Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. LAY ABSTRACT: Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

Advanced production scheduling for batch plants in process industries

An Advanced Planning System (APS) offers support at all planning levels along the supply chain while observing limited resources. We consider an APS for process industries (e.g. chemical and pharmaceutical industries) consisting of the modules network design (for long–term decisions), supply network planning (for medium–term decisions), and detailed production scheduling (for short–term decisions). For each module, we outline the decision problem, discuss the specifi cs of process industries, and review state–of–the–art solution approaches. For the module detailed production scheduling, a new solution approach is proposed in the case of batch production, which can solve much larger practical problems than the methods known thus far. The new approach decomposes detailed production scheduling for batch production into batching and batch scheduling. The batching problem converts the primary requirements for products into individual batches, where the work load is to be minimized. We formulate the batching problem as a nonlinear mixed–integer program and transform it into a linear mixed–binary program of moderate size, which can be solved by standard software. The batch scheduling problem allocates the batches to scarce resources such as processing units, workers, and intermediate storage facilities, where some regular objective function like the makespan is to be minimized. The batch scheduling problem is modelled as a resource–constrained project scheduling problem, which can be solved by an efficient truncated branch–and–bound algorithm developed recently. The performance of the new solution procedures for batching and batch scheduling is demonstrated by solving several instances of a case study from process industries.

Invasion and persistence of Mycoplasma bovis in embryonic calf turbinate cells.

Mycoplasma bovis is a wall-less bacterium causing bovine mycoplasmosis, a disease showing a broad range of clinical manifestations in cattle. It leads to enormous economic losses to the beef and dairy industries. Antibiotic treatments are not efficacious and currently no efficient vaccine is available. Moreover, mechanisms of pathogenicity of this bacterium are not clear, as few virulence attributes are known. Microscopic observations of necropsy material suggest the possibility of an intracellular stage of M. bovis. We used a combination of a gentamicin protection assay, a variety of chemical treatments to block mycoplasmas entry in eukaryotic cells, and fluorescence and transmission electron microscopy to investigate the intracellular life of M. bovis in calf turbinate cells. Our findings indicate that M. bovis invades and persists in primary embryonic calf turbinate cells. Moreover, M. bovis can multiply within these cells. The intracellular phase of M. bovis may represent a protective niche for this pathogen and contribute to its escape from the host's immune defense as well as avoidance of antimicrobial agents.

Geographical Dialectology

This chapter examines how linguists have investigated the very obvious fact that different places house different dialects. We will not look at the results of such work nor how they have been used to answer linguistic and sociolinguistic questions (see Britain 2009, in press). Here we simply examine the steps dialectologists take and have taken to conduct multi-locality research on language variation. In order to do so, five studies from different time periods are presented and critiqued, examining a number of key methodological elements in each: 1. The aim of geographical dialectology is to examine variation across space, in different places. How do dialectologists then decide which places in that space to analyse? Why choose one village and not its neighbour? Why avoid that city? This question goes to the very heart of the geographical motivation of the research. 2. What sorts of speakers will be sampled from these locations? 3. What type of data is to be collected from these speakers? 4. In what circumstances is that data to be recorded? Who will collect it, in what setting and how will the voices of the speakers be captured for later analysis? As we will see, dialectological methodologies always involve compromises, no approach is ever flawless. Ultimately, a good number of difficult practical decisions have to be taken – how long can this research take, and what are the financial restrictions on the project? As we will see geographical dialectology is probably the most expensive and the most time consuming of all forms of language variation research.

Wnt activation of immortalized brain endothelial cells as a tool for generating a standardized model of the blood brain barrier in vitro

Reproducing the characteristics and the functional responses of the blood-brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.

Spider Ecophysiology

With over 43,000 species, spiders are the largest predacious arthropod group. They have developed key characteristics such as multi-purpose silk types, venoms consisting of hundreds of components, locomotion driven by muscles and hydraulic pressure, a highly evolved key-lock mechanism between the complex genital structures, and many more unique features. After 300 million years of evolutionary refinement, spiders are present in all land habitats and represent one of the most successful groups of terrestrial organisms. Ecophysiology combines functional and evolutionary aspects of morphology, physiology, biochemistry and molecular biology with ecology. Cutting-edge science in spiders focuses on the circulatory and respiratory system, locomotion and dispersal abilities, the immune system, endosymbionts and pathogens, chemical communication, gland secretions, venom components, silk structure, structure and perception of colours as well as nutritional requirements. Spiders are valuable indicator species in agroecosystems and for conservation biology. Modern transfer and application technologies research spiders and their products with respect to their value for biomimetics, material sciences, and the agrochemical and pharmaceutical industries.

Cultural diasporas

This study examines the contribution that artists from a non-EU background make towards cultural life and cultural industries in Europe and beyond. In particular, it looks at how such artists form "diasporas" which in turn create networks of cultural exchange inside the EU and with third countries. It provides examples of these activities in three broad diaspora groups of African, Balkan and Turkish background.