Pharmaceutical Manufacturing Processes Research Articles

Biomass-Derived Nanoporous Carbon Honeycomb Monoliths for Environmental Lipopolysaccharide Adsorption from Aqueous Media

After undergoing biological treatment, wastewater still contains substances with endotoxic activity, such as lipopolysaccharide. However, due to the increasing practice of treating wastewater to make it suitable for drinking (potable reuse), the removal of these endotoxic active materials is crucial. These substances can be harmful to human health, leading to a condition called endotoxaemia. Furthermore, environmental endotoxins pose risks to pharmaceutical manufacturing processes and the quality of the final pharmaceutical products. Ultimately, the most significant concern lies with the patient, as exposure to such substances can have adverse effects on their health and well-being. Activated carbon has a proven efficiency for endotoxin removal; rice husk (RH), as a type of natural lignocellulosic agricultural waste, is a unique carbon precursor material in terms of its availability, large-scale world production (over 140 million tons annually), and is characterized by the presence of nanoscale silica phytoliths, which serve as a template to create additional meso/macropore space within the nanoscale range. High surface area RH/lignin-derived honeycomb monoliths were prepared in this study via extrusion, followed by carbonization and physical and chemical activation to develop additional pore space. The nanoporosity of the carbon honeycomb monoliths was established by means of low-temperature nitrogen adsorption studies, using calculations based on QSDFT equilibrium and BJH models, as well as mercury intrusion porosimetry (MIP) and SEM investigations. An alternative method for the elimination of the bacterial lipopolysaccharide (LPS)—a conventional marker—using filtration in flowing recirculation systems and the adsorbent activity of the monoliths towards LPS was investigated. Since LPS expresses strong toxic effects even at very low concentrations, e.g., below 10 EU/mL, its removal even in minute amounts is essential. It was found that monoliths are able to eliminate biologically relevant LPS levels, e.g., adsorption removal within 5, 30, 60, 90, and 120 min of circulation reached the values of 49.8, 74.1, 85.4, 91.3%, and 91.6%, respectively.

A Sustainability-Oriented Digital Twin of the Diamond Pilot Plant

The pharmaceutical industry is undergoing a significant transition from batch to continuous manufacturing, driven by increasing regulatory requirements and sustainability pressures. Digital twins (DTs) play a pivotal role in facilitating this transition by enabling real-time data visualisation, process optimisation, and predictive analytics. While substantial progress has been made in the development and application of DTs, particularly in industries such as energy and automotive, there remains a critical need for further research and development focused on creating sustainability-oriented digital twins tailored to pharmaceutical processes. In the pharmaceutical sector, DTs are being progressively utilised not only for real-time monitoring and analysis but also as dynamic training platforms for engineers and operators, enhancing both operational efficiency and workforce competency. This paper examines the University of Sheffield’s Diamond Pilot Plant (DiPP), a facility showcasing the future of pharmaceutical manufacturing through the integration of Industry 4.0 technologies and advanced sensors. This paper focuses on developing a data-driven model to predict energy consumption in a twin-screw granulator (TSG) within the DiPP. The model, based on second-degree polynomial regression, demonstrates strong predictive accuracy with R-squared values exceeding 0.8. By optimising energy performance indicators, this work aims to improve the sustainability of pharmaceutical manufacturing processes. This research contributes to the field of pharmaceutical manufacturing by providing a foundation for creating energy models and advancing the development of comprehensive DT.

Optimization and Evaluation of Cannabis-Based Magistral Formulations: A Path to Personalized Therapy.

The official implementation of pharmaceutical-grade cannabis raw materials for medicinal use has permitted doctors to prescribe and pharmacists to prepare cannabis-based formulations. The objective of the pharmaceutical development and manufacturing process optimization work was to propose a suppository formulation containing doses of 25 mg and 50 mg of tetra-hydrocannabinol (∆-9-THC) as an alternative to existing inhalable or orally administered formulations. The formulation could be used for rectal or vaginal administration, thereby providing dosage control in the treatment of endometriosis and other conditions involving pain. In this study, two substrates from suppositories with standardized Cannabis extractum normatum (CEX) were used: cocoa butter and Witepsol® H15. The long-term stability of CEX was investigated over a period of up to 24 months. The concentrations of ∆-9-THC, cannabidiol (CBD), and cannabinol (CBN) were determined using an HPLC method. Furthermore, the water content of the extract, the ethanol residue, and the microbiological purity were determined. The pharmaceutical properties of CEX-incorporated suppositories, namely content uniformity, hardness, softening time, total deformation time, disintegration time, and the release profile of ∆-9-THC, CBD, and CBN, were evaluated in order to develop optimal preparation procedures for pharmacists. Following a 24-month stability study on CEX, no significant alterations in component content were observed beyond the specified requirements. The disintegration time, total deformation time, and hardness of the suppositories based on Witepsol® H15 with CEX were found to be longer and higher, respectively, than those of suppositories formulated with cocoa butter. In vitro studies demonstrated that suppositories prepared with Witepsol® H15 exhibited superior release of ∆-9-THC compared to those prepared with cocoa butter. We suggest that pharmacists making prescription drugs in a pharmacy setting in the form of medical marijuana suppositories will receive a better release profile of the drug by choosing Witepsol® H15 as a substrate.

Exploring the impact of material selection on the efficacy of hot-melt extrusion.

Hot-melt extrusion (HME) has emerged as a versatile and efficient technique in pharmaceutical formulation development, particularly for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review delves into the fundamental principles of HME, exploring its application in drug delivery systems. A comprehensive analysis of polymers utilized in HME, such as hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone, is presented, highlighting their roles in achieving controlled drug release and improved stability. The incorporation of plasticizers, such as triacetin, poly(propylene glycol), glycerol, and sorbitol, is critical in reducing the glass transition temperature (Tg) of polymer blends, thereby enhancing the processability of HME formulations. A comparison of Tg values for various polymer-plasticizer combinations is discussed using different predictive models. For researchers and industry professionals looking to optimize drug formulation strategies, this article offers valuable insights into the mechanisms through which HME enhances drug solubility and bioavailability two critical factors in oral drug delivery. Furthermore, by reviewing recent patents and marketed formulations, the article serves as a comprehensive resource for understanding both the technical advancements and commercial applications of HME. Readers will gain a deep understanding of the role of polymers and additives in HME, alongside future perspectives on how emerging materials and techniques could further revolutionize pharmaceutical development. This review is essential for those aiming to stay at the forefront of pharmaceutical extrusion technologies and their potential to improve therapeutic outcomes. The review concludes that meticulous material selection is vital for advancing pharmaceutical manufacturing processes and ensuring optimal outcomes in HME applications, thereby enhancing the overall efficacy of drug delivery systems.

Effects of electroosmosis and entropy generation on a particulate-fluid suspension through peristaltic motion of Prandtl fluid: a numerical investigation

In thermodynamics, engineering, and environmental science, entropy generation are useful for comprehending complicated phenomena like heat transfer and fluid dynamics, analysing irreversibility, and optimising energy systems. Particulate-fluid flow with chemical reactions are employed in pharmaceutical manufacturing, catalytic converters, and combustion processes. This study provides insights into mass and thermal transmission analysis and influences of electroosmosis on flow of the Prandtl fluid in peristaltic micro-channel. The flow is also investigated considering the multiphase phenomenon influenced by chemical reaction. The flow problem modelling utilises lubrication theory with lengthy wavelengths and creeping flow assumptions. Furthermore, using Debye linearisation, the Poisson equation is simplified. The consequent structures for coupled ordinary differential equations have been handled by numerical solutions computed by using a highly efficient shooting technique with the help of NDSolve tool in Mathematica. It is concluded graphically that the profile of velocity declines with the increasing variation of porosity factor while enhances with the rise in Helmholtz-Smoluchowski velocity parameter. Thermal distribution increases with higher values of solid particle concentration and porous surface. It is evident that the concentration profile diminishes with the porosity coefficient but rises with the Helmholtz-Smoluchowski velocity factor.

Numerical study of entropy production and EMHD effects in a peristaltic motion of Prandtl fluid with solid particles and porous medium

Particulate-fluid flow involving chemical reactions plays a crucial role in pharmaceutical manufacturing, catalytic converters, and combustion processes. This research focuses on the analysis of mass and thermal transfer, highlighting the influence of electroosmosis and magnetic forces on the flow of Prandtl fluid through a peristaltic porous micro-channel. In addition, the multiphase flow attitude, affected by chemical reactions, is extensively examined. The flow model is formulated by utilizing the lubrication theory estimation, integrating lengthy-wavelength and creeping flow approximation to simplify the considered problem. To further simplify the problem, Debye linearization is used, resulting in a set of two ordinary differential equations. The outcomes indicate that velocity drops with rising magnetic field, while it enhances with the Helmholtz-Smoluchowski velocity coefficient. Furthermore, thermal distribution increases with greater concentrations of solid fragments and greater magnetic field. These findings provide valuable insights into optimizing mass and thermal conveyance in peristaltic problems, with potential appliances spanning numerous industrial and biomedical areas.

The effect of fenton oxidation on the quality of pharmaceutical industry wastewater: a case study of bod, cod, toc, and turbidity parameters

Abstract Chemical residues from pharmaceutical manufacturing processes possess the potential to pollute the environment, particularly the aquatic ecosystem. Environmental indicators include COD, BOD, TOC, and turbidity levels that exceed limits set by regulations. This research is focused on investigating fluctuations in the quantities of wastewater contaminant parameters from pharmaceutical manufacturing facilities before and after treatment with the fenton oxidation method, as well as examining the effectiveness of the fenton oxidation process on water quality using predetermined parameters. This study involves independent variables that included various dosages of Fe2+ and H2O2. Adjusting the pH of the water after stirring to 7 stimulates the flocculation process, which effectively eliminates contaminants, specifically variant 15g FeSO4 and 100 ml H2O2 which successfully lowers turbidity by 99.55%, reduces BOD by 60%, COD removal by 98.69%, and reduces TOC by 92.94%. Control variables include initial contaminant amount, pH, temperature and pressure, fenton oxidation process duration, and instrument conditions.

Model-based real-time optimization in continuous pharmaceutical manufacturing

In this work, real-time optimization (RTO) schemes are proposed and applied on a continuous pharmaceutical manufacturing process which consists of three units: synthesis unit, hot melt extrusion unit and direct compaction line. The developed RTO strategies calculate the operating conditions by optimizing the considered objective functions while satisfying the specific constraints. Moreover, the RTO schemes can cope with intentional changes in the process and unintentional changes such as disturbances. Results from simulations and experiments are presented in this work. An advantageous performance is achieved when using the developed schemes.

3D printing novel enteric capsule shells for personalized drug delivery

Individualized drug delivery presents a viable strategy for enhancing medication efficacy and patient safety. It involves producing small batches of custom dosages tailored to each patient’s individual needs. However, current pharmaceutical manufacturing processes are not designed for personalized dosage forms. Additive manufacturing processes have great potential in the pharmaceutical industry due to the customizable nature of 3D printing technologies and the increasing demand for customized pharmaceutics and drug delivery systems. Conventional enteric capsules are prepared by dip coating to achieve gastro-resistant release, but the manufacturing process is erratic and unreliable. This study aimed to investigate the feasibility of manufacturing enteric capsules from enteric polymers using the hot melt extrusion (HME) and fused filament fabrication (FFF) process. HME was utilized to prepare filaments using enteric polymers, Hypromellose acetate succinate (HPMC-AS), and Eudragit-L 100–55, with plasticizers, sorbitol, and polyethylene glycol 4000 (PEG-4000), and a thermoplastic polymer, polyvinyl alcohol (PVA). A computer-aided design program was utilized to design size 0 capsules. The prepared capsule design and filaments were used to fabricate capsules using the FFF process. Powdered red dye was used to simulate the drug and its release from FFF fabricated capsules was evaluated in simulated gastric and intestinal fluids, pH 1.2 and 6.8, respectively. Various combinations of enteric polymer, plasticizer, and thermoplastic polymer were examined. Thermogravimetric analysis (TGA) showed that the temperatures used for processing polymer blends were well below their thermal degradation temperatures, and dye release profiles were generated using image analysis software. This study demonstrates that capsules made with HPMCAS, PEG-4000, and PVA via the FFF process are suitable for controlling drug release and that the release profile can be modified by making small changes to the formulation.

A Review on Pharmaceutical Process Validation

This article provides an introduction and a brief of process validation in the pharmaceutical manufacturing process. Process validation deals with process design aspects and maintaining process control during commercialization. It also conveys that process validation is an ongoing program and aligns process validation activities with the product life cycle. When considering any product, quality is always a mandatory must-have. As a result, drugs must be produced with the greatest quality requirements. Process validation is a key stage in assessing and maintaining the quality of the final product. This article goes over the following topics: introduction, validation type, prospective validation, retrospective validation, concurrent validation, revalidation validation, process validation elements, documentation, validation master plan, validation methodology, and validation report. Process validation also emphasizes the role of objective statistics, statistical tools, and analyses, as well as understanding, identification, and control of variability, and assures consistent quality/productivity throughout the product's lifecycle. The validation research establishes and documents the accuracy, sensitivity, specificity, and repeatability of the firm's test techniques. Thus, validation is a vital component of quality assurance. In recent years, the importance of validation has grown significantly.

P19-72 Comparative risk profile of Dichloromethane (DCM) and non-halogenated solvent alternatives in pharmaceutical manufacturing processes

P19-72 Comparative risk profile of Dichloromethane (DCM) and non-halogenated solvent alternatives in pharmaceutical manufacturing processes

Non-invasive estimation of the powder size distribution from a single speckle image

Non-invasive characterization of powders may take one of two approaches: imaging and counting individual particles; or relying on scattered light to estimate the particle size distribution (PSD) of the ensemble. The former approach runs into practical difficulties, as the system must conform to the working distance and other restrictions of the imaging optics. The latter approach requires an inverse map from the speckle autocorrelation to the particle sizes. The principle relies on the pupil function determining the basic sidelobe shape, whereas the particle size spread modulates the sidelobe intensity. We recently showed that it is feasible to invert the speckle autocorrelation and obtain the PSD using a neural network, trained efficiently through a physics-informed semi-generative approach. In this work, we eliminate one of the most time-consuming steps of our previous method by engineering the pupil function. By judiciously blocking portions of the pupil, we sacrifice some photons but in return we achieve much enhanced sidelobes and, hence, higher sensitivity to the change of the size distribution. The result is a 60 × reduction in total acquisition and processing time, or 0.25 seconds per frame in our implementation. Almost real-time operation in our system is not only more appealing toward rapid industrial adoption, it also paves the way for quantitative characterization of complex spatial or temporal dynamics in drying, blending, and other chemical and pharmaceutical manufacturing processes.

An experimental study on flow behaviour of pharmaceutical powders during suction filling

Die filling is a crucial step in the pharmaceutical tablet manufacturing process. For industrial-scale production using rotary presses, suction filling is typically employed due to its significant efficiency advantages over gravity filling. Despite its widespread use, our understanding of the suction filling process remains limited. Specifically, there is insufficient comprehension of how filling performance is influenced by factors such as suction velocity, filling velocity, and the properties of the powder materials. Building on our previous research, this study aims to further investigate the effects of powder properties and process parameters (e.g., filling velocity, suction velocity, fill depth) on suction filling behaviour. A systematic experimental investigation was conducted using a model suction filling system, considering both cohesive and free-flowing pharmaceutical powders. The effect of fill depth on suction filling of these powders was examined at different filling and suction velocities. The results demonstrate that two distinctive flow regimes for suction filling can be identified: slow filling and fast filling. These regimes are delineated by a critical filling-to-suction velocity ratio. In the slow filling regime, the filling-to-suction velocity ratio is lower than the critical ratio, meaning that the filling phase is slower than the suction phase. Conversely, the fast filling regime occurs when the filling-to-suction velocity ratio exceeds the critical ratio, implying that the filling phase is faster than the suction phase. This study reveals, for the first time, that when the powder flow pattern during suction filling is dominated by plug flow, full die fill (i.e., the fill ratio equals unity) is achieved in the slow filling regime. However, in the fast filling regime, incomplete die fill is obtained. It is also found that when plug flow prevails during fast filling, the fill ratio has an inverse correlation with the filling-to-suction velocity ratio. This study further reveals that when the plug flow assumption is valid, the filling ratio at various fill-to-suction velocity ratios can be well predicted mathematically. Furthermore, it is also found that once the powder flow pattern differs from the ideal plug flow, which could be induced by the filling conditions and powder cohesion, the fill ratio can be overpredicted.

Digital twinning, prediction and multi-objective optimization of an azeotrope system separation process in pharmaceutical manufacturing process

Digital twin is to make full use of the physical model, sensor update, operation history and other data to integrate multidisciplinary, multi-physical quantity, multi-scale and multi-probability simulation process, and to complete the full life cycle process of the corresponding physical equipment in the virtual space. In this paper, digital twin technology was used to simulate the production process of a pharmaceutical workshop, thus realizing solvent recovery by an azeotrope system separation process. The separation was optimized by multi-objective genetic algorithm. separation process, wherein the polynomial curve fitting and entropy-weighted TOPSIS data evaluation algorithms were combined to optimize the operating parameters, then the solvent purity and yield reach 99.96 % and 77.9 %, respectively, which is much higher than the corporate requirements. In addition, the effectiveness of the digital twin in providing data-driven prediction capability was verified by a CNN-LSTM-based regression prediction model, and the CNN-LSTM model has an accuracy of more than 98.9 % for all prediction results. Finally, a 3D visualization model was built using the Unity engine, enabling researchers to visualize and explore changes in key metrics during the separation process. This study can provide some guidance for digital transformation and intelligent development in pharmaceutical industry.

Mass Inspection and Contaminants Inspection Technology in the Pharmaceutical Manufacturing Process

Mass Inspection and Contaminants Inspection Technology in the Pharmaceutical Manufacturing Process

A systematic comparison of four pharmacopoeial methods for measuring powder flowability

Powder flow is one of the crucial factors affecting several pharmaceutical manufacturing processes. Problems due to insufficient powder flow reduce production process efficiency and cause suboptimum product quality. The U.S. Pharmacopoeia has specified four methods to evaluate the flowability of pharmaceutical powders, including angle of repose (AoR), compressibility index (CI) and Hausner ratio (HR), Flow through an orifice, and shear cell. Comparison within and between those methods with 21 powders (covering a wide range of flowability) was performed in this study. Strong correlation was observed between fixed base cone AoR, and fixed height cone AoR (R2 = 0.939). CI and HR values calculated from a tapped density tester (meeting USP standards), manual tapping, and Geopyc® correlated strongly (R2 > 0.9). AoR, CI/HR, minimum diameter for flowing through an orifice (dmin), and shear cell results generally correlate strongly for materials with flowability worse than Avicel® PH102. Both shear cell and CI/HR methods can reliably distinguish powders exhibiting poor flow. For materials with good flow, the ability to distinguish powders follows the order of AoR ≈ CI/HR > shear cell > dmin. The systematic comparison of the four common methods provides useful information to guide the selection of methods for future powder flow characterization. Given the limitations observed in all four methods, we recommend that multiple techniques should be used, when possible, to more holistically characterize the flowability of a wide range of powders.

Diversification of Pharmaceutical Manufacturing Processes: Taking the Plunge into the Non-PGM Catalyst Pool.

Recent global events have led to the cost of platinum group metals (PGMs) reaching unprecedented heights. Many chemical companies are therefore starting to seriously consider and evaluate if and where they can substitute PGMs for non-PGMs in their catalytic processes. This review covers recent highly relevant applications of non-PGM catalysts in the modern pharmaceutical industry. By highlighting these selected successful examples of non-PGM-catalyzed processes from the literature, we hope to emphasize the enormous potential of non-PGM catalysis and inspire further development within this field to enable this technology to progress toward manufacturing processes. We also present some historical contexts and review the perceived advantages and challenges of implementing non-PGM catalysts in the pharmaceutical manufacturing environment.

Theoretical Approaches to Process Validation in Pharmaceutical Manufacturing Process

Under the more general statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act, validation of manufacturing processes is deemed a legal part of current good manufacturing practice for active pharmaceutical ingredients (APIs). Validation of manufacturing processes is required by the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR 211.100 and 211.110). A medication should be created that is suitable for its intended purpose, according to the fundamental tenet of quality assurance. Procedure Validation is the collection and estimation of data that proves a process can reliably produce high-quality goods, starting with process design and continuing through commercial production. Three stages of validation are suggested by the 2011 USFDA process validation guideline - Process design, Process qualification, Continued Process qualification. An introduction and broad review of process validation in the pharmaceutical manufacturing process, specifically in the tablet manufacturing process, are provided in this article. Process validation ensures that a process will consistently create a product that meets its predefined quality features and qualities. It is a crucial step in the design, prototyping, and manufacturing processes. Since quality is always a necessary precondition for any product, pharmaceuticals must be produced to the greatest standards of quality. Furthermore, end-product testing does not ensure the product's quality on its own; rather, quality assurance methods need to be applied to incorporate the product's quality throughout the whole process, rather than only testing it at the conclusion.

Isolation and purification of high molecular weight adiponectin from human plasma fraction

Adiponectin, a crucial protein hormone originating from adipose tissue, regulates key metabolic processes, including lipid metabolism, mitochondrial activity, and insulin sensitivity. These pleiotropic roles of adiponectin, along with its inverse correlation with metabolic disorders such as obesity, type II diabetes, and atherosclerosis, establish this protein as a potential therapeutic target. However, due to this complexity, challenges have arisen in its production with a natural conformation in bacterial or mammalian expression systems, hindering clinical translation. Furthermore, while inducers for adiponectin secretion or chemical agonists targeting adiponectin receptors have shown promise in laboratory settings, clinical studies with these agents have not yet been conducted. This study proposes a method for isolating and purifying natural high molecular weight (HMW) adiponectin from discarded plasma fractions during the conventional pharmaceutical protein manufacturing process. The process involved Cohn-Oncley fractionation, initial chromatography using reduced cellufine formyl, and subsequent purification via DEAE Sepharose chromatography. Characterization involved gel electrophoresis and biological assays on a hepatocyte cell-line. The purification process effectively captured adiponectin from the I + III paste, demonstrating that this fraction contained a significant portion of total plasma adiponectin. The two-step chromatography led to highly purified HMW adiponectin, confirmed by native-PAGE showing a 780 kDa multimeric complex. Biological assessments demonstrated normal downstream signaling, with HMW adiponectin inducing AMPK phosphorylation. This study demonstrates the feasibility of obtaining purified HMW adiponectin by repurposing plasma fractionation processes. It offers a promising avenue for the HMW adiponectin production, tapping into HMW adiponectin’s therapeutic potential against metabolic disorders while optimizing plasma resource utilization in healthcare.

The feasibility of Raman spectroscopy for accurate assessment of essential criteria in pharmaceutical industry by investigation of Metformin hydrochloride tableting process

AbstractAnalytical and real‐time technology in pharmaceutical manufacturing process is an important need to ensure that manufactured drugs are safe and effective. Raman spectroscopy is an emerging technique that is able to perform quantitative analysis nondestructively due to the molecular structure of many drugs. Monitoring the content uniformity and quantification of active pharmaceutical ingredient (API) in the tablet preparation process, without the assistance of solvent, is one of the key concerns in the formulation design in order to provide stable, pure, and homogenous finished products. In this study, we investigated the possibility of using Raman data as an analytical method to quantify API, the intra‐ and inter‐sample uniformity of content in the tableting process of Metformin hydrochloride tablets (C4H11N5.HCl). Analysis of all standard samples for prediction of API uniformity represents an acceptable accuracy and precision with a relative standard deviation of 2.55%. Further investigation of tablets regarding to relative Raman intensity of some characteristic peaks demonstrates the amount of API content with an accuracy of ≥96%. These values have a good adaption with pharmacopeia monograph. Findings reveal that the Raman method can be routinely utilized for quantifying API, controlling the content uniformity and the stability of drugs in different stages of manufacturing.