Tennessee

https://digitalcommons.library.umaine.edu/mmb-vp/2578/thumbnail.jp

Depth-integrated steric height as a tool for detecting non-Sverdrup behavior in the global ocean

Godfrey\u27s (1989) (referred to below as G89) calculation of the global field of annual mean Depth-Integrated Steric Height, or Sverdrup et al.\u27s (1942) Transport Function, (Q) is revisited, using newer products for wind stresses, temperature and salinity. Observed Q and its wind-estimated equivalent QW are compared more extensively along eastern oceanic boundaries than in G89. Q and QW are also compared along the inner edge of the Pacific western boundary, at locations where G89 theory suggests that such a comparison is possible. A similar comparison along the western Atlantic improves after a 16 Sv correction for the supply of North Atlantic Deep Water. The observed circumpolar zero contour of Q is used to define an ACC boundary. South of it, G89 fails grossly as expected. North of the boundary in each ocean basin, a tongue of high Q, about 1000 km wide, extends much farther eastward from its western boundary source than in comparable features in the northern hemisphere. The uninterrupted existence of this tongue across the full width of the Indian Ocean occurs because there is no analog in Q to the strong meridional tip jet west of southern Tasmania, found in QW—i.e. the East Australian Current is weaker in observed Q than predicted by G89. Elsewhere, each MTJ in QW does have an analog in observed Q; but the latter jets tend to follow local Sverdrup flow rather than being zonal. A final section provides qualitative discussion of the possible dynamics of these observed departures of Q from Sverdrup balance, north of the ACC

Tennessee

Red tinted photograph of a man with red and green detailing in the background.https://scholarsjunction.msstate.edu/cht-sheet-music/2720/thumbnail.jp

GMP design of a single-use integrated continuous bio manufacturing system

This presentation will show design work by Pfizer and Boehringer Ingelheim on a single-use integrated continuous system for GMP Biomanufacturing including consideration of scale, facility-fit, automation, single-use devices, hardware, and process control and monitoring. The scale of the system needs to be appropriate for the expected quantities of drug substance needed and needs to fit within the constraints of the GMP facility, including physical size and interaction with other facility systems. The system automation needs to control and monitor the entire process, since the upstream and downstream are integrated and the downstream operates semi-continuously. This presentation will discuss the challenges of designing an automation scheme capable of controlling an integrated upstream and downstream process along with the unique features that proved enabling to the integrated system. The single use devices and instruments in the system, including those made with additive manufacturing, are the process contact surfaces, so they need to be compatible with all the process fluids, perform consistently over process cycling and be constructed with sanitary design appropriate for GMP biomanufacturing. The system hardware provides the interface between the automation and the single-use devices controlling operations and the single-use instruments monitoring in-line process data. The design also needs to consider on-line instrument needs and off-line sampling analysis for a continuous flowing process stream

Viral clearance considerations for continuous viral inactivation

Continuous low pH viral inactivation has been considered by Boehringer Ingelheim, Pfizer, and other companies who are investing in integrated processing. In continuous viral inactivation, a critical parameter that poses a new challenge is the exact incubation time of the product stream. In a continuous space, the concept of time translates in the product flow rate, incubation volume, and dispersion effects. To address dispersion, we define the minimum residence time, tmin, as the time when the first product element exits the tubular chamber. In this work, we characterize the tmin for a novel, scalable, and sturdy tubular reactor design that can serve as an incubation chamber for a process capable to produce \u3e1kg of product. In addition, we provide robust data for a scale down model suitable for viral studies. We propose an innovative in-line spiking methodology to validate the minimum residence time using viruses. This methodology can be used as a viral clearance platform for continuous low pH virus inactivation. Finally, we propose a trace response method to be used as a way to verify that the process was properly set up

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p

From development to implementation with a fully integrated downstream bioprocess

Boehringer Ingelheim and Pfizer have developed a unique continuous bioprocess consisting of a short duration perfusion upstream and fully integrated downstream. The process is designed to generate at least 1 kg of material from a 100 L bioreactor in approximate 2 weeks. The upstream strategy utilizes a non-steady state, short duration perfusion process to achieve volumetric productivities ranging from 0.5 to 4 g/L/day. This creates a unique challenge for the downstream process as the titer and impurity load change over the duration of the culture. To accommodate upstream, a fully integrated downstream process was created using a combination of traditional batch unit operations and continuous bioprocessing. The system design includes a pair of small proteins A columns operated consecutively, a continuous low pH inactivation chamber (cVI), an anion exchange chromatography column, a single pass tangential flow filter, a virus filter and batch UFDF. The key to the system is three distinct operation modes including continuous, periodic and batch phases. The resulting hybrid system provides flexible and robust downstream processing of the continuous perfusion bioreactor. We have successfully used this new downstream process at the predicted manufacturing scale to generate clinical quality drug substance for multiple monoclonal antibodies. With the success of the new integrated system, our team is shifting its focus to implementation on a clinical program. A key element of the ongoing work is to establish the control and robustness of novel elements of our process such as confirming that the critical pH has been achieved during cVI and demonstrating robust impurity removal for dynamic loading on an AEX polishing step. In this talk, we will explain our approach to integrated continuous downstream processing and our strategy for future implementation. Data from at-scale demonstration runs will show the robustness of the process over a wide range of loading conditions. This will include product quality data including HCP, DNA, charge variants and aggregate removal that is consistent with batch processes. Process data will show the control and robustness of the approach

Balancing continuous, integrated, and batch processing

We are building a new disposable manufacturing system to support the development and manufacturing of mAb and mAb-related products. We have made choices that are different than many others in the field of continuous and integrated processing. These choices avoid many misperceptions about continuous processing, are consistent with a staged approach to implementation, and facilitate manufacturing in either large-scale disposable or stainless manufacturing facilities. We have avoided the use of long-term steady-state perfusion. This mode of perfusion suffers from long development times, long manufacturing duration, extended Process Performance Qualification, large media consumption and perceived concerns about product quality variability and contamination. The system uses a short duration (\u3c15 days) non-steady state perfusion with perfusion rates as low as 0.3 bioreactor volumes per day. On-line UPLC is used to monitor product titer and quality. As a consequence of non-steady state perfusion operation, the integrated downstream is capable of handling day to day variability of 0.5g/L/day to 4g/L/day. The downstream avoids the use of SMB or PCC; rather, it integrates two batch chromatographic steps, a continuous virus inactivation step, and avoids in-process pooling. The product is stored after the second chromatography step for the duration of the batch. When the batch is complete, the pooled product is batched through a virus reduction filter and UFDF to make the bulk drug substance. Running these last two processes on the entire product pool at once allows an easy definition of a batch, without worry about pooling drug substance with different product quality profiles. The result is an integrated, semi-continuous manufacturing process that mitigates many of the concerns felt by the batch-processing community

iSKID: From integrated pilot scale runs to GMP implementation approach

One of the most compelling business reasons for integrated processing is the ability to de-risk capital investment due to a significantly more productive process that takes less space and fewer campaigns to generate clinical and commercial material. Boehringer Ingelheim and Pfizer developed the iSKID, a fully integrated and automated system that hydraulically links the perfusion bioreactor with several downstream unit operations (2xProtein A columns, continuous viral inactivation, AEX in flow through mode, and SPTFF). The Protein A elution cycles are discrete and separated by \u3e2hrs, allowing the ability to discard cycles that do not meet process specifications. The discreteness between product cycles and hydraulic linkage enables the sanitization between cycles for a robust bioburden control strategy. Each cycle is captured in a single use mixer (SUM), where the product is pooled in stable conditions until viral filtration, ultrafiltration/diafiltration and final filtration are performed in batch mode. Identical iSKID prototypes at 100L scale were used at three different sites to generate product quality, process, and bioburden data from three different molecules. The data has been used to understand implementation gaps in GMP facilities and process platforms (CMC1/CMC2). In addition, the team identified specific items to present to the FDA’s Emerging Technology Team (ETT). These items include our strategies for batch definition, microbial control, and process control. In this talk, we will use the data generated from the consistency runs to elaborate on the robustness of the process and touch upon the strategies to be presented to the ETT

Photon-Photon and Electron-Photon Colliders with Energies Below a TeV

We investigate the potential for detecting and studying Higgs bosons in $\gamma\gamma$ and $e\gamma$ collisions at future linear colliders with energies below a TeV. Our study incorporates realistic $\gamma\gamma$ spectra based on available laser technology, and NLC and CLIC acceleration techniques. Results include detector simulations. We study the cases of: a) a SM-like Higgs boson based on a devoted low energy machine with $\sqrt{s_{ee}}\le 200$ GeV; b) the heavy MSSM Higgs bosons; and c) charged Higgs bosons in $e\gamma$ collisions.We investigate the potential for detecting and studying Higgs bosons in $\gamma\gamma$ and $e\gamma$ collisions at future linear colliders with energies below a TeV. Our study incorporates realistic $\gamma\gamma$ spectra based on available laser technology, and NLC and CLIC acceleration techniques. Results include detector simulations. We study the cases of: a) a SM-like Higgs boson based on a devoted low energy machine with $\sqrt{s_{ee}}\le 200$ GeV; b) the heavy MSSM Higgs bosons; and c) charged Higgs bosons in $e\gamma$ collisions