Advanced analytical and microbial methods for biopharmaceutical and pharmaceutical products and processes

EngD ThesisIn recent years, pharmaceutical research has begun to shift from the development of small molecule chemical entities, to complex high value, low volume biologics. The cost of batch losses or product recall due to the presence of microbial, chemical or physical contaminants can have serious implications for a business. It is therefore important that as the complexity of pharmaceutical products increases, the techniques utilised in the analysis and characterisation of these products and their excipients also moves forward, thereby ensuring product quality and patient safety. This research explores three areas of analysis and characterisation relating to pharmaceutical products: microbial testing; oxidative stability testing and container integrity testing. The detection and identification of microbiological contamination using traditional microbial methods (TMMs) have a number of limitations such as long testing times and reliance on subjective assessment leading to operator error. More recently developed rapid microbial methods (RMMs) have been designed to overcome these limitations and their uptake would enable microbial testing to align with the process analytical technology (PAT) approach to process monitoring and control. A review of available techniques and those implemented by a large pharmaceutical company, GlaxoSmithKline has highlighted that a number of RMMs are being utilised, but their widespread adoption in the pharmaceutical industry faces several barriers including: economic and financial; institutional; legislative and regulatory; and technical. Another important area of pharmaceutical product analysis is that of oxidative stability testing. A comparison was undertaken of two machines for measuring oxidative stability (the Rancimat (Metrohm) and the ACL Instrument (ACL Instruments, Switzerland) to investigate their performance and assess their applicability for the testing of pharmaceutical excipients. The testing of corn oil, selected as a model substance, revealed a strong correlation between the results from the two machines. An aspect of oxidative stability testing is concerned with residual levels of peroxides therefore the ACL Instrument was compared to iodometric titration, a highly empirical traditional approach, for the quantification of peroxides in corn and Menhaden oil. Good correlation was found between peroxide levels measured by the two methods, but the results from the ACL Instrument showed a dependence on oil type, meaning that a standard would be required each oil type. Additional testing was carried out on Page | iii polysorbates, pharmaceutical excipients that are known to pose stability issues in final formulations, due to containing residual amounts of peroxides. Using the ACL Instrument it was possible to detect differences in oxidative stability between grades and types of polysorbate. It was not possible to discriminate between batches of the same grade. The final testing that is carried out on pharmaceutical products stored in glass vials, is container integrity testing. High voltage leak detection (HVLD) is one method utilised and concerns exist as to whether the high voltages present can cause ozone formation in the container headspace, leading to degradation of the drug product. A method involving potassium indigo trisulphonate was developed for the detection of ozone and a test protocol implemented. This approach showed that ozone was produced in containers with a low fill volume, but at a very low concentration and hence it should not affect the stability of the final product. The research carried out in this thesis has drawn together evidence on RMMs; furthered understanding of the applicability of oxidative stability testing for pharmaceutical excipients; and has highlighted the importance of investigating the effect of container integrity testing methods on the final pharmaceutical product

Valuing indigenous biodiversity in the freshwater environment

Biosecurity incursion response decisions require timely, high quality information involving science and economics. The value of the impact on indigenous biodiversity is a key aspect of the economics typically involving cost-benefit analysis. The hypothetical incursion of Biosecurity New Zealand’s top priority weed hydrilla (Hydrilla verticillata) in a typical New Zealand lake (Lake Rotoroa otherwise known as Hamilton Lake) elicits dollar values of impacts on indigenous biodiversity in a freshwater environment. Using the stated preference tool, Choice Modelling, the experimental design was maximised for efficiency of Willingness to Pay (WTP) estimation. The survey method of community meetings of four population samples at varying distances to the incursion site is a cross between a mail survey and an individual interview survey. Results show an efficient design with minimal sample size and biodiversity attributes that have values statistically different from zero but not statistically different between locations.Non-market valuation, biosecurity, biodiversity, Community/Rural/Urban Development, Crop Production/Industries, Environmental Economics and Policy, Land Economics/Use,

The prenatal narratives and lived experience of individuals with Down’s syndrome

This portfolio has three parts: a systematic literature review, an empirical paper and appendices. This thesis aims to explore the opinions and experiences of prenatal testing from the perspective of parents of children with Down’s Syndrome and the lived experiences of personal growth in individuals with Down’s Syndrome.Part one: Systematic Literature ReviewThis review aims to draw together the experiences and opinions of parents of individual living with Down’s Syndrome on prenatal testing. Twelve studies were identified for inclusion in this review. Five superordinate themes were identified through thematic synthesis; decision-making and reason for not testing, professionals, post-test emotions, societal opinions, opinions on the logistics of testing. Conclusions and implications are discussed.Part two: Empirical PaperPart two contains a qualitative empirical study, exploring the opportunities and experiences of personal growth of individuals with Down’s Syndrome.Six individuals with Down’s Syndrome were interviewed using semi-structured interviews. These were analysed using interpretive phenomenological analysis. Four superordinate themes were identified. This research highlighted the opportunities and ability for individuals living with Down’s Syndrome to experience personal growth, a marker of quality of life. The need to further acceptance and provision of opportunities is also discussed

Linking emerging contaminants to production and consumption practices

Emerging contaminants (ECs) associated with consumer products such as pharmaceuticals, personal care products, and plastics, are an issue of growing concern for water quality and human and environmental health. Growth in use of products associated with ECs is an outcome of growing populations, increased incomes and the emergence of new consumer products. Two examples are used illustrate the value of social science research in understanding patterns of consumption and sources of ECs, in order to identify potential interventions to reduce ECs in the environment—flushing inappropriate materials down the toilet, and antibiotic use in global livestock production. Antimicrobial resistance is a major policy driver to control the use of antibiotics in human healthcare and livestock production. Global antibiotic consumption increased 65% 2000–2015. Disposal of products, including unused pharmaceuticals and plastics, is influenced by regulation, consumer behavior, and infrastructure. This range of factors and trends demonstrates the complexity in understanding why ECs enter the aquatic environment and the extent that the issue can be tackled at the source rather than mitigated once in the environment

The Angel of Art Sees the Future Even as She Flies Backwards: Enabling Deep Relational Encounter Through Participatory Practice-Based Research.

This research addresses the current lack of opportunity within interdisciplinary arts practices for deep one-to-one relational encounters between creative practitioners operating in applied arts, performance, and workshop contexts with participant-subjects. This artistic problem is situated within the wider culture of pervasive social media, which continues to shape our interactions into forms that are characteristically faster, shorter, and more fragmented than ever before. Such dispersal of our attention is also accelerating our inability to deeply focus or relate for any real length of time. These modes of engaging within our technologically permeated, cosmopolitan and global society is escalating relational problems. Coupled with a constant bombardment of unrealistic visual images, mental health difficulties are also consequently rising, cultivating further issues such as identity ‘splitting’, (Lopez-Fernandez, 2019). In the context of the arts, this thesis proposes that such relational lack cannot be solved by one singular art form, one media modality, one existing engagement approach, or within a short participatory timeframe. Key to the originality of my thesis is the deliberate embodiment of a maternal experience. Feminist Lise Haller-Ross’ proposes that there is a ‘mother shaped hole in the art world’ and that, ‘as with the essence of the doughnut – we don’t need another hole for the doughnut, we need a whole new recipe’ (conference address, 2015). Indeed, her assertion encapsulates a need for different types of artistic and relational ingredients to be found. I propose these can be discovered within particular forms of maternal love; nurture; caring, and through conceptual relational states of courtship; intercourse; gestation, and birth. Furthermore, my maternal emphasis builds on: feminist, artist, and psychotherapist Bracha Ettinger’s (2006; 2015) notions of maternal, cohabitation and carrying; architect and phenomenologist Juhani Pallasmaa’s (2012) views on sensing and feeling; child psychoanalyst Donald Winnicott’s (1971) thoughts on transitional phenomena and perceptions of holding. Such psychotherapeutic and phenomenological theories are imbricated in-action within my multimodal arts processes. Additionally, by deliberately not privileging the ocular, I engage all my project participants senses and distil their multimodal data through an extended form of somatic and artistic Interpretive Phenomenological Analysis (IPA), (Smith, Flowers, and Larkin, 2009). IPA usefully focuses on the importance of the thematic and idiographic in terms of new knowledge generation, with an analytical focus on lived experience. Indeed, whilst the specifics of the participants in my minor and major projects are unique, my research activates and makes valid, findings that are collectively beneficial to the disciplines of applied and interdisciplinary arts; the field of practice-based research, and beyond. My original contribution to new knowledge as argued by this thesis, comprises both this text exposition and my practice. This sees the final generation of a new multimodal arts Participatory Practice-Based Framework (PartPb). Through this framework, the researcher-practitioner is seen to adopt a maternal role to gently guide project participants through four phases of co-created multimodal artwork generation. The four participatory ‘Phases’ are: Phase 1: Courtship – Digital Dialogues; Phase 2: Intercourse – Performative Encounters; Phase 3: Gestation – Screen Narratives; Phase 4: Birth – Relational Artworks. The framework also contains six researcher-only ‘Stages’: Stage 1: Participant Selection; Stage 2: Checking Distilled Themes; Stage 3: Location and Object Planning; Stage 4: Noticing, Logging, Sourcing; Stage 5: Collaboration and Construction; Stage 6: Releasing, Gifting, Recruiting. This new PartPb framework, is realised within a series of five practice-based (Pb) artworks called, ‘Minor Projects 1-5’, (2015-16) and Final Major Project, ‘Transformational Encounters: Touch, Traction, Transform’ (TETTT), (2018). These projects are likewise shaped through action-research processes of iterative testing, as developed from Candy and Edmonds (2010) Practice-based Research (PbR) trajectory. In my new PartPb framework, Candy, and Edmonds’ PbR processes are originally combined with a form of Fritz and Laura Perl’s Gestalt Experience Cycle (1947). This innovative fusion I come to term as a form of ‘Feeling Architecture,’ which is procedurally proven to hold and carry both researcher and participants alike, safely, ethically, and creatively through all Phases and Stages of artefact generation. Specifically, my new multimodal PartPb framework offers new knowledge to the field of Practice-Based Research (PbR) and practitioners working in multimodal arts and applied performance contexts. Due to its participatory focus, I develop on the term Practice-Based Research, (Candy and Edmonds, 2010) to coin the term Participatory Practice-Based Research, (PartPbR). The unique combination of multimodal arts and social-psychological methodologies underpinning my framework also has the potential to contribute to broader Arts, Well-Being, and Creative Health agendas, such as the UK government’s Social Prescribing and Arts and Health initiatives. My original framework offers future researchers’ opportunities to further develop, enhance and enrich individual and community well-being through its application to their own projects, and, in doing so, also starts to challenge unhelpful art binaries that still position community arts practices as somehow lesser to higher art disciplines

Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies

<p>Abstract</p> <p>Background</p> <p>Bovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows (“BNP dams”). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and β-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured <it>in vitro</it> from sternal biopsies taken at 24 hours and 6 days post-challenge.</p> <p>Results</p> <p>Clonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced.</p> <p>Conclusion</p> <p>This study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types.</p

Co-designing Infrastructures

Co-designing Infrastructures tells the story of a research programme designed to bring the power of engineering and technology into the hands of grassroots community groups, to create bottom-up solutions to global crises. Four projects in London are described in detail, exemplifying community collaboration with engineers, designers and scientists to enact urban change. The projects co-designed solutions to air pollution, housing, the water-energy-food nexus, and water management. Rich case-study accounts are underpinned by theories of participation, environmental politics and socio-technical systems. The projects at the heart of the book are grounded in specific settings facing challenges familiar to urban communities throughout the world. This place-based approach to infrastructure is of international relevance as a foundation for urban resilience and sustainability. The authors document the tools used to deliver this work, providing guidance for others who are working to deliver local technical solutions to complex social and environmental problems around the world. This is a book for engineers, designers, community organisers and researchers. Co-authored by researchers, it includes voices of community collaborators, their experiences, frustrations and aspirations. It explores useful theories about infrastructure, engineering and resilience from international academic research, and situates them in community-based co-design experience, to explain why bottom-up approaches are needed and how they might succeed