A Simple and Cost-Effective Technique to Monitor the Sublimation Flow During Primary Drying of Freeze-Drying Using Shelf Inlet/Outlet Temperature Difference or Chamber to Condenser Pressure Drop.

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.

In-lab synthesized turn-off fluorescence sensor for estimation of Gemigliptin and Rosuvastatin polypill appraised by Spider diagram, AGREE and whiteness metrics.

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.

A non-invasive multipoint product temperature measurement for pharmaceutical lyophilization.

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.

Binder jetting 3D printing of challenging medicines: From low dose tablets to hydrophobic molecules.

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.

Evaluation of portable devices for medicine quality screening: Lessons learnt, recommendations for implementation, and future priorities.

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy.

Wireless sensor networks for pharmaceutical lyophilization: Quantification of local gas pressure and temperature in primary drying.

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.

Cycle Development in a Mini-Freeze Dryer: Evaluation of Manometric Temperature Measurement in Small-Scale Equipment.

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.

Design of a vertical Loss-in-Weight feeder prototype with experimental proof of concept validation.

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.

Two-dimensional moisture content and size measurement of pharmaceutical granules after fluid bed drying using near-infrared chemical imaging.

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.

Model predictive control in pharmaceutical continuous manufacturing: A review from a user's perspective.

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.

A Review on the Current Methods of Chinese Hamster Ovary (CHO) Cells Cultivation for the Production of Therapeutic Protein.

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.

Peptide Isolation via Spray Drying: Particle Formation, Process Design and Implementation for the Production of Spray Dried Glucagon.

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.

CFD-DEM -DDM Model for Spray Coating Process in a Wurster Coater.

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.

3D-Printing with precise layer-wise dose adjustments for paediatric use via pressure-assisted microsyringe printing.

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.

Surface Composition and Aerosolization Stability of an Inhalable Combinational Powder Formulation Spray Dried Using a Three-Fluid Nozzle.

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 (23) 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.

Electrospinning/electrospraying coatings for metal microneedles: A design of experiments (DOE) and quality by design (QbD) approach.

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.

Twin-screw melt granulation: Current progress and challenges.

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.

Freeze-drying in protective bags: Characterization of heat and mass transfer.

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-ß-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 Kv 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.

Comparative investigations on key factors and print head designs for pharmaceutical inkjet printing.

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.

Functional similarity of modified cascade impactor to deposit drug particles on cells.

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.