Fast process development, flexible production and the utilization of advanced process conditions are the main goals of modular and continuous small-scale plants (MCSPs). A configurable layout of the modules and the use of predefined equipment enable a quick and reliable conceptual process development and scale-up of continuous processes. Therefore, a computer-assisted selection methodology was developed and is presented, which allows the quick selection of plug flow reactor equipment for homogeneous liquid phase reactions. It identifies a favorable technical apparatus and the configuration in the early stages of process development. This can lead to the effective planning and guiding of scale-up experiments and closes the gap between lab and process development.

Selection of Technical Reactor Equipment for Modular, Continuous Small-Scale Plants

https://hal.archives-ouvertes.fr/hal-01313233/document

Robust dynamic schedule coordination control in the supply chain

Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

Continuous Pharmaceutical Manufacturing (CPM) has recently emerged as a promising alternative to current batch production methods, which require significant expenditures in order to ensure product quality and process reliability. Advances in new continuous synthesis routes, demonstrations of full end-to-end continuous drug production and comparative technoeconomic analyses of potential cost advantages have all contributed to the advent of CPM and the strong interest of academic, corporate and regulatory beneficiaries. Continuous flow chemistry has been demonstrated for a variety of Active Pharmaceutical Ingredients (APIs), and there have been several landmark studies demonstrating practical CPM by illustrating the full design from raw materials to final product formulation. Fully continuous separations are critical to maximizing the CPM potential, but they are frequently not eludicated. This paper presents the formulation and solution of a nonlinear optimization problem for the CPM of ibuprofen. Adapting ...

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Technoeconomic Optimization of a Conceptual Flowsheet for Continuous Separation of an Analgaesic Active Pharmaceutical Ingredient (API)

An integrated multi-stage scheduling and routing problem with alternative machines at each supply chain (SC) stage and non-preemptive operations is studied. The peculiarity of the considered problem is the consideration of both continuous flows in operations and discrete assignments. Such problems are typical in the process industry. Taking into account the basic aspects that pertain to this case, a dynamic decomposition of the problem on the basis of optimal programme control is proposed. A particular feature and novelty of the presented study is the consideration of non-preemptive operations and their execution dynamics. The solution is based on a combined application of discrete and continuous optimization. With the special properties of the proposed scheduling model, it becomes possible to develop an optimal solution to the integrated scheduling and routing of jobs. Since the schedule generation is formulated in control terms, the models of scheduling and adaptation can be integrated. From the practical point of view, such integration can be advantageous subject to further dynamic analysis of the robustness, stability, and adaptability of SC schedules.

Multi-stage supply chain scheduling with non-preemptive continuous operations and execution control

Small-scale continuous technologies also fall under the process intensification umbrella which offers new opportunities through energy-intensive processes or devices, especially pertinent in the production of pharmaceutical molecules. The focus of this work is to develop a systematic method for the application of a modular tubular reactor with heat exchange to a number of reaction types. A dynamic optimisation is performed around the entire system with the objective to match the process conditions to the chemistry. A degree of freedom in the internal geometry is exploited as a manipulated variable to control the progression of reaction. The novel ‘green’ three step synthetic route of ibuprofen is highlighted. A crude yield of 90% at a residence time of 33 seconds is optimally found. Crucially, this efficient three-step process requires no purification of intermediates, thus saving time and energy as well as the reduction in total organic waste emission in the subsequent downstream.

Robust optimisation methodology for the process synthesis of continuous technologies

We are in an era where the objectives of process systems engineering (PSE) and process intensification (PI) are aligning. Micro-to-millimetre range reactors are well known in literature for the property of very efficient heat exchange and control, thus the design concept for such reactors allows for great flexibility in adapting the process for new reaction schemes. The novel ‘green’ synthetic route of the ibuprofen compound developed by BHC in the mid- 1980's requires efficient temperature control and thus lends itself to continuous processing. However, downstream of the reaction phase is rarely considered for further intensification, despite the plethora of proven continuous downstreamtechnologies.Thus,inthisworkweconsidertheentireprimary manufacturing stage, from reaction to crystallisation, with the intent of introducing intensification where needed, be it via a continuous option or innovation. Novel pharmaceutical production lines are thus ideal for exploring this paradigm shift, by introducing systematic process design, modern analytics and advanced control.

Plant-wide optimisation and control of a multi-scale pharmaceutical process

Taking the heat off the process

The full potential of a novel continuous reactor is addressed via the relationship between process design, the ability in handling the constraints and the optimisation framework. A Model Predictive Controller is developed to maximise the yield under hard input and state constraints. Simulations show that the designed control system gives high reaction yield and ensures that the temperatures inside the reactor are within a predefined limit. The challenges of an efficient start-up phase and the transition to the optimal operating point are also investigated by means of an event-driven approach.

Robert Ashe

Papers

Robust optimisation methodology for the process synthesis of continuous technologies

Plant-wide optimisation and control of a multi-scale pharmaceutical process

Taking the heat off the process

Modelling and Control of the Variable Channel Reactor