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In continuous powder handling processes, precise and consistent feeding is crucial for ensuring the quality of the final product. The intermixing effect caused by agitators, which alters the powder's bulk density, flow rate, and flow patterns, plays a significant role in this process, yet it is often overlooked. This study combines discrete element method (DEM) modeling and experiments using a commercial-scale feeder to propose a Digital Twin (DT) framework. The DEM model accurately captures key flow features, such as bypass trajectories, stagnant zones, and preferential flow patterns, while providing quantitative predictions for the feed factor and zones prone to material accumulation. Scenario analysis is performed to identify the most favorable operating ranges of the screw-agitator ratio and screw speed, considering the cohesive properties of the powder. The study demonstrates that powders with poor flow characteristics require tighter operational constraints, as the screw-agitator ratio is susceptible to variations in mass feed rate. This contribution highlights the importance of selecting an appropriate screw-agitator ratio instead of maintaining a fixed value. Properly choosing this ratio helps determine an optimal operation window, which aims to achieve a minimum agitation level needed to induce unhindered flow and reduce variability in the mass flow rate., (© 2024. The Author(s).)

This study investigates particle size segregation within the powder chamber of a vacuum drum-based capsule filling machine using various stirrer types and proposing novel designs to mitigate segregation. The stirrer is essential to the process, ensuring uniform density during volume-based filling. Three lactose grades, comprising 10% fine, 80% medium, and 10% coarse particles, were used, with tracer particles replacing fine or coarse particles, respectively. Dosages were collected over time for a line-array of five bores, and tracer concentrations were analysed using UV-Vis spectrophotometry. By visual assessments and stagnant zone observations particle segregation was evaluated and quantified by normalised tracer concentrations. Both standard and modified stirrers were examined under the same conditions. Stirrer type significantly influenced particle segregation, with the "spike" standard stirrer yielding the highest segregation, while the modified "3-wire m " and "coreless 3-wire m " stirrers exhibited superior performance, minimizing differences between fine and coarse particle concentrations and eliminating stagnant zones. These findings highlight promising prospects for further analysing the "3-wire m " and "coreless 3-wire m " stirrers. In that respect additional variables such as stirrer speed, rotation direction, and level of vacuum, need to be considered. Stirrer design significantly impacts vacuum drum-based capsule filling machine performance, ensuring reliable pharmaceutical capsule filling. This study offers insights into optimizing the industrial process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hot melt extrusion by a co-rotating twin screw extruder is an important process in the pharmaceutical industry. Especially for quality by design aspects, a comprehensive process understanding is indispensable. The performance of conveying elements was determined as critical process parameter, and therefore an experimental and numerical framework was developed to analyze and compare variations. A test rig capable of measuring volume flow, pressure and torque with high accuracy and precision was designed and built. The 3D simulation was performed using computational fluid dynamics (CFD). A stationary model with impulse transmission and an apparent motion of the screws was applied. The experimental data were fitted to the model of Pawlowski, and parameters for the pressure (A 1 , A 2 ) and power characteristics (B 1 , B 2 ) were determined. Good agreement between experimental data and the model was observed. The simulation was significantly faster compared to common methods, and the results were consistent with the literature. Systematic investigations of a native and worn screw were performed with CFD resulting in a transport capacity increase and a pressure build up decrease for all tested screw elements. An experimental and simulation setup was generated to assess the performance of co-rotating twin screw elements. The experiments provided high-quality data, and the simulations exhibited high flexibility with low computational effort.

A variety of strategies for producing high-quality nanoparticles have been reported in recent years. Batch-based bottom-up and top-down technologies are generally the most efficient methods, but present a number of challenges, particularly in terms of variability, safety, sustainability and large-scale production. In this study, a scalable, semi-continuous production line was built by connecting individual processing units, including a high shear mixing device, the Microfluidizer® technology and a cooling system. Each unit was equipped with an adequate temperature control to allow solvent-free production of solid lipid nanoparticles (consisting of Precirol® ATO 5 or Gelucire® 43/01) and nanostructured lipid carriers (additionally comprising Labrafac™ lipophile WL 1349). Subsequently, critical formulation parameters and critical process parameters (CPPs) of the individual processing units and their effects on particle size (i.e., critical quality attribute (CQA)) were investigated to identify appropriate input parameters for the subsequent Design of Experiment (DoE) studies conducted after linking the process units to a semi-continuous production line. For particle size monitoring, spatially resolved dynamic light scattering (SR-DLS) measurements were conducted and compared to standard DLS measurements to evaluate the applicability of SR-DLS as an inline monitoring tool. It was found that matrix composition, emulsifier concentration, pressure and number of cycles when processing through Microfluidizer® processor were the most influencing parameters. By optimizing these parameters, five-times higher throughputs could be achieved by the semi-continuous manufacturing line. In addition, the particle size measurements with SR-DLS confirmed the feasibility of implementing this technology for real-time particle size monitoring as an important safety factor in quality control., Competing Interests: Declaration of competing interest The authors confirm that they do not have any relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

STERIS and W.L. GORE collaborated on a case study testing the compatibility of a new prefilled syringe plunger design with VHP terminal sterilization. VHP chamber conditions require deep vacuum pulsing, which may represent challenges to prefilled syringe container integrity. The growing industry trend toward VHP sterilization is driven by the FDA search for alternative sterilization methods to EO and the recent publication of a VHP specific process standard. The purpose of the study is to test and report compatibility of the new 0.5 mL GORE IMPROJECT plunger, a silicone free syringe solution for ophthalmic application, with VHP sterilization. Various challenges have been reported when using conventional, siliconized, prefilled syringe systems for intravitreal injections such as subvisible particles, inflammation, silicone floaters, and intraocular pressure increases. The GORE plunger eliminates the need for silicone oil as a lubricant on the plunger and barrel, while meeting strict container closure and terminal sterilization requirements of ophthalmic applications. This case study presents successful results of deep vacuum VHP terminal sterilization process compatibility with the GORE plunger design and material composition. Test results include primary container integrity, stopper off-gassing/ingress, and visual inspection. Principles of VHP vacuum sterilization process, test cycle configuration, and its main parameters are presented., (© PDA, Inc. 2024.)

Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of a stream sampler to develop a near infrared (NIR) calibration model for blend uniformity monitoring in a continuous manufacturing mixing process. Feeding and mixing characterizations were performed for three loss-in-weight feeders and a commercial continuous mixer to prepare powder blends of 2.5-7.5 % w/w ibuprofen DC 85 W with a total throughput of 33 kg/h. The NIR spectral acquisition was performed after the mixing stage using a stream sampler for flowing powders. A continuous mixer shaft speed of 250 RPM was selected to operate the mixing process based on a variability analysis developed with in-line spectral data acquired using the stream sampler at 6 RPM. A partial least squares regression (PLS-R) model was performed and evaluated, yielding a root-mean-square error of prediction (RMSEP) of 0.39 % w/w and a bias of 0.05 % w/w. An independent experimental run conducted two days later revealed that the continuous mixing process and the NIR calibration model presented low day-to-day variation. The minimum practical error (MPE) and sill values through variographic analysis showed low variance associated with the sampling process using the stream sampler. Results demonstrated the promising capacity of the stream sampler coupled to an NIR probe to be implemented within continuous manufacturing processes for the real-time determination of API concentration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As lyophilization continues to be a critical step in the manufacturing of sensitive biopharmaceuticals, challenges often arise during the scale up to commercial scale or the transfer from one manufacturing site to another. While data from the small-scale development of the lyophilization cycle is abundant it is typically much more difficult to extract important information from commercial scale cycles, due to the lack of process analytical technologies available on the commercial line. There is often a reluctance to include wireless temperature or pressure probes during GMP operations due to the additional contamination risk, and retrofitting equipment such as the TDLAS can be prohibitively expensive. Further, as products become more advanced, the cost of consuming the product or even the availability of material may limit the opportunities to run commercial scale trials. This paper presents two novel methods to garner critical cycle information to allow for the evaluation of cycle performance without the need for expensive analytical equipment, costly revalidation and line downtime. Critically, this can be achieved using commonly available temperature and capacitance probes on existing commercial scale equipment. The first method is a calorimetric method, based on quantifying the differences in heat transfer liquid temperature between the shelf inlet and shelf outlet. This change in temperature results from the on-going sublimation, an endo-thermic reaction occurring during lyophilization. The second method uses the differential pressure between the chamber and condenser resulting from the vapor flow from vial to condenser during primary drying. As stated by the authors both methods align well and provide valuable cycle characterization data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Gemigliptin-Rosuvastatin single-pill combination is a promising therapeutic tool in the effective control of hyperglycemia and hypercholesterolemia. Organic sensors with high quantum yields have profoundly significant applications in the pharmaceutical industry, such as routine quality control of marketed formulations. Herein, the fluorescence sensor, 2-Morpholino-4,6-dimethyl nicotinonitrile 3, (λex; 226 nm, λem; 406 nm), was synthesized with a fluorescence quantum yield of 56.86% and fully characterized in our laboratory. This sensor showed high efficiency for the determination of Gemigliptin (GEM) and Rosuvastatin (RSV) traces through their stoichiometric interactions and simultaneously fractionated by selective solvation. The interaction between the stated analytes and sensor 3 was a quenching effect. Various experimental parameters and the turn-off mechanism were addressed. The adopted approach fulfilled the ICH validation criteria and showed linear satisfactory ranges, 0.2-2 and 0.1-1 μg/mL for GEM and RSV, respectively with nano-limits of detection less than 30 ng/mL for both analytes. The synthesized sensor has been successfully applied for GEM and RSV co-assessment in their synthetic polypill with excellent % recoveries of 98.83 ± 0.86 and 100.19 ± 0.64, respectively. No statistically significant difference between the results of the proposed and reported spectrophotometric methods in terms of the F- and t-tests. Ecological and whiteness appraisals of the proposed study were conducted via three novel approaches: the Greenness Index via Spider Diagram, the Analytical Greenness Metric, and the Red-Green-Blue 12 model. The aforementioned metrics proved the superiority of the adopted approach over the previously published one regarding eco-friendliness and sustainability. Our devised fluorimetric turn-off sensing method showed high sensitivity, selectivity, feasibility, and rapidity with minimal cost and environmental burden over other sophisticated techniques, making it reliable in quality control labs., (© 2024. The Author(s).)

Monitoring product temperature during lyophilization is critical, especially during the process development stage, as the final product may be jeopardized if its process temperature exceeds a threshold value. Also, in-situ temperature monitoring of the product gives the capability of creating an optimized closed-loop lyophilization process. While conventional thermocouples can track product temperature, they are invasive, limited to a single-point measurement, and can significantly alter the freezing and drying behavior of the product in the monitored vial. This work has developed a new methodology that combines non-invasive temperature monitoring and comprehensive modeling. It allows the accurate reconstruction of the complete temperature profile of the product inside the vial during the lyophilization process. The proposed methodology is experimentally validated by combining the sensors' wirelessly collected data with the advanced multiphysics simulations. The flexible wireless multi-point temperature sensing probe is produced using micro-manufacturing techniques and attached outside the vial, allowing for accurate extraction of the product temperature., (© 2022. The Author(s).)

Increasing access to additive manufacturing technologies utilising easily available desktop devices opened novel ways for formulation of personalized medicines. It is, however, challenging to propose a flexible and robust formulation platform which can be used for fabrication of tailored solid dosage forms composed of APIs with different properties (e.g., hydrophobicity) without extensive optimization. This manuscript presents a strategy for formulation of fast dissolving tablets using binder jetting (BJ) technology. The approach is demonstrated using two model APIs: hydrophilic quinapril hydrochloride (QHCl, logP = 1.4) and hydrophobic clotrimazole (CLO, logP = 5.4). The proposed printing method uses inexpensive, well known, and easily available FDA approved pharmaceutical excipients. The obtained model tablets had uniform content of the drug, excellent mechanical properties, and highly porous structure resulting in short disintegration time and fast dissolution rate. The tablets could be scaled and obtained in predesigned shapes and sizes. The proposed method may find its application in the early stages of drug development where high flexibility of the formulation is required and the amount of available API is limited., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Wireless sensor networks have become prolific in a wide range of industrial processes and offer several key advantages over their wired counterparts in terms of positioning flexibility, modularity, interconnectivity, and data routing. We demonstrate their utility in pharmaceutical lyophilization by developing a series of wireless devices to measure spatial variations in gas pressure and temperature during primary drying. The influence of shelf temperature, chamber pressure, excipient concentration, and dryer configuration are explored for various representative cycles using a laboratory-scale pharmaceutical lyophilizer. Pressure and temperature variations across the shelf for these cases are shown to vary up to 1.2 Pa and 10 °C, respectively. Experimental measurements are supported by computational fluid dynamics simulations to reveal the mechanisms driving the vapor flow. The measurements and simulation data are then combined to estimate the shelf-wise sublimation rate in the inverse sense to within a deviation of 3% based on comparison with gravimetric data. We then apply the sublimation rate profile to obtain the vial heat transfer coefficient and product mass transfer resistance for a 5% w/v mannitol formulation. Finally, these parameters are applied to a one-dimensional quasi-steady heat transfer model to predict the evolution of the product temperature over the course of primary drying. Thermocouple measurements of product temperature are compared directly to the simulated data and demonstrate accuracy comparable to existing published one-dimensional models., (Copyright © 2021. Published by Elsevier B.V.)

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy., Competing Interests: The authors have declared that no competing interests exist.

Loss-in-Weights (LiW) feeders are commonly oriented in a horizontal way. In this work, an experimental proof of concept, including mechanical and electrical design, construction, and operation, of a vertical LiW feeder prototype is performed. In a systematic design process, based on functional design specifications, the semi-automated vertical LiW feeder for dosing a wide range of powders, especially cohesive ones, is developed. The new dosing machine is assessed with regard to a number of key features such as high dosing accuracy, first-in-first-out powder discharge, easily interchange of the powder container, and flexibility in controlling the speed of the auger and stirrer motors independently. An experimental sensitivity analysis to study the functionality of the dosing machine and to investigate the weight variability of the weighing platform, i.e. mass flow rate, and quantity of dosed mass, is carried out. The results of the sensitivity analysis and the powder dosing tests of five diverse powders using different auger and stirrer geometries verified the proof of concept prototype.HighlightsA systematic design approach for validating a proof of concept of a vertical loss in weight feeder is appliedA full mechanical CAD design and implementation along with electric installation and software programming are executedSensitivity analysis approach is performed to validate the functionality of the semi-automated machine and successfully dispense dissimilar powders tested with different process parametersThe machine is characterized with a number of key features: first-in-first-out powder discharge, high dosing accuracy, flexible and modular concept design, flexibility in controlling the speed of the auger and the stirrer independently, lightweight and user-friendly design.

The objective of this research was to assess the applicability of manometric temperature measurement (MTM) and SMART™ for cycle development and monitoring of critical product and process parameters in a mini-freeze dryer using a small set of seven vials. Freeze drying cycles were developed using SMART™ which automatically defines and adapts process parameters based on input data and MTM feedback information. The freeze drying behavior and product characteristics of an amorphous model system were studied at varying wall temperature control settings of the cylindrical wall surrounding the shelf in the mini-freeze dryer. Calculated product temperature profiles were similar for all different wall temperature settings during the MTM-SMART™ runs and in good agreement with the temperatures measured by thermocouples. Product resistance profiles showed uniformity in all of the runs conducted in the mini-freeze dryer, but absolute values were slightly lower compared to values determined by MTM in a LyoStar™ pilot-scale freeze dryer. The resulting cakes exhibited comparable residual moisture content and optical appearance to the products obtained in the larger freeze dryer. An increase in intra-vial heterogeneity was found for the pore morphology in the cycle with deactivated wall temperature control in the mini-freeze dryer. SMART™ cycle design and product attributes were reproducible and a minimum load of seven 10R vials was identified for more accurate MTM values. MTM-SMART™ runs suggested, that in case of the wall temperature following the product temperature of the center vial, product temperatures differ only slightly from those in the LyoStar™ freeze dryer.

In pharmaceutical wet granulation, drying is a critical step in terms of energy and material consumption, whereas granule moisture content and size are important process outcomes that determine tabletting performance. The drying process is, however, very complex due to the multitude of interacting mechanisms on different scales. Building robust physical models of this process therefore requires detailed data. Current data collection methods only succeed in measuring the average moisture content of a size fraction of granules, whereas this property rather follows a distribution that, moreover, contains information on the drying patterns. Therefore, a measurement method is devised to simultaneously characterise the moisture content and size of individual pharmaceutical granules. A setup with near-infrared chemical imaging (NIR-CI) is used to capture an image of a number of granules, in which the absorbance spectra are used for deriving the moisture content of the material and the size of the granules is estimated based on the amount of pixels containing pharmaceutical material. The quantification of moisture content based on absorption spectra is performed with two different regression methods, Partial Least Squares regression (PLSR) and Elastic Net Regression (ENR). The method is validated with particle size data for size determination, loss-on-drying (LOD) data of average moisture contents of granule samples and, finally, batch fluid bed experiments in which the results are compared to the most detailed method to date. The individual granule moisture contents confirmed again that granule size is an important factor in the drying process. The measurement method can be used to gain more detailed experimental insight in different fluidisation and particulate processes, which will allow building of robust process models., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pharmaceutical continuous manufacturing is considered as an emerging technology by the regulatory agencies, which have defined a framework guided by an effective quality risk management. With the understanding of process dynamics and the appropriate control strategy, pharmaceutical continuous manufacturing is able to tackle the Quality-by-Design paradigm that paves the way to the future smart manufacturing described by Quality-by-Control. The introduction of soft sensors seems to be a helpful tool to reach smart manufacturing. In fact, soft sensors have the ability to keep the quality attributes of the final drug product as close as possible to their references set by regulatory agencies and to mitigate the undesired events by potentially discard out of specification products. Within this review, challenges related to implementing these technologies are discussed. Then, automation control strategies for pharmaceutical continuous manufacturing are presented and discussed: current control tools such as the proportional integral derivative controllers are compared to advanced control techniques like model predictive control, which holds promise to be an advanced automation concept for pharmaceutical continuous manufacturing. Finally, industrial applications of model predictive control in pharmaceutical continuous manufacturing are outlined. Simulations studies as well as real implementation on pharmaceutical plant are gathered from the control of one single operation unit such as the tablet press to the control of a full direct compaction line. Model predictive control is a key to enable the industrial revolution or Industry 4.0., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Most of the clinical approved protein-based drugs or under clinical trials have a profound impact on the treatment of critical diseases. The mammalian eukaryotic cells culture approaches, particularly the CHO (Chinese Hamster Ovary) cells are mainly used in the biopharmaceutical industry for the mass-production of the therapeutic protein. Recent advances in CHO cell bioprocessing to yield recombinant proteins and monoclonal antibodies have enabled the expression of quality protein. The developments of cell lines are possible to enhance specific productivity. As a result, it holds an interesting area for academic as well as industrial researchers around the world. This review will focus on the recent progress of the mammalian CHO cells culture technology and the future scope of further development for the mass-production of protein therapeutics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Spray drying plays an important role in the pharmaceutical industry for product development of sensitive bio-pharmaceutical formulations. Process design, implementation and optimisation require in-depth knowledge of process-product interactions. Here, an integrated approach for the rapid, early-stage spray drying process development of trehalose and glucagon on lab-scale is presented., Methods: Single droplet drying experiments were used to investigate the particle formation process. Process implementation was supported using in-line process analytical technology within a data acquisition framework recording temperature, humidity, pressure and feed rate. During process implementation, off-line product characterisation provided additional information on key product properties related to residual moisture, solid state structure, particle size/morphology and peptide fibrillation/degradation., Results: A psychrometric process model allowed the identification of feasible operating conditions for spray drying trehalose, achieving high yields of up to 84.67%, and significantly reduced levels of residual moisture and particle agglomeration compared to product obtained during non-optimal drying. The process was further translated to produce powders of glucagon and glucagon-trehalose formulations with yields of >83.24%. Extensive peptide aggregation or degradation was not observed., Conclusions: The presented data-driven process development concept can be applied to address future isolation problems on lab-scale and facilitate a systematic implementation of spray drying for the manufacturing of sensitive bio-pharmaceutical formulations.

A multiscale model by coupling computational fluid dynamics (CFD) with a discrete element model (DEM) and discrete droplet model (DDM) is developed to simulate a lab-scale Wurster coater. Two case studies are conducted to study the effect of particle shape in the system. In the first case study, 45,000 spherical particles are coated for 5 s while for the second case study, a mixture of 22,500 spherical particles and 22,500 cylindrical particles is simulated. The residence time distributions (RTD) of particles in different spray zones are compared, and the best spray zone is derived by analysing the positions of spray droplet-particle contacts. The simulation results show that the RTD of the particles within an accurate spray zone can provide valuable information on the final product's particles size distribution. Furthermore, the coefficient of variation (COV) for the coating mass received by the particles is studied for both case studies., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The establishment of 3D-printing as manufacturing process for oral solid dosage forms enables new options for the individualized medicine. The aim of this work was to develop a novel drug-printing model using pressure-assisted microsyringe (PAM) technology, which allows the precise dispensing of drug substances. Printed tablets with different numbers of layers, mimicking different doses for pediatric subgroups, were analyzed regarding mass variation, friability, thickness and disintegration time. Furthermore, the uniformity of dosage units and the dissolution behavior were investigated. Friability was <0.3% in all cases, which demonstrates the ability of PAM printing to manufacture robust solid dosage. Disintegration results showed the dependency of the disintegration on the number of layers and therefore on the compact mass of polymer. However, all tablets disintegrated within 3 min and fulfilled the requirements of immediate release tablets of the USP and orodispersible tablets according to the Ph. Eur. Results of uniformity dosage units confirmed the successful manufacturing of the intended individualized doses. Drug dissolution appeared to be dependent on the number of layers. An increase of layers resulted in a decrease of the drug release rate. Further, the drug release could be correlated to the surface area/volume (SA/V) ratio., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The research presented here shows QbD implementation for the optimisation of the key process parameters in electrohydrodynamic atomisation (EHDA). Here, the electrosprayed nanoparticles and electrospun fibers consisting of a polymeric matrix and dye. Eight formulations were assessed consisting of 5% w/v of polycaprolactone (PCL) in dichloromethane (DCM) and 5% w/v polyvinylpyrrolidone (PVP) in ethanol. A full factorial DOE was used to assess the various parameters (applied voltage, deposition distance, flow rate). Further particle and fiber analysis using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), particle/fiber size distribution. In addition to this in vitro release studied were carried out using fluorescein and Rhodamine B as model dyes and in vitro permeation studies were applied. The results show a significant difference in the morphology of resultant structures as well as a more rapid release profile for the PVP particles and fibers in comparison to the sustained release profiles found with PCL. In vitro drug release studies showed 100% drug release after 7 days for PCL particles and showed 100% drug release within 120 min for PVP particles. The release kinetics and the permeation study showed that the MN successfully pierced the membrane and the electrospun MN coating released a large amount of the loaded drug within 6 h. This study has demonstrated the capability of these robust MNs to encapsulate a diverse range drugs within a polymeric matrix giving rise to the potential of developed personalised medical devices., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Twin-screw melt granulation (TSMG) is a new alternative method for granulation that offers several advantages over wet and dry granulation methods. TSMG has rapidly gained interest over recent years in the pharmaceutical industry. Since it is an inherently continuous process with controlled temperature and shear history, TSMG produces products with more consistent quality than the batch process. Several studies have investigated how various formulation and processing parameters influence granulation behavior and granule properties; however, there are still challenges that require a better mechanistic understanding. This review summarizes the current progress of TSMG while highlighting how various formulation and process parameters affect the physicochemical properties of granules. The challenges related to the process-induced physicochemical changes of drug substances are also discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: This study aims to understand the impact of spray drying nozzles on particle surface composition and aerosol stability., Methods: The combination formulations of colistin and azithromycin were formulated by 2-fluid nozzle (2 N) or 3-fluid (3 N) spray drying in a molar ratio of 1:1. A 3-factor, 2-level (2 3 ) factorial design was selected to investigate effects of flow rate, inlet temperature and feed concentration on yield of spray drying and the performance of the spray dried formulations for the 3 N., Results: FPF values for the 2 N formulation (72.9 ± 1.9% for azithromycin & 73.4 ± 0.8% for colistin) were higher than those for the 3 N formulation (56.5 ± 3.8% for azithromycin & 55.1 ± 1.6% for colistin) when stored at 20% RH for 1 day, which could be attributed to smaller physical size for the 2 N. There was no change in FPF for both drugs in the 2 N formulation after storage at 75% RH for 90 days; however, there was a slight increase in FPF for colistin in the 3 N formulation at the same storage conditions. Surface enrichment of hydrophobic azithromycin was measured by X-ray photoelectron spectroscopy for both 2 N and 3 N formulations and interactions were studied using FTIR., Conclusions: The 3-fluid nozzle provides flexibility in choosing different solvents and has the capability to spray dry at higher feed solid concentrations. This study highlights the impact of hydrophobic azithromycin enrichment on particle surface irrespective of the nozzle type, on the prevention of moisture-induced deterioration of FPF for hygroscopic colistin.

During lyophilisation of highly potent Active Pharmaceutical Ingredients (APIs) potential contamination of the freeze-drier is an important safety issue. Since the stoppers are in semistoppered position during the lyophilization process, API may contaminate the chamber and cross-contamination may occur as well. In this study two protective bags, which enclose each tray and their influence on heat and mass transfer during freeze-drying were investigated. Sublimation tests were performed using either purified water or solutions containing trehalose as well as hydroxypropyl-β-cyclodextrin (HPbCD) as bulking agents. During sublimation tests with purified water both bags clearly influenced heat and mass transfer compared to unpacked reference vials. The bag, which was originally designed to be used for steam sterilization, had a massive impact on drying characteristics. The bag membrane becomes the rate limiting factor, generating a separate compartment within the bag. In this compartment vapor pressure is much higher compared to the chamber pressure during primary drying, leading to altered drying conditions. However, drying was still possible. The other bag, which was specifically designed for lyophilization, also had an impact on drying behavior which could be assigned to the foil between shelf and bottom of the vials. This was detectable as differences in K v values. Membrane resistance, however, becomes negligible when 10% (w/w) trehalose or HPbCD solutions were dried using the later bag as containment. The data reported in this work demonstrate the relevance and value of sublimation tests to understand the lyophilization process, especially when new components are implemented. The data should be considered, when freeze-drying shall be performed using such bags., Competing Interests: Declaration of Competing Interest Rebecca Chamberlain and Jonas Schlauersbach were employees of Bayer AG during the conduction of the experiments reported here., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The interest in using inkjet printing as manufacturing technology for personalized medicine has increased in recent years. The print head is the centrepiece of an inkjet printer. For pharmaceutical approaches, various types of printing equipment were tested in the past, but comparative investigations in relation to pharmaceutical use are still lacking. In the present study, two piezoelectric print heads of different designs (Spectra SE-128 AA and Konica Minolta KM512SHX) were systematically compared with the objective of deepening the process understanding and identifying the key factors on the resulted quantities. As substrates, oral thin films made from 15% (w/w) hypromellose (HPMC) casting solution were used. The Spectra print head with bigger nozzles was more efficient in one pass and resulted in less scattering (RSD ≤ 5%). Furthermore, it was found that liquid excipients like polyethylene glycol 400 characterized by low vapour pressure and limited penetration into the HPMC based films are not suitable. The choice of the printed geometry plays a subordinate role when printing the same surface area, whereas the composition of the inks, set process parameters as well as the size and functionality of the nozzles have a significant impact on the final printed quantity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Manufacture of sterile products must strictly follow carefully established and validated analytical methods of manufacture and control. Based on this consideration, we evaluated scientific literature describing settle plates and active air sampler monitoring effectiveness. A contamination control strategy should be implemented by pharma manufacturers, especially for aseptic productions, to assess the effectiveness of environmental monitoring and demonstrate that the process is under statistical control. It is of key importance for microbiological monitoring data to correlate as best as possible with total particle monitoring data so that each batch release is reliably supported., (© PDA, Inc. 2020.)

Cleaning validation acceptance criteria in multiproduct facilities are established using maximum allowable carryover calculations. Carryover calculations incorporate the shared equipment surface area between two products to ensure that an acceptable limit for residue from the previously manufactured product to the subsequent product is determined. The shared surface area can be limited to areas where carryover presents the highest risk to product quality or patient safety. In these cases, specifically for biologic drug substance manufacturing, the shared surface area is limited to equipment after the purification process based on the assumption that the purification process would remove potential product fragment residues from the previous product. Until now, this assumption has been based on empirical knowledge without experimental data quantifying the clearance or removal of potential residues. We present a three-part study that determined the effects of cleaning conditions on selected monoclonal antibodies (mAbs) and the generation of degraded fragments and evaluated the clearance of both the degraded mAb1 in a laboratory setting and the degraded fragments in the presence of a subsequent product, assessing the risk of co-purification. Several analytical techniques were used, including gel electrophoresis, capillary zone electrophoresis/laser-induced florescence detection, and liquid chromatography-mass spectrometry. Protein fragment generation was demonstrated for five different mAbs from different immunoglobulin G subclasses. The clearance of the degraded fragments in the absence and presence of the subsequent product was demonstrated by calculating fold clearance and log reduction value (LRV) for each chromatography step. The data showed that the fragments generated during cleaning could be removed by the purification process. The fold clearances were determined to be values of 5400 (3.7 LRV) in the absence of subsequent product and 4428 (3.6 LRV) in the presence of subsequent product. The results supported the removal of product residues from shared surface areas by the purification process in multiproduct biologic drug substance manufacturing facilities., (© PDA, Inc. 2020.)

Pulmonary drug delivery is a non-invasive and effective route for local or systemic drug administration. Despite several products in the market, the mechanism of drug absorption from the lungs is not well understood. An in vitro model for aerosol deposition and transport across epithelia that uses particle deposition may be a good predictor of and help understand in vivo drug disposition. The objective of this study was to examine the uptake of HFA fluticasone (Flovent HFA) particles at various stages of the Next Generation Impactor (NGI) by human Calu-3 cell line derived from human bronchial respiratory epithelial cell monolayer. Particles were directly deposited on Calu-3 cells incorporated onto stages 3, 5, and 7 of the NGI at the air-liquid interface (ALI). We modified the NGI apparatus to allow particle deposition directly on cells and determined the in vitro deposition characteristics using modified NGI. Particles of different size ranges showed different in vitro epithelial transport rates. This study highlights the need to develop in vitro test systems to determine the deposition of aerosol particles on cell monolayers by simultaneously considering aerodynamic properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A novel sampler device for flowing powders was tested to quantify drug concentrations as low as 0.76% w/w in pharmaceutical powder blends. The sampler device was developed based on the powder flow behavior within a tablet press feed frame, following the principles laid down in the Theory of Sampling. Two Near-Infrared (NIR) spectroscopic calibration models were developed with powder blends that varied from 0.52 to 2.52% w/w and 1.51-4.52% w/w. The calibration models were able to determine caffeine concentration in test set blends with root mean square error of predictions and bias below 0.1% w/w. Samples were collected from the sampler device and analyzed by ultraviolet-visible (UV-Vis) to determine the caffeine concentration. A high agreement between the in-line NIR predictions and the sampled UV-Vis results was found. The paddle wheel speed in the sampler can be varied up to ±10% without affecting NIR predictions; however, the models did not respond adequately to a 25% increase in this speed. Variographic analysis showed that the sampler device may quantify low drug concentrations with nugget effects below 0.0050 (%w/w) 2 . This study demonstrate that the sampler device may handle throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Optical Coherence Tomography (OCT) is a high-resolution and non-invasive cross-sectional imaging technique mainly used for medical imaging and industrial non-destructive testing. However, its feasibility in the quantification of pulmonary drug deposition has not been investigated. In this study, an optically accessible airway model of the upper airway and the tracheobronchial tree was used, and experiments were performed at flow rates of 40 L/min, 60 L/min and 80 L/min. Drug deposition in different regions of the airway cast has been determined and quantified from OCT images of the deposition layer. Regionally resolved measurement of deposition shows that flow rate has a significant effect (p = 0.04) on the average thickness of the deposition layer in the upper airway but not in the tracheobronchial tree under these test conditions. These localized and high-resolution measurements of deposition also demonstrate that the flow rate can influence the spatial uniformity of the deposition layer. The technique is able to provide significant regional drug deposition details, including the thickness, spatial deposition pattern and micro-cavities in the deposition layer, that would potentially serve to assess the efficacy of inhalation drug delivery systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Press-coated tablets have become an indispensable dosage form in chronotherapeutic drug delivery. Drug release from press-coated tablets has been extensively studied, yet there is little knowledge about their mechanical characteristics. This study aimed to systematically investigate the effects of critical factors on the structure, layer adhesion, and delamination tendency of the tablets. Material elasticity was found to play an important role in determining tablet structure in that excessive elastic mismatch between core and shell materials caused tablet defects during decompression and ejection. Unlike bilayer tablets, the overall strength of press-coated tablets was more affected by binding capacity of coating materials than by the core properties. Shell/core ratio was another factor affecting tablet integrity against external stresses. To mitigate the risk of delamination, poor layer adhesion must be compensated by increasing the coating thickness or enhanced by optimizing the formulation and process (e.g., core plasticity/brittleness, initial core solid fraction, and compression speed). X-ray micro-computed tomography revealed the presence of a shell-core gap and inhomogeneous density distribution within the tablet where the side coat appeared as the least dense and weakest region. These findings will enable the improvement of tablet quality and widen the application of press coating in industrial manufacturing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

An idealized nasal replica that mimics average regional deposition of nasal spray pump droplets in human nasal airways would potentially be useful in expediting the development of nasal spray products. The aim of this study was to validate an idealized nose, previously developed using in silico simulations, by comparing with regional deposition in realistic, sectioned nasal replicas obtained from in vitro deposition experiments. The realistic nasal airway replicas of five subjects obtained from computerized tomography were manufactured in plastic using rapid prototyping. The idealized nose was made using the same build procedure. A commercial nasal spray pump (NasalCrom, 5.2 mg cromolyn sodium per spray) was then actuated repeatably into each replica under a steady inspiratory flow of 7.5 L/min at two different orientations (45° and 60° from the horizontal). Sectioned replicas were disassembled, and the mass fraction of drug deposited on the surface of each anatomical region was determined. It was found that regional deposition of spray droplets in the idealized replica agreed well with average regional deposition in the realistic replicas. Regional deposition also agreed with previously published in vivo regional deposition using the same spray pump., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Conventional nebulisation has the disadvantages of low aerosol output rate and potential damage to macromolecules due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). HYDRA (HYbriD Resonant Acoustics) technology has been shown to overcome these problems by using a hybrid combination of surface and bulk sound waves to generate the aerosol droplets. We report the first in vivo human lung deposition study on such droplets. Twelve healthy adult subjects inhaled saline aerosols radiolabelled with technetium-99 m complexed with diethylene triamine penta-acetic acid ( 99m Tc-DTPA). The distribution of the aerosolised droplets in the lungs was imaged by single photon emission computed tomography combined with low dose computed tomography (SPECT/CT). The volume median diameter and geometric standard deviation of the droplets were 1.32 ± 0.027 µm and 2.06 ± 0.040, respectively. The mean delivery efficiency from the nebuliser into the body was 51.2%. About 89.1 ± 4.3% and 2.3 ± 1.4% of the inhaled radiolabelled dose deposited in the lungs and oropharynx, respectively. The deposition was symmetrical and diffusive between the two lungs, with a mean penetration index of 0.82. Thus, the prototype HYDRA nebuliser showed excellent in vivo aerosol deposition performance, demonstrating its potential to be further developed for clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Poor aqueous solubility of active pharmaceutical ingredients (API) is nowadays a major issue in the pharmaceutical field. The combinatorial chemistry provides more and more API with a great therapeutic potential, but with a low aqueous solubility. Among the strategies to overcome this drawback, the use of amorphous solid dispersions (ASD), as well as the increase of surface area, is widely used. The three dimensional (3D) printing technologies appear to be innovative tools allowing the construction of any unconventional forms with different composition, structure or infill; especially by using ASD materials. This review aims to deliver notions about the different 3D printing techniques found in the literature to improve aqueous solubility of several API, namely nozzle-based method, inkjet methods and laser- based methods, as well as guide formulator in terms of formulation parameters that have to be optimized to allow the most suitable impression of innovative medicines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ultrafiltration/diafiltration (UF/DF) plays an important role in the manufacturing of biopharmaceuticals. Monitoring critical process parameters and quality attributes by process analytical technology (PAT) during those steps can facilitate process development and assure consistent quality in production processes. In this study, a lab-scale cross-flow filtration (CFF) device was equipped with a variable pathlength (VP) ultraviolet and visible (UV/Vis) spectrometer, a light scattering photometer, and a liquid density sensor (microLDS). Based on the measured signals, the protein concentration, buffer exchange, apparent molecular weight, and hydrodynamic radius were monitored. The setup was tested in three case studies. First, lysozyme was used in an UF/DF run to show the comparability of on-line and off-line measurements. The corresponding correlation coefficients exceeded 0.97. Next, urea-induced changes in protein size of glucose oxidase (GOx) were monitored during two DF steps. Here, correlation coefficients were ≥ 0.92 for static light scattering (SLS) and dynamic light scattering (DLS). The correlation coefficient for the protein concentration was 0.82, possibly due to time-dependent protein precipitation. Finally, a case study was conducted with a monoclonal antibody (mAb) to show the full potential of this setup. Again, off-line and on-line measurements were in good agreement with all correlation coefficients exceeding 0.92. The protein concentration could be monitored in-line in a large range from 3 to 120 g L - 1 . A buffer-dependent increase in apparent molecular weight of the mAb was observed during DF, providing interesting supplemental information for process development and stability assessment. In summary, the developed setup provides a powerful testing system for evaluating different UF/DF processes and may be a good starting point to develop process control strategies. Graphical Abstract Piping and instrumentation diagram of the experimental setup and data generated by the different sensors. A VP UV/Vis spectrometer (FlowVPE, yellow) measures the protein concentration. From the data of the light scattering photometer (Zetasizer, green) in the on-line measurement loop, the apparant molecular weight and z-average are calculated. The density sensor (microLDS) measures density and viscosity of the fluid in the on-line loop.

smartPearls technology is one appropriate method to produce anti-psoriatic curcumin (Cur) topical delivery system. To prevent the sedimentation of loaded silica and release changing over the storage, which are disadvantages of smartPearls production, extra glycyrrhizic acid (GA) was added in classical smartPearls ingredients (active and porous material) to get an improved smartPearls production (Cur-GA-silica). The capacity of Cur-GA-silica to remain the gelation state after mixing with water was superior compared to that of the solid cluster without GA and that of the physical mixture of Cur, GA and silica. The Cur-GA-silica practically contained Cur with 1.68% ± 0.12% and showed significant difference with Cur raw drug powder in kinetic solubilities (4.55 ± 0.78 µg/mL vs 0 in 5 min; 3.26 ± 0.17 µg/mL vs 0 in 4 h) which was traceable to the amorphous state of Cur-GA-silica detected by X-ray diffractometer. With the amorphous Cur, two times as much penetrated Cur in Cur-GA-silica as in Cur raw drug powder was achieved on the imiquimod-induced psoriasis-like mice model. The anti-psoriatic efficacy of Cur-GA-silica was confirmed by Psoriasis Area and Severity Index (PASI) evaluation, histological evaluation and decreased IL-17A in the imiquimod-induced psoriasiform mouse skin analyzed by enzyme-linked immunosorbent assay. In conclusion, with the addition of GA, a stable amorphous curcumin topical vehicle fabricated by smartPearls technology without extra dermal matrix is available and facilitates penetration efficacy and anti-psoriatic capacity in imiquimod-induced psoriasiform mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the impact of remote sterile product pharmacist checks when used with a gravimetric-based technology-assisted workflow (TAWF) system on product checking accuracy, pharmacist review time, workload sharing, cost savings, and staff perceptions., Methods: A double-arm, prospective study was conducted at 4 pharmacy locations for a 90-day period. Each compounded sterile product (CSP) checked by a remote pharmacist was also checked by a local pharmacist at the site of CSP preparation. An anonymous, online survey was emailed to staff before and after implementation to evaluate perceptions of the accuracy, timeliness, safety, potential impact, and value of the remote process., Results: There was no statistically significant difference in the numbers of errors detected through the remote process and through the current, nonremote process (P = 0.177). The median pharmacist review time in the local process was significantly lower (P < 0.001). Remote pharmacists in the study workflow verified 30.4% of the total number of CSPs verified in the 90-day period. Annualized cost savings were calculated to be $23,770.08. Percent agreement increased from the preimplementation to the postimplementation period for survey questions about the safety of the remote process, opportunity for workload sharing, and optimization of current workflow. Percent agreement decreased for questions about the accuracy, timeliness, and value of the remote process and its impact on job security., Conclusion: The study demonstrated that with use of a gravimetric-based TAWF system, there was no difference in the accuracy and safety of sterile product pharmacist checks performed remotely and those performed at the product preparation site. In addition, the remote process allows for opportunities for workload sharing and cost savings., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Flow chemistry is an area of contemporary chemistry exploiting the hydrodynamic conditions of flowing liquids to provide particular environments for chemical reactions. These particular conditions of enhanced and strictly regulated transport of reagents, improved interface contacts, intensification of heat transfer, and safe operation with hazardous chemicals can be utilized in chemical synthesis, both for mechanization and automation of analytical procedures, and for the investigation of the kinetics of ultrafast reactions. Such methods are developed for more than half a century. In the field of chemical synthesis, they are used mostly in pharmaceutical chemistry for efficient syntheses of small amounts of active substances. In analytical chemistry, flow measuring systems are designed for environmental applications and industrial monitoring, as well as medical and pharmaceutical analysis, providing essential enhancement of the yield of analyses and precision of analytical determinations. The main concept of this review is to show the overlapping of development trends in the design of instrumentation and various ways of the utilization of specificity of chemical operations under flow conditions, especially for synthetic and analytical purposes, with a simultaneous presentation of the still rather limited correspondence between these two main areas of flow chemistry.

The challenges in transferring and executing a near-infrared (NIR) spectroscopic method for croscarmellose (disintegrant) in binary blends for a continuous manufacturing (CM) process are presented. This work demonstrates the development of a NIR calibration model and its use to determine the blending parameters needed for binary blends at a development plant and later used to predict CM process blends. The calibration models were developed with laboratory scale powder blends ranging from 4.32%-64.77 (%w/w) of croscarmellose and evaluated using independent test blends. The selected model was then transferred to the continuous manufacturing development site to determine the croscarmellose concentration for spectra collected in real-time. A total of 18 development plant runs were monitored using an in-line NIR spectrometer, however, these spectra showed high baseline variations. The baseline variations were caused by the poor flow of the material within the system. An inconsistent bias which varied from 2.51 to 14.95 (%w/w) was observed in the predictions of croscarmellose. High baseline spectra were eliminated and the bias was significantly reduced by 42-51%. Experiments at lower flow rate speeds did not show significant changes in baseline and bias values showed more consistency. The calibration model was then transferred to two NIR spectrometers installed at-line at the commercial site, where powder samples were collected at the beginning middle and end of each CM plant run. The NIR calibration model predicted disintegrant concentration from the powder samples. Results showed the bias values for the NIR (1) varied from 0.74 to 2.21 (%w/w) and NIR (2) from 0.28 to 3.39 (%w/w). Average concentration values for both equipments were very close to the reference concentration values of 43.18 and 50.98 (%w/w). The study showed the model was able to identify flow issues, identified as baseline shifts, that could be used to alert to problems in the powder bed that may warrant diversion from a production line. These powder flow problems such as air gaps and inconsistent powder bed height affected the NIR spectra collected at the development plant and provided results with high bias. A lower bias was obtained in samples collected at line after blending., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Low volume aseptic filling of parenterals, particularly monoclonal antibodies is becoming increasingly important with the development of more and more intravitreal drugs and high concentrated formulations. Especially monoclonal antibodies are very delicate products to fill and the use of the right fill finish equipment plays an important role during process development. Protein aggregation can occur under conditions described in literature and can be influenced by the fill finish processing. The mechanism of product stress inside the filling systems is yet not fully understood. This study evaluated three different dosing systems to assess protein degradation caused by the shear rate during low volume filling of monoclonal antibodies. The newly developed quantitative liposomal shear stress model revealed the highest shear rate in the radial peristaltic pump, followed by the rotary piston pump and the linear peristaltic pump. In contrast to that, we found the highest sub-visible particle counts (>2 µm) in the rotary piston pump. We used computational fluid dynamics for a better and deeper understanding of filling processes inside the different dosing systems. Our results document that the rotary piston pump creates a recirculation zone inside the cylinder, where the protein formulation could be trapped and be exposed to the shear stress multiple times resulting in a cumulative shearing. This finding could serve as an explanation for the highest sub-particle counts in low volume filling using a rotary piston pump., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Powder caking can dramatically affect powder handling and downstream production processes. Understanding the key factors that contribute to bulk powder caking is crucial. This article introduces the Hirschberg caking device (HCD), which is a 3D-printed device allowing for parallel testing of powder caking in a cylindrical geometry. In the HCD setup, the powder sample is stored in controlled conditions in the sample holder. On removal of the sample holder, the caked powder will remain in the shape determined by the sample geometry while the remaining powder will fall down. Caking indices can be calculated based on image analysis and weight measurement. The results obtained for the caking of lactose monohydrate with the HCD were in good agreement with the results obtained by a ring shear tester. In addition, a strain tester was used to measure the strength of the formed cakes. Using this approach, critical storage conditions and the required concentration of a given anticaking agent (talc) for lactose monohydrate could be identified. This work demonstrates the potential of rapid prototyping in powder characterization by introducing a fast and affordable approach for exploring and trouble-shooting powder caking., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This article aims to investigate how a small-scale freeze-dryer can be used for process design. The system encompasses a temperature controlled metallic ring that surrounds a small batch of vials, in contact with the external vials through removable thermal conductors. The temperature of the ring can be modified to keep a constant difference with the temperature of one or more vials of the batch. In this article, an extensive validation of the system is given, considering 10% w/w sucrose and 5% w/w mannitol solutions, processed in different types of vials (6 R and 20 R) and in different operating conditions. The micro freeze-dryer was also shown to be able to provide accurate estimates of the overall heat transfer coefficient from the shelf to the product in the vials (K v ) and of the resistance of the dried cake to vapor flux (R p ): both values appeared to be very close to those obtained for the same case studies in a pilot-scale unit. Finally, the use of the micro freeze-dryer to control product temperature and drying time values to simulate a pilot-scale unit was addressed, thus demonstrating the adequacy of this system for process scaleup., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A novel sensor based on a modification of glassy carbon electrode (GCE) with NH 2 -functionalized multi-walled carbon nano-tubes (NH 2 fMWCNTs) is reported and its applicability to the electrochemical sensing of Propafenone (PPF) demonstrated. The electrochemical catalytic activity was also utilized as a sensitive detection method for the investigation of the detailed redox mechanism of PFF using cyclic and and differential pulse voltammetry. The surface morphology of the sensor was investigated by SEM armed with EDX probe. Electrochemical impedance spectroscopy was employed as well to define the electron transfer capability of modified and bare electrodes. Key experimental and instrumental conditions related to electrochemical determination by cyclic, differential pulse, and square wave voltammetry, such as amount of modifier, pH, scan rate, accumulation time and potential were studied and optimized. The results have shown a significant enhancement of the peak current after modifying the electrode; the calibration curves of PPF offering good linearity from 0.1 to 10 μM, limit of quantification (LOQ) being 0.03 μM and limit of detection (LOD) 0.01 μM, both when using DPV technique. The proposed sensor was successfully applied to the determination of PFF in dosage form without any special purification, separation or pre-treatment steps. The results of analyses obtained with the proposed sensor were satisfactory and fully statistically relevant., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The equipment capability curve is one of the bounding elements of the freeze-drying design space, and understanding it is critical to process design, transfer, and scale-up. The second bounding element of the design space is the product temperature limit beyond which the product collapses. The high cost associated with freeze-drying any product renders it crucial to operate using the most efficient cycle within the limits of the equipment and the product. In this work, we present a computational model to generate the equipment capability curve for 2 laboratory scale freeze-dryers and compare the results to experimentally generated equipment capability curves. The average deviations of the modeling results from the experiments for the 2 lyophilizers modeled are -4.8% and -7.2%. In addition, we investigate the effect of various numerical and geometric parameters on the simulated equipment capability. Among the numerical parameters, the chamber wall thermal boundary conditions exert the largest influence with a maximum value of 12.3%. Among the geometric parameters, the inclusion of the isolation valve reduces the equipment capability by 23.7%. Larger isolation valves, required for controlled nucleation technology, choke the flow in the duct at lower sublimation rates, thereby lowering the equipment capability limit., (Copyright © 2019. Published by Elsevier Inc.)

The aim of this work was to develop a PAT platform consisting of four complementary instruments for the characterization of electrospun amorphous solid dispersions with meloxicam. The investigated methods, namely NIR spectroscopy, Raman spectroscopy, Colorimetry and Image analysis were tested and compared considering the ability to quantify the active pharmaceutical ingredient and to detect production errors reflected in inhomogeneous deposition of fibers. Based on individual performance the calculated RMSEP values ranged between 0.654% and 2.292%. Mid-level data fusion consisting of data compression through latent variables and application of ANN for regression purposes proved efficient, yielding an RMSEP value of 0.153%. Under these conditions the model could be validated accordingly on the full calibration range. The complementarity of the PAT tools, demonstrated from the perspective of captured variability and outlier detection ability, contributed to model performance enhancement through data fusion. To the best of the author's knowledge, this is the first application of data fusion in the field of PAT for efficient handling of big-analytical-data provided by high-throughput instruments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Capsule filling is frequently accomplished via the dosator process. Controlling the main quality attributes, i.e., the fill weight and the fill weight variability, requires excellent process understanding. For the investigation of critical process parameters of low-dose capsule filling, DEM simulations were used. Two contact models (Hertz model and Luding model) were calibrated and validated to represent the lactose powder Lactohale 100. Both models gave good results, yet the Luding model resulted in better predictions. Since the dosator process is a volume-based approach, the dosator geometry is an important factor. We provide evidence that not only the volume, but also the proportions of the dosator affect the capsule fill weight. Slim nozzle chambers cause lower mass due to increased wall friction impact. The process is not volumetric, as a fill weight to volume correlation does not exist. Furthermore, the fill weight increases with higher powder beds and smaller gaps between the nozzle tip and the container bottom due to higher densification of the powder. Fill weight variations due to bed inhomogeneity were investigated by varying the bulk density of the initial powder bed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Switching from batch to continuous pharmaceutical production offers several advantages, such as an increased productivity, a steady product quality, and decreased costs. This paper presents a control strategy for direct compaction on a continuous tablet production line consisting of two feeders, one blender, and a tablet press (TP). A data-driven, linear modeling approach is applied in order to develop a Smith predictor for active pharmaceutical ingredient concentration control and a model predictive controller responsible for the TP hopper level. Additionally, in case of severe concentration variations out-of-specification material can be discarded before it enters the TP. The effectiveness of the control concept is tested not only in simulations but also by implementing it on a real pilot plant., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Policosanols (PCs) are a mixture of long chain primary aliphatic alcohols mainly known for their ability to reduce cholesterol level. Due to this property, there is an increasing interest in the extraction process of these compounds. In this context, beeswax, a natural product produced by honey bees of the genus Apis, is a promising source for their extraction and purification. The present research work was aimed at the development of a new procedure for the extraction and purification of PCs from yellow beeswax by using microwave-assisted technology, which hitherto has never been applied to this mixture. The developed process comprises three main steps: 1) microwave-assisted trans-esterification; 2) microwave-assisted hydrolysis; 3) final purification by means of preparative liquid chromatography. The final step is responsible for the increased purity of PCs, thanks to the removal of undesired compounds, such as natural paraffins. The predominant alcohols investigated in this work are tetracosanol (C 24 OH), hexacosanol (C 26 OH), octacosanol (C 28 OH), triacontanol (C 30 OH) and dotriacontanol (C 32 OH). Compound identification was performed using GC-EI-MS, while GC-FID analysis was chosen for the quantification of the main fatty alcohols present in the product. This new method represents a useful tool for the production of PCs from beeswax to be used in pharmaceuticals and nutraceuticals for human use, feed and veterinary supplements., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A fast, reproducible, non-destructive method to confirm raw material identification in real-time upon material receipt within a warehouse environment is desired. Current practices in pharmaceutical manufacturing often employ compendia methods for raw material identification tests, which require sample preparation prior to time-consuming chemical analysis and often employ subjective spectral comparisons. We have developed, qualified, and validated a rapid objective identity method ("Rapid ID") by Raman spectroscopy using the Bruker BRAVO handheld Raman spectrometer for 46 common raw materials used in upstream and downstream biopharmaceutical cell culture-based processes. Materials in the Raman identification library include amino acids and other solid neat organic chemicals, liquid organics, polyatomic salts, polymers, emulsifiers, peptides, aqueous solutions, and buffers. Selection of reference spectra and hit quality index limit(s) was based upon a comprehensive spectral survey across multiple suppliers and lots to account for normal cause spectral variation. Method repeatability and reproducibility, selectivity, and robustness against various operational and environmental factors (e.g., instrumental variance, material packaging, and thermal effects) were evaluated. Benefits of a handheld Raman Rapid ID approach include significant reduction of the time for raw material quality release from weeks to minutes, enhanced objectivity, and robust data integrity via autonomous electronic reporting. In addition, routine collection of rich spectroscopic data on raw materials can be leveraged to support further continuous improvement initiatives, including routine monitoring of method performance, continuous improvement of the library, proactive detection of shifts in raw material properties, and provision of data for investigations focused on raw materials. Rapid ID methods are consistent with the move toward the principles of Pharma 4.0-high automated processes with continuous process verification and a holistic control strategy. LAY ABSTRACT: A fast, reproducible, non-destructive method is desired to confirm raw material identification in real time upon receipt within a warehouse environment. We have developed, qualified and validated a rapid objective identity method ("Rapid ID") by Raman spectroscopy using the Bruker BRAVO handheld Raman spectrometer for 46 common raw materials used in upstream and downstream biopharmaceutical cell culture-based processes. Benefits of a handheld Raman Rapid ID approach include significant time reduction of raw material quality release from weeks to minutes, enhanced objectivity, and robust data integrity via autonomous electronic reporting. Rapid ID methods are consistent with the move toward the principles of Pharma 4.0: high automated processes with continuous process verification and a holistic control strategy., (© PDA, Inc. 2019.)

In the current study, the ability to use in-line NIR inside the feed frame of a tablet press to monitor the residence time distribution inside the tablet press was investigated. Pulse-response experiments were performed. In-line measurements inside the feed frame were compared to measurements on the actual produced tablets and the influence of different tableting parameters on the concentration profiles were studied. Turret speed had a major influence on the concentration profiles and RTD parameters. The in-line and off-line concentration profiles did not align with each other as spiking material was still detected in the tablets when no spiking material was observed in the powder blend by the in-line measuring method. The cause of this mismatch between the in-line and off-line curves was the in-line measuring position. By adjusting the position of the NIR probe to the bottom of the feed frame instead of at the top of the feed frame, a perfect alignment between in-line and off-line concentration curves was acquired. In-line measurements at the bottom of the feed frame could, if optimisation to avoid probe fouling is possible, be ideal for real-time measurement and control of the blend concentration during tableting. When probe fouling cannot be avoided, the correlation between the in-line measured concentration at the top of the feed frame and the concentration of the produced tablets should be investigated and modelled to enable real-time measurement and control based on in-line measurements., (Copyright © 2019 Elsevier B.V. All rights reserved.)