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22 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2023 PharmTech.com continuous manufacturing Process description T he cont i nuou s ph a r m a ce ut ic a l A PI m a nu f a c- t ur i ng pi lot-pla nt has t h ree f lex ible modu les as shown in Figure 1. Module 1 is focused on feeding, mixing, pre-heating, and dispensing. Module 2 in- cludes a reaction system (tubular reactor). Module 3 performs separation and purification either using chromatographic separation technique or continu- ous crystallization technique. A digital twin of continuous API manufacturing process The process f lowsheet model is the heart of the dig- ital twin and consists of mathematical representa- tion of t hree modules wit h t he options of adding more as needed. The first module is for feeding and dispensing, and it consists of a refill unit, feed tank, pump, mixing, and preheater. The second module is for performing the chemical reactions required to produce the target APIs. This module consists of tubular reactors placed inside a heating and cooling jacket. Lastly, the third module is focused on sep- aration of the API from impurities. A continuous chromatographic model is currently used for sepa- ration purposes that can be easily replaced with any ot her t y pe of separation techniques, such as con- tinuous cr ystallization. Currently, the developed model librar y consists of 32 units across 10 t y pes that have been used to generate the integrated f low- sheet model. The model has been validated using experimental data. Our approach for the integrated mo d e l i n g of a cont i nuou s A PI m a nu f a c t u r i n g s y s tem foc u ses on c reat i ng t h ree modu les, d i s- cussed below, which can be f lex ibly combined to simulate many systems. Module 1: Reactant storage, dispensing, preheating, and mixing This module enables the design, simulation, scale-up, optimization, and control of four needed process functions: storing reactants and solvents for contin- uous feeding; dispensing reactants in solution at the desired mass f low rate; mixing all incoming streams rapid ly a nd homogeneou sly; a nd adju s t i ng t he temperatures of process streams. Figure 2 shows a process diagram of the module displaying storage, controlled f low rate, mixing, and pre-heating. The controlled variables are the refill amount and frequency, the overall process stream mass f low rate, the reactant ratio, and the tempera- tures of streams. The reactants are pre-heated before being brought into contact so that the reaction time and reactor temperature can be carefully controlled. This approach eliminates most heat transfer limita- tions during process scale-up. These f unctions have been modeled using mass a nd energ y ba la nces to dy na m ica l ly pred ict t he composition of the eff luent stream as a function of the input variables, the intrinsic dynamics of system subcomponents, and any perturbations or changes in settings. If the system is designed to have excess heating/cooling capacit y, and as long as the mi x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igure 3: Schematic representation of the PFR reactor module displaying the monitoring of conversion and temperature. FIGURE 1. Modular continuous API manufacturing process. FIGURE 2. A flexible dispensing/ heating/mixing module able to mix two reactants in any desired proportion and deliver them as a homogeneous stream heated to a desired temperature. ALL FIGURES COURTESY OF THE AUTHOR.