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Chimeric antigen receptor (CAR) T cells are considered a potentially disruptive cancer therapy, showing highly promising results. Their recent success and regulatory approval (both in the USA and Europe) are likely to generate a rapidly increasing demand and a need for the design of robust and scalable manufacturing and distribution models that will ensure timely and cost-effective delivery of the therapy to the patient. However, there are challenging tasks as these therapies are accompanied by a series of constraints and particularities that need to be taken into consideration in the decision-making process. Here, we present an overview of the current state of the art in the CAR T cell market and present novel concepts that can debottleneck key elements of the current supply chain model and, we believe, help this technology achieve its long-term potential.

In this paper, we describe POP, a MATLAB toolbox for parametric optimization. It features (a) efficient implementations of multiparametric programming problem solvers for multiparametric linear and quadratic programming problems and their mixed-integer counter-parts, (b) a versatile problem generator capable of creating random multiparametric programming problems of arbitrary size, and (c) a comprehensive library of multiparametric programming test problems featuring benchmark test sets for multiparametric linear, quadratic, mixed-integer linear, and mixedinteger quadratic programming problems. In addition, POP is equipped with a graphical user interface which enables the userfriendly use of all functionalities of POP and a link to the solvers of the Multi-Parametric Toolbox (MPT), as well as the ability to design explicit MPC problems. These features are demonstrated in detailed computational studies providing insights into the versatility and applicability of POP. Additionally, the example of a periodic chromatographic system is used to show the scalability of multiparametric programming in general and POP, in particular.Article pubs.acs.org/IECR

Aim: To investigate the effect of vitamin C and E supplementation in the levels of nitrite, nitric oxide (NO) related metabolite, and ocular surface parameters in diabetic patients. Methods: 50 patients with non-insulin dependent diabetes mellitus were given vitamin C (1000 mg/day) and vitamin E (400 IU/day) supplementation for 10 days. Nitrite levels in tears were measured by photometric determination before and after vitamin supplementation. Tear function parameters (Schirmer test I, BUT, ocular ferning test) and brush cytology analysis of the conjunctival epithelium were also evaluated. Results: Nitrite levels were found to be significantly reduced (p<0.05) after 10 days of vitamin C and E supplementation. Improved values for Schirmer test, BUT test, and ocular ferning test were also found. Goblet cell density and grading of squamous metaplasia showed a significant improvement. Conclusions: Oxidative stress and free radical production are elevated in diabetes mellitus. Antioxidants, such as vitamin C and vitamin E, probably have an important role in reducing the oxidative damage produced by nitric oxide and other free radicals and improving the ocular surface milieu.

The multicolumn countercurrent solvent gradient purification process (MCSGP) is a semicontinuous, chromatographic separation process used in the production of monoclonal antibodies) . The process is characterized by high model complexity and periodicity that challenge the development of control strategies, necessary for feasible and efficient operation and essential toward continuous production. A novel approach for the development of control policies for the MCSGP process, which enables efficient continuous process control is presented. Based on a high fidelity model, the recently presented PAROC framework and software platform that allows seamless design and in-silico validation of advanced controllers for complex systems are followed. The controller presented in this work is successfully tested against disturbances and is shown to efficiently capture the process periodic nature. V C 2016 American Institute of Chemical Engineers AIChE J, 62: 2341AIChE J, 62: -2357AIChE J, 62: , 2016 Keywords: process control, continuous biomanufacturing, multiparametric control IntroductionMonoclonal antibodies (mAbs) play a vital role in the treatment of infectious diseases, cancer, and autoimmune diseases.1 They are characterized, however, by high prices (approximately $35000 p/a per patient for mAbs treating cancer conditions) 2 that arise from their high production costs. Although over the past few years their market has been rapidly increasing, 3 the emergence of biosimilars and the introduction of novel therapeutic agents drives their biomanufacturing toward alternative routes of lower operating costs. 4 MAb production consists of the upstream processing (USP), where the cells are cultured and the therapeutic agent is produced, and the downstream processing (DSP) that involves the isolation/ purification steps of the targeted product. Under high titers, however, DSP can become significantly expensive, mostly due to equipment and consumables costs. [5][6][7][8][9] This along with the increasing demand on product quality and higher titers 3,5 drive advances in mAb biomanufacturing toward continuous operation. 4 Here, we focus on the development of advanced control strategies for the multicolumn countercurrent solvent gradient purification process (MCSGP), 10 aiming to drive the system toward continuous operation. MCSGP is a semicontinuous, chromatographic separation process of biomolecules, based on ion-exchange firstly presented by . 11 The process is described by complex partial differential and algebraic equations (PDAEs), involving highly nonlinear terms and is governed by periodic operation profiles that render control studies difficult to perform. There have been several works that have studied the optimization and control of such systems. Degerman et al. (2006) 12 use a nonlinear performed optimization studies on a nonlinear chromatography model to define the optimal operation points that will meet the purity Corresponding concerning this article should be addressed to E. Pistikopoulos at stratos@tamu.edu. constrai...

A great challenge when conducting ex vivo studies of leukaemia is the construction of an appropriate experimental platform that would recapitulate the bone marrow (BM) environment. Such a 3D scaffold system has been previously developed in our group [1]. Additionally to the BM architectural characteristics, parameters such as oxygen and glucose concentration are crucial as their value could differ between patients as well as within the same patient at different stages of treatment, consequently affecting the resistance of leukaemia to chemotherapy. The effect of oxidative and glucose stress-at levels close to human physiologic ones-on the proliferation and metabolic evolution of an AML model system (K-562 cell line) in conventional 2D cultures as well as in 3D scaffolds were studied. We observed that the K-562 cell line can proliferate and remain alive for 2 weeks in medium with glucose close to physiological levels both in 20 and 5% O2. We report interesting differences on the cellular response to the environmental, i.e., oxidative and/or nutritional stress stimuli in 2D and 3D. Higher adaptation to oxidative stress under non-starving conditions is observed in the 3D system. The glucose level in the medium has more impact on the cellular proliferation in the 3D compared to the 2D system. These differences can be of significant importance both when applying chemotherapy in vitro and also when constructing mathematical tools for optimisation of disease treatment.

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Current industrial trends encourage the development of sustainable, environmentally friendly processes with minimal energy and material consumption. In particular, the increasing market demand in biopharmaceutical industry and the tight regulations in product quality necessitate efficient operating procedures that guarantee products of high purity. In this direction, process intensification via continuous operation paves the way for the development of novel, eco-friendly processes, characterized by higher productivity and lower production costs. This work focuses on the development of advanced control strategies for (i) a cell culture system in a bioreactor and (ii) a semicontinuous purification process. More specifically, we consider a fed-batch culture of GS-NS0 cells and the semicontinuous Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) for the purification process. The controllers are designed following the PAROC framework/software platform and their capabilities are assessed in silico, against the process models. It is demonstrated that the proposed controllers efficiently manage to increase the system productivity, returning strategies that can lead to continuous, stable process operation. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:966-988, 2017.