Continuous Manufacturing Technology Research Articles

Manufacturing process of liposomal Formation: A coarse-grained molecular dynamics simulation

A method of producing liposomes has been previously developed using a continuous manufacturing technology that involves a co-axial turbulent jet in co-flow. In this study, coarse-grained molecular dynamics (CG-MD) simulations were used to gain a deeper understanding of how the self-assembly process of liposomes is affected by the material attributes (such as the concentration of ethanol) and the process parameters (such as temperature), while also providing detailed information on a nano-scale molecular level. Specifically, the CG-MD simulations yield a comprehensive internal view of the structure and formation mechanisms of liposomes containing DPPC, DPPG, and cholesterol molecules. The importance of this work is that structural details on the molecular level are proposed, and such detail is not possible to obtain through experimental studies alone. The assessment of structural properties, including the area per lipid, diffusion coefficient, and order parameters, indicated that a thicker bilayer was observed at higher ethanol concentrations, while a thinner bilayer was present at higher temperatures. These conditions led to more water penetrating the interior of the bilayer and an unstable structure, as indicated by a larger contact area between lipids and water, and a higher coefficient of lipid lateral diffusion. However, stable liposomes were found through these evaluations at lower ethanol concentrations and/or lower process temperatures. Furthermore, the CG-MD model was further compared and validated with experimental and computational data including liposomal bilayer thickness and area per lipid measurements.

Characterizing a design space for a twin-screw wet granulation process: A case study of extended-release tablets

Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.

Statistical Study of the Process Parameters for Achieving Continuous Consolidation of a Thermoplastic Composite.

Manufacturing components using thermoplastic composite materials necessitates a judicious balance among fabrication parameters, cost considerations and the ultimate quality of the elements produced. Continuous manufacturing technologies, exemplified by methods such as continuous compressing molding and glide forming, seek to revolutionize production through their continuous processing approach. This study aimed to investigate the effects different process parameters have on the final quality of the manufactured parts when a continuous manufacturing technology, such as glide forming, is applied to thermoplastic composite materials. An experimental rig was designed, and 19 samples were prepared using a unidirectional-carbon-fiber-reinforced LM-PAEK (low-melting polyaryletherketone) composite. The process parameters studied were temperature, pressure and forming speed. The quality of the final parts was evaluated based on their thickness and consolidation levels. The findings underscore the feasibility of leveraging continuous manufacturing technologies for producing components using thermoplastic composite materials, but the process parameters must be carefully controlled to ensure the quality of the final part. The models obtained could be used as a post-processing tool to predict thickness and consolidation levels when simulating the manufacture of a component on macroscale levels. Further research is needed to optimize the process parameters and study their effects on other thermoplastic composite materials.

Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations.

5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.

Current status, trends, and challenges of continuous manufacturing technology for oral traditional Chinese medicine solid preparations

In recent years, continuous manufacturing technology has attracted considerable attention in the pharmaceutical industry. This technology is highly sought after for its significant advantages in cost reduction, increased efficiency, and improved productivity, making it a growing trend in the future of the pharmaceutical industry. Compared to traditional batch production methods, continuous manufacturing technology features real-time control and environmentally friendly intelligence, enabling pharmaceutical companies to produce drugs more efficiently. However, the adoption of continuous manufacturing technology has been slow in the field of traditional Chinese medicine(TCM) pharmaceuticals. On the one hand, there is insufficient research on continuous manufacturing equipment and technology that align with the characteristics of TCM preparations. On the other hand, the scarcity of talent with diverse expertise hampers its development. Therefore, in order to promote the modernization and upgrading of the TCM pharmaceutical industry, this article combined the current development status of the TCM industry to outline the development status and regulatory requirements of continuous manufacturing technology. At the same time, it analyzed the problems with existing TCM manufacturing models and explored the prospects and challenges of applying continuous manufacturing technology in the field of TCM pharmaceuticals. The analysis focused on continuous manufacturing control strategies, technical tools, and pharmaceutical equipment, aiming to provide targeted recommendations to drive the development of the TCM pharmaceutical industry.

Research progress and maturity assessment of continuous manufacturing of traditional Chinese medicine

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.

The Rocky Road to a Digital Lab.

The pharmaceutical industry has begun incorporating continuous manufacturing technology in synthetic routes toward active pharmaceutical ingredients (APIs). The development of smart manufacturing routes can be accelerated by utilizing digitalization, process analytical technology (PAT), and data-rich experimentation from an early stage. Here, we present the key aspects of implementing automated flow chemistry reactor platforms with real-time process analytics. Based on our experiences in this field, we aim to highlight the potential of these platforms to conduct self-optimization, automated reaction model building, dynamic experiments and to implement advanced process control strategies.

Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate.

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.

White paper: Achieving high hoop strength for composite profiles using pull-winding

In straight tubes, any force applied to the cylindrical wall causes hoop stress. Tool handles, a mop handle for example, experience hoop stress when being used actively or roughly handled. To ensure composite tubes can meet these challenges, the profiles must be manufactured with cross-aligned fibers, providing extra stiffness and high mechanical strength in transverse direction. Here Lauri Turunen, product business owner for tubes, tool handles and telescoping poles and pull-winding expert at Exel Composites, compares different manufacturing techniques and explores how the continuous manufacturing technology of pull-winding can achieve high hoop strength.

Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation

In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

Microalgae-based circular supply chain configurations using Industry 4.0 technologies for pharmaceuticals

Renewable feedstocks and Industry 4.0 technologies in supply chains could operationalise circular economy and promote sustainable development. This study explores potential supply network configurations utilising microalgae feedstocks, whose bioactive morphology provides promising commercial opportunities, supported by continuous manufacturing technologies. Specifically, continuous microalgae cultivation photobioreactors and acoustic-based extractors, which leverage data, sensing, computation, and intelligent interconnection, enable centralised and decentralised network configurations. First, a value chain mapping approach was applied to the US pharmaceutical industry to illuminate how emerging microalgae platform technologies could stimulate the reconfiguration of medicine supply networks. Second, supply network modelling and scenario analysis allowed to explore supply chain configuration options for breast cancer pharmaceuticals in Texas. This research reveals that microalgae-based pharmaceutical supply networks using Industry 4.0 technologies could facilitate distributed manufacturing capabilities. The findings provide a foundation for galvanising future efforts toward exploiting renewable feedstocks and smart technologies for designing circular manufacturing networks.

Development of a continuous synthesis process for carbamazepine using validated in-line Raman spectroscopy and kinetic modelling for disturbance simulation

Mitigation of failure modes in the continuous synthesis (CS) of a drug substance (DS) has the potential to widen the adoption of continuous manufacturing (CM) technologies by the pharmaceutical industry.

Digital supply network design: a Circular Economy 4.0 decision-making system for real-world challenges

This research introduces the idea of ‘Circular Economy 4.0’ to reflect the emergence of ‘digitalised’ sustainable supply networks. While often characterised by enhanced productivity and resource/energy efficiency, current perspectives are largely descriptive with limited practical relevance. A hierarchical decision-making framework and a multi-level simulation modelling and optimisation technique are constructed to explore the interplay between Circular Supply Chains and Industry 4.0. The real-world case of blue-green algae as renewable feedstock – to derive value-added omega-3 oils and biofertilisers – is investigated to develop ‘Circular Economy 4.0’ perspectives. The emerging circular supply network utilises micro-factories (i.e., photobioreactors), continuous manufacturing technologies (i.e., piezoelectric transducers), and drone operations for feedstock availability monitoring. This study contributes to theory and practice by building on the limited empirical research exploring determinants of successful transitions in Circular Economy-Industry 4.0 network contexts. Four design principles are proposed that capture the interplay between digital technologies and network design configurations, e.g., centralised – semi-centralised – decentralised. Modelling is developed across macro-, meso-, and micro-levels of analysis. Results demonstrate significant gains in terms of resources utilisation and market dynamics, enabled by the adoption of digital operations in a circular economy context, with initial insights on the evolution of such networks.

Identification of continuous twin-screw melt granulation mechanisms for different screw configurations, process settings and formulation

Twin-screw melt granulation (TSMG) is a promising continuous manufacturing technology for the processing of high drug load formulations and to formulate heat- and moisture-sensitive active pharmaceutical ingredients (APIs). This study evaluates the influence of process parameters for TSMG, mainly focusing on the effect of the screw configuration combined with screw speed, throughput and barrel temperature, to elucidate the melt granulation mechanisms. For the kneading zone, the stagger angle was varied between 30°, 60° and 90°, and investigated for both the forward and the reversed direction. In addition to the process parameters, the influence of the formulation differing in their API-binder miscibility was evaluated. As responses, the granule (size, friability and porosity) and process properties such as torque were evaluated, indicating that the screw configuration is the most influential factor. Nucleation, consolidation and breakage are the granulation mechanisms for the forward and the neutral configuration, while consolidation and densification with shear elongation are identified for the reversed configuration. The formulations differ mainly in the forward and neutral configuration since the immiscible formulation shows a bimodal granule size distribution with a larger fraction of fines and weaker granules is obtained. For the reversed configuration, similar granulation mechanisms are seen for both formulations.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150g/h), extruder screw speed (150-300rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25μm from ~80μm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650g/h), lower extruder screw speed (150rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

Evaluation of different types of mannitol for dry granulation by roller compaction

Dry granulation by roller compaction (RC) is a continuous manufacturing technology increasingly used in the pharmaceutical industry for improving bulk density and flowability of powder mixtures or for preventing segregation issues of highly potent drugs prior to tableting. Dry granulation is ideally applied to moisture and heat sensitive drugs with added benefits also in terms of costs and lower equipment footprint. Mannitol is a polyol widely used in pharmaceutical formulations: particularly in orally dispersible tablets and powders and chewable tablets, where its high solubility and pleasant organoleptic properties make it an excipient of choice. Mannitol is available in several grades with different technological characteristics for adapting to various applications. In view of the use of mannitol for the formulation of active ingredients with poor flowability and compaction, the present work was aimed at analyzing the properties of the different commercial types of mannitol when used for dry granulation by roller compaction to obtain tablets. Mannitol raw materials and granules prepared by roller compaction at different pressure were characterized for particle size distribution, bulk density, flow properties, specific surface area and ability to tableting. Granules with proper size (500–1500 μm), increased bulk density and adequate flow properties could be obtained. Increased specific surface area of the granules suggested a fragmentation of the particles during roller compaction even at relatively low processing pressure confirming the brittleness of the materials. For all materials tested, satisfactory properties for enabling tableting process were shown.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs.

The subject of crystal engineering started in the 1970s with the study of topochemical reactions in the solid state. A broad chemical definition of crystal engineering was published in 1989, and the supramolecular synthon concept was proposed in 1995 followed by heterosynthons and their potential applications for the design of pharmaceutical cocrystals in 2004. This review traces the development of supramolecular synthons as robust and recurring hydrogen bond patterns for the design and construction of supramolecular architectures, notably, pharmaceutical cocrystals beginning in the early 2000s to the present time. The ability of a cocrystal between an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer to systematically tune the physicochemical properties of a drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is the hallmark of the pharmaceutical cocrystals platform, as a bridge between drug discovery and pharmaceutical development. With the design of cocrystals via heterosynthons and prototype case studies to improve drug solubility in place (2000-2015), the period between 2015 to the present time has witnessed the launch of several salt-cocrystal drugs with improved efficacy and high bioavailability. This review on the design, synthesis, and applications of pharmaceutical cocrystals to afford improved drug products and drug substances will interest researchers in crystal engineering, supramolecular chemistry, medicinal chemistry, process development, and pharmaceutical and materials sciences. The scale-up of drug cocrystals and salts using continuous manufacturing technologies provides high-value pharmaceuticals with economic and environmental benefits.

Coarse-Grained Molecular Dynamics Simulations of Paclitaxel-Loaded Polymeric Micelles.

A continuous manufacturing technology based on coaxial turbulent jet in coflow was previously developed to produce paclitaxel-loaded polymeric micelles. Herein, coarse-grained molecular dynamics (CG-MD) simulations were implemented to better understand the effect of the material attributes (i.e., the drug-polymer ratio and the ethanol concentration) and process parameters (i.e., temperature) on the self-assembly process of polymeric micelles as well as to provide molecular details on micelle instability. An all-atom (AA) poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) polymer model was developed as the reference for parameterizing a coarse-grained (CG) model, and the AA polymer model was further validated with experimental glass transition temperature (Tg). The model transferability was verified by comparing structural properties between the AA and CG models. The CG model was further validated with experimental data, including micelle particle size measurements and drug encapsulation efficiency. Furthermore, the encapsulation of paclitaxel into the polymeric micelles was included in the simulations, taking into consideration the interactions between the paclitaxel and the polymers. The results from various points of view demonstrated a strong dependence of the shape of the micelles on the drug encapsulation, with micelles transitioning from spherical to ellipsoidal structures with an increasing paclitaxel amount. Simulation data were also used to identify the critical aggregation number (i.e., the number of polymer and drug molecules required for transition from one shape to another). Improved micellar structural stability was found with a larger micellar size and less solvent accessibility. Lastly, an evaluation was performed on the micellar dissociation free energy using a steered molecular dynamics simulation over a range of temperatures and ethanol concentrations. These simulations revealed that at higher ethanol and temperature conditions, micelles become destabilized, resulting in greater paclitaxel release. The increased drug release was determined to originate from the solvation of the hydrophobic core, which promoted micellar swelling and an associated reduction in hydrophobic interactions, leading to a loosely packed micellar structure.

A Comparative Investment Analysis of Batch Versus Continuous Pharmaceutical Manufacturing Technologies.

PurposeThis study examines the risks and economics associated with investing in continuous (CM) versus conventional batch manufacturing for production of oral solid dosage pharmaceutical (OSD) products in the USA and abroad.MethodsA stochastic net present value (NPV) simulation of brand and generic manufacturing for new facilities is conducted comparing batch and continuous manufacturing processes leveraging actual industry financial revenue and cost information, and detailed engineering cost information of batch and CM manufacturing processes from a seminal manufacturing cost analysis of these two technologies.ResultsWhen looking at comparing investment in either CM or batch for a new U.S. facility, the results clearly suggest that the lower costs associated with CM technology should lead to both brand and generic companies investing in the more CM manufacturing technology. The simulation analysis demonstrated that under current U.S. tax rates, investing in batch technology at U.S. sites would be economically more attractive than investing in batch technology in China or India. Investing in CM technology in the USA under current tax rates results in positive expected net NPVs over batch technology investments in China or India for both brand and generic companies. U.S. tax policy has a material impact on whether pharmaceutical companies would decide to invest on the USA or not for their manufacturing.ConclusionsResults indicate that continuous manufacturing has the potential to make manufacturing of OSD pharmaceuticals more economically attractive in the USA than foreign manufacturing of those products.

Development of Tazverik® Tablet with Continuous Manufacturing Technology in Eisai

Development of Tazverik^® Tablet with Continuous Manufacturing Technology in Eisai