Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts

The Hitchhiker's Guide to Flow Chemistry

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

http://science.sciencemag.org/content/sci/352/6281/61.full.pdf

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system

Mechanical properties in the semi-solid state and hot tearing of aluminium alloys

The Food and Drug Administration (FDA) regulates pharmaceutical drug products to ensure a continuous supply of high-quality drugs in the USA. Continuous processing has a great deal of potential to address issues of agility, flexibility, cost, and robustness in the development of pharmaceutical manufacturing processes. Over the past decade, there have been significant advancements in science and engineering to support the implementation of continuous pharmaceutical manufacturing. These investments along with the adoption of the quality-by-design (QbD) paradigm for pharmaceutical development and the advancement of process analytical technology (PAT) for designing, analyzing, and controlling manufacturing have progressed the scientific and regulatory readiness for continuous manufacturing. The FDA supports the implementation of continuous manufacturing using science- and risk-based approaches.

/pdf/modernizing-pharmaceutical-manufacturing-from-batch-to-a85rskttu4.pdf

Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

/pdf/end-to-end-continuous-manufacturing-of-pharmaceuticals-3q0w3omsiq.pdf

End‐to‐End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation

The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuous process has not been built at large scale, so Wroth factors and other assumptions were used to estimate costs. Capital expenditures for continuous production were estimated to be 20 to 76% lower, depending on the drug loading, KI cost, and process chosen; operating expenditures were estimated to be between 40% lower and 9% higher. The novel continuous process with recycling coupled to a novel direct tablet formation process yields the best overall cost savings in each drug loading/KI price scenario: estimated savings range from 9 to 40%. Overall cost savings are also given assuming the yield in the continuous case is 10% above and 10% below that of the batch process. Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate.

Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing

The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuou...

/pdf/economic-analysis-of-integrated-continuous-and-batch-32w8azsybv.pdf

Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study

Modeling and optimization of polygeneration energy systems

https://www.pure.ed.ac.uk/ws/files/24789834/CACE_03_2016.pdf

Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) Cases: ibuprofen and artemisinin

Pharmaceutical corporations face rapidly rising process research and development (RD they however suffer disadvantages such as limited heat transfer and mixing scalability and low operational asset efficiency. Continuous Pharmaceutical Manufacturing (CPM) has a documented potential to reduce cost, as continuous production techniques can be easier to scale up and can be designed to be more efficient in terms of both solvent and energy use: therefore, it is both timely and important to explore the expanding feasibility limits of this emerging technology. The literature has been extensively surveyed in order to identify a series of candidate Active Pharmaceutical Ingredients (API) for flowsheet synthesis, process modelling and mass balance simulation toward rapid assessment of CPM potential. Ibuprofen [2-(4-isobutylphenyl)propanoic acid], the widely used non-steroidal anti-inflammatory drug (NSAID), has emerged as an ideal CPM candidate because it is in high global demand and can generate significant profit margins. The flowsheet is based on a published organic synthesis pathway and produces 50 kg of ibuprofen annually using three plug flow reactors (PFRs) in series, followed by a final separation for purification. Kinetic and thermodynamic parameter estimation modelling has been employed in order to compute essential data for design, and all PFR reactors have been designed based on reported conversions of feed and intermediate organic molecules in the respective organic synthesis reactions. Theoretically computed reactor designs are in good agreement with experimental prototypes constructed for the same organic synthesis, as well as in with previously reported CPM systems. The developed continuous final separation performs very well in accordance with green chemistry principles, with relatively low environmental impact ( E -factor  = 25.4).

/pdf/process-modelling-and-simulation-for-continuous-qy8uk7ud3a.pdf

Dimitrios I. Gerogiorgis

Papers

Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing

Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study

Modeling and optimization of polygeneration energy systems

Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) Cases: ibuprofen and artemisinin

Process modelling and simulation for continuous pharmaceutical manufacturing of ibuprofen