

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass