Minitablets current use and future opportunities - An APV course on manufacturing, packaging, characterization and use of minitablets.

Recently, APV organized in collaboration with Fette Compacting GmbH a course on current use and future opportunities of minitablets. The course including a workshop was attended by 30 participants and focused on the manufacturing, packaging, characterization and medical use of minitablets. It took place at the Headquarter of Fette Compacting GmbH in Schwarzenbek. This article provides an overview on the topics presented and discussed during the course.

Quality control evaluation of paediatric chocolate-based dosage forms: 3D printing vs mold-casting method.

Pharmaceutical compounding is a core activity in the preparation of patient-specific dosage forms. In the current study we aimed to investigate whether 3D printing could be employed for the preparation of pediatric-friendly personalized dosage forms that fulfil the acceptance criteria specified in the pharmacopoeias for conventional dosage forms. We then compared the 3D printed dosage forms with the same formulations prepared with mold-casting, a method frequently applied during pharmaceutical compounding. The molded dosage forms failed to pass most of the quality control tests, including the mass uniformity and content uniformity tests, as well as dose accuracy, contrary to the 3D printed, which not only passed all tests but also enabled precision overdose adjustment. Hence, 3D printing of chocolate-based dosage forms may effectively serve as an acceptable alternative method to mold casting in compounding patient-specific medication at the point-of-care.

A method for estimating the impact of new vaccine technologies on vaccination coverage rates.

Vaccines are one of the most cost-effective tools for improving human health and well-being. The impact of a vaccine on population health is partly determined by its coverage rate, the proportion of eligible individuals vaccinated. Coverage rate is a function of the vaccine presentation and the population in which that presentation is deployed. This population includes not only the individuals vaccinated, but also the logistics and healthcare systems responsible for vaccine delivery. Because vaccine coverage rates remain below targets in many settings, vaccine manufacturers and purchasers have a shared interest in better understanding the relationship between vaccine presentation, population characteristics, and coverage rate. While there have been some efforts to describe this relationship, existing research and tools are limited in their ability to quantify coverage rate changes across a broad set of antigens, vaccine presentations, and geographies. In this article, we present a method for estimating the impact of improved vaccine technologies on vaccination coverage rates. It is designed for use with low- and middle-income country vaccination programs. This method uses publicly available data and simple calculations based on probability theory to generate coverage rate values. We first present the conceptual framework and mathematical approach. Using a Microsoft Excel-based implementation, we then apply the method to a vaccine technology in early-stage development: micro-array patch for a measles-rubella vaccine (MR-MAP). Example outputs indicate that a complete switch from the current subcutaneous presentation to MR-MAP in the 73 countries ever eligible for Gavi support would increase overall vaccination coverage by 3.0-4.9 percentage points depending on the final characteristics of the MR-MAP. This change equates to an additional 2.6-4.2 million children vaccinated per year. Our method can be readily extended to other antigens and vaccine technologies to provide quick, low-cost estimates of coverage impact. As vaccine manufacturers and purchasers face increasingly complex decisions, such estimates could facilitate objective comparisons between options and help these decision makers obtain the most value for money.

Performance and paroxetine stability in tablets manufactured by fused deposition modelling-based 3D printing.

OBJECTIVES: The objective of this study was to develop a method for the preparation and characterization of paroxetine (PRX) tablets, obtained by coupling hot-melt extrusion and fused deposition modelling (FDM)-based three-dimensional printing (3DP) technology. The impact of the printing process parameters on the drug stability and on the tablets performance was assessed. METHODS: Tablets were obtained by FDM of hot-melt extruded PRX-loaded filaments. Physicochemical, thermal, spectroscopic, diffractometric analysis and in-vitro dissolution tests of the intermediate products and the finished dosage forms were performed. KEY FINDINGS: The characterization of printed tablets evidenced mass and dimensions uniformity, and consistency of drug content and dissolution profile. The formation of amorphous solid dispersions and interaction of formulation components throughout the manufacturing process were demonstrated. Layer thickness, printing temperature, printing and travelling speeds, and infill were the most impacting process parameters on both the physicochemical properties and the in-vitro performance of the 3D-printed tablets. CONCLUSIONS: PRX tablets, meeting compendial limits, were manufactured by 3DP, envisaging their clinical use as individually designed dosage forms. The assessment of the impact of processing parameters on the printed tablets provided insights, which will ultimately allow streamlining of the 3D process set-up for quicker and easier production of patient-centric medicines.

Towards Pharma 4.0 in clinical trials: A future-orientated perspective.

Pharma 4.0, a technology ecosystem in drug development analogous to Industry 4.0 in healthcare, is transforming the traditional approach to drug discovery and development, aligning product quality with less time to market, and creating intelligent stakeholder networks through effective collaborations. The wide range of potential Pharma 4.0 networks have produced several conceptualizations, which have led to a lack of clarity and definition. The main emphasis of this paper is on the clinical trial stage of drug development in the Pharma 4.0 era. It highlights the merged computerized technologies that are currently used in clinical research, and proposes a framework for integrating Pharma 4.0 technologies. The impact of and barriers to employing the proposed framework are discussed, highlighting its potential and some future research applications.

Can preclinical drug development help to predict adverse events in clinical trials?

The development of novel therapeutics is associated with high rates of attrition, with unexpected adverse events being a major cause of failure. Serious adverse events have led to organ failure, cancer development and deaths that were not expected outcomes in clinical trials. These life-threatening events were not identified during therapeutic development due to the lack of preclinical safety tests that faithfully represented human physiology. We highlight the successful application of several novel technologies, including high-throughput screening, organs-on-chips, microbiome-containing drug-testing platforms and humanised mouse models, for mechanistic studies and prediction of toxicity. We propose the incorporation of similar preclinical tests into future drug development to reduce the likelihood of hazardous therapeutics entering later-stage clinical trials.

[Advances in Pharmaceutical Manufacturing Process Management -From Physical Pharmaceutics to Automatic Pharmaceutical Production].

Since entering graduate school 43 years ago, I have been studying physical pharmaceutics with a focus on the effects of environmental factors on pharmaceutical properties of solid oral dosage forms during the manufacturing process. I have reported on changes in the characteristics of pharmaceutical products during manufacturing processes, such as grinding, mixing, granulation, and tableting owing to complicated phenomena based on chemical reactions or the crystalline polymorphic transitions of bulk drugs and excipients. To develop modern pharmaceutical manufacturing processes based on process analysis technology (PAT) as a next generation good manufacturing practice, real-time monitoring was introduced in these processes using a non-destructive analytical method, such as the near-infrared spectroscopy combined with chemometrics. Many case studies related to the mixing, granulation, tableting, and coating processes involving PAT have been reported. In those studies, I focused on clarifying the physical and chemical mechanism through "design space" representation. Additionally, non-destructive analytical methods, including X-ray computed tomography, audible acoustic emission, Raman spectroscopy, terahertz spectroscopy, and infrared thermal imaging analysis were applied as novel candidate analytical methods to the pharmaceutical process to monitor critical quality attributes. To achieve this purpose in various pharmaceutical dosage forms, I have been attempting the assembly of a modern manufacturing process managed through a "design space" paradigm involving in-line monitoring using novel analytical methods, multivariate analyses, and feed-back systems.

Impact of formulation on the quality and stability of freeze-dried nanoparticles.

Freeze-drying is an effective approach to improve the long-term stability of nanomedicines. Lyoprotectants are generally considered as requisite excipients to ensure that the quality of nanoparticles is maintained throughout the freeze-drying process. However, depending on the type of nanoparticles, the needs for lyoprotectants or the challenges they face during freeze-drying may be different. In this study, we compared and identified the impact of freeze-drying on key characteristics of three types of nanoparticles: solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. Sucrose, trehalose, and mannitol were added to nanoparticle suspensions before freeze-drying. The same conservative freeze-drying conditions with controlled ice nucleation at -8 °C were employed for all formulations. The collapse temperatures of nanoparticle formulations were found to be the same as those of the lyoprotectant added, except PN formulation. Likely the poly(vinyl alcohol) (PVA) in the formulation induced a higher collapse temperature and retardation of drying of PNs. Freeze-drying of both SLNs and liposomes without lyoprotectants increased particle size and polydispersity, which was resolved by adding amorphous disaccharides. Regardless of the addition of lyoprotectants, freeze-drying did not alter the size of PNs possibly due to the protection from PVA. However, lyoprotectants were still necessary to shorten the reconstitution time and reduce the residual moisture. In conclusion, different types of nanoparticles face distinct challenges for freeze-drying, and lyoprotectants differentially affect various stability and quality attributes of freeze-dried nanoparticles.

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.

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.

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.

Hot-Melt Extrusion: a Roadmap for Product Development.

Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.

Patient-Derived Organoids as a Model for Cancer Drug Discovery.

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell-cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue-tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.

Design of bivalent ligands targeting putative GPCR dimers.

G protein-coupled receptors (GPCRs) have been exploited as primary targets for drug discovery, and GPCR dimerization offers opportunities for drug design and disease treatment. An important strategy for targeting putative GPCR dimers is the use of bivalent ligands, which are single molecules that contain two pharmacophores connected through a spacer. Here, we discuss the selection of pharmacophores, the optimal length and chemical composition of the spacer, and the choice of spacer attachment points to the pharmacophores. Furthermore, we review the most recent advances (from 2018 to the present) in the design, discovery and development of bivalent ligands. We aim to reveal the state-of-the-art design strategy for bivalent ligands and provide insights into future opportunities in this promising field of drug discovery.

Advancing automation in Compound Management: a novel industrial process underpinning drug discovery.

Faced with ageing infrastructure and ever-increasing demands from hit discovery and lead optimisation functions, AstraZeneca has chosen to develop innovative technologies and process solutions to support the future of drug discovery. These include the miniaturisation of compound storage tubes for high-density storage and rapid access to the corporate collection for feeding samples to the predicted tripling number of high throughput screening (HTS) campaigns. The acoustically- compatible tubes also enable the first fully-acoustic plate production process for faster sample supply to screening with less waste and continued high quality. Operating at a smaller scale reduces compound synthesis, storage, and consumption, prompting miniaturisation of upstream chemistry and downstream biological assays, while offering a transformative and sustainable solution to many drug discovery issues applicable across the industry.

Modulating target engagement of small molecules via drug delivery: approaches and applications in drug discovery and development.

Drug-delivery technologies for modified drug release have been in existence for decades, but their utilization has been largely limited to post-launch efforts improving therapeutic outcomes. Recently, they have gained renewed importance because the pharmaceutical industry is steadily shifting to a more integrated discovery-development approach. In discovery, modulating target engagement via drug-delivery technologies can enable crucial pharmacological studies for building well-defined criteria for molecular design. In development, earlier implementation of delivery technologies can enhance the value of drug products through reduced dosing frequency and improved tolerability and/or safety profile, thereby leading to better adherence and therapeutic effectiveness.

Pharmaceutical Technology Innovation Strategy Based on the Function of Blood Transport Proteins as DDS Carriers for the Treatment of Intractable Disorders and Cancer.

Blood transport proteins are biogenic molecules with unique and interesting inherent characteristics that make up living organisms. As the utilization of their inherent characteristics can be a groundbreaking strategy to resolve and improve several clinical problems, attempts have been made to develop pharmaceutical and biomedical preparations based on blood transport proteins for the treatment and diagnosis of disorders. Among various blood transport proteins, we focus on the immense potential of hemoglobin and albumin to serve as carriers of biomedical gases (oxygen and carbon monoxide) and anticancer agents (low-molecular compounds and antisense oligodeoxynucleotides), respectively, for the development of innovative drug delivery systems (DDS) to treat intractable disorders and solid cancers. In this review, I introduce the pharmaceutical technology, strategies, and application of DDS carriers that have been designed on the basis of the structure and function of hemoglobin and albumin. In addition, the prospect of using hemoglobin and albumin as materials for DDS carriers is discussed.