E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals

Hu, Chuntian; Testa, Christopher J.; Born, Stephen C.; Wu, Wei; Shvedova, Khrystyna; Sayin, Ridade; Halkude, Bhakti S.; Casati, Federica; Ramnath, Anjana; Hermant, Paul; Takizawa, Bayan; O’Connor, Thomas; Yang, Xiaochuan; Ramanujam, Sukumar; Mascia, Salvatore

doi:10.1039/d0gc01397h

Cited by 24 publications

(19 citation statements)

References 41 publications

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“…A second concept, the continuous rotary plate filter (CRPF) was invented as part of an integrated continuous manufacturing pilot plant of Continuus Pharmaceuticals. Recent studies showed the potential of combined filtration and washing in the CRPF as a part of an end-to-end continuous manufacturing process [10,[23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

2022

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The continuous vacuum screw filter (CVSF) for small-scale continuous product isolation of suspensions was operated for the first time with cuboid-shaped and needle-shaped particles. These high aspect ratio particles are very common in pharmaceutical manufacturing processes and provide challenges in filtration, washing, and drying processes. Moreover, the flowability decreases and undesired secondary processes of attrition, breakage, and agglomeration may occur intensively. Nevertheless, in this study, it is shown that even cuboid and needle-shaped particles (l-alanine) can be processed within the CVSF preserving the product quality in terms of particle size distribution (PSD) and preventing breakage or attrition effects. A dynamic image analysis-based approach combining axis length distributions (ALDs) with a kernel-density estimator was used for evaluation. This approach was extended with a quantification of the center of mass of the density-weighted ALDs, providing a measure to analyze the preservation of the inlet PSD statistically. Moreover, a targeted residual moisture below 1% could be achieved by adding a drying module (Tdry = 60 °C) to the modular setup of the CVSF.

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Section: Introductionmentioning

confidence: 99%

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

2022

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“…Motivated by the benefits shown in Fig. 1 [6][7][8][9][10], the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches [1,6,8,[10][11][12][13][14][15][16][17][18]. A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [13].…”

Section: Introductionmentioning

confidence: 99%

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

2021

J Flow Chem

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Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.

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“…A few of the most advanced examples include; the flow synthesis of quinolone antibiotic ciprofloxacin, [7] end‐to‐end manufacturing process for aliskiren hemifumarate [8] solid‐supported synthesis of imatinib [9] development of a single dedicated platform for the multiple drug molecules [10] flow synthesis of rolipram using heterogeneous catalyst [11] four‐step continuous flow process for antihistamines from bulk alcohols, [12] seven‐step continuous flow synthesis of linezolid molecule [13] and continuous flow synthesis and purification of ibuprofen [14] . The development and operation of fully automated pilot plant enables efficient and end‐to‐end integrated continuous manufacturing of the pharmaceutical product and small drug molecules, [15–17] including continuous solvent recovery for sustainable manufacturing [18] Recently, Kappe et al. has developed a real‐time analysis platform and fully integrated multistep synthesis of an active pharmaceutical ingredient, mesalazine [19] …”

Section: Introductionmentioning

confidence: 99%

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

Patil

Atapalkar

Kulkarni

2021

Chemistry A European J

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Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.

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E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals

Abstract:
Much less waste was generated by the end-to-end Integrated Continuous Manufacturing (ICM) process compared to the batch process.

Cited by 24 publications

References 41 publications

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

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E-factor analysis of a pilot plant for end-to-end integrated continuous manufacturing (ICM) of pharmaceuticals

Abstract: Much less waste was generated by the end-to-end Integrated Continuous Manufacturing (ICM) process compared to the batch process.

Cited by 24 publications

References 41 publications

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

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Product

Resources

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Abstract:
Much less waste was generated by the end-to-end Integrated Continuous Manufacturing (ICM) process compared to the batch process.