Delivering a toolbox of flexible platforms for clinical and commercial bioprocessing production: ‘Defining the business drivers for development and implementation’

Despite the growing success, the biopharmaceutical industry continues to face competitive challenges from multiple sources. The cost pressures include evolving reimbursement, global competition and loss of drug exclusivity. As a result, there is a significant drive to boost the overall productivity of bio therapeutic programs by shortening development timelines and lowering both development and production costs, while maintaining product quality. Low cost production solutions must be aggressively pursued due to the large number of drug candidates in development, and their relatively high dosing requirements. The industry is facing an expanding range of modalities such as bispecifics and nanobodies, that provide a more heterogeneous product pipeline and a wider range of product demand (kg/yr). In addition supply chains need to be more responsive to the patient needs in a more personalized approach. These industry challenges need flexible solutions that can provide agility and lower cost. The presentation will discuss the business case, development and implementation of such a toolbox of low cost flexible platform solutions to meet a range of scenarios faced in clinical development, that also provide a line of sight to commercial. Examples will include the simple single use fed batch process for low demand processes versus advanced integrated/continuous automated processing for higher demands. The implementation strategy through the clinical phases to commercial will be discussed for commodity mAb production using a fully automated continuous process with product attribute control and real time release. This provides a supply responsive approach to rapid changes in demand to provide a ‘supply on demand’ process. This production synchronization should provide a responsive approach to changing drug demand, shorten clinical and commercial timelines and minimize inventory costs. These cost reduction initiatives, in combination with regional manufacturing, should help to expand patient accessibility to biologics and vaccines

Protein Refinery Operations Lab (PRO Lab): A sandbox for continuous protein production & advanced process control

Significant strides towards implementation of continuous bioprocessing are being made at an ever increasing rate. Advances in technology for traditional unit operations such as cell-retention devices in perfusion cell culture, continuous multi-column chromatography (CMCC) and single-pass tangential flow filtration have led to demonstrations of both semi-continuous and fully-continuous protein production processes operating at periodic steady states at the pilot-scale. Previous proof of concept work at Merck & Co., Inc. has shown an automated (DeltaV) and single-use monoclonal antibody (mAb) purification scheme through Protein A CMCC and pH viral inactivation with minimal human interaction for 30 days fed from a perfusion bioreactor1. This automation scheme has since been expanded to encompass an integrated mAb upstream and platform downstream process, resulting in an entirely automated ‘protein refinery’ sandbox. In this presentation a vision for a continuous bioprocessing facility of the future will be presented wherein the integration of Process Analytical Technologies (PAT), Multivariate Data Analysis, (MVDA), and feedback control strategies will lead to more streamlined plant operations and high product quality consistency. A discussion of how the control strategies put into place in PRO Lab lays the groundwork for this vision and how PRO Lab will be used to pilot PAT, MVDA, and feedback control as they become mature enough for integration into the continuous platform will be provided. These tools, working together, and validated in the sandbox environment, will ultimately enable real-time-release of drug substance. PRO Lab will also enable better holistic process understanding by enabling perturbation analysis and propagation throughout the production line. Process and product quality consistency data through a period of \u3e30days will be presented from PRO Lab as an initial step towards toward the ultimate vision of an automated well-controlled, well characterized protein refinery

From lab coats to hard hats: Implementation of GMP continuous manufacturing on the road to commercial readiness

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Continuous virus filtration: An existing technology with a promising future

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Implementing connected processes at-scale - Challenges and opportunities for streamlining operations

In response to increased demands placed on biopharmaceutical manufacturers to diversify portfolios and to reduce costs, bioprocesses are being intensified to allow for significant protein production in ≤2,000L single-use bioreactors. Many biopharmaceutical manufacturers are maturing continuous bioprocessing platforms to meet these demands. Hardware, which was once thought to be novel and high-risk for failure, is now being proven as robust at-scale. When coupled with single-use technology, these processes enable biomanufacturing facilities to be built faster at a lower cost, with more flexibility for reconfiguration and support of regional manufacturing. Many challenges remain to achieving this final vision including liquid management for large-scale perfusion operations, overcoming product sieving decay often encountered in filtration-based cell retention devices, and bioburden control for long duration operations. In a collaborative case study, Merck & Co., Inc. and Just Biotherapeutics will demonstrate a strategy leveraging fully single-use equipment and connected operations for an extended duration at manufacturing-scale (500L). This presentation will highlight bioreactor performance with the deployment of media concentrate technology to ease the logistical, staffing and space constraints of a traditional perfusion process, as well as implementation of large-scale microfiltration membranes for cell retention with consistently high protein transmission. In addition, data will be presented not only on the performance of a linked continuous multi-column protein A chromatography capture step, but also bioburden monitoring from multiple points in the process. Advancements implemented during this campaign as well as valuable lessons learned will open the door to further expanding the continuous boundary of connected operations and continuous bioprocessing

Continuous bioprocessing and process analytical technologies: A path towards quality by design

Recent success in monoclonal antibody based immuno-oncology therapeutics such as Keytruda® has initiated a revolution within the Biopharmaceutical Industry. Development efforts to support this class of molecules include single-use technology, continuous production, process analytical technology (PAT), information technology (IT), multivariate data analysis (MVDA), and efforts towards real time release testing (RTRT). Merck’s vision for a next-generation large molecule production facility aligns with these six key principles, as demonstrated by the construction of a continuous monoclonal antibody (mAb) production pilot plant named the Protein Refinery Operations lab (PROLab) within Merck Bioprocess Development. Quality-by-Design (QbD) principles are maturing for the development of standard batch-based therapeutic protein manufacturing processes. Outside of the insight gained through similar techniques applied to unit operations run in a continuous mode, similar approaches for the dependencies created by connected and continuous processes are still in their infancy. Previously, a methodology for characterizing holistic downstream process performance through real time perturbation analysis, where the response to an upstream stimulus is monitored at several unit operations simultaneously was presented to start applying QbD principles to continuous bioprocessing. Here, the authors build upon the concept of perturbation analysis by presenting case studies where advanced PAT tools have been embedded in PROLab operation. At-line and off-line process and product quality data from continuous upstream and downstream production will be presented over the course of long term perfusion cell culture with variable production rates. Specific emphasis will be placed on the performance of bioreactor cell retention and clarification trains, and post-chromatographic ultrafiltration unit operations. This process understanding can then be utilized to place PAT tools at the appropriate locations in the process to achieve product attribute control and ultimately to assure uninterrupted supply of therapeutic proteins to patient

Design of a GMP-ready single-pass tangential flow filtration (SPTFF) and inline diafiltration (LILDF) system for continuous manufacturing operations

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Maintaining Personal Resiliency: Lessons Learned from Evangelical Protestant Clergy

Despite the prominence of clergy in providing human services, and the work-related stressors they experience, clergy health and coping responses have rarely been the focus of psychological research. We report two studies. In the first, we evaluated responses of 398 senior pastors to three open-ended questions regarding personal coping, structural support for their work, and remediation efforts in times of distress. In the second study, Christian mental health professionals and Christian education professionals identified Protestant Christian clergy who exemplify emotional and spiritual health. Twenty-six participated in individual 30-minute interviews. Respondents emphasized the importance of being intentional in maintaining balance in life and developing healthy relationships. They also value a vital spiritual life, emphasizing both their sense of calling into ministry the importance of spiritual disciplines, and an ongoing awareness of God's grace. We suggest ways that Christian mental health professionals can support pastors in preventive and remedial roles. </jats:p

Reframing Kurtz’s Painting: Colonial Legacies and Minority Rights in Ethnically Divided Societies

Minority rights constitute some of the most normatively and economically important human rights. Although the political science and legal literatures have proffered a number of constitutional and institutional design solutions to address the protection of minority rights, these solutions are characterized by a noticeable neglect of, and lack of sensitivity to, historical processes. This Article addresses that gap in the literature by developing a causal argument that explains diverging practices of minority rights protections as functions of colonial governments’ variegated institutional practices with respect to particular ethnic groups. Specifically, this Article argues that in instances where colonial governments politicize and institutionalize ethnic hegemony in the pre-independence period, an institutional legacy is created that leads to lower levels of minority rights protections. Conversely, a uniform treatment and depoliticization of ethnicity prior to independence ultimately minimizes ethnic cleavages post-independence and consequently causes higher levels of minority rights protections. Through a highly structured comparative historical analysis of Botswana and Ghana, this Article builds on a new and exciting research agenda that focuses on the role of long-term historio-structural and institutional influences on human rights performance and makes important empirical contributions by eschewing traditional methodologies that focus on single case studies that are largely descriptive in their analyses. Ultimately, this Article highlights both the strength of a historical approach to understanding current variations in minority rights protections and the varied institutional responses within a specific colonial government

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI