Engineering challenges in therapeutic protein product and process design

Biologics represent the fastest growing sector of the pharmaceutical industry, yet their manufacture lags significantly behind that of small molecule drugs. This paper discusses the main product-related and process-related challenges during the development and production of therapeutic proteins, with particular focus on product heterogeneity and process monitoring and analytics. Emphasis is placed on novel contributions from the field of computational research that aim to enable the application of model-based process control strategies or are working towards the development of a digital twin of bioprocesses. Lastly, we review promising developments in the paradigm shift from batch to continuous processing

Emerging challenges and opportunities in pharmaceutical manufacturing and distribution

The rise of personalised and highly complex drug product profiles necessitates significant advancements in pharmaceutical manufacturing and distribution. Efforts to develop more agile, responsive, and reproducible manufacturing processes are being combined with the application of digital tools for seamless communication between process units, plants, and distribution nodes. In this paper, we discuss how novel therapeutics of high-specificity and sensitive nature are reshaping well-established paradigms in the pharmaceutical industry. We present an overview of recent research directions in pharmaceutical manufacturing and supply chain design and operations. We discuss topical challenges and opportunities related to small molecules and biologics, dividing the latter into patient- and non-specific. Lastly, we present the role of process systems engineering in generating decision-making tools to assist manufacturing and distribution strategies in the pharmaceutical sector and ultimately embrace the benefits of digitalised operations

Assisting continuous biomanufacturing through advanced control in downstream purification

Aiming to significantly improve their processes and secure market share, monoclonal antibody (mAb) manufacturers seek innovative solutions that will yield improved production profiles. In that space, continuous manufacturing has been gaining increasing interest, promising more stable processes with lower operating costs. However, challenges in the operation and control of such processes arise mainly from the lack of appropriate process analytics tools that will provide the required measurements to guarantee product quality. Here we demonstrate a Process Systems Engineering approach for the design a novel control scheme for a semi-continuous purification process. The controllers are designed employing multi-parametric Model Predictive Control (mp-MPC) strategies and the successfully manage to: (a) follow the system periodicity, (b) respond to measured disturbances and (c) result in satisfactory yield and product purity. The proposed strategy is also compared to experimentally optimized profiles, yielding a satisfactory agreement

Assessment of intermediate storage and distribution nodes in personalised medicine

Chimeric Antigen Receptor (CAR) T cell therapies are a type of patient-specific cell immunotherapy demonstrating promising results in the treatment of aggressive blood cancer types. CAR T cells follow a 1:1 business model, translating into manufacturing lines and distribution nodes being exclusive to the production of a single therapy, hindering volumetric scale up. In this work, we address manufacturing capacity bottlenecks via a Mixed Integer Linear Programming (MILP) model. The proposed formulation focuses on the design of candidate supply chain network configurations under different demand scenarios. We investigate the effect of an intermediate storage upstream of the network to: (a) debottleneck manufacturing lines and (b) increase facility utilisation. In this setting, we assess cost-effectiveness and flexibility of the supply chain and we evaluate network performance with respect to: (a) average production cost and (b) average response treatment time. The trade-off between cost-efficiency and responsiveness is examined and discussed

DigiGlyc: A hybrid tool for reactive scheduling in cell culture systems

Chinese hamster ovary (CHO) cell culture systems are the most widely used platform for the industrial production of monoclonal antibodies (mAbs). The optimisation of manufacturing conditions for these high-value products is largely conducted off-line with little or no monitoring of mAb quality in-process. Here, we propose DigiGlyc, a hybrid model of these systems that predicts the critical quality attribute of mAb galactosylation. Having shown that DigiGlyc describes a wide range of experimental data well, we demonstrate that it can be used for the design of reactive optimisation studies. This hybrid formulation offers considerable gains in computational speed compared to mechanistic models with no loss in fidelity and can therefore underpin future online control and optimisation studies

Autologous CAR T-cell therapies supply chain: challenges and opportunities?

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

Towards unravelling the kinetics of an acute myeloid leukaemia model system under oxidative and starvation stress: a comparison between two- and three-dimensional cultures.

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

Towards unravelling the kinetics of an acute myeloid leukaemia model system under oxidative and starvation stress: a comparison between two- and three-dimensional cultures

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