Scalable processes to manufacture nanoparticulate dosage forms for oral vaccination

Polymeric nanoparticles are promising drug delivery systems and antigen-carriers for vaccination. They may enhance the severity or the type of the antigen-specific immune response and may facilitate needle-free vaccination via the oral or respiratory route. However, the translation of nanoparticulate systems from bench to bedside remains a major challenge. Among the reasons are the limited knowledge and control of critical process parameters during early research, and the poor scalability to and reproducibility in clinical research and the commercial stage. This thesis presents a novel, easily scalable and potentially continuous method for manufacturing antigen-loaded polymeric nanoparticles. The method allows for effective tuning of the nanoparticle size with economically interesting yield, relevant antigen-loading capacity and retained antigen integrity across a batch size range of four orders of magnitude, but with limited loading efficiency. Nanoparticle properties were comparable between scales, but the process parameters were not found to be independent of or proportional to scale. Two continuous methods were developed to simultaneously prepare and dry such nanoparticles for improved process efficiency, and to manufacture enteric-matrix multiparticulates for oral dosing. Further optimization is required to achieve full scalability, improve the cost-effectiveness of the processes, and to demonstrate the functionality for an oral vaccine.Polymerbasierte Nanopartikel sind vielversprechende Trägersysteme für therapeutische Anwendungen und Impfungen. Solche Systeme können Umfang und Art der antigen-spezifischen Immunreaktion maßgeblich beeinflussen sowie die orale oder inhalative Gabe ermöglichen. Allerdings stellt die Translation von Forschungsergebnissen in die Klinik eine große Herausforderung dar, die von der eingeschränkten Kenntnis und Kontrolle kritischer Prozessparameter sowie der ungenügenden Skalierbarkeit zu klinischer Entwicklung und kommerzieller Herstellung erschwert wird. Hier wurde eine neue, skalierbare und potentiell kontinuierliche Herstellungsmethode für antigen-beladene polymerbasierte Nanopartikel entwickelt. Sie ermöglicht das Anpassen der Partikelgröße bei wirtschaftlich interessanter Ausbeute, relevanter Antigenbeladung und erhaltener Antigenintegrität über vier Größenordnungen von Losgrößen, allerdings bei limitierter Antigenausbeute. Ähnliche Partikeleigenschaften wurden über verschiedene Losgrößen erzielt, jedoch waren die Prozessparameter nicht unabhängig von oder proportional zum Prozessvolumen. Eine kontinuierliche Methode zur effizienten weil simultanen Generierung und Trocknung von Nanopartikeln wurde entwickelt, sowie eine weitere zur Herstellung magensaftresistenter multipartikulärer Pulver zur oralen Anwendung. Weitere Prozessoptimierung ist notwendig für vollständige Skalierbarkeit und verbesserte Wirtschaftlichkeit, sowie der Beweis der Anwendbarkeit für die orale Impfung

Representing and Utilizing DDI in Relational Databases

This document is primarily intended for implementers of DDI-based metadata stores who are considering different technical options for housing and managing their metadata. The Data Documentation Initiative (DDI) metadata specification is expressed in the form of XML schema. With version 3, the DDI specification has become quite complex, including 21 namespaces and 846 elements. Organizations employing DDI, or considering doing so, may want to 1. store and manage the metadata elements in relational databases, for reasons of integration with existing systems, familiarity with the concepts of relational databases (such as Structured Query Language), systems performance, and/or other reasons; 2. select only the subset of the available DDI metadata elements that is of utility to their work, and have the flexibility of capturing metadata they need that would not fit into the DDI model. This paper discusses advantages and disadvantages of the relational database approach to managing DDI. It also describes methods for modeling DDI in relational databases and for formally defining subsets of DDI to employ in this environment.

International Access to Administrative Data for Germany and Europe

In the last years access to research data has made a lot of progress in EU countries. Nevertheless transnational access to confidential microdata - although there are some developments like Data without Boundaries - is still complicated and needs improvement. The first part of the paper describes the (international) access to highly sensitive German administrative labour market data and how this international access is expanded within the research data centre in research data centre (RDC in RDC) approach. In the second part a broader view of international access to official microdata in the EU will be given. Starting with a brief overview of the EU-funded project Data without Boundaries (DwB) a possible roadmap for international access in Europe and beyond is presented

Towards a Continuous Manufacturing Process of Protein-Loaded Polymeric Nanoparticle Powders

To develop a scalable and efficient process suitable for the continuous manufacturing of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing ovalbumin as the model protein. PLGA nanoparticles were prepared using a double emulsification spray-drying method. Emulsions were prepared using a focused ultrasound transducer equipped with a flow cell. Either poly(vinyl alcohol) (PVA) or poloxamer 407 (P-407) was used as a stabilizer. Aliquots of the emulsions were blended with different matrix excipients and spray dried, and the yield and size of the resuspended nanoparticles was determined and compared against solvent displacement. Nanoparticle sizes of spray-dried PLGA/PVA emulsions were independent of the matrix excipient and comparable with sizes from the solvent displacement method. The yield of the resuspended nanoparticles was highest for emulsions containing trehalose and leucine (79%). Spray drying of PLGA/P-407 emulsions led to agglomerated nanoparticles independent of the matrix excipient. PLGA/P-407 nanoparticles pre-formed by solvent displacement could be spray dried with limited agglomeration when PVA was added as an additional stabilizer. A comparably high and economically interesting nanoparticle yield could be achieved with a process suitable for continuous manufacturing. Further studies are needed to understand the robustness of a continuous process at commercial scale

Representing and Utilizing DDI in Relational Databases

This document is primarily intended for implementers of DDI-based metadata stores who are considering different technical options for housing and managing their metadata. The Data Documentation Initiative (DDI) metadata specification is expressed in the form of XML schema. With version 3, the DDI specification has become quite complex, including 21 namespaces and 846 elements7. Organizations employing DDI, or considering doing so, may want to 1. store and manage the metadata elements in relational databases, for reasons of integration with existing systems, familiarity with the concepts of relational databases (such as Structured Query Language), systems performance, and/or other reasons; 2. select only the subset of the available DDI metadata elements that is of utility to their work, and have the flexibility of capturing metadata they need that would not fit into the DDI model. This paper discusses advantages and disadvantages of the relational database approach to managing DDI. It also describes methods for modeling DDI in relational databases and for formally defining subsets of DDI to employ in this environmen

Focusing Knowledge-based Graph Argument Mining via Topic Modeling

Decision-making usually takes five steps: identifying the problem, collecting data, extracting evidence, identifying pro and con arguments, and making decisions. Focusing on extracting evidence, this paper presents a hybrid model that combines latent Dirichlet allocation and word embeddings to obtain external knowledge from structured and unstructured data. We study the task of sentence-level argument mining, as arguments mostly require some degree of world knowledge to be identified and understood. Given a topic and a sentence, the goal is to classify whether a sentence represents an argument in regard to the topic. We use a topic model to extract topic- and sentence-specific evidence from the structured knowledge base Wikidata, building a graph based on the cosine similarity between the entity word vectors of Wikidata and the vector of the given sentence. Also, we build a second graph based on topic-specific articles found via Google to tackle the general incompleteness of structured knowledge bases. Combining these graphs, we obtain a graph-based model which, as our evaluation shows, successfully capitalizes on both structured and unstructured data

Identifying Quality Factors for Self-Tracking Solutions: A Systematic Literature Review

Self-tracking solutions have become globally widespread, as they promise numerous advantages (e.g. improving health) to their users. Despite their benefits, such solutions are often abandoned due to quality issues. This phenomenon can also be observed for digitized products in general. As self-tracking solutions are hybrid products, combining digital and physical components, traditional domain-independent and abstract quality models like the prominent ISO 25000 standard seem to not cover quality in an appropriate way. We address these issues by answering the research question of which factors affect quality perceptions of different stakeholder groups when interacting in a wearable ecosystem. We use a systematic literature review based on a research protocol to identify and analyze 98 quality-influencing factors from 19 studies that we cluster in a map. The identified factors are compared to the ISO 25000 standard, showing that certain factors like hedonic motivation are unconsidered thoroughly in the existing standard