Monitoring and control of reproducibility in quasi-continuous integrated production processes of Active Pharmaceutical Ingredients

The development of integrated production processes include the combination and transformation of current batch oriented unit operations into linked sequential/parallel production strategies. The presented process starts with a two-stage upstream consisting of cell cultivation and subsequent protein production, which in turn results in a five step downstream process, consisting of cell clarification via a separator, retention of cellular debris using microfiltration, concentration of the secreted product by ultrafiltration with subsequent buffer exchange through diafiltration, followed by a final purification using column chromatography. The three main operations cell breeding, protein production and the complete downstream line are running in series, but also in parallel with a one-day-offset each. Such strategies were developed at HAW Hamburg [Luttmann et al., 2015]. To achieve reproducible process conditions, the process development was done in accordance with the known industry guidelines from FDA and ICH regarding QbD and PAT. In this context the identification of optimal Design Spaces and Control Spaces was in the foreground. The in-line measurement of important media components and cell physiological parameters as well as the on-line evaluation of process reproducibility, are remaining unsolved problems in industrial biotechnology - irrespective of whether a process is operated batch wise or continuously. A way out of this dilemma can be found by on-line MVDA data processing. This paper describes a comprehensive application of MVDA in process monitoring and control using the example of an integrated production of potential Malaria vaccines with Pichia pastoris. Cell mass, glycerol and secreted target proteins as well as cell internal AOX content are measured with NIR-, Raman- and 2D-Fluorescence-spectrometry. Here, intensive off-line analysis of the concerned process variables form the foundation for the training of spectral observations as well as for the evaluation of cell specific reaction rates from routinely measured on-line variables with MVDA-investigations. The main approach of MVDA was an on-line monitoring of reproducibility of involved unit operations. This was achieved by off-line modeling of Golden Batch tunnels and on-line evaluation of the process trajectories using SIPAT® and SIMCA® software tools. On top of this, on-line process prediction and on-line Golden Batch control were implemented. The prediction is based on IBR-Imputation by Regression (SIMCA® Q) and the control of processes evolving outside their Golden Batch limitations is based on BOBYQA-Bound Optimization by Quadratic Approximation (SIMCA® online). Such methods for process monitoring and control of quasi continuous pharmaceutical production pave the way for Real Time Release of APIs. All approaches have been approved and tested in real industrial-like production processes which have been performed over several weeks

A comprehensive study in PAT-applications for a QbD-compliant development of continuous biopharmaceutical production

The development of continuously operated integrated pharmaceutical production processes needs a tremendous expenditure. Beside the installation of a full-scale production, scale-down concepts are essential to meet the QbD-specifications of the FDA. In this presentation the surrounding PAT-field of such a plant for production of potential Malaria vaccines (shown in ICB I and ICB II) is discussed in order to create model based QbD-compliant strategies. This includes fully automated processing, global process monitoring with additional classical and spectroscopic measurement procedures including enhanced data processing and MVDA. A full-scope model of the plant allows an in-silico development of process control. The two-stage upstream line is scaled-down in a sixfold sequential/parallel operated bioreactor plant including flow analysis at-line measurements for substrates- and target protein-detection. This plant allows a fully automated simultaneous DoE-process optimization and identification of CPP-Critical Process Parameters. The DoE-model and Monte Carlo simulations create also the Design Space and the Control Space of QbD-production. Similar methods are used in the down-stream area for optimization of cyclic protein purification. These methods are applied with an AEKTAT avant which is developed especially for DoE. The main focus of the work lies on the development of a global MVDA-based monitoring system for biotechnological variables like cell mass, glycerol-, ammonium-, total secreted-, and target protein-concentration but also on the evaluation of process quality (reproducibility) of the running processes. Applications of NIR-, Raman-, and 2D-Fluorescence-Spectroscopy and the appropriate PLSR-modeling leads to a partly success. This was improved by using the nonlinear SVR-Support Vector-machine Regression. However, a MVDA-application with only classical process variables from agitation, aeration, temperature, feeding, pH, pO2, and process balances creates astonishing results in a satisfying bio-monitoring up to the on-line detection of the secreted target protein concentration. The quality of running processes was evaluated with a GB-Golden Batch approach. The GB-tunnel was created with data from QbD-conformed process courses and then used for an on-line observation and prediction of actual first principal components. A MPC-Model Predictive Control was also implemented in order to avoid a leaving of the GB-tunnel by correction of process set-points. These methods open the way to an on-line release of pharmaceutical products

Imaging foreign bodies in head and neck trauma: a pictorial review

Open injuries bear the risk of foreign body contamination. Commonly encountered materials include gravel debris, glass fragments, wooden splinters or metal particles. While foreign body incorporation is obvious in some injury patterns, other injuries may not display hints of being contaminated with foreign body materials. Foreign objects that have not been detected and removed bear the risk of leading to severe wound infections and chronic wound healing disorders. Besides these severe health issues, medicolegal consequences should be considered. While an accurate clinical examination is the first step for the detection of foreign body materials, choosing the appropriate radiological imaging is decisive for the detection or non-detection of the foreign material. Especially in cases of impaired wound healing over time, the existence of an undetected foreign object needs to be considered. Here, we would like to give a practical radiological guide for the assessment of foreign objects in head and neck injuries by a special selection of patients with different injury patterns and various foreign body materials with regard to the present literature

Revisiting the personal protective equipment components of transmission-based precautions for the prevention of COVID-19 and other respiratory virus infections in healthcare

The COVID-19 pandemic highlighted some potential limitations of transmission-based precautions. The distinction between transmission through large droplets vs aerosols, which have been fundamental concepts guiding infection control measures, has been questioned, leading to considerable variation in expert recommendations on transmission-based precautions for COVID-19. Furthermore, the application of elements of contact precautions, such as the use of gloves and gowns, is based on low-quality and inconclusive evidence and may have unintended consequences, such as increased incidence of healthcare-associated infections and spread of multidrug-resistant organisms. These observations indicate a need for high-quality studies to address the knowledge gaps and a need to revisit the theoretical background regarding various modes of transmission and the definitions of terms related to transmission. Further, we should examine the implications these definitions have on the following components of transmission-based precautions: (i) respiratory protection, (ii) use of gloves and gowns for the prevention of respiratory virus infections, (iii) aerosol-generating procedures and (iv) universal masking in healthcare settings as a control measure especially during seasonal epidemics. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice.</p

Revisiting the personal protective equipment components of transmission-based precautions for the prevention of COVID-19 and other respiratory virus infections in healthcare

The COVID-19 pandemic highlighted some potential limitations of transmission-based precautions. The distinction between transmission through large droplets vs aerosols, which have been fundamental concepts guiding infection control measures, has been questioned, leading to considerable variation in expert recommendations on transmission-based precautions for COVID-19. Furthermore, the application of elements of contact precautions, such as the use of gloves and gowns, is based on low-quality and inconclusive evidence and may have unintended consequences, such as increased incidence of healthcare-associated infections and spread of multidrug-resistant organisms. These observations indicate a need for high-quality studies to address the knowledge gaps and a need to revisit the theoretical background regarding various modes of transmission and the definitions of terms related to transmission. Further, we should examine the implications these definitions have on the following components of transmission-based precautions: (i) respiratory protection, (ii) use of gloves and gowns for the prevention of respiratory virus infections, (iii) aerosol-generating procedures and (iv) universal masking in healthcare settings as a control measure especially during seasonal epidemics. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice

Revisiting the personal protective equipment components of transmission-based precautions for the prevention of COVID-19 and other respiratory virus infections in healthcare

The COVID-19 pandemic highlighted some potential limitations of transmission-based precautions. The distinction between transmission through large droplets vs aerosols, which have been fundamental concepts guiding infection control measures, has been questioned, leading to considerable variation in expert recommendations on transmission-based precautions for COVID-19. Furthermore, the application of elements of contact precautions, such as the use of gloves and gowns, is based on low-quality and inconclusive evidence and may have unintended consequences, such as increased incidence of healthcare-associated infections and spread of multidrug-resistant organisms. These observations indicate a need for high-quality studies to address the knowledge gaps and a need to revisit the theoretical background regarding various modes of transmission and the definitions of terms related to transmission. Further, we should examine the implications these definitions have on the following components of transmission-based precautions: (i) respiratory protection, (ii) use of gloves and gowns for the prevention of respiratory virus infections, (iii) aerosol-generating procedures and (iv) universal masking in healthcare settings as a control measure especially during seasonal epidemics. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice.</p

Metatranscriptome Profiling Indicates Size-Dependent Differentiation in Plastic and Conserved Community Traits and Functional Diversification in Dinoflagellate Communities

Communities of microscopic dinoflagellates are omnipresent in aquatic ecosystems. Consequently, their traits drive community processes with profound effects on global biogeochemistry. Species traits are, however, not necessarily static but respond to environmental changes in order to maintain fitness and may differ with cell size that scales physiological rates. Comprehending such trait characteristics is necessary for a mechanistic understanding of plankton community dynamics and resulting biogeochemical impacts. Here, we used information theory to analyze metatranscriptomes of micro- and nano-dinoflagellate communities in three ecosystems. Measures of gene expression variations were set as a proxy to determine conserved and plastic community traits and the environmental influence on trait changes. Using metabarcoding, we further investigated if communities with a more similar taxon composition also express more similar traits. Our results indicate that plastic community traits mainly arise from membrane vesicle associated processes in all the environments we investigated. A specific environmental influence on trait plasticity was observed to arise from nitrogen availability in both size classes. Species interactions also appeared to be responsible for trait plasticity in the smaller-sized dinoflagellates. Additionally, the smaller-sized dinoflagellate communities are characterized by the expression of a large pool of habitat specific genes despite being taxonomically more similar across the habitats, in contrast to the microplanktonic assemblages that adapted to their environments by changing species composition. Our data highlight the functional diversification on the gene level as a signature of smaller sized dinoflagellates, nitrogen availability and species interactions as drivers of trait plasticity, and traits most likely linked to fitness and community performance

Views on the Past, Present, and Future of Business and Information Systems Engineering

‘‘The times they are a-changin,’’ a famous song title by Bob Dylan, also applies to our profession and our subject of study. Information technology has always been a driver for innovation. The recent years, however, have seen IT-based innovations that truly impact everybody’s lives. Everything that can be digitized will be digitized, and this trend is continuing at an amazing speed. For a discipline that looks at the design and utilization of information systems these are exciting times. Yet, it is also a time full of challenges. While our discipline has much to contribute, it competes with other disciplines for topics and ideas. Also, the scope of topics studied has become broader and broader, and so have our methods. While initial work in Business and Information Systems Engineering (BISE) was often rooted in artificial intelligence, database systems, or operations research, the community has adopted new approaches to address new types of problems. Nowadays, we also have a strong group of academics working primarily with empirical methods or methods from microeconomics, to name just a few. This development towards a more multiparadigmatic discipline also had its challenges and there were controversial discussions along the way

Customer Interaction and Innovation in Hybrid Offerings:Investigating Moderation and Mediation Effects for Goods and Services Innovation

Hybrid offerings are bundles of goods and services offerings provided by the same firm. Bundling value offerings affects how firms innovate, interact with customers, and customize their goods and services. However, it remains unclear how customer interaction might drive the innovation performance of various bundled components. Therefore, this study investigates the effects of customer interactions and service customization on both goods and services innovations in a hybrid offering context, using a unique data set of 146 information technology and manufacturing firms. Customer interaction appears beneficial to both goods and services innovation in a hybrid offerings context, but service customization has different direct effects on goods versus services innovation. As a potential mediator, customer knowledge mobilization resources exert different effects on the goods and services elements of hybrid offerings. Furthermore, for high-interaction customers, medium levels of technical modularity lead to most favorable innovation outcomes for services innovation. The results thus suggest that providers of hybrid offerings should foster customer interactions, to drive the innovation performance of the good and service components, while still making sure to implement service customization strategies. These findings have notable implications for service innovation research