Process Modeling, Simulation, and Technoeconomic Evaluation of Separation Solvents for the Continuous Pharmaceutical Manufacturing (CPM) of Diphenhydramine

Continuous pharmaceutical manufacturing (CPM) is a promising new paradigm to produce active pharmaceutical ingredients (APIs), allowing reduced equipment dimensions, lower waste production and energy consumption, and safer operation in comparison to the industrially dominant batch methods. Rufinamide is an antiepileptic agent whose demonstrated continuous flow synthesis (featuring three reactions in flow) circumvents the accumulation of toxic and explosive organoazide intermediates. To ascertain the feasibility and viability of this continuous synthetic route, systematic process modelling and costing is required. This paper presents a technoeconomic analysis of the upstream continuous flow synthesis of rufinamide via steady-state process modelling and plantwide simulation. Reaction kinetics and Arrhenius parameters are estimated from previously published experimental data, and plug flow reactor (PFR) volumes are calculated towards rigorous plant costing. Continuous reactor and separator units have been designed, and the CPM flowsheet is compared vs. the batch production method, with respect to technical efficiency and profitability. Plantwide costing via an established economic analysis methodology has been pursued to enable a detailed comparison of cost items towards process scale up,as well as motivate the need for further systematic optimisation

Technoeconomic evaluation of separation solvents and technologies for Continuous Pharmaceutical Manufacturing (CPM) of Four Key Drug Substances (DS)

Continuous Pharmaceutical Manufacturing (CPM) has the potential to revolutionise the pharmaceutical industry via operating and economic benefits over traditional batch techniques. Establishing efficient continuous separation processes following continuous flow syntheses of Active Pharmaceutical Ingredients (APIs) is essential to obtain the desired physical form of drug substance (DS) and successful CPM implementation. Process modelling and optimisation are essential tools for rapid screening of design alternatives to establish cost optimal process configurations for separation unit operations in integrated upstream CPM plants. This paper presents the technoeconomic optimisation for total cost minimisation for the continuous liquid-liquid extraction (LLE) of (S)-warfarin and the continuous mixed suspension mixed product removal (MSMPR) crystallisation of cyclosporine, paracetamol and aliskiren. Optimisation of continuous LLE of (S)-warfarin compares candidate separation solvents and operating temperatures with solvent feed rate and LLE tank residence time as decision variables; optimisation of continuous crystallisation processes compares the number of implemented crystallisers with MSMPR operating temperatures and residence times as decision variables. Capital (CapEx), operating (OpEx) and total expenditures are compared for different designs, elucidating cost-optimal configurations for each API with their attained recoveries and respective operating conditions. This work demonstrates the value of total cost minimisation via nonlinear optimisation prior to expensive experimental investigations and the potential of the economic benefits attainable via CPM for these APIs.</p

Dynamic simulation, optimisation AND ECONOMIC ANALYSIS of FED-BATCH vs. perfusion bioreactors for advanced mAb manufacturing

The variation of antigen binding sites on monoclonal antibodies (mAbs) enables manufacturing of the latter for targeted treatment of a variety of ailments, including cancer types and autoimmune diseases. Fed-batch operation of biochemical reactors used to manufacture mAbs grants the ability to manipulate cell dynamics via intermittent feeding of nutrients/substrates. Regulatory authority agendas (e.g. the U.S. Food &amp; Drug Administration) consider the development of continuous technologies (e.g. perfusion reactors) as essential towards improved technoeconomic potential and biopharmaceuticals quality control. This paper presents dynamic simulations for multiple operational scenaria of a fed-batch and a perfusion reactor, in which a hybridoma cell culture is used to secrete mAb glycoforms. A novel dynamic optimisation of the fed-batch as well as perfusion reactors has also been conducted towards maximising the total mAb mass produced. Nonlinear Programming (NLP) formulations with the use of APOPT and IPOPT solvers have been employed to derive the manipulation, state and controlled variable trajectories, to achieve the mAb production maximisation objective. The detailed technoeconomic analysis clearly highlights strong benefits for the fed-batch bioreactor (especially over a plant-life time horizon), but also showcases a definite cost-related promise of perfusion bioreactor technologies, given the higher mAb yield.</p

No More Than Three: Technoeconomic Mixed Integer Nonlinear Programming Optimization of Mixed Suspension, Mixed Product Removal Crystallizer Cascades for Melitracen, an Antidepressant API

Mixed Suspension, Mixed Product Removal (MSMPR) crystallizers have been considered in numerous cases as a continuous mode of operation in the production of Active Pharmaceutical Ingredients (APIs). The steady-state continuous MSMPR crystallization of melitracen via cooling has been recently demonstrated in the literature, with crystallization kinetic parameters regressed from experimental data. Mixed Integer Nonlinear Programming (MINLP) has been implemented extensively for the optimization of separation process designs in various manufacturing sectors, but not for systematic design and screening of MSMPR cascade flowsheet configurations. This study performs MINLP optimization to maximize the Net Present Value (NPV) of a MSMPR cascade for continuous melitracen crystallization with solid recycling. Process flowsheets consider varying numbers of crystallizers and recycle stream feed point location. First, the MSMPR model describing API solubility, crystallization kinetics, population balance equations, and process mass balances is described. The MINLP problem and constraints are then described with detailed costing equations. The optimal flowsheet configuration for both considered plant capacities (103 and 104 kg API yr–1) is three crystallizers with recycling fed to the first and last vessels. This study illustrates rapid screening of continuous crystallization cascades via MINLP optimization, toward fully Continuous Pharmaceutical Manufacturing (CPM) plant designs

Flow synthesis kinetics for lomustine, an anti-cancer active pharmaceutical ingredient

Continuous flow synthesis of active pharmaceutical ingredients (APIs) can offer access to process conditions that are otherwise hazardous when operated in batch mode, resulting in improved mixing and heat transfer, which enables higher yields and greater reaction selectivity. Reaction kinetic parameter estimation from flow synthesis data is an essential activity for the development of process models for drug substance manufacturing unit operations and systems, facilitating a reduction of experimental effort and accelerating development. The flow synthesis of lomustine, an anti-cancer API, in two flow reactors (carbamylation + nitrosation stages) was recently demonstrated by Jaman et al. (Org. Process Res. Dev., 2019, 23, 334). In this study, we postulate kinetic rate laws based on hereby proposed reaction mechanisms presented for the first time in the literature for this API synthesis. We then perform kinetic parameter regression for the proposed rate laws, on the basis of published data, towards establishing reactor models. For the carbamylation (irreversible reaction), we compare two candidate reaction rate laws, an overall third-order rate law (first-order in each reagent) deriving best fit. For the nitrosation, we propose two substitution reactions on the basis of published mechanisms (a rate-limiting equilibrium step, followed by a fast irreversible reaction) with very good model fit