Continuous Manufacturing System Research Articles

Experimental and statistical study on the effect of process parameters on the quality of continuous fiber composites made via additive manufacturing

Ongoing research in additive manufacturing towards structural and industrial application has led to the use of commingled roving as a manufacturing feedstock for printing high fiber volume fraction composites. The prospects of using this technology for high performance applications necessitates the need for a comprehensive experimental investigation into the effects of processing parameters on the quality of an additively manufactured composite printed from commingled roving feedstock. In this work, transverse flexure and void fraction matrix pyrolysis testing are both performed to evaluate composite quality. The transverse flexure test is a testing approach that evaluates the quality of the interfacial fiber-matrix bond while the void fraction test estimates the void content in the printed composite. A full observational study consisting of 27 different test combinations is done to investigate the effects of three different process parameters namely, temperature, pressure, and print speed across three different levels. Composite samples were made from commingled roving of E-glass and amorphous PET using an in-house built continuous fiber composite digital manufacturing system. Least squares regression analysis is performed to study the main, interaction and quadratic effects of process parameters. A statistical regression model having an R2 adjusted value of 80.1% is generated from the transverse flexure study, which is used to explain main and interaction effects and also predict performance. Response surface plots are also generated and are used to optimize process parameters which can subsequently be of help in scaling up composite manufacturing. Results show that all three process parameters are highly statistically significant at the 0.01 level of significance. Pressure * Temperature and Pressure * Printspeed are significant interaction terms. Pressure plays a weightier role when print speed is increased or temperature is decreased as it closes more voids that would ordinarily have been introduced because of drop in polymer melt viscosity. Micrographic analysis is also performed.

Developing a Modular Continuous Drug Product Manufacturing System with Real Time Quality Assurance for Producing Pharmaceutical Mini-Tablets

The pharmaceutical industry has shown keen interest in developing small-scale modular manufacturing systems for producing medicinal products. These systems offer agile and flexible manufacturing, and are well-suited for use in situations requiring rapid production of drugs such as pandemics and humanitarian disasters. The creation of such systems requires the development of modular facilities for making solid oral drug products. In recent years, however, the development of such facilities has seen limited progress. This study presents a development of a prototype modular system that uses drop on demand (DoD) printing to produce personalized solid oral drug products. The system's operation is demonstrated for manufacturing mini-tablets, a category of pediatric drug products, in continuous and semi-batch modes. In this process, the DoD printer is used to generate molten formulation drops that are solidified into mini-tablets. These dosages are then extracted, washed and dried in a continuous filtration and drying unit which is integrated with the printer. Process monitoring tools are also incorporated in the system to track the critical quality attributes of the product and the critical process parameters of the manufacturing operation in real time. Future areas of innovation are also proposed to improve this prototype unit and to enable the development of advanced drug manufacturing systems based on this platform.

Analysis of a production line subject to degradation and preventive maintenance

This paper considers a continuous flow manufacturing system with two machines subjected to condition-based preventive maintenance, and separated by an intermediate buffer of finite capacity. Each machine can degrade into several discrete states characterized by different degradation levels and performance parameters, ranging from perfect functioning to complete failure. Unlike the existing literature, the proposed approach considers various side effect costs, including the cost related to quality deterioration. A methodology is developed to describe the degradation stochastic process, and to analyze the complex trade-off between the condition-based preventive maintenance and the buffer capacity. The obtained results show the importance of considering quality-related and other possible costs when selecting preventive maintenance policy to optimize the performance of the manufacturing system. It is also shown that the selection of preventive maintenance actions should be considered from the view of the whole system, rather than individual machines. The optimal solution depends on the different degradation levels of the upstream and downstream machines.

Microfluidic Device-Enabled Mass Production of Lipid-Based Nanoparticles for Applications in Nanomedicine and Cosmetics

The preparation of lipid-based nanoparticles (LNPs) using microfluidic devices offers significant advantages, such as precise size control and easy scale-up, in a continuous manufacturing system. However, improvements in this preparation method are needed to enhance LNP productivity to meet commercial, such as clinical and consumer, demands. Feeding a highly concentrated lipid solution into microfluidic devices to obtain a high concentration of LNPs is one of the ways to boost productivity. However, this has not been investigated in detail because a high concentration of lipids in ethanol makes it difficult to control the size and dispersity of LNPs. We previously developed iLiNP, a microfluidic device with simple baffle mixer structures, which can achieve rapid ethanol dilution. The applicability of iLiNP for producing LNPs by feeding a highly concentrated lipid solution has not been investigated. Herein, we demonstrate the preparation of monodispersed LNPs using a highly concentrated lipid solution. We compare the performance of iLiNP with those of three commercially available microfluidic devices. The area of the aqueous–ethanol interface and the dilution rate of ethanol significantly affects the size controllability and dispersity of LNPs at high lipid concentrations. Compared with other microfluidic devices, iLiNP could produce smaller and more concentrated (particles/mL) LNPs. We show that by controlling the LNP size using microfluidic devices, especially iLiNP, it is possible to feed highly concentrated lipid solutions. This feature of iLiNP could be a time- and cost-saving option for the mass production of LNPs for application in nanomedicine and cosmetics.

Applying probabilistic material flow analysis for quality control and management of waste recycling in steelmaking

In modern steelmaking, multiple processes comprise a continuous manufacturing system, but not all phosphorus content data are connected or integrated into a holistic and systematic database. Disconnected data hinder the improvement of material management and resource efficiency in the industry. The objective of this study was to establish a method to evaluate material flows, reduce uncertainty, and perform quality control for waste recycling in the steelmaking industry. The results indicate that 10% of the phosphorus input is present in the final products, 30% accumulates in the slags, and more than 60% of the total mass remains in the processes. Comparing the material flow analysis results obtained using static and probabilistic approaches, the partition ratio of the phosphorus content in slags changes from 24.07% to 40.78%, but that in processes changes from 49.10% to 68.05%. This indicates that the variations in phosphorus content in slags and processes might affect the effectiveness of slag recycling and might increase the resource consumption required to maintain the quality of final products. The probability of forming substandard products in the baseline scenario is 0.43. Adopting a 50% removal rate, the probabilities of forming substandard products are reduced to 0.36 (waste removal scenario), 0.38 (slag reduction scenario), and 0.31 (raw material treatment scenario). The performance of raw material treatment and waste removal is more efficient for quality control. The method used in this study can be applied to evaluate the possible outcomes of waste recycling and reduce the probability of forming substandard products.

Optimization of process parameter involved in the effectiveness evaluation of continuous line manufacturing system (CLMS)

To sustain in the global competitive market, the manufacturing organizations are adopting tools like Total Productive Maintenance (TPM), Lean Manufacturing (LM), etc. Implementation of these tools was assessed by an effectiveness index called Overall Equipment Effectiveness (OEE) Throughput Effectiveness (TE). Overall Manufacturing Line Effectiveness (OMLE) used as the performance evaluation index for the integrated tool {[}Total Productive Lean Manufacturing --TPLM{]} implementation performance has been assessed. OMLE is a robust metric of manufacturing performance that incorporates the measures like Line Availability (LA), Line Production Quality Performance (LPQP) of the product line. OMLE offers a means of controlling the whole production process by analyzing results from the totality of events with or without inventory between the processes in the product line. In the presentpaper, the attempt made towards identifying the bottleneck parameter (Losses in the processes --category A, the Cycle time in the processes-category B, Inventory between the process -- category C) in the bottleneck processes of the n number of the processes product line through programming (software in C). Also, the top three parameters of the processes in the n process product line have been obtained easily towards executing improvements by the engineers and managers. Analyze it with the change of inventory and zero inventory between the five, seven, and nine different processes product line processes. The suggested improvement activities (obtained from the OMLE evaluation and optimization program) are validated in south India's real case study organization and improved the bottleneck processes and losses in the product line.

PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy

The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With mu...

Residence time distribution as a traceability method for lot changes in a pharmaceutical continuous manufacturing system

Residence time distribution (RTD) models were developed to track raw material lots and investigate batch transitions in a continuous manufacturing system. Two raw materials with similar physical properties (granular metformin and lactose) were identified via Principal Component Analysis (PCA) from a library of bulk material properties and used to simulate the switching of lots during production. In-line near-infrared (NIR) spectra were collected with the powder flowing through a chute in a continuous manufacturing system to monitor metformin and lactose concentration in step-change experiments with Partial Least Squares (PLS) models. RTD provided an understanding of raw material propagation through the continuous manufacturing system. Transition times between raw material changes were identified using the results of two multivariate approaches PLS and PCA. The methodology was implemented to discriminate the transition zone in a raw material change, contributing to design control strategies for acceptance and diverting mechanisms.

Artificial neural networks in tandem with molecular descriptors as predictive tools for continuous liposome manufacturing

The current study utilized an artificial neural network (ANN) to generate computational models to achieve process optimization for a previously developed continuous liposome manufacturing system. The liposome formation was based on a continuous manufacturing system with a co-axial turbulent jet in a co-flow technology. The ethanol phase with lipids and aqueous phase resulted in liposomes of homogeneous sizes. The input features of the ANN included critical material attributes (CMAs) (e.g., hydrocarbon tail length, cholesterol percent, and buffer type) and critical process parameters (CPPs) (e.g., solvent temperature and flow rate), while the ANN outputs included critical quality attributes (CQAs) of liposomes (i.e., particle size and polydispersity index (PDI)). Two common ANN architectures, multiple-input-multiple-output (MIMO) models and multiple-input–single-output (MISO) models, were evaluated in this study, where the MISO outperformed MIMO with improved accuracy. Molecular descriptors, obtained from PaDEL-Descriptor software, were used to capture the physicochemical properties of the lipids and used in training of the ANN. The combination of CMAs, CPPs, and molecular descriptors as inputs to the MISO ANN model reduced the training and testing mean relative error. Additionally, a graphic user interface (GUI) was successfully developed to assist the end-user in performing interactive simulated risk analysis and visualizing model predictions.

The Performance Value of Quantitative Feeder Used by Continuous Manufacturing System for the Direct Compression

The Performance Value of Quantitative Feeder Used by Continuous Manufacturing System for the Direct Compression

Research progress of continuous manufacturing and process knowledge system of traditional Chinese medicine

In the past few years, continuous manufacturing(CM) has been put forward by the FDA. Pharmaceutical enterprises are encouraged to promote the implementation of CM, which has become a hot research direction of pharmaceutical technology. In February 2019, the FDA issued a draft guideline for the implementation of CM, which greatly promoted the development of CM and provided reference for continuous manufacturing of traditional Chinese medicine(TCM). The production process of TCM is a complex system. With the innovation of production equipment and the promotion of automation and informatization of TCM production, the exis-ting policies, regulations and traditional production control capacity are difficult to meet the market demand for high-quality TCM pro-ducts. In this paper, we reviewed the new technologies and methods of quality control in accordance with the characteristics of TCM production by referring to modern manufacturing technology, information technology and quality control technology. Based on the "QbD" theory and "PAT" technology, process knowledge system(PKS), an advanced control strategy, was proposed to provide a reference for the implementation of CM in TCM production.

Improved Manufacturability and In Vivo Comparative Pharmacokinetics of Dapagliflozin Cocrystals in Beagle Dogs and Human Volunteers

Dapagliflozin (DAP), which improves glycemic control in patients with type 2 diabetes mellitus, has poor physical properties against heat and moisture, thus hindering its manufacturing potential. The superior physicochemical properties of a recently developed cocrystal of DAP and citric acid (DAP cocrystal) in comparison with those of DAP and Forxiga®, a patented solvate form with propandiol monohydrate, were identified via structural analysis and moisture sorption isotherm. For the first time, the formulation, manufacturability, and in vivo bioavailability of DAP cocrystals were successfully investigated to develop oral dosage forms that substitute Forxiga®. The intrinsic dissolution rate of DAP cocrystal was controlled by varying particle size distribution. Unlike the direct compression (DC), roller compaction (RC) was more preferable to obtain good flowability of dry granules for a continuous manufacturing system. The cocrystal structure was maintained throughout the stability assessment period. In Vitro dissolution pattern differences of the optimized DAP cocrystal tablet with RC and the reference tablet, Forxiga® 10 mg, were pharmaceutically equivalent within 5% in four different media. Furthermore, comparative pharmacokinetic analysis confirmed that a 10 mg DAP cocrystal tablet with RC was bioequivalent to a 10 mg Forxiga® tablet, as assessed in beagle dogs and human volunteers.

Control of residence time of pharmaceutical powder in a continuous mixer with impeller and scraper.

The control of residence time in a powder mixing process was investigated toward the development of a continuous pharmaceutical manufacturing system. A powder mixer equipped with an impeller and a scraper, which was designed for a continuous granulation machine, was used. The mixing homogeneity and dynamic behavior of the powder in the mixer were investigated by using a tracer, acetaminophen, in impulse- and step-response experiments. The homogeneity of the mixture was guaranteed by the high rotation speed of the impeller, independent of the speed of the scraper. The mean residence time of the powder was controlled by changing the scraper speed. The hold-up weight in the mixer was also changed by the scraper speed. In the measurement of the hold-up weight, the scraper speed also affected the powder filling density. These results confirmed that the scraper equipped in the mixer transported powder towards the exit of the mixer, and that both the scraper's rotation speed and its shape are key parameters for flexibly controlling the residence time of powder in the mixer. These experimental results can provide useful information for adjusting the residence time in order to optimize conditions for the corresponding continuous granulation system.

Development of Direct Compression Continuous Manufacturing System for Low-Dose Drug Products

Development of Direct Compression Continuous Manufacturing System for Low-Dose Drug Products

A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients

Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in recent years. Most Nutsche filters offer a versatile solution as compact filtration and drying devices. However, conventional drying processes tend to generate a large amount of lumps, usually requiring further mechanical processing of the isolated drug substance before it can be formulated. In this work, we present a compact, automatable filtration device that takes advantage of a unique impeller design and in situ measurements of the drying heat duty to integrate mechanical processing into the drying step. By preventing the formation of dry lumps during drug substance drying, and breaking needle-like crystals through the developed agitation program, the resulting powder can be directly used for tablet formulation. This device, designed to fit in a compact continuous manufacturing module, has the potential to reduce manufacturing costs and footprint, while allowing for the low-shear mechanical processing of heat-sensitive compounds.

A MULTI-CRITERIA DECISION MAKING MODEL FOR CERAMIC TILES CONVEYOR SELECTION

Material handling is one of the activities in manufacturing that can drastically affect not only the production cost but also the performance of the entire line, particularly in continuous and transfer manufacturing system. Therefore, selecting the most appropriate material handling equipment is a critical decision that should be could be carefully studied in the early stages of manufacturing system design. This paper is mainly concerned with selecting the most appropriate conveyor for handling ceramic tiles during it production phases. The handling process in this application is characterized by dealing with fragile product as well as exposure to high temperature. Generally, such a decision inherently entails several conflicting qualitative and quantitative criteria. Accordingly, a multi-criteria decision making model has been developed using the Analytic Hierarchy Process (AHP) to assist the system designer in selecting the most appropriate conveyor. In this study, four conveyor alternatives have been considered. The results of the model implementation recommended slat conveyors as the best alternative for serving in the ceramic tile manufacturing environment, followed by belt and chain conveyors, while the last one in the ranking is the roller conveyor. Besides, the developed model can be used to perform sensitivity analysis to explore how the decision could be affected in response to changes in the decision maker’s preferences related to the considered criteria.

Continuous manufacturing of a pharmaceutical cream: Investigating continuous powder dispersing and residence time distribution (RTD)

Recently, an innovative continuous manufacturing technology for a pharmaceutical oral suspension was proposed, based on two consecutive mixing units. A limitation of this technology is the need to dissolve or disperse powder-based raw materials in a liquid via a batch step before continuous manufacturing. Therefore, the aim of the current study was to develop and investigate a method to introduce powders continuously into the existing equipment via the implementation of two upstream continuous unit operations: a powder feeder and powder dispersing unit. A pharmaceutical cream was selected as model formulation to demonstrate the flexibility of the continuous manufacturing technology towards different types of semi-solid and liquid formulations. The ability to continuously feed and disperse active pharmaceutical ingredient (API) using the proposed method was assessed via an experimental design, in which the impact of several process parameters of the powder dispersing unit on the API concentration (relative error (RE) and relative standard deviation (RSD)) was examined. A Raman spectroscopic method was developed to quantify the API concentration in-line after the powder dispersing step. The API concentration was independent of the process parameters and fell within the acceptance limits, except for two experimental runs where a deviating API concentration was observed. These results demonstrate that the continuous powder feeding and dispersing method was suitable, and that a completely continuous manufacturing system was obtained. To achieve raw material traceability and understanding the mixing behavior, the residence time distribution (RTD) of a tracer inside the continuous manufacturing equipment was determined using a colorimetric technique. The time required to remove all tracer from the powder dispersing unit operation was very long (1481 s) and therefore the volume inside this unit operation should be reduced by designing new equipment with smaller dimensions. At the two consecutive mixing units, the peak and mean residence time were influenced by throughput, whereas mixing speed in both mixing units had a significant impact on the degree of axial mixing. Finally, the continuously manufactured cream had a similar rheological behavior as the original batch-wise manufactured cream.

Design of a register controller considering inherent characteristics of a roll-to-roll continuous manufacturing system

Roll-to-roll (R2R) continuous printing has served as a breakthrough for the mass production of flexible electronic devices. However, high-precision register control is an obstacle in the printing of multilayer flexible electronics with complex structures. In this study, we investigated the characteristics of register control and determined the inherent factors of register controllers that can generate register errors that cannot be solved by theory-based control methods. Considering these innate factors, we propose a design for a high-precision register controller. Our experimental results show that register errors that could not be solved by previous control methods are not generated in the proposed register control design. Further, the proposed design provides high-precision and stable control while maximizing the control rate in an industrial R2R printing machine. The study results suggest that innate factors in register controllers must be considered to achieve high-precision and stable register control within ± 10–30 μm. We also present guidelines for designing a high-precision register controller.

Continuous manufacturing of orally dissolving webs containing a poorly soluble drug via electrospinning

An orally dissolving web (ODW) formulation of poorly soluble carvedilol (CAR) was developed and manufactured continuously using electrospinning (ES) as a key technology. Phase solubility tests revealed that hydroxypropyl-β-cyclodextrin (HPβCD) solubilizer alone cannot ensure sufficient solubility (6.25 mg CAR in 20 mL) in the oral cavity even if citric acid was present to ionize the basic drug. In turn, electrospun amorphous nanofibers of polyvinylpyrrolidone K30 (PVPK30) and CAR exhibited notable supersaturation of the drug in the presence of citric acid. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of CAR. The final ODW was prepared by layering the nanofibers onto pullulan, a well-soluble polysaccharide film carrying citric acid. The double-layered formulation showed ultrafast disintegration and dissolution modeling the oral cavity meeting regulatory requirements (<30 s). The continuous production was accomplished using our recently developed continuous model system by controlled deposition of the nanofibers onto the carrier film strained to a wheel collector and followed by cutting into final dosage units. Performance tests of the continuous system revealed satisfactory content uniformity over time (average acceptance value = 9.45), while residual solvent content measurements showed trace amounts of ethanol (EtOH) after production and acceptable dimethyl-formamide (DMF) content with secondary drying at room temperature. The presented work demonstrates how ES can be part of a continuous manufacturing system as an advanced drying tool during the formulation of challenging drugs.

A continuous manufacturing concept for a pharmaceutical oral suspension

The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed via peristaltic pumps to the mixing compartment, which consists of two consecutive mixing units. An experimental design was used to study the influence of several process parameters (throughput, mixing speed in mixing unit 1 and mixing speed in mixing unit 2) on the quality attributes of the oral suspension. The pH, density, active pharmaceutical ingredient (API) concentration, sedimentation after 30 days (expressed by the sedimentation volume) and rheological characteristic (yield stress) of the suspension were determined. No significant influence of the process parameters on the pH, density and API concentration was observed. The throughput and mixing speed in mixing unit 1 had a significant impact on both the sedimentation volume and yield stress, and were therefore critical to acquire physical stable suspensions. Furthermore, the yield stress measured one day after production was predictive for the occurrence of sedimentation in the suspensions after 30 days. When selecting the optimal process settings, the continuously manufactured suspension had a similar product quality as the original batch-processed suspension and even possessed a higher yield stress. This study demonstrated that the investigated innovative continuous manufacturing technology is suitable for the manufacturing of a commercially available pharmaceutical suspension and that the product quality can be optimized by adjusting the process parameters.