Impact of Poloxamer 188 variability on biologics manufacturing: Mitigations and causal investigation

Poloxamer 188 (P188), a water-soluble, synthetic copolymer with hydrophilic as well as lipophilic properties, is widely used as a cell protectant for bubble-induced shear during cultivation of suspension-adapted mammalian cells for large-scale production of protein-based therapeutics. Poor cell growth and lower product yield has been recently observed at commercial scales in more than one Chinese hamster ovary-based manufacturing process within Roche network when specific lots of P188 were used. An investigation is being conducted to unearth the root cause of “poor-performing” P188 lots and to identify means to mitigate the product supply risks. P188 raw material is currently sourced from a single vendor with additional supply constraints and risks associated with the impending change in the vendor manufacturing facility and location. These factors further exacerbate the supply risks for the drugs produced by Roche. A multi-pronged approach has been undertaken. A small-scale bioreactor based screening assay was developed where a model commercial cell line was subjected to a relatively high shear stress environment to differentiate between good-performing and poor-performing lots. To discern the root cause for the lot-specific loss of P188 functionality, analytical fingerprinting methods have been used to test different hypotheses including presence of high molecular weight species1. Pilot-scale fractionation was performed using good- and poor-performing P188 lots to isolate fractions with different molecular weight and characterized using methods including LC-MS/MS and 2D NMR. The structure elucidation results were further evaluated to discern the cell-protective functionality of the different fractions. Lastly, in order to ensure uninterrupted supply of our medicines to patients, a comprehensive evaluation of an alternate manufacturer of poloxamer 188 was performed. Taken together, the findings from this investigation provide insights to understanding a long-standing risk in biopharmaceutical manufacturing

Adult Learning in the Context of the Interreligious Dialogue Process: A Collaborative Research Study Involving Christians, Jews and Muslims

This paper reports on a collaborative qualitative research study where the purpose was to explore the nature of the learning that occurs in the interreligious dialogue process. Participants were 20 Christian, Jewish and Muslim adults who have participated in interreligious dialogue, for a period of more than a year

Adult Learning in the Context of Interreligious Dialogue: A Collaborative Research Study Involving Christians, Jews, and Muslims

What do American Jews really know about Muslims? What do American Muslims really know about Jews? These questions undergird this account of how two religious adult educators--a Jew and a Muslim--came to engage in collaborative, dialogic, relational and transformational interreligious learning and research. Emerging out of this collaborative doctoral research project at National-Louis University, this study addresses two different dimensions of research and practice in the field of adult education: the nature of adult learning in the interreligious dialogue process and the role of collaborative methods in research methodology. Adult learning in the context of interreligious dialogue can best be described as incremental transformative learning, characterized by collaborative learning, which is mediated through symbols and metaphors in various forms. Learning in this context fosters adult development in the spiritual dimension. Interreligious dialogue engages the whole person in that it is linked to the learner\u27s cognitive, affective, and symbolic domains of meaning making. The stories and experiences shared by the participants led to a schematic organized around three central themes: motivations rooted in openness and significant past experiences; interreligious learning as a threefold affective, cognitive, and symbolic knowledge construction process, and social action as inspiration and outcome of interreligious dialogue. A metaphor to describe the interaction and impact of these three themes that emerged from the data is that of interreligious dialogue as a pool of water. This study is rooted in a constructivist theoretical framework in which the concepts of collaboration and research as artistic endeavor are prominent. It was conducted as a fully collaborative venture. This important collaborative research partnership led to the creation of a new collaborative inquiry data gathering method (CIMCAM). It also led to significant insights into the role of collaborative learning in the research process

A qualitative meta-synthesis for a theory of interfaith/interreligious learning through dialogue

Interfaith/interreligious (IF/IR) dialogue offers a context through which individuals within various religious communities can learn from and with each other. There are unique aspects to this learning environment. First, learning through conversation. Second, learning through conversation about a difficult topic. And third, learning from and with a religious other. To best understand what learning through IF/IR dialogue is, researchers would benefit from a nuanced understanding of the complexities of the learning environment and the participants within it. In this qualitative meta-synthesis, we examine current research on IF/IR dialogue to outline a theory of dialogical IF/IR learning

Dealing with Religious, Cultural, and Spiritual Pluralism in Adult and Higher Education Practice in an Age of Terrorism: Challenges and Controversies

This symposium addresses the challenges, controversies, and perceived responsibilities in dealing with religious, cultural, and spiritual pluralism in adult education practice from the perspective of a multiple presenters of different positionalities and spiritual traditions

Collaborative Inquiry: Expanding the Boundaries of Knowledge Construction in Graduate Adult Education Research

The purpose of this roundtable session is to share ideas about collaborative inquiry as a research methodology. Facilitators include a faculty member from a doctoral program that encourages collaborative learning and collaborative inquiry, and two students, from the same doctoral program, who completed a fully collaborative doctoral research project

The Intersecting Roles of Religion, Culture, and Spirituality in Emancipatory Adult Education

This paper discusses why considering the intersection of religion, spirituality, and culture is important in emancipatory education efforts and provides discussion of approaches for doing so in practice

Genome-wide transcriptome analysis reveals that a pleiotropic antibiotic regulator, AfsS, modulates nutritional stress response in Streptomyces coelicolor A3(2)

<p>Abstract</p> <p>Background</p> <p>A small "sigma-like" protein, AfsS, pleiotropically regulates antibiotic biosynthesis in <it>Streptomyces coelicolor</it>. Overexpression of <it>afsS </it>in <it>S. coelicolor </it>and certain related species causes antibiotic stimulatory effects in the host organism. Although recent studies have uncovered some of the upstream events activating this gene, the mechanisms through which this signal is relayed downstream leading to the eventual induction of antibiotic pathways remain unclear.</p> <p>Results</p> <p>In this study, we employed whole-genome DNA microarrays and quantitative PCRs to examine the transcriptome of an <it>afsS </it>disruption mutant that is completely deficient in the production of actinorhodin, a major <it>S. coelicolor </it>antibiotic. The production of undecylprodigiosin, another prominent antibiotic, was, however, perturbed only marginally in the mutant. Principal component analysis of temporal gene expression profiles identified two major gene classes each exhibiting a distinct coordinate differential expression pattern. Surprisingly, nearly 70% of the >117 differentially expressed genes were conspicuously associated with nutrient starvation response, particularly those of phosphate, nitrogen and sulfate. Furthermore, expression profiles of some transcriptional regulators including at least two sigma factors were perturbed in the mutant. In almost every case, the effect of <it>afsS </it>disruption was not observed until the onset of stationary phase.</p> <p>Conclusion</p> <p>Our data suggests a comprehensive role for <it>S. coelicolor </it>AfsS as a master regulator of both antibiotic synthesis and nutritional stress response, reminiscent of alternative sigma factors found in several bacteria.</p

Shared Governance in an Adult Education Doctoral Program: “Self-Directed Learning meets Democratic Process” – A Delicate Balance of Intent, Implementation, and Impact

This symposium explores the governance component offered within a doctoral program in which students were given the opportunity to engage in collective decision-making through democratic process. Panelists, most of whom were research participants for the dissertation upon which this exploration is based, represent cohort groups from 1996 through 2007

Technical assessment approach for vendor initiated changes of direct materials

Hundreds of direct materials are used for each biologic production process. Vendor initiated changes (VIC) to the production process, packaging, raw material sources, and other aspects of these direct materials can and will happen. Each change could have the potential for both process and product impact not only to one product, but to every product that uses it across a manufacturing network. In order to ensure these changes are assessed appropriately and in a timely manner, procedures and processes need to be in place both from the customer and supplier. In addition, if changes are complex, communication between both parties is often necessary. Complex changes may also require a deeper level of collaboration between multiple functional groups from the customer and supplier. This poster will describe Roche/Genentech’s approach for technical assessments of VICs to ensure they are evaluated properly by the necessary subject matter experts (SMEs). It will highlight case studies such as a complex VIC pertaining to Poloxamer 188 (P188) and the effective collaboration between Roche/Genentech and its supplier. Poloxamer 188 is a complex nonionic tri-block co-polymer composed of a central hydrophobic chain of polyoxypropylene (PPO) flanked by two hydrophilic chains of polyoxyethylene (PEO) which is used in biopharmaceutical manufacturing for the cultivation of mammalian cells. The supplier informed Roche/Genentech of a production site change of P188 through the VIC business process. The complexity associated with the site change VIC was further compounded by an ongoing investigation based on observed low cell growth and product yield for some large-scale biomanufacturing processes at Roche/Genentech. Lot-to-lot variability in P188 was identified as the primary source of the observed low growth and yield even though all release specifications were met (Figure below). Please click Additional Files below to see the full abstract