The continuous quest for materials capable of providing sustained release of antimicrobial drugs is particularly important for indwelling medical applications. In this study, we utilized amoxicillin as a model active pharmaceutical ingredient (API) to investigate the feasibility of using porous media – specifically, functionalized calcium carbonate (FCC) microparticles – as a primary drug carrier embedded within an ethyl cellulose (EC) polymer film. Our main objective was to prolong and sustain the release of the API. The fabrication process of the microparticle containing film involved two key steps: loading the model API into the FCC particles and then embedding these loaded particles into the polymeric film. Amoxicillin was loaded into the FCC particles using a solvent evaporation method. Detailed characterization through Scanning Electron Microscopy (SEM), lab- and synchrotron-based XRD revealed that amoxicillin precipitated both inside and on the surface of the FCC particles, predominantly in an amorphous form. Additionally, ultraviolet-visible (UV-vis) spectroscopic data demonstrated an increased release rate from the porous FCC compared to direct dissolution of pure amoxicillin powder. Embedding amoxicillin preloaded porous FCC particles in the EC film led to a more rational sustained release compared with powder amoxicillin embedded directly in the film, advantageously delivering the same amount of amoxicillin over a longer period; a result that may be relevant for indwelling medical devices such as urinary catheters, vascular access devices or wound drains

When producing starch microspheres in aqueous two-phase systems (ATPS), a continuous-phase polymer is employed to induce segregative phase separation. This creates a continuous polymer-rich phase, in which starch-rich phase droplets can be dispersed and crystallised into solid, semi-crystalline starch microspheres. This study aims to explore how polymers with different chemical structures and sizes affect phase behaviour in starch-based ATPS and the formation of starch microspheres. The polymers studied were polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), poly(2-ethyl-2-oxazoline) (PEtOx) and hydroxypropyl methylcellulose (HPMC). To reach a starch concentration in the starch-rich phase (55 %) that yielded solid starch microspheres, less PEG (32 %) than PVP (39 %) or PEtOx (42 %) were required in the continuous phase. The sizes of the polymers had little or no effect on the water distribution in the ATPS. The governing factor is the water activity within the system. The water activity in the starch-rich phase must be low enough to allow for crystallisation within the predetermined time frame. Accordingly, the polymer concentration must be selected so that this water activity condition is reached. The viscosity of the continuous phase significantly impacted the microsphere production. It needs to be high enough to prevent the coalescence of starch droplets as they transition to solid gels, but not so high that it hinders emulsification. While polymer choice affected particle size and aggregation, it did not notably change the interior structure, surface morphology, crystal type, or thermal behaviour of the dried starch microspheres. This opens up the possibility to optimise the production of microspheres by changing polymers, while tuning the starch crystallisation through control of the water activity in the starch phase

Protein drugs, such as therapeutic antibodies, are complex and require careful handling to maintain their efficacy and quality. Stress factors in hospitals, like temperature variations and mechanical shocks during transport, may negatively impact the stability of protein drugs (e.g. various monoclonal antibodies). The pharmaceutical industry possesses extensive knowledge about their product formulations but often the transfer of knowledge from lab studies into in-hospital handling procedures is challenging. To address this gap and find a way to bridge academia, healthcare, and industry, seven semi-structured interviews were conducted with experts from pharmaceutical companies across five countries. This study aimed to explore the opinions of formulation experts regarding stress evaluation in clinical settings. Thematic analysis of the interviews revealed four key themes: The human factor in clinical sites, clinical sites as data providers, potential complexities in conducting tests within a clinical setting, and challenges associated with product-specific methods, equipment and devices. This study also suggests tools for setting up clinical test beds that can help the pharmaceutical industry improve stress evaluation and understand clinical product handling. Direct collaboration with clinical sites is crucial, as experts perceive improved evaluation methods and education to be necessary for ensuring safe medicines for patients.

Starch microspheres are employed in medicinal products as embolization agents and drug delivery vehicles. For the encapsulation of sensitive ingredients, mild cross-linking techniques are needed, prompting interest in physical cross-linking via starch crystallization. This study investigates starch microsphere formation and crystallization kinetics in aqueous two-phase systems (ATPS) with various continuous phase polymers, using confocal Raman microscopy, X-ray scattering, isothermal calorimetry, and light microscopy. The results showed that the solidification of starch particles depends on the ATPS polymers, being fastest in polyethylene glycol (PEG), followed by poly(2-ethyl-2-oxazoline) (PEtOx), and polyvinyl pyrrolidone (PVP). Confocal Raman microscopy can be used to follow the crystallization process, and its results match those from X-ray crystallography. Raman microscopy demonstrated uniform structural changes from amorphous to crystalline starch, with PEG and PEtOx facilitating faster crystallization than PVP. X-ray diffraction and isothermal calorimetry also demonstrated faster crystal growth and heat flow development in PEG and PEtOx formulations compared to PVP. Analysis of the kinetics using the Avrami model indicated that crystallization is uniform across the microspheres. Combining these results with light microscopy observations revealed that starch solidification occurs in the early stages of the crystallization process. In conclusion, the continuous phase polymer impacts the crystallization kinetics and structural evolution of starch microspheres, with PVP leading to slower crystallization compared to PEG and PEtOx. This suggests that polymer selection is crucial for tailoring the crystallization process of starch-based microspheres.

This article compares and explores vacuum foam-drying as an alternative drying technology to freeze-drying and spray drying for a recombinant human lipase as the model protein. Materials characteristics such as structure, surface composition and the solid-state properties of the dry materials were compared and investigated. Moreover, the technical functionality in terms of reconstitution characteristics and the lipase stability were also investigated. The stability of the lipase was evaluated through activity measurements. Sucrose and dextran D40 (40 kDa) were used as matrix former and the surfactant α-dodecyl maltoside was used as surface active additive. The study demonstrated that the drying technique greatly influenced the material structure and composition which in turn affected the reconstitution characteristics. The lipase was overrepresented at the material surface in declining order spray-dried > vacuum foam-dried > freeze-dried. The lipase activity was retained up to 10 % lipase content in solids, but at 20 % lipase a loss of activity was observed for all drying techniques. Phase separation in the solid material may be an explanation. Vacuum foam-drying shows promise as an alternative drying technique for the lipase, and potentially other proteins. 

This paper explores how vacuum foam-drying of a protein is influenced by formulation parameters by investigating the foam structure, physical properties of the foam, and the stability of the protein. Recombinant human bile salt-stimulated lipase was used as a model of a protein drug. The stability of the lipase was evaluated through activity measurements. Two disaccharides (sucrose and trehalose), strongly tending to an amorphous form, were used as matrix formers, and the physical properties were assessed through residual water content, glass transition temperature, and crystalline state. Moreover, some formulations included surfactants with different sizes and structures of the head group. The alkyl chain length was kept constant to only investigate the impact of the surfactant head group, in the presence of the lipase, on the foamability and surface coverage of the lipase. The study demonstrated that the lipase allowed for a dry, solid foam with a foam overrun of up to 2600 %. The wall thickness of the dry, solid foam was estimated to be 20–50 µm. Clear differences between sucrose and trehalose as matrix former were identified. The lipase showed no tendency to lose activity because of the drying and rehydration, despite a proportion of the lipase covering the surfaces of the dry material. 

Biopharmaceuticals are complex biological molecules that require careful storage and handling to ensure medication integrity. In this study, a work system analysis of real-world protein drug (PD) handling was performed with the following goals: identify main barriers and facilitators for successful adherence to accepted recommendations in PD handling, analyse differences in two organizations, and define a Best Current Practice in the real-life handling of PDs based on the results of the work system analysis. Observational study was held in two university hospitals in Spain and Sweden. Based on the Systems Engineering Initiative for Patient Safety (SEIPS) model, the tools chosen were: the PETT scan, in order to indicate the presence of barriers or facilitators for the PETT components (People, Environment, Tools, Tasks); the Tasks and tools matrices to construct a checklist to record direct observations during the real-life handling of biopharmaceuticals, and the Journey map to depict the work process. Observations were performed between March and November 2022. Each episode of direct observation included a single protein drug in some point of the supply chain and considered all the elements in the work system. Based on the results of the work system analysis and the literature review, the authors propose a list of items which could be assumed as Best Current Practice for PDs handling in hospitals. There were a total of 34 observations involving 19 PDs. Regarding People involved in the work process, there was a diversity of professionals with different previous training and knowledge, leading to an information gap. With respect to Environment, some structural and organizational differences between hospitals lead to risks related to the time exposure of PDs to room temperature and mechanical stress. Some differences also existed in the Tools and Tasks involved in the process, being especially relevant to the lack of compatibility information of PDs with new technologies, such as pneumatic tube system, robotic reconstitution, or closed-system transfer devices. Finally, 15 suggestions for best current practice are proposed. Main barriers found for compliance with accepted recommendations were related to the information gap detected in professionals involved in the handling of protein drugs, unmonitored temperature, and the lack of compatibility information of protein drugs with some new technologies. By applying a Human Factors and Systems Engineering Approach, the comparison of two European hospitals has led to a suggested list of Best Current Practices in the handling of protein drugs in a hospital. 

This article evaluates the current gaps around the impact of post-manufacturing processes on the product qualities of protein-based biologics, with a focus on user centricity. It includes the evaluation of the regulatory guidance available, describes a collection of scientific literature and case studies to showcase the impact of post-manufacturing stresses on product and dosing solution quality. It also outlines the complexity of clinical handling and the need for communication, and alignment between drug providers, healthcare professionals, users, and patients. Regulatory agencies provide clear expectations for drug manufacturing processes, however, guidance supporting post-product manufacturing handling is less defined and often misaligned. This is problematic as the pharmaceutical products experience numerous stresses and processes which can potentially impact drug quality, safety and efficacy. This article aims to stimulate discussion amongst pharmaceutical developers, health care providers, device manufacturers, and public researchers to improve these processes. Patients and caregivers’ awareness can be achieved by providing relevant educational material on pharmaceutical product handling. 

Objective: This paper investigates the critical role of material thickness in freeze-dried pellets for enhancing the storage stability of encapsulated bacteria. Freeze dried material of varying thicknesses obtained from different annealing durations is quantified using Scanning Electron Microscopy (SEM) and X-ray microtomography (μCT), the material thickness is then correlated to the storage stability of the encapsulated cells. Methods: A formulation comprising of sucrose, maltodextrin, and probiotic cells is quenched in liquid nitrogen to form pellets. The pellets undergo different durations of annealing before undergoing freeze-drying. The material thickness is quantified using SEM and μCT. Storage stability in both oxygen-rich and oxygen-poor environments is evaluated by measuring CFU counts and correlated with the pellet structure. Results: The varying annealing protocols produce a range of material thicknesses, with more extensive annealing resulting in thicker materials. Storage stability exhibits a positive correlation with material thickness, indicating improved stability with thicker materials. Non-annealed pellets exhibit structural irregularities and inconsistent storage stability, highlighting the impracticality of avoiding annealing in the freeze-drying process. Conclusions: Extensive annealing not only enhances the storage stability of probiotic products but also provides greater control over the freeze-drying process, ensuring homogeneous and reproducible products. This study underscores the importance of material thickness in freeze-dried pellets for optimizing storage stability for probiotic formulations, and emphasize the necessity of annealing as a critical step in freeze-drying quenched pellets to achieve desired structural and stability outcomes.

Starch is generally regarded as safe for human consumption and has therefore attracted interest for several applications as medicinal products. This chapter focuses specifically on starch microspheres as carriers for drug delivery and as a medical device for, for example, vascular occlusion. Several methods for the preparation of starch microspheres by chemical or physical cross-linking are presented. The properties of the starch microspheres are affected by the production method, which also influences what applications they are suited for, and how active substances can be included in the microspheres. The current and potential applications of starch microspheres in drug delivery, vascular occlusion, and advanced wound care are reviewed.