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.

Replicates Number for Drug Stability Testing during Bioanalytical Method Validation-An Experimental and Retrospective Approach.

BACKGROUND: The stability of a drug or metabolites in biological matrices is an essential part of bioanalytical method validation, but the justification of its sample size (replicates number) is insufficient. The international guidelines differ in recommended sample size to study stability from no recommendation to at least three quality control samples. Testing of three samples may lead to results biased by a single outlier. We aimed to evaluate the optimal sample size for stability testing based on 90% confidence intervals. METHODS: We conducted the experimental, retrospective (264 confidence intervals for the stability of nine drugs during regulatory bioanalytical method validation), and theoretical (mathematical) studies. We generated experimental stability data (40 confidence intervals) for two analytes-tramadol and its major metabolite (O-desmethyl-tramadol)-in two concentrations, two storage conditions, and in five sample sizes (n = 3, 4, 5, 6, or 8). RESULTS: The 90% confidence intervals were wider for low than for high concentrations in 18 out of 20 cases. For n = 5 each stability test passed, and the width of the confidence intervals was below 20%. The results of the retrospective study and the theoretical analysis supported the experimental observations that five or six repetitions ensure that confidence intervals fall within 85-115% acceptance criteria. CONCLUSIONS: Five repetitions are optimal for the assessment of analyte stability. We hope to initiate discussion and stimulate further research on the sample size for stability testing.

The History, Present and Future of Allergen Standardization in the United States and Europe.

The topic of standardization in relation to allergen products has been discussed by allergists, regulators, and manufacturers for a long time. In contrast to synthetic medicinal products, the natural origin of allergen products makes the necessary comparability difficult to achieve. This holds true for both aspects of standardization: Batch-to-batch consistency (or product-specific standardization) and comparability among products from different manufacturers (or cross-product comparability). In this review, we focus on how the United States and the European Union have tackled the topic of allergen product standardization in the past, covering the early joint standardization efforts in the 1970s and 1980s as well as the different paths taken by the two players thereafter until today. So far, these two paths have been based on rather classical immunological methods, including the corresponding benefits like simple feasability. New technologies such as mass spectrometry present an opportunity to redefine the field of allergen standardization in the future.

Quality by design tools reducing the gap from bench to bedside for nanomedicine.

Pharmaceutical nanotechnology research is focused on smart nano-vehicles, which can deliver active pharmaceutical ingredients to enhance their efficacy through any route of administration and in the most varied therapeutical application. The design and development of new nanopharmaceuticals can be very laborious. In recent years, the application of mathematics, statistics and computational tools is emerging as a convenient strategy for this purpose. The application of Quality by Design (QbD) tools has been introduced to guarantee quality for pharmaceutical products and improve translational research from the laboratory bench into applicable therapeutics. In this review, a collection of basic-concept, historical overview and application of QbD in nanomedicine are discussed. A specific focus has been put on Response Surface Methodology and Artificial Neural Network approaches in general terms and their application in the development of nanomedicine to monitor the process parameters obtaining optimized system ensuring its quality profile.

Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group.

Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development.

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.

Digital twin of low dosage continuous powder blending - Artificial neural networks and residence time distribution models.

In this paper we present a thorough description of the digital twin development for a continuous pharmaceutical powder blending process in accordance with the Process Analytical Technologies (PAT) and Quality by Design (QbD) guidelines. A low-dosage system of caffeine active pharmaceutical ingredient (API) and dextrose excipient was examined via continuous blending experiments. Near infrared (NIR) spectroscopy-based process analytics were applied; quantitative evaluation of spectra was achieved using multivariate data analysis. The blending system was represented with mechanistic residence time distribution (RTD) models and two types of recurrent artificial neural networks (ANN), experimental datasets were used for model training or fitting and validation. Detailed comparison of the two modelling approaches, the optimization of the model-based digital twin, and efficiency of the soft sensor-based process monitoring is presented through several validating simulations. Both RTD models and nonlinear autoregressive neural networks demonstrated excellent predictive power for the low dosage blending process. RTD models can prove to be more advantageous in industrial development as they are less resource-intensive to develop and prediction accuracy on low concentration levels lacks dependency from the precision of chemometric calibration. Reduced material costs and limited development timeframe render the digital twin an efficient tool in technological development.

AAPS Perspective on the EURL Recommendation on the use of Non-Animal-Derived Antibodies.

In May 2020, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) published a recommendation report entitled "Recommendation on nonanimal-derived antibodies". In this report, the EURL ECVAM specifically states: "Therefore, taking into consideration the ESAC Opinion on the scientific validity of replacements for animal-derived antibodies, EURL ECVAM recommends that animals should no longer be used for the development and production of antibodies for research, regulatory, diagnostic and therapeutic applications. The provisions of Directive 2010/63/EU should be respected, and EU countries should no longer authorise the development and production of antibodies through animal immunisation, where robust, legitimate scientific justification is lacking." (1). Here, we are providing the American Association of Pharmaceutical Scientists (AAPS) opinion on the EURL ECVAM recommendation report. In brief, there has been a clear and strong progress in reduction of animal use in the drug discovery and development process, including significant reduction of animal use in production of antibody reagents. Yet, it is proposed that more data need to be generated, shared and discussed within the scientific community before a decision to implement the change to non-animal derived antibodies is made.

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.

Determination of the potency of a cell-based seasonal quadrivalent influenza vaccine using a purified primary liquid standard.

In Japan, the practical application of completely cell-based seasonal influenza vaccines is under consideration. Considering the good correlation between the immunogenicity of egg-based influenza vaccines and the hemagglutinin (HA) content determined by the single radial immunodiffusion (SRD) assay, we determined the potency of the first cell-based quadrivalent vaccine experimentally generated in Japan using the SRD assay in this study. A primary liquid standard (PLS) and reference antigen were generated from the purified vaccine virus, and a sheep antiserum was produced against the HA of the vaccine virus. Since the purity of the PLS affects the reliability of vaccine potency testing, the purification steps are significant. We successfully prepared a purified PLS nearly free of cell debris. The HA content in the PLS was first estimated from the total amount of viral protein and the percentage of HA content determined by SDS-PAGE analysis. The HA content in the reference antigen was calibrated to that in the PLS via the SRD assay. The vaccine potency, that is, the HA content in each vaccine, was finally measured using the corresponding reference antigen. Ultimately, the measured vaccine potency of the monovalent vaccine was similar to that of the quadrivalent vaccine.

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.

Real-time quantification of low-dose cohesive formulations within a sampling interface for flowing powders.

This study investigates the performance of a sampling interface for monitoring cohesive, flowing powder formulations with Hausner's Ratio and Carr's Index higher than 1.5 and 35%, respectively. The sampler device was operated in combination with near-infrared (NIR) spectroscopy to quantify ibuprofen concentrations between 1.5 and 4.5% w/w. NIR spectra also provided essential information to study the process dynamics within the sampler. The 200 spectra per blend obtained demonstrated a continuous powder flow with no evidence of agglomerates or segregation within the sampler for a blend of 6 kg. A NIR calibration model was optimized to predict independent test blends, delivering root mean square error of predictions and bias under 0.1% w/w. The test blends were within specifications according to the requirements of European Pharmacopeia. Variographic analysis demonstrated that the sampler device may determine low drug concentration in cohesive powder blends, presenting sampling errors below 0.011 (%w/w)2. This analysis also demonstrated that an increase in the blend compressibility leads to a slight rise in sampling errors within the sampler device. The sampler device offers statistical robustness in the evaluation of blend uniformity, providing greater confidence in the quality determination of the cohesive powder blends without significantly affecting its flow properties.

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.

A cross-industry forum on benchmarking critical quality attribute identification and linkage to process characterization studies.

Identification of Critical Quality Attributes (CQAs) and subsequent characterization in process development studies are the key elements of quality by design (QbD) for biopharmaceutical products. Since the inception of ICH Q8R2, several articles have been published on approaches to conducting CQA risk assessments as well as the application to process understanding. A survey was conducted by multiple companies participating in an International Consortium working group on the best practices for identifying CQAs with linkages to process characterization (PC) studies. The results indicate that the companies surveyed are using similar approaches/timing to identify CQAs during process development. Consensus was also observed among the companies surveyed with approaches to linkage of CQAs to process characterization studies leading to impact to control strategies and lifecycle management.

Discrete element modeling for continuous powder feeding operation: Calibration and system analysis.

Research emphases on extensive experimental studies and modeling efforts have been on the rise for the development of accurate predictive models of pharmaceutical unit operations and 'digital-twin' framework for continuous manufacturing lines. These exhaustive studies have been conducted at different process conditions to acquire comprehensive knowledge of effects of process parameters on the overall process dynamics. However, there still lacks a detailed understanding of material property effects of pharmaceutical powders on process operation. To address this issue, a discrete element modeling (DEM) approach combined with material calibration is applied for simulation of feeder unit to obtain particle-level insight into effects of material properties on feeder performance with focus on particle flow and powder mixing within the feeder unit. Bulk calibration is implemented to accurately represent powder material properties within the DEM framework. Different refill situations are simulated using DEM to observe powder mixing, measured at the outlet. Feeder DEM simulations are further applied to understand correlations of material properties on feeder operation. These studies provide a detailed physical insight and particle-scale information into the powder mechanics during powder feeding operation.

Farmacia Militar en la crisis sanitaria por la COVID-19 / Military Pharmacy in health crisis due to COVID-19

La especialidad fundamental Farmacia del Cuerpo Militar de Sanidad, tiene como cometidos la dirección de los órganos e instalaciones de los servicios farmacéuticos, el abastecimiento y mantenimiento de los recursos sanitarios, la formulación de especificaciones técnicas, la catalogación de productos farmacéuticos, el análisis de productos químicos, biológicos y toxicológicos, así como protección sanitaria en ambiente nuclear, biológico y químico. A través de las diferentes estructuras de las Fuerzas Armadas en las que se integran oficiales farmacéuticos, se han empleado todas las capacidades disponibles con el fin de dar respuesta a la reciente crisis sanitaria por la COVID-19 ocasionada por el virus SARS-CoV-2. Así, se ha participado en el planeamiento y ejecución de la Operación Balmis, bajo la autoridad del Jefe de Estado Mayor de la Defensa (JEMAD) y el Comandante del Mando de Operaciones (CMOPS), con acciones de análisis de la información y asesoramiento en el ámbito farmacéutico. Por otra parte, Farmacia Militar ha centrado esfuerzos en la fabricación y logística del recurso sanitario siguiendo los criterios de eficacia y eficiencia exigidos en esta excepcional situación, abarcando el proceso completo desde la gestión de la adquisición o producción propia, hasta la distribución o dispensación del recurso tanto en el seno de las Fuerzas Armadas, como en las solicitudes de apoyo realizadas por autoridades civiles en materia de sanidad. Por último, se ha potenciado la capacidad diagnóstica de los laboratorios con presencia farmacéutica, implementado nuevas técnicas de detección del agente viral e incluyendo nuevos parámetros bioquímicos relacionados con COVID-19 en la cartera de servicios. La nueva magnitud de los recursos sanitarios implicados en esta crisis sanitaria ha identificado la necesidad de constituir una reserva estratégica en el ámbito nacional, para la acción conjunta de las Fuerzas Armadas y el Ministerio de Sanidad

The Ministry of Defence's Pharmaceutical Services have the task of directing organisms and facilities of the pharmaceutical services, the supply and maintenance of medical materiel, the formulation of technical specifications, the cataloguing of pharmaceutical products, the analysis of chemical, biological and toxicological products as well as health protection in nuclear, biological and chemical environments. Through the different structures of the Armed Forces in which pharmaceutical officers are integrated, all available capabilities have been utilized in order to respond to the recent health crisis COVID-19 caused by the SARS-CoV-2. As such, this has been carried out in the planning and execution of Operation Balmis, under the authority of the Chief of Defence Staff (JEMAD in Spanish) and the Commander of the Operations Command (CMOPS in Spanish), with tasks such as providing pharmaceutical information and advice. On the other hand, the Military Pharmacy has focused its efforts on military manufacturing and logistics of pharmaceuticals and medical materiel following the criteria of effectiveness and efficiency required in these unprecedented circumstances, covering the entire process from the management of acquisition or production, to distribution or dispensation both within the Armed Forces, and in requests for support made by civilian authorities in matters of health. Finally, the diagnostic capabilities of laboratories with a pharmaceutical presence has been enhanced, new detection techniques for the viral agent have been implemented and new biochemical parameters related to COVID-19 have been included in the service portfolio. The new magnitude of pharmaceuticals and medical materiel involved in this health crisis has highlighted the need to constitute a national strategic pharmaceutical stockpile, for a joint Armed Forces - Ministry of Health action

Good design practices for an integrated containment and production system for advanced therapies.

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application.

Industry One-Voice-of-Quality (1VQ) Solutions: Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)-through Enhanced Science and Risk-Based Approaches.

Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.