Process simulation based decisional tool to evaluate strategies for continuous downstream bioprocess implementation - A CDMO perspective

To maintain a competitive space in the rapidly expanding and highly competitive market, many biopharmaceutical companies are outsourcing to contract development and manufacturing organizations (CDMOs) to accelerate research and development, shorten the time to market, alleviate internal capacity and technical constraints, and reduce risks associated with production [1]. To acquire new and maintain current clients, CDMOs must have strong, diverse technical offerings for development, manufacture, and testing of products with competitive pricing and timelines [2]. Adopting innovative technologies like continuous downstream processing can help debottleneck the process and reduce processing time, which is the most appealing to CDMOs as it translates to an increased number of batches per year. The majority of continuous processing assessments to date have focused on cost of goods and not on the time reduction potential [3-7]. End-to-end continuous downstream processing is not always practical as CDMOs must accommodate a wide range of molecules and processes. Hence, it is imperative to evaluate and customize continuous production based on client needs. Application of process simulation as a decisional tool to select an appropriate downstream processing strategy was evaluated. Two modelling programs were evaluated: BioSolve Process and SuperPro Designer®. Fully continuous and hybrid (continuous Protein A operation only) downstream processing were assessed for a 2000 L fed-batch bioreactor producing 1, 5, and 10 g/L of monoclonal antibody at 40 and 200 kg production demands. Hybrid and continuous processing decreased batch duration by 20% and 60%, respectively. Continuous processing was more favorable for higher titer processes (≥ 5 g/L). The largest cost reductions were observed for 5 and 10 g/L titer processes during 40 kg production. The results highlight the business case for continuous downstream bioprocessing especially at a CDMO. Selection of a processing method will be influenced by a range of factors and the impact can easily be assessed using process simulation. Therefore, it is recommended that CDMOs use process simulation to ensure the most favorable processing strategy is selected. [1] O. Gassmann, A. Schuhmacher, M. von Zedtwitz, G. Reepmeyer, The Make-or-Buy Challenge: How to In-and Outsource Innovation, Leading Pharmaceutical Innovation, Springer2018, pp. 79-110. [2] R. Hernandez, Contract Biomanufacturing Firms Become More Specialized, BioPharm International, 28 (2015) 22-27. [3] D. Pollard, M. Brower, Y. Abe, A.G. Lopes, Standardized Economic Cost Modeling for Next-Generation MAb Production, BioProcess Int, (2016). [4] A. Xenopoulos, A new, integrated, continuous purification process template for monoclonal antibodies: process modeling and cost of goods studies, Journal of biotechnology, 213 (2015) 42-53. [5] J. Hummel, M. Pagkaliwangan, X. Gjoka, T. Davidovits, R. Stock, T. Ransohoff, R. Gantier, M. Schofield, Modeling the Downstream Processing of Monoclonal Antibodies Reveals Cost Advantages for Continuous Methods for a Broad Range of Manufacturing Scales, Biotechnology journal, (2018) 1700665. [6] J. Pollock, J. Coffman, S.V. Ho, S.S. Farid, Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture, Biotechnology progress, 33 (2017) 854-866. [7] S. Klutz, L. Holtmann, M. Lobedann, G. Schembecker, Cost evaluation of antibody production processes in different operation modes, Chemical Engineering Science, 141 (2016) 63-74

Bose-Einstein condensation with magnetic dipole-dipole forces

Ground-state solutions in a dilute gas interacting via contact and magnetic dipole-dipole forces are investigated. To the best of our knowledge, it is the first example of studies of the Bose-Einstein condensation in a system with realistic long-range interactions. We find that for the magnetic moment of e.g. chromium and a typical value of the scattering length all solutions are stable and only differ in size from condensates without long-range interactions. By lowering the value of the scattering length we find a region of unstable solutions. In the neighborhood of this region the ground state wavefunctions show internal structures not seen before in condensates. Finally, we find an analytic estimate for the characteristic length appearing in these solutions.Comment: final version, 4 pages, 4 figure

Ground state and elementary excitations of single and binary Bose-Einstein condensates of trapped dipolar gases

We analyze the ground-state properties and the excitation spectrum of Bose-Einstein condensates of trapped dipolar particles. First, we consider the case of a single-component polarized dipolar gas. For this case we discuss the influence of the trapping geometry on the stability of the condensate as well as the effects of the dipole-dipole interaction on the excitation spectrum. We discuss also the ground state and excitations of a gas composed of two antiparallel dipolar components.Comment: 12 pages, 9 eps figures, final versio

All-Optical Programmable Disaggregated Data Centre Network realized by FPGA-based Switch and Interface Card

This paper reports an FPGA-based switch and interface card (SIC) and its application scenario in an all-optical, programmable disaggregated data center network (DCN). Our novel SIC is designed and implemented to replace traditional optical network interface cards, plugged into the server directly, supporting optical packet switching (OPS)/optical circuit switching (OCS) or time division multiplexing (TDM)/wavelength division multiplexing (WDM) traffic on demand. Placing the SIC in each server/blade, we eliminate electronics from the top of rack (ToR) switch by pushing all the functionality on each blade while enabling direct intrarack blade-to-blade communication to deliver ultralow chip-to-chip latency. We demonstrate the disaggregated DCN architecture scenarios along with all-optical dimension-programmable N × M spectrum selective Switches (SSS) and an architecture-on-demand (AoD) optical backplane. OPS and OCS complement each other as do TDM and WDM, which can support variable traffic flows. A flat disaggregated DCN architecture is realized by connecting the optical ToR switches directly to either an optical top of cluster switch or the intracluster AoD optical backplane, while clusters are further interconnected to an intercluster AoD for scaling out

Treatment of backscattering in a gas of interacting fermions confined to a one-dimensional harmonic atom trap

An asymptotically exact many body theory for spin polarized interacting fermions in a one-dimensional harmonic atom trap is developed using the bosonization method and including backward scattering. In contrast to the Luttinger model, backscattering in the trap generates one-particle potentials which must be diagonalized simultaneously with the two-body interactions. Inclusion of backscattering becomes necessary because backscattering is the dominant interaction process between confined identical one-dimensional fermions. The bosonization method is applied to the calculation of one-particle matrix elements at zero temperature. A detailed discussion of the validity of the results from bosonization is given, including a comparison with direct numerical diagonalization in fermionic Hilbert space. A model for the interaction coefficients is developed along the lines of the Luttinger model with only one coupling constant $K$. With these results, particle densities, the Wigner function, and the central pair correlation function are calculated and displayed for large fermion numbers. It is shown how interactions modify these quantities. The anomalous dimension of the pair correlation function in the center of the trap is also discussed and found to be in accord with the Luttinger model.Comment: 19 pages, 5 figures, journal-ref adde

Prospective Study of TMVR Using Balloon-Expandable Aortic Transcatheter Valves in MAC: MITRAL Trial 1-Year Outcomes

OBJECTIVES: The aim of this study was to evaluate 1-year outcomes of valve-in-mitral annular calcification (ViMAC) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial. BACKGROUND: The MITRAL trial is the first prospective study evaluating the feasibility of ViMAC using balloon-expandable aortic transcatheter heart valves. METHODS: A multicenter prospective study was conducted, enrolling high-risk surgical patients with severe mitral annular calcification and symptomatic severe mitral valve dysfunction at 13 U.S. sites. RESULTS: Between February 2015 and December 2017, 31 patients were enrolled (median age 74.5 years [interquartile range (IQR): 71.3 to 81.0 years], 71% women, median Society of Thoracic Surgeons score 6.3% [IQR: 5.0% to 8.8%], 87.1% in New York Heart Association functional class III or IV). Access was transatrial (48.4%), transseptal (48.4%), or transapical (3.2%). Technical success was 74.2%. Left ventricular outflow tract obstruction (LVOTO) with hemodynamic compromise occurred in 3 patients (transatrial, n = 1; transseptal, n = 1; transapical, n = 1). After LVOTO occurred in the first 2 patients, pre-emptive alcohol septal ablation was implemented to decrease risk in high-risk patients. No intraprocedural deaths or conversions to open heart surgery occurred during the index procedures. All-cause mortality at 30 days was 16.7% (transatrial, 21.4%; transseptal, 6.7%; transapical, 100% [n = 1]; p = 0.33) and at 1 year was 34.5% (transatrial, 38.5%; transseptal, 26.7%; p = 0.69). At 1-year follow-up, 83.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.1 mm Hg (IQR: 5.6 to 7.1 mm Hg), and all patients had ≤1+ mitral regurgitation. CONCLUSIONS: At 1 year, ViMAC was associated with symptom improvement and stable transcatheter heart valve performance. Pre-emptive alcohol septal ablation may prevent transcatheter mitral valve replacement-induced LVOTO in patients at risk. Thirty-day mortality of patients treated via transseptal access was lower than predicted by the Society of Thoracic Surgeons score. Further studies are needed to evaluate safety and efficacy of ViMAC

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in 2015 October, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1%-2.5% dips, named Elsie, Celeste, Skara Brae, and Angkor, which persist on timescales from several days to weeks. Our main results so far are as follows: (i) there are no apparent changes of the stellar spectrum or polarization during the dips and (ii) the multiband photometry of the dips shows differential reddening favoring non-gray extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale ≪1 μm, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term secular dimming, which may be caused by independent processes, or probe different regimes of a single process