Continuous Manufacturing: Definitions and Engineering Principles

Khinast, Johannes; Bresciani, Massimo

doi:10.1002/9781119001348.ch1

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…An integrated continuous manufacturing plant contains numerous operations, beginning with active pharmaceutical ingredient (API) synthesis, purification, crystallization, and drying in primary manufacturing (dry powder as an intermediate product) and continuing with feeding, blending, tableting/capsule filling, optional coating, and packaging in secondary manufacturing (e.g., such an end-to-end continuous manufacturing approach to tablet production was proposed by Mascia et al).…”

Section: Introductionmentioning

confidence: 99%

Continuous Drying of Pharmaceutical Powders Using a Twin-Screw Extruder

Kreimer

Aigner

Lepek

et al. 2018

Org. Process Res. Dev.

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Continuous manufacturing of pharmaceuticals offers such benefits as production flexibility, reduced drug product costs, and improved product quality. Moving toward continuous manufacturing requires suitable small-scale equipment, either by development of new equipment or optimization of existing equipment. In primary manufacturing, particle properties are often altered during crystallization and have to be restored during subsequent processing. Drying a crystallized product is one of the most challenging steps, especially since attrition and agglomeration can occur. To that end, we investigated the drying behavior of a crystalline model compound with moisture levels of up to 10 wt % in a corotating twin-screw extruder. The feed mass flows on a piece of small-scale equipment used for pharmaceutical production varied between 0.5 and 2.0 kg/h. Experiments were conducted to evaluate the drying performance in various process settings. Because of a very narrow and consistent residence time distribution, extrusion drying has the potential for pharmaceutical compound drying. In our study, we successfully accomplished drying of a crystalline product with very little agglomeration and/or attrition in some process settings while preserving a crystal size similar to that of the raw material. The reduction in particle size occurred as a result of long residence times (low extruder screw speed) and a decrease in the residual moisture of the product. The aim of our work was to show the potential of extruder drying as a novel continuous manufacturing process for pharmaceuticals and to enable further process development.

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Section: Introductionmentioning

confidence: 99%

Continuous Drying of Pharmaceutical Powders Using a Twin-Screw Extruder

Kreimer

Aigner

Lepek

et al. 2018

Org. Process Res. Dev.

Self Cite

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“…Introducing a selected number of steps may impart additional flexibility to the CM as well. 21 As CM has a small footprint, they can be set up in a flexible and portable facility. For instance, a small-scale capsule-filling machine of a benchtop hot-melt extruder can just occupy a few square meters of floor space.…”

Section: Advantages Of CM Processmentioning

confidence: 99%

Can Continuous Manufacturing of Topical Semisolids by Hot Melt Extrusion Soon Be a Reality?

Matadh,

Echanur,

Suresh

et al. 2023

Mol. Pharmaceutics

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For more than five decades, pharmaceutical manufacturers have been relying heavily on batch manufacturing that is a sequential, multistep, laborious, and time-consuming process. However, late advances in manufacturing technologies have prompted manufacturers to consider continuous manufacturing (CM) is a feasible manufacturing process that encompasses fewer steps and is less tedious and quick. Global regulatory agencies are taking a proactive role to facilitate pharmaceutical industries to adopt CM that assures product quality by employing robust manufacturing technologies encountering fewer interruptions, thereby substantially reducing product failures and recalls. However, adopting innovative CM is known to pose technical and regulatory challenges. Hot melt extrusion (HME) is one such state-of-the-art enabling technology that facilitates CM of diverse pharmaceutical dosage forms, including topical semisolids. Efforts have been made to continuously manufacture semisolids by HME integrating the principles of Quality by Design (QbD) and Quality Risk Management (QRM) and deploying Process Analytical Technologies (PAT) tools. Attempts have been made to systematically elucidate the effect of critical material attributes (CMA) and critical process parameters (CPP) on product critical quality attributes (CQA) and Quality Target Product Profiles (QTPP) deploying PAT tools. The article critically reviews the feasibility of one of the enabling technologies such as HME in CM of topical semisolids. The review highlights the benefits of the CM process and challenges ahead to implement the technology to topical semisolids. Once the CM of semisolids adopting melt extrusion integrated with PAT tools becomes a reality, the process can be extended to manufacture sterile semisolids that usually involve more critical processing steps.

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“…Tank-in-series (TIS) and axial dispersion (AD) models were used for RTD modeling. TIS models were developed by Equations (10) and (11) using the combination of plug flow models and multiple same sized continuously stirred tank reactors. The model bases on three parameters.…”

Section: Operation Block Modelmentioning

confidence: 99%

“…Measuring and modeling of the residence time distribution (RTD) represent a key part in the development, as RTD describes process dynamics [ 8 ] and can be used in the new aspects of continuous technologies. Publications address batch definition, and material traceability using the RTD of the system [ 10 , 11 , 12 , 13 ]. Research studies show the relation between the required sampling frequency for analytical measurements and the process dynamics [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Process Design of Continuous Powder Blending Using Residence Time Distribution and Feeding Models

et al. 2020

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The present paper reports a thorough continuous powder blending process design of acetylsalicylic acid (ASA) and microcrystalline cellulose (MCC) based on the Process Analytical Technology (PAT) guideline. A NIR-based method was applied using multivariate data analysis to achieve in-line process monitoring. The process dynamics were described with residence time distribution (RTD) models to achieve deep process understanding. The RTD was determined using the active pharmaceutical ingredient (API) as a tracer with multiple designs of experiment (DoE) studies to determine the effect of critical process parameters (CPPs) on the process dynamics. To achieve quality control through material diversion from feeding data, soft sensor-based process control tools were designed using the RTD model. The operation block model of the system was designed to select feasible experimental setups using the RTD model, and feeder characterizations as digital twins, therefore visualizing the output of theoretical setups. The concept significantly reduces the material and instrumental costs of process design and implementation.

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Continuous Manufacturing: Definitions and Engineering Principles

Cited by 10 publications

References 20 publications

Continuous Drying of Pharmaceutical Powders Using a Twin-Screw Extruder

Continuous Drying of Pharmaceutical Powders Using a Twin-Screw Extruder

Can Continuous Manufacturing of Topical Semisolids by Hot Melt Extrusion Soon Be a Reality?

Process Design of Continuous Powder Blending Using Residence Time Distribution and Feeding Models

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