Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin

Increasing Research and Development (R&D) costs, growing competition from generic manufacturers and dwindling market introduction rates for novel drug products bolster the efforts of pharmaceutical firms to secure competitiveness by investigating Continuous Pharmaceutical Manufacturing (CPM). The present paper explores the CPM of two key Active Pharmaceutical Ingredients (APIs), ibuprofen and artemisinin: cost savings and material efficiency benefits are evaluated for CPM vs. batch processing, with two continuous options for each API. Capital Expenditure (CapEx) savings of up to 57.0% and 19.6% and corresponding Operating Expenditure (OpEx) savings of up to 51.6% and 29.3% have been determined for ibuprofen and artemisinin, respectively. Total projected cost savings for a 20-year plant lifetime can reach 54.5% and 20.1%, respectively. Environmental (E)-factors (mass of waste generated per unit mass of product) of 43.4 (for ibuprofen) and 12.2 (for artemisinin) have been computed, indicating environmental and material efficiency advantages for these conceptual continuous pharmaceutical processes.     

Structural design of fully thermally coupled distillation column using approximate group methods

The thermally coupled distillation column systems can save energy and capital cost compared with traditional distillation columns. Since the thermally coupled column system was introduced, the design concerns have been peeped out due to more degrees of freedom. This paper introduces a new design method that can be used to determine the structure of thermally coupled distillation column systems, namely the number of stages in all sections of the column system. The design method employs the approximate group methods. To explore the design performance of the proposed design method, three feed systems are analyzed to investigate its usefulness. The design procedure gives the optimum structure for a given ternary separation; with given product specifications various design methods can yield approximately the same results. Like structure designs, the optimal internal flow distributions are examined. The results indicate that the method works well for a variety of process conditions.     

Graphical design and analysis of thermally coupled sidestream columns using column profile maps and temperature collocation

A systematical procedure is presented to design thermally coupled sidestream units like side rectifiers and side strippers are presented in this article. The method combines the column profile map technique to assess topological characteristics of the specific configuration with temperature collocation to rigorously ensure a realizable column design, without making assumptions with regard to the phase equilibrium or product specifications. The proposed methodology offers a unique graphical insight into the challenging problem of thermally coupled column synthesis. Techniques are presented for highlighting superior designs or eliminating inferior ones, based on vapor flow rate, number of stages, and thermodynamic efficiency. Design parameters such as the feed and side‐draw trays that may require insight or experience are products of the procedure. Design solutions obtained using this methodology can be used to initialize the state of the art process flow sheeting tool, AspenPlus?, which typically leads to fast convergence to the desired product purities without further adjustments. © 2010 American Institute of Chemical Engineers AIChE J, 2011     

Integration of Design and Control: A Robust Control Approach Using MPC

This paper presents a new method to integrate process control with process design. The process design is based on steady‐state costs, .i.e., capital and operating costs. Control is incorporated into the design in terms of a variability cost. This term is calculated based on the non‐linear process model, represented here as a nominal linear model supplemented with model parameter uncertainty. Robust control tools are then used within the approach to assess closed‐loop robust stability and to calculate closed‐loop variability. The integrated method results in a non‐linear constrained optimization problem with an objective function that consists of the sum of the steady costs and the variability cost. Optimization using the traditional sequential approach and the new integrated method was applied to design a multi‐component distillation column using a Model Predictive Control (MPC) algorithm. The optimization results show that the integrated method can lead to significant cost savings when compared to the traditional sequential approach. In addition, an RGA analysis was performed to study the effects of process interactions on the optimization results.     

Flowsheet simulation of aqueous two‐phase extraction systems for protein purification

BACKGROUND: Aqueous two‐phase extraction (ATPE) has many advantages as an efficient, inexpensive large‐scale liquid–liquid extraction technique for protein separation. However, the realization of ATPE as a protein separation technology at industrial scales is rather limited due to the large, multidimensional design space and the paucity of design approaches to predict phase and product behavior in an integrated fashion with overall system performance. This paper describes a framework designed to calculate suitable flowsheets for the extraction of a target protein from a complex protein feed using ATPE. The framework incorporated a routine to set up flowsheets according to target protein partitioning behavior in specific ATPE systems and a calculation of the amounts of phase‐forming components needed to extract the target protein. The thermodynamics of phase formation and partitioning were modeled using Flory‐Huggins theory and calculated using a Gibbs energy difference minimization approach. RESULTS: As a case study, suitable flowsheets to recover phosphofructokinase from a simple model feedstock using poly(ethylene glycol)‐dextran (PEG6000‐DxT500) and poly(ethylene glycol)‐salt (PEG6000‐Na₃PO₄) two‐phase systems were designed and the existence of feasible solutions was demonstrated. The flowsheets were compared in terms of product yield, product purity, phase settling rate and scaled process cost. The effect of the mass flowrates of phase‐forming components on product yield and purity was also determined. CONCLUSION: This framework is proposed as a basis for flowsheet optimization for protein purification using ATPE systems. Copyright © 2010 Society of Chemical Industry     

Technoeconomic Mixed Integer Nonlinear Programming (MINLP) optimization for design of Liquid-Liquid Extraction (LLE) cascades in continuous pharmaceutical manufacturing of atropine

Continuous Pharmaceutical Manufacturing (CPM) offers operational and economic benefits over the currently dominant methods implemented by industry. The demonstrated continuous flow synthesis of atropine facilitates modeling and optimization of its upstream continuous manufacturing. This study implements MINLP optimization of a continuous Liquid-Liquid Extraction (LLE) flowsheet superstructure for total cost minimization of an upstream atropine CPM plant. The steady-state process model considers reactor design from regressed kinetic parameters including investigation of maximum allowable PFR reactor dimensions to maximize the benefits of API flow synthesis. Continuous LLE modeling considers solute partitioning between phases, UNIFAC-modeled liquid–liquid equilibria and mass transfer correlations for LLE design. Optimal LLE design configurations from the considered superstructure require fresh solvent added to the first vessel in co-current flow in addition to the countercurrent flow in the cascade. Optimization results indicate toluene as the best solvent choice, with total costs of 3.944 × 10⁶ GBP for a plant capacity of 10³ kg API year⁻¹.     

Dividing Wall Distillation Columns: Optimization and Control Properties

The optimal design of dividing wall columns is a non‐linear and multivariable problem, and the objective function used as optimization criterion is generally non‐convex with several local optimums. Considering this fact, in this paper, we studied the design of dividing wall columns using as a design tool, a multi‐objective genetic algorithm with restrictions, written in Matlab^TM and using the process simulator Aspen Plus^TM for the evaluation of the objective function. Numerical performance of this method has been tested in the design of columns with one or two dividing walls and with several mixtures to test the effect of the relative volatilities of the feed mixtures on energy consumption, second law efficiency, total annual cost, and theoretical control properties. In general, the numerical performance shows that this method appears to be robust and suitable for the design of sequences with dividing walls.     

Methodology for design and analysis of reactive distillation involving multielement systems

A new methodology for design and analysis of reactive distillation has been developed. In this work, the element-based approach, coupled with a driving force diagram, has been extended and applied to the design of a reactive distillation column involving multielement (multicomponent) systems. The transformation of ordinary systems to element-based ones and the aggregation of non-key elements allow the important design parameters, such as the number of stages, feed stage and minimum reflux ratio, to be determined by using simple diagrams similar to those regularly employed for non-reactive systems consisting of two components. Based on this methodology, an optimal design configuration is identified using the equivalent binary-element-driving force diagram. Two case studies of methyl acetate (MeOAc) synthesis and methyl-tert-butyl ether (MTBE) synthesis have been considered to demonstrate the successful applications of the methodology. Moreover, energy requirements for various column configurations corresponding to different feed locations are determined to verify whether the optimal design can be identified by following the proposed methodology.     

Analysis and optimization of cross-flow reactors with distributed reactant feed and product removal

A systematic and general model was proposed for the simulation of cross-flow reactors with product removal and reactant feed policies. Six types of cross-flow reactors were analyzed for reversible series-parallel reaction systems and their optimal feed distributions were determined by maximizing the desired product yield at the outlet of the reactor. The performances of reactors with different types of feed policies were compared at their optimal operating conditions. For irreversible reaction systems with lower order in distributed reactant for the desired reaction than those for undesired reactions, a higher yield and selectivity of the desired product could be achieved with the reactors with staged feed than with conventional co-feed reactors and a sufficiently high residence time was required by staged feed reactors to significantly improve the desired product yields and selectivities over those obtained by a co-feed reactor. However, for reversible reaction systems, the desired product yield always reached a maximum value, and then dropped down as the residence time increased. In addition to the kinetic order and residence time requirements, the rate constants of the reactions involved have to fall within certain ranges for the distributed feed reactor to obtain a higher maximum yield than one-stage co-feed reactors. Optimally distributed feed reactors always give higher maximum product yields than evenly distributed reactors with the same number of feed points. However, the improvement of yields is not as great as that between co-feed reactors and evenly distributed reactors. On the other hand, for reaction systems with higher order with respect to the distributed reactant in the desired reaction than the undesired reactions, co-feed reactors always give higher yield than staged feed reactors.     

Dynamic Matrix Control of a Bubble‐Column Reactor for Microbial Synthesis Gas Fermentation

A spatiotemporal metabolic model of a representative syngas bubble‐column reactor was applied to design and evaluate dynamic matrix control (DMC) schemes for regulation of the desired by‐product ethanol and the undesired by‐product acetate. This model was used to develop linear step response models for controller design and also served as the process in closed‐loop simulations. A 2 × 2 DMC scheme with manipulation of the liquid and gas feed flows to the column provided a superior performance to proportional integral (PI) control due to slow process dynamics combining the multivariable and constrained nature of the control problem. Ethanol concentration control for large disturbances was further improved by adding the flow of a pure hydrogen stream as a third manipulated variable. The advantages of DMC for syngas bubble‐column reactor control are demonstrated and a design strategy for future industrial applications is provided.     

A framework for assessing the solutions in chromatographic process design and operation for large‐scale manufacture

Chromatographic separation of biopharmaceuticals is complex and tools for the prediction of performance and the trade‐offs necessary for efficient operation are limited and time‐consuming. This complexity is due to the large number of possible column aspect ratios that satisfy process and economic needs. This paper demonstrates a framework for the design and analysis of chromatographic steps. The functionalities are illustrated by application to a Protein A separation where the effects of column diameter, bed length and linear flow rate on cost of goods (COG/g) and productivity (g h^?1) are investigated so as to identify the optimal operating strategy. Results are presented as a series of ‘windows of operation’ to address key design and operating decisions. The tool allows the designer to customise limiting constraints based on product‐ and process‐specific knowledge. Results indicate the significant impact on COG/g of column oversizing and how this can be balanced by increased levels of productivity. Copyright © 2006 Society of Chemical Industry     

Optimization and Control of Pressure Swing Adsorption Processes Under Uncertainty

The real‐time periodic performance of a pressure swing adsorption (PSA) system strongly depends on the choice of key decision variables and operational considerations such as processing steps and column pressure temporal profiles, making its design and operation a challenging task. This work presents a detailed optimization‐based approach for simultaneously incorporating PSA design, operational, and control aspects under the effect of time variant and invariant disturbances. It is applied to a two‐bed, six‐step PSA system represented by a rigorous mathematical model, where the key optimization objective is to maximize the expected H₂ recovery while achieving a closed loop product H₂ purity of 99.99%, for separating 70% H₂, 30% CH₄ feed. The benefits over sequential design and control approach are shown in terms of closed‐loop recovery improvement of more than 3%, while the incorporation of explicit/multiparametric model predictive controllers improves the closed loop performance. © 2012 American Institute of Chemical Engineers AIChE J, 59: 120–131, 2013     

Rigorous synthesis and simulation of complex distillation networks

Recent insights for better understanding the thermodynamic foundations of separation processes have renewed the interest in exploring energy‐efficient distillation networks. Complex column networks have substantial potential for energy savings over conventional configurations. This article introduces a computational algorithm for synthesizing such complex energy‐efficient networks. A robust feasibility criterion drives the selection of design specification and operating conditions. It will be shown that columns composed of sections whose liquid stage composition profiles have no gaps are realizable. To prove the rigor of design computations, numerous separation networks were synthesized and validated with the Aspen flowsheet simulator. By using our computational results as input, AspenPlus simulations converged in a few iterations. Our method builds on temperature collocation, a thermodynamically motivated search method for determining feasible operating conditions and design details for achieving the desired product targets. Our findings suggest that significant energy savings can be realized with rigorous complex networks synthesis for industrial separation problems. © 2010 American Institute of Chemical Engineers AIChE J, 2011     

Methodology for the design and evaluation of distillation systems: Exergy analysis,economic features and GHG emissions

This work presents a process design methodology that evaluates the distillation systems based on exergetic, economic, and greenhouse gas (GHG) emission aspects. The aim of the methodology is to determine how these three features should be applied in process design to obtain information about the accuracy of the design alternatives. The methodology is tested and demonstrated on three different energy‐integrated distillation systems: the direct sequence with backward heat‐integration (DQB), fully thermally coupled distillation column (FTCDC), and sloppy distillation system with forward heat‐integration (SQF). The average relative emission saving is the highest for the DQB scheme and this sequence shows the most flexible range of use. The case studies prove the accuracy of our evaluation methodology. On the other hand, it highlights and demonstrates that the exergy analysis can predict the results of the economic study and the environmental evaluation to make the decisions, associated with process design, much simpler. © 2009 American Institute of Chemical Engineers AIChE J, 2010     

Periodic reactive flow simulation: Proof of concept for steam cracking coils

Streamwise periodic boundary conditions (SPBCs) have been successful in reducing the computational cost of simulating high aspect ratio processes. Extending beyond the classic assumptions of constant property flows, a novel approach incorporating non‐equilibrium kinetics was developed and implemented for the simulation of an industrial propane steam cracker. Comparison with non‐periodic benchmarks provided validation as relative errors on the main product yields were consistently below 1% for different reactor configurations. A further order‐of‐magnitude reduction of the radial errors on product concentrations was obtained via an intuitive correction method based on the concept of local fluid age. The computational speedup achieved through application of SPBCs was a factor 16–250 compared to the non‐periodic simulations. The presented methodology thus serves as a quick screening tool for the development of novel reactor designs and unlocks the potential for using more elaborate kinetic models or a more fundamental approach toward turbulence modeling. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1715–1726, 2017     

Minimum energy of multicomponent distillation systems using minimum additional heat and mass integration sections

Heat and mass integration to consolidate distillation columns in a multicomponent distillation configuration can lead to a number of new energy efficient and cost‐effective configurations. In this work, a powerful and simple‐to‐use fact about heat and mass integration is identified. The newly developed heat and mass integrated configurations, which we call as HMP configurations, involve first introducing thermal couplings to all intermediate transfer streams, followed by consolidating columns associated with a lighter pure product reboiler and a heavier pure product condenser. A systematic method of enumerating all HMP configurations is introduced. The energy savings of HMP configurations is compared with the well‐known fully thermally coupled (FTC) configurations. HMP configurations can have very similar and sometimes even the same minimum total vapor duty requirement as the FTC configuration is demonstrated, while using far less number of column sections, intermediate transfer streams, and thermal couplings than the FTC configurations. © 2018 American Institute of Chemical Engineers AIChE J, 64: 3410–3418, 2018     

Influence of fiber slippage coefficient distributions on the geometry and performance of composite pressure vessels

In this article, the effects of several slippage coefficient distributions on the geometry, fiber trajectories, and the structural efficiency of non‐geodesic domes are evaluated for composite pressure vessels. Several functions, which ensure C¹ continuity of the winding trajectories, are respectively used to describe the slippage coefficient distributions along the fiber paths. With the aid of the fiber slippage law and the optimality condition of equal shell strains, the differential equations that govern the non‐geodesics–based dome shapes and related fiber trajectories are formulated. The meridian profiles and winding angle developments of the carbon–epoxy domes are obtained based on the given slippage coefficient distributions; their structural performances are then determined and compared with each other. The results conclude that the non‐geodesic dome designed using the maximum constant slippage coefficient exhibits better performance than those using other slippage coefficient distributions; this is mainly triggered by maximum utilization of the longitudinal strength of the laminate. It is also revealed that the structural efficiency of domed pressure vessels can be improved using non‐geodesics that provide higher degrees of freedom in the design of filament wound structures. POLYM. COMPOS., 315–321, 2016. © 2014 Society of Plastics Engineers     

Process Intensification for the Recovery of Hydrogen Cyanide in the Andrussow Process

The aim of this work was to determine a cost-optimal design of the distillation unit of the Andrussow process. For this purpose, a feed with a mass flow rate of 121 t h⁻¹ and a concentration of ca. 2 wt % hydrogen cyanide (HCN) was considered. An approach for a cost-optimal process intensification was developed with the goal to achieve the desired product qualities, while minimizing the organonitrile accumulation in the column. For this purpose, the simple distillation column of the established cost-optimal design of the base case was extended to a configuration with a side stripper with taking into consideration heat integration in the process. It was found that this new configuration allows a much smaller accumulation of organonitriles in the main column; reducing thereby the operation issues of the process while decreasing considerably the total annual cost of the distillation unit by 61 % as compared to that of the base case design.     

Dynamic risk analysis using alarm databases to improve process safety and product quality: Part II—Bayesian analysis

Part II presents step (iii) of the dynamic risk analysis methodology; that is, a novel Bayesian analysis method that utilizes near‐misses from distributed control system (DCS) and emergency shutdown (ESD) system databases—to calculate the failure probabilities of safety, quality, and operability systems (SQOSs) and probabilities of occurrence of incidents. It accounts for the interdependences among the SQOSs using copulas, which occur because of the nonlinear relationships between the variables and behavior‐based factors involving human operators. Two types of copula functions, multivariate normal and Cuadras–Augé copula, are used. To perform Bayesian simulation, the random‐walk, multiple‐block, Metropolis–Hastings algorithm is used. The benefits of copulas in sharing information when data are limited, especially in the cases of rare events such as failures of override controllers, and automatic and manual ESD systems, are presented. In addition, product‐quality data complement safety data to enrich near‐miss information and to yield more reliable results. Step (iii) is applied to a fluidized‐catalytic‐cracking unit (FCCU) to show its performance. © 2011 American Institute of Chemical Engineers AIChE J, 2012     

Miniplanttechnik zur Schwermetallentfernung mittels reaktiver Extraktionsverfahren

Mini‐plants offer enormous time and cost savings during the development of an industrial process. First product samples and the performance of the whole process with all recycle streams is the result, eliminating the need for pilot scale experiments. The potential use of reactive processes in a mini‐plant environment is discussed on different extraction techniques as are liquid‐liquid extraction, non‐dispersive membrane extraction and solvent impregnated resins.