Process Modelling And Simulation For Continuous Pharmaceutical Manufacturing Pdf
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Lecture 9 – Modeling, Simulation, and Systems Engineering. Development steps. For ‘controls’ simulation, model. Process maps in semiconductor manufacturing. Epitaxial growth (semiconductor process) – process map for run-to-run control. INTRODUCTION TO MODELING AND SIMULATION Anu Maria. Modeling is the process of producing a model; a model. Than continuous simulation but it is much simpler to implement, and hence, is used in a wide variety of situations. Figure 1 is a schematic of a simulation study. Continuous processing in pharmaceutical manufacturing Download continuous processing in pharmaceutical manufacturing or read online books in PDF, EPUB, Tuebl, and Mobi Format. Click Download or Read Online button to get continuous processing in pharmaceutical manufacturing book now. This site is like a library, Use search box in the widget to.
Pharmaceutical corporations face rapidly rising R&D as well as production costs. Batch production processes are dominant in the pharmaceutical industry and have multiple advantages, including equipment flexibility, efficient high-fidelity quality control and the ability to recall specific batches; however, they suffer known disadvantages such as limited heat transfer and mixing scalability, and low operational asset efficiency. Continuous Pharmaceutical Manufacturing (CPM) has a documented promise to suppress costs (Schaber et al., 2011) and foster profitability. Continuous production techniques (Behr et al., 2004) can be easier to scale up and can be designed to be often more efficient in terms of both solvent and energy use (Kockmann et al., 2008). Therefore it is both timely and important to explore the expanding feasibility and applicability limits of this emerging technology, which has been repeatedly demonstrated (Mascia et al., 2013).
The literature has been extensively surveyed in order to identify a series of candidate Active Pharmaceutical Ingredients (API) suitable for CPM production. Ibuprofen (2-(4-isobutylphenyl)propanoic acid), the widely used non-steroidal anti-inflammatory drug, has emerged as an ideal candidate, because it is in high global demand and can provide a market share of appropriate size. Flowsheet synthesis and process modeling are vital for rapidly evaluating R&D potential evaluation. The flowsheet we have considered is based on a published organic synthesis pathway (Bogdan et al., 2009) and produces Ibuprofen using three plug flow reactors (PFRs) in series, followed by a final purification separation. Kinetic and thermodynamic parameter estimation modelling has been employed in order to compute essential data for design and the PFRs have been designed based on reported conversions of feedstock and intermediate organic molecules. The theoretically computed PFR volumes are in good agreement with experimental prototypes constructed for the same organic synthesis reactions.
The development of a continuous final purification step after the third PFR is also essential. The current state of the art relies on a batch process comprising 15 distinct steps in order to obtain Ibuprofen crystals at 99% purity. To fully realise the benefits of CPM, a suitable continuous alternative is necessary and has been designed. Hexane is a promising solvent for separating Ibuprofen, and a high recovery has indeed been achieved. Plantwide economic optimization has thus been considered to explore and ensure the viability and profitability of the proposed design, which is most promising if installed in an existing production facility.
REFERENCES
Behr, A., Brehme, V. a., Ewers, C.L.J., Grön, H., Kimmel, T. et al., 2004. New developments in chemical engineering for the production of drug substances. Eng. Life Sci. 4, 15–24. doi:10.1002/elsc.200406127
Bogdan, A.R., Poe, S.L., Kubis, D.C., Broadwater, S.J., McQuade, D.T., 2009. The continuous-flow synthesis of Ibuprofen. Angew. Chem. Int. Ed.48(45), 8547–8550. doi:10.1002/anie.200903055
Kockmann, N., Gottsponer, M., Zimmermann, B., Roberge, D.M., 2008. Enabling continuous-flow chemistry in microstructured devices for pharmaceutical and fine-chemical production. Chem. – Eur. J. 14, 7470–7477. doi:10.1002/chem.200800707
Mascia, S., Heider, P.L., Zhang, H., Lakerveld, R., Benyahia, B., Barton, P.I., Braatz, R.D., Cooney, C.L., Evans, J.M.B., Jamison, T.F., Jensen, K.F., Myerson, A.S., Trout, B.L., 2013. End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation. Angew. Chem. Int. Ed. 125(47), 12585–12589. doi:10.1002/ange.201305429
Schaber, S.D., Gerogiorgis, D.I., Ramachandran, R., Evans, J.M.B., Barton, P.I., Trout, B.L., 2011. Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind. Eng. Chem. Res. 50, 10083–10092. doi:10.1021/ie2006752
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Continuous Pharmaceutical Manufacturing (CPM) has been recognized as an increasingly promising multidisciplinary research domain, addressing the significant obstacles hampering sustainable profitability (increasing R&D costs, globalized competition, licensing protocols, legal and regulatory landscape changes). Introducing a viable alternative to traditional batch production processes, CPM has an expanding potential capable of achieving lower costs (Schaber et al., 2011), higher yields, more economical heat and solvent use, high mass transfer rates, rapid scalability and elimination of intermediate storage (Calabrese and Pissavini, 2011). The technical viability and process efficiency of CPM prototypes must however be investigated in detail, in order to ensure successful pilot-scale demonstrations (Mascia et al., 2013) which can be used toward reliable production-scale implementations keenly pursued by pharmaceutical corporations (Poechlauer et al., 2013).
Organic flow synthesis literature must thus be (and indeed, has been) extensively surveyed to identify a wide range of Active Pharmaceutical Ingredients (APIs) whose production has already been accomplished in continuous mode at laboratory scale. A wide range of promising API candidates have thus been identified as suitable for CPM implementation (Jolliffe and Gerogiorgis, 2015a), including ibuprofen and artemisinin, which have already been examined in recent publications (Jolliffe and Gerogiorgis, 2015b). Systematic flowsheet synthesis, process modelling and simulation are essential towards rapidly assessment of CPM potential, and are already widely applied for CPM case studies (Gernaey et al., 2012).
The present paper focuses on a plantwide process modeling and simulation study for the production of diphenhydramine, a first-generation antihistamine which has been developed and has anticholinergic, antitussive, antiemetic and sedative properties and is mainly used to treat allergies, drug-induced parkinsonism and other neurological symptoms; moreover, it has a strong hypnotic effect and is and FDA-approved nonprescription sleep aid, especially in the form of diphenhydramine citrate. Our process model is developed on the basis of a published continuous flow synthesis (Snead and Jamison, 2013), which demonstrates that this economically and societally important API can be produced using Plug Flow Reactors (PFRs) with molten ammonium salts, thereby allowing for heating heat well above the boiling point of all reaction components. Moreover, this method also achieves solvent and waste minimization, thereby reducing operating costs and suppressing hazards associated with excess and disposal of chemicals.
Process modelling and steady-state simulations have been conducted toward process design for the respective CPM routes, with novel kinetic expressions developed on the basis of published kinetic data from experimental campaigns and thermodynamic property estimations essential for process design. Economic evaluations of the respective plant construction and operation venture can accordingly be performed on the basis of plantwide mass and molar balances, in order to quantitatively evaluate the viability of a production-scale CPM process.
LITERATURE REFERENCES
1. Calabrese, G.S., Pissavini, S., 2011. From batch to continuous flow processing in chemicals manufacturing. AIChE J., 57(4): 828-834.
2. Gernaey, K.V., Cervera-Padrell, A.E., Woodley, J.M., 2012. A perspective on PSE in pharmaceutical process development and innovation, Comput. Chem. Eng., 42(1): 15-29.
3. Jolliffe, H.G., Gerogiorgis, D.I., 2015a. Process modelling and simulation for continuous pharmaceutical manufacturing of ibuprofen, Chem. Eng. Res. Des., 97: 175-191.
4. Jolliffe, H.G., Gerogiorgis, D.I., 2015b. Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin, Comp.-Aided Chem. Eng. (in press).
5. Mascia, S., Heider, P.L., Zhang, H. et al., 2013. End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification and final dosage formation, Angew. Chem. Int. Ed. 52(47): 12359-12363.
6. Poechlauer, P., Colberg, J., Fisher, E., et al., 2013. Pharmaceutical roundtable study demonstrates the value of continuous manufacturing in the design of greener processes, Org. Proc. Res. Dev.17(12): 1472-1478.
7. Schaber, S.D., Gerogiorgis, D.I. et al., 2011. Economic comparison of integrated continuous and batch pharmaceutical manufacturing: a case study, Ind. Eng. Chem. Res.50(17): 10083-10092.
8. Snead, D.R., Jamison, T.F., 2013. End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts, Chem. Sci. 4(7): 2822-2827.
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