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The refined Developability Classification System (rDCS) provides a comprehensive animal-free approach for assessing biopharmaceutical risks associated with developing oral formulations. This work demonstrates practical application of a recently advanced rDCS framework guiding formulation design for six diverse active pharmaceutical ingredients (APIs) and compares rDCS classifications with those of the Biopharmaceutics Classification System (BCS). While the BCS assigns five of the APIs to class II/IV, indicating potentially unfavorable biopharmaceutical attributes, the rDCS provides a more nuanced risk assessment. Both BCS and rDCS assign acetaminophen to class I at therapeutic doses. Voriconazole and lemborexant (both BCS II) are classified in rDCS class I at therapeutic doses, indicating suitability for development as conventional oral formulations. Fedratinib is classified as BCS IV but the rDCS indicates a stratified risk (class I, IIa or IIb), depending on the relevance of supersaturation/precipitation in vivo. Voxelotor and istradefylline (both BCS II) belong to rDCS class IIb, requiring solubility enhancement to achieve adequate oral bioavailability. Comparing the rDCS analysis with literature on development and pharmacokinetics demonstrates that the rDCS reliably supports oral formulation design over a wide range of API characteristics, thus providing a strong foundation for guiding development. [Display omitted] [ABSTRACT FROM AUTHOR]

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits. [Display omitted] • The importance of integrating results and information from all stability activities to inform the next steps in a drug development process is emphasized. • Predictions from the accelerated stability testing (APS) model were successfully applied and matched against the real-time stability data of the final drug product composition. • Confidence gained by shelf-life predictions allowed for adjustment of the clinical stability protocol, enabling the reduction of testing points and climates. • The APS model provided crucial information on the shelf-life limiting attributes, thereby informing limits in the drug product initial clinical specification. • The shelf-life limiting degradation product could be considered qualified, justified by available metabolite data, thus underscoring the importance of qualification of impurities. [ABSTRACT FROM AUTHOR]

Deep infection is the second most common complication of arthroplasty following loosening of the implant. Antibiotic-loaded bone cements (ALBCs) and high concentrations of systemic broad-spectrum antibiotics are commonly used to prevent infections following injury and surgery. However, clinical data fails to show that ALBCs are effective against deep infection, and negative side effects can result following prolonged administration of antibiotics. Additionally, the rise of multidrug resistant (MDR) bacteria provides an urgent need for alternatives to broad-spectrum antibiotics. Phage therapy, or the use of bacteriophages (viruses that infect bacteria) to target pathogenic bacteria, might offer a safe alternative to combat MDR bacteria. Application of phage therapy in the setting of deep infections requires formulation strategies that would stabilize bacteriophage against chemical and thermal stress during bone-cement polymerization, that maintain bacteriophage activity for weeks or months at physiological temperatures, and that allow for sustained release of phage to combat slow-growing, persistent bacteria. Here, we demonstrate the formulation of three phages that target diverse bacterial pathogens, which includes spray-drying of the particles for enhanced thermal stability at 37 °C and above. Additionally, we use atomic layer deposition (ALD) to coat spray-dried powders with alumina to allow for delayed release of phage from the dry formulations, and potentially protect phage against chemical damage during bone cement polymerization. Together, these findings present a strategy to formulate phages that possess thermal stability and sustained release properties for use in deep infections. [ABSTRACT FROM AUTHOR]

This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for in vitro drug release and in vivo drug absorption in rats. All drugs showed similar release profiles in vitro from both jelly formulations, except for the faster release from pectin jelly at neutral pH. In contrast, in vivo absorption of ATE but not of ANT from jelly formulations was significantly lower than from solution. Absorption of ATE and MET was low from agar jelly after oral administration, whereas additional water intake significantly increased the absorption. The process of drug absorption was described by the compartmental model consisting of jelly, intestinal fluid, and blood compartments. Drugs in the jelly diffuse into the intestinal fluid and then permeate the intestinal membrane. By considering the rate-limiting process, membrane permeability-dependent drug absorption from agar jelly and the effects of water intake were identified. In conclusion, jelly formulations may potentially decrease and delay drug oral absorption, especially of poorly permeable drugs. Intestinal fluid volume is one of the important factors to control the drug absorption. [Display omitted] • Although oral jelly formulations are often used for pediatric or elderly patients because of their high swallowability, the precise process and mechanism of gastrointestinal (GI) drug absorption from oral jelly formulations are not fully understood. This study examined the process of drug absorption from oral jelly formulations. • In this study, the compartmental model was used to describe the unique process of drug absorption from oral jelly formulations, in which drugs dissolved in the jelly reach the intestinal fluid via diffusion through the jelly matrix. By defining the rate-limiting process of drug absorption from oral jelly formulations, the effects of the membrane permeability of the drug and GI fluid volume were identified. • The correlation between in vitro drug release and in vivo oral absorption from oral jelly formulations observed in this study will help to consider the bioequivalence of oral jelly formulations with other formulations (e.g., solution, tablet). • To clearly demonstrate the effect of membrane permeability, three model drugs with different permeabilities were incorporated in the jelly and administered to rats as a cassette. • Two different methods, intra-intestinal and oral administration, were used for in vivo drug administration to rats. The results of the intra-intestinal administration study revealed the basic mechanism of drug absorption from oral jelly formulations, whereas the oral administration study highlighted the clinical importance of water intake for drug absorption. [ABSTRACT FROM AUTHOR]

The purpose of the study was to develop an amorphous solid dispersion (ASD) of a poorly soluble compound (AK100) and investigate the impact of different surfactants on its dissolution, supersaturation and membrane transport. The solubility of the AK100 was determined in crystalline and amorphous form in the absence and presence of three surfactants at different concentrations: sodium dodecyl sulphate (SDS), polysorbate 80 (PS80) and D-α-tocopherol polyethylene glycol succinate (TPGS). The relation between solubility and surfactant solubilization was evaluated using a computational model. The ASD powder was prepared by solvent evaporation for non-sink dissolution experiments with and without the pre-dissolved surfactants. A transport study with Caco-2 cells was conducted to evaluate the impact of surfactants-based formulation on membrane transport. Both the corresponding crystalline and amorphous solubility of AK100 increased linearly as a function of the surfactant concentrations. The supersaturation was maintained for at least three hours in absence of surfactant and in presence of TPGS, whereas supersaturation declined with SDS and PS80. As expected, the membrane flux of the AK100 was higher for the ASD than for the crystalline powder, and further increased with increased concentration of TPGS. The supersaturation ratio based on the activity-based calculation from Caco-2 cells study was always higher than that of the concentration-based one for the amorphous and crystalline forms of AK100. This study shows how additional solubilizing excipients during formulation development can improve the resulting dissolution and phase behavior of supersaturated drug solution. [ABSTRACT FROM AUTHOR]

This special edition of the Journal of Pharmaceutical Sciences is dedicated to Professor Lynne S. Taylor (Retter Distinguished Professor of Pharmacy, Department of Industrial and Molecular Pharmaceutics, Purdue University), to honor her distinguished career as a pharmaceutical scientist and educator. The goal of this commentary is to provide an overview of Professor Taylor's career path, summarize her key research contributions, and provide some insight into her personal and professional contributions as an educator, mentor, wife, mother, friend, and adventurer. [ABSTRACT FROM AUTHOR]

For decades, drug delivery scientists have been performing trial-and-error experimentation to manually sample parameter spaces and optimize release profiles through rational design. To enable this approach, scientists spend much of their career learning nuanced drug-material interactions that drive system behavior. In relatively simple systems, rational design criteria allow us to fine tune release profiles and enable efficacious therapies. However, as materials and drugs become increasingly sophisticated and their interactions have non-linear and compounding effects, the field is suffering the Curse of Dimensionality which prevents us from comprehending complex structure-function relationships. In the past, we have embraced this complexity by implementing high-throughput screens to increase the probability of finding ideal compositions. However, this brute force method was inefficient and led many to abandon these fishing expeditions. Fortunately, methods in data science including artificial intelligence / machine learning (AI/ML) are providing ideal analytical tools to model this complex data and ascertain quantitative structure-function relationships. In this Oration, I speak to the potential value of data science in drug delivery with particular focus on polymeric delivery systems. Here, I do not suggest that AI/ML will simply replace mechanistic understanding of complex systems. Rather, I propose that AI/ML should be yet another useful tool in the lab to navigate complex parameter spaces. The recent hype around AI/ML is breathtaking and potentially over inflated, but the value of these methods is poised to revolutionize how we perform science. Therefore, I encourage readers to consider adopting these skills and applying data science methods to their own problems. If done successfully, I believe we will all realize a paradigm shift in our approach to drug delivery. [Display omitted] • Complex drug-material interactions challenge the design of drug delivery systems. • Machine learning is useful for navigating large parameter spaces and structure-function modeling. • When coupled with automation, the drug delivery community may see significant gains in productivity. [ABSTRACT FROM AUTHOR]

The characteristics of subvisible particles (SbVPs) are critical quality attributes of injectable and ophthalmic solutions in pharmaceutical manufacturing. However, current compendial SbVP testing methods, namely the light obstruction method and the microscopic particle count method, are destructive and wasteful of target samples. In this study, we present the development of a non-destructive SbVP analyzer aiming to analyze SbVPs directly in drug product (DP) containers while keeping the samples intact. Custom sample housings are developed and incorporated into the analyzer to reduce optical aberrations introduced by the curvature of typical pharmaceutical DP sample containers. The analyzer integrates a light-sheet microscope structure and models the side scattering event from a particle with Mie scattering theory with refractive indices as prior information. Equivalent spherical particle size under assigned refractive index values is estimated, and the particle concentration is determined based on the number of scattering events and the volume sampled by the light sheet. The resulting analyzer's capability and performance to non-destructively analyze SbVPs in DP containers were evaluated using a series of polystyrene bead suspensions in ISO 2R and 6R vials. Our results and analysis show the particle analyzer is capable of directly detecting SbVPs from intact DP containers, sorting SbVPs into commonly used size bins (e.g. ≥ 2 µm, ≥ 5 µm, ≥ 10 µm, and ≥ 25 µm), and reliably quantifying SbVPs in the concentration range of 4.6e2 to 5.0e5 particle/mL with a margin of ± 15 % error based on a 90 % confidence interval. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the mechanical stresses and strains acting on pharmaceutical glass tubing vials during freezing and thawing of model pharmaceutical formulations. Strain measurements were conducted inside of a laboratory-scale freeze-dryer using a custom wireless sensor. In both sucrose and trehalose formulations at concentrations between 5 % and 20 % w/v, the strain measurements initially increased before peaking in magnitude at temperatures close to the respective glass transition temperatures of the maximally freeze concentrated solutes, Tg'. We attribute this behavior to a shift in the mechanical properties of the frozen system from a purely elastic glass below Tg' to a viscoelastic rubber-like material above Tg'. That is, when the interstitial region becomes mechanically compliant at temperature above Tg'. The outputs were less predictable below 5 % w/v and tended to exhibit two separate peaks in strain output, one near the equilibrium melting temperature of pure ice and the other near Tg'. The peaks merged at concentrations between 4 and 5 % w/v where the largest strain magnitude was observed. The strain on primary packaging has traditionally been applied to evaluate the risk of damage or breakage due to, for example, crystallization of excipients. However, data collected during this study suggest there may be utility in formulation design or as a process analytical technology to minimize potentially destabilizing stresses and strains in the frozen formulation. [ABSTRACT FROM AUTHOR]

The Arrhenius energy of activation of unfolding Ea unfolding and Gibbs free energy of unfolding ΔG unfolding have been calculated utilizing DSC differential scanning calorimetry for 4 mAbs (1 biosimilar) in 3 formulations. DSC derived ΔTm melting temperature changes for each mAb domain (CH2, Fab, CH3) at calorimetric scan rates at 60 °C, 90 °C, 150 °C and 200 °C / hr. were utilized to calculate the kinetic Ea unfolding. The DSC derived Ea trend with observed aggregate formation and can be used to predict%HMW formation post 9-month storage at 5 °C and 40 °C for all formulations analyzed. Additionally, thermodynamic ΔG unfolding energies were also derived (Tm, ΔCp and ΔH measurements) for each mAb at every scan rate to observe scan rate dependence of ΔG and for extrapolation to 0 °C/hr. (to report ΔG at true equilibrium conditions). Both derived thermodynamic ΔG and kinetic Ea energies were combined to build full energetic landscapes for mAb unfolding and aggregation. Statistical multivariate analysis of kinetic (Ea CH2, Ea Fab, Ea CH3) energies, thermodynamic (ΔG 5 ° C and ΔG 40 ° C) energies and in-silico modeled surface properties was also performed. Analysis revealed key significant parameters contributing to aggregation. These parameters were utilized to build predictive aggregation models for 25 mg/mL mAb formulations stored 9-months at 5 °C and 40 °C. [ABSTRACT FROM AUTHOR]

The formulation of paediatric medicines faces significant challenges to meet the requirements for safe and accurate administration, while maintaining a suitable taste. Multiparticulate formulations have a strong potential to address these challenges because they combine dose flexibility with ease of administration. Understanding the stability of multiparticulate formulations over storage as a function of time and environmental parameters, such as humidity and temperature, is important to manage their commercialisation and use. In this work, we have expanded the toolkit of available techniques for studying multiparticulates beyond those such as scanning electron microscopy (SEM) and confocal laser scanning microscopy. We include advanced methods of environmentally-controlled SEM to monitor temperature- and humidity-induced changes in-situ , and a variety of Raman spectroscopies including stimulated Raman scattering microscopy to identify and localise the different ingredients at the surface and inside the multiparticulates. These techniques allowed unprecedented monitoring of specific changes to the particulate structure and distribution of individual ingredients due to product aging. These methods should be considered as valuable novel tools for in-depth characterisation of multiparticulate formulations to further understand chemical changes occurring during their development, manufacturing and long-term storage. We envisage these techniques to be useful in furthering the development of future medicine formulations. [Display omitted] • Raman spectroscopy mapping of the surface of multiparticulates, with corresponding scanning electron microscopy (SEM) imaging to combine chemical and physical information. • Accelerated aging studies within environmental SEM (ESEM), combined with Raman spectroscopy point measurements to identify chemical and structural changes. • Stimulated Raman scattering (SRS) microscopy imaging to rapidly identify the location of the API and excipients across large particle populations. • Insights into the behaviour of poloxamer 407 and glyceryl dibehenate in multiparticulates when exposed to different environmental conditions. [ABSTRACT FROM AUTHOR]

• This study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. • The possibility to apply a modelling approach to scale-up from compaction simulator to roller compaction would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. • One correction factor is identified as the optimal trade-off between the SF prediction accuracy on the roller compactor and its applicability to a wide range of formulations. Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet. [ABSTRACT FROM AUTHOR]

Transport of biopharmaceuticals from a hospital to a patient's home is scarcely researched but it is essential to investigate the effects of such transport on the stability of the drug, before home-based care can take place. In this study, transport of biopharmaceuticals in vials that are marketed as ready-to-administer from a hospital pharmacy to patients' homes was investigated. Immunoglobulin packages were tracked with 10 G and 25 G shock indicators and temperature data loggers. In the control group, immunoglobulins were transported from the hospital pharmacy to the outpatient daycare unit. During the transport process to patients' homes (n = 39), almost half of the packages were shocked with 25 G and more than half of all packages exceeded the required temperature range. Fortunately, the results found do not affect the stability of the ready-to-administer vials with immunoglobulins. However, these results indicate that the transport of biopharmaceuticals should be better controlled as not all biopharmaceuticals or formulations are so stable. Therefore, results of this pilot study provide a basis for recommendations for home-based therapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to describe the nutritional strategies used on Canadian dairy farms with automated milking systems (AMS), both at the feed bunk and the concentrate offered at the AMS, as well as to determine what dietary components and nutrients, as formulated, were associated with milk production and milking behaviors on those farms. Formulated diets (including ingredients and nutrient content) and AMS data were collected from April 1, 2019, until September 30, 2020, on 160 AMS farms (eastern Canada [East] = 8, Ontario [ON] = 76, Quebec [QC] = 22, and western Canada [West] = 54). Both partial mixed ration (PMR) and AMS concentrate samples were collected from May 1 to September 30, 2019, on 169 farms (East = 12, ON = 63, QC = 42, West = 52). We collected AMS milking data for 154 herds. For each farm (n = 161), milk recording data were collected and summarized by farm to calculate average milk yield and components. Multivariable regression models were used to associate herd-level formulated nutrient composition and feeding management practices with milk production and milking behavior. Milk yield (mean ± SD = 37.0 ± 0.3 kg/d) was positively associated with the PMR ether extract (EE) concentration (+0.97 kg/d per percentage point [ p.p. ] increase) and with farms that fed barley silage as their major forage source (n = 16; +2.18 kg/d) as compared with haylage (n = 42), whereas farms that fed corn silage (n = 96; +1.23 kg/d) tended to produce more milk than farms that fed haylage. Greater milk fat content (4.09 ± 0.28%) was associated with a greater PMR-to-AMS concentrate ratio (+0.02 p.p. per unit increase) and total diet net energy for lactation (+0.046 p.p. per 0.1 Mcal/kg increase), but a lesser percentage of NFC of the PMR (−0.016 p.p. per p.p. increase of NFC percentage). Milk protein content (3.38 ± 0.14%) was positively associated with the forage percentage of the PMR (+0.003 p.p. per p.p. increase of forage percentage) and the total diet starch percentage (+0.009 p.p. per p.p. increase of starch percentage), but was negatively associated with farms feeding corn silage (−0.1 p.p. compared with haylage) as their major forage. Greater milking frequency (2.77 ± 0.40 milkings/d) was observed on farms with free-flow cow traffic systems (+0.62 milkings/d) and was positively associated with feed push-up frequency (+0.013 milkings/d per additional feed push-up), but negatively associated with PMR NFC content and forage percentage of the total ration (−0.017 milkings/d per p.p. increase of forage percentage). Lastly, greater milking refusal frequency (1.49 ± 0.82 refusals/d) was observed on farms with free-flow cow traffic systems (+0.84 refusals/d) and farms feeding barley silage (+0.58 refusals/d) than with guided flow and farms feeding either corn silage or haylage, respectively. These data give insight into the ingredients, nutrient formulations and type of diets fed on AMS dairy farms across Canada and the association of those factors with milk production and milking behaviors. [ABSTRACT FROM AUTHOR]

• Provided comprehensive overview of all the 20 oligonucleotide drug products commercially approved till March 2024. • Focused on nature, formulation composition, presentation, primary packaging, in-use stability, and long-term stability. • Proposed generalized formulations that could be used as a starting point in early phase development of an oligonucleotide molecule recognizing that safety and efficacy must be established by controlled preclinical and clinical investigations. Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 – 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies. [ABSTRACT FROM AUTHOR]

Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying mechanism and probable root causes are not well characterized. Mostly, the phenomenon is attributed to the presence of crystallizing excipients, such as mannitol in the formulation, while other potential factors are often underestimated or not well studied. In this work we document a systematic multipronged approach to characterize and identify potential root cause(s) of vial breakage during lyophilization. Factors associated with formulation, product configuration, primary container and production process stress conditions were identified and their impact on vial breakage was studied in both lab and manufacturing scale conditions. Studies included: 1) strain gauge and lyophilization analysis for stress on glass vials with different formulation conditions and fill volumes, 2) manufacturing fill-finish process risk assessment (ex. loading and frictive force impact on the vials), and 3) glass vial design and ruggedness (ex. glass compression resistance or burst strength testing). Importantly, no single factor could be independently related to the extent of vial breakage observed during production. However, a combination of formulation, fill volume, and vial weakening processes encountered during at-scale production, such as vial handling, shelf loading and unloading, were identified to be the most probable root causes for the low levels of vial breakage observed. The work sheds light on an often-encountered problem in the pharmaceutical industry and the results presented in this paper argue against the simplistic root-cause explanations reported in literature. The work also provides insight into the possibility of implementing mitigative approaches to minimize or eliminate vial breakage associated with lyophilized drug products. [ABSTRACT FROM AUTHOR]

[Display omitted] • This review provides a systematic summary of FDA-approved biologic-device combination products regarding their device configurations, routes of administration, formulations, instructions for use, etc. • While prefilled syringes, autoinjectors and pen injectors remain as the mainstay of medical devices, innovative modifications like dual-chamber design and novel devices like on-body injector also emerged as promising presentations. • Insulin related combination products are all delivered by pen injectors with multi-dose cartridges subcutaneously. Vaccine-device combination products are presented with PFS and administered through the intramuscular route. • Around 40 % of products employ high-concentration formulations (≥ 100 mg/mL), and 78 % of mAb products are at high concentrations. With the remarkably strong growth of the biopharmaceutical market, an increasing demand for self-administration and rising competitions attract substantial interest to the biologic-device combination products. The ease-of-use of biologic-device combination products can minimize dosing error, improve patient compliance and add value to the life-cycle management of biological products. As listed in the purple book issued by the U.S. Food and Drug Administration (FDA), a total of 98 brand biologic-device combination products have been approved with Biologic License Application from January 2000 to August 2023, where this review mainly focused on 63 products containing neither insulin nor vaccine. Prefilled syringes (PFS) and autoinjectors are the most widely adopted devices, whereas innovative modifications like needle safety guard and dual-chamber design and novel devices like on-body injector also emerged as promising presentations. All 16 insulin products employ pen injectors, while all 19 vaccine products are delivered by a PFS. This review provides a systematic summary of FDA-approved biologic-device combination products regarding their device configurations, routes of administration, formulations, instructions for use, etc. In addition, challenges and opportunities associated with biologic-device compatibility, regulatory complexity, and smart connected devices are also discussed. It is believed that evolving technologies will definitely move the boundaries of biologic-device combination product development even further. [ABSTRACT FROM AUTHOR]

Residual volumes of infusion solutions vary greatly due to container and dimensional variances. Manufacturers use overfill to compensate, but the exact amounts vary significantly. This variability in overfill – when carrier solutions are used to dilute other parenteral preparations – may lead to variable concentrations and dosing, hence, potential risk for patients. We analyzed the overfill and residual volume of 22 pre-filled infusion containers and evaluated the impact on the (simulated) dosing accuracy of a therapeutic drug product for different handling scenarios. In addition, compendial properties of the diluents (i.e. sub-visible particles, pH, color and opalescence) were assessed. The overfill and residual volume between different containers for the same diluent varied. As container size increased, the relative volume of overfill decreased while the residual volume remained constant. The design and material of the containers (e.g. port systems) defined the residual volume. Different handling scenarios led to differences in dosing accuracy. As a result, no universal approach applicable for all containers can be defined. To ensure the right dose, it is recommended to pre-select the preferred diluent, evaluate fill volumes of carrier solutions, and assess in-use compatibility of the product solution with its diluent in terms of concentration and volume. [Display omitted] [ABSTRACT FROM AUTHOR]

• A dual adjuvant system was developed for the R0.6C and ProC6C malaria vaccines. • R0.6C and ProC6C vaccines were manufactured under cGMP. • The drug products and adjuvants were stable for pharmacy handling at 4 °C and 25 °C. • Repeated dose toxicity studies showed the drug products were safe, immunogenic and functional. • Long-term stability studies support stability over planned clinical trials. Two malaria transmission-blocking vaccine (TBV) candidates, R0.6C and ProC6C, have completed preclinical development including the selection of adjuvants, Alhydrogel® with or without the saponin based adjuvant Matrix-M™. Here, we report on the final drug product (formulation) design of R0.6C and ProC6C and evaluate their safety and biochemical stability in preparation for preclinical and clinical pharmacy handling. The point-of-injection stability studies demonstrated that both the R0.6C and ProC6C antigens are stable on Alhydrogel in the presence or absence of Matrix-M for up to 24 h at room temperature. As this is the first study to combine Alhydrogel and Matrix-M for clinical use, we also evaluated their potential interactions. Matrix-M adsorbs to Alhydrogel, while not displacing the > 95 % adsorbed protein. The R0.6C and ProC6C formulations were found to be safe and well tolerated in repeated dose toxicity studies in rabbits generating high levels of functional antibodies that blocked infection of mosquitoes. Further, the R0.6C and ProC6C drug products were found to be stable for minimally 24 months when stored at 2–8 °C, with studies ongoing through 36 months. Together, this data demonstrates the safety and suitability of the L. lactis expression system as well as supports the clinical testing of the R0.6C and ProC6C malaria vaccine candidates in First-In-Human clinical trials. [ABSTRACT FROM AUTHOR]

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development – used to predict response to a hypothetical risk of variation – become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle. [ABSTRACT FROM AUTHOR]

Protein products in hospitals often have to be compounded before administration to the patient. This may comprise reconstitution of lyophilizates, dilution, storage, and transport. However, the operations for compounding and administration in the hospital may lead to changes in product quality and possibly even impact patient safety. We surveyed healthcare practitioners from three clinical units using a questionnaire and open dialogue to document common procedures and their justification and to document differences in handling procedures. The survey covered dose compounding, transportation, storage and administration. One key observation was that drug vial optimization procedures were used for some products, e.g., use of one single-use vial for several patients. This included the use of spikes and needles or closed system transfer devices (CSTDs). Filters or light protection aids were used only when specified by the manufacturer. A further observation was a different handling of the overfill in pre-filled infusion containers, possibly impacting total dose. Lastly, we documented the complexity of infusion administration setups for administration of multiple drugs. In this case, flushing procedures or the placement and use of filters in the setup vary. Our study has revealed important differences in handling and administration practice. We propose that drug developers and hospitals should collaborate to establish unified handling procedures. [ABSTRACT FROM AUTHOR]

This study proposes the application of carboxymethyl starch derivatives as tablet coatings affording gastro-protection. Carboxymethyl starch (CMS) films were obtained by casting of aqueous filmogenic starch solutions with or without plasticizers and their structural organization was followed using Fourier transform infrared (FTIR), Thermogravimetric analysis (TGA), X-ray diffraction (XRD). Together with data from mechanical tests (tensile strength, elongation, Young's modulus) the results were used to select filmogenic formulations adapted for coatings of tablets. The behaviour of these films was evaluated in simulated gastric and intestinal fluids. The effect of plasticizers (glycerol and sorbitol) on the starch organization, on the rate of drying of the films and on the water vapor absorption was also analyzed. Various types of starch have been compared and the best results were found with high amylose starch (HAS) that was carboxymethylated in an aqueous phase to obtain carboxymethyl high amylose starch (CMHAS). The CMHAS coating solutions containing sorbitol or glycerol as plasticizers have been applied with an industrial pan coater and the final tablets exhibited a good gastro-resistance (up to 2h) in simulated gastric fluid followed by disintegration in simulated intestinal fluid (SIF). The CMHAS derivatives present a high potential as coatings for nutraceutical and pharmaceutical solid dosage forms. [Display omitted] • Homogeneous coatings were obtained using an aqueous formulation of CMHAS and sorbitol plasticizer. • CMHAS enteric coatings resisted for 2h in gastric acidity (pH 1.2) and were disrupted only at neutral pH 6.8. • Reduced solubility and high mechanical strength of CMHAS cast films are predictive for the selection of a good enteric coating formulation. • In the presence of alpha-amylase at neutral pH the coatings were totally disintegrated. • Amylose: Amylopectin ratio and gelatinization conditions are determinants for the CMHAS coating features. [ABSTRACT FROM AUTHOR]

Orbital shaking in a glass vial is a commonly used forced degradation test to evaluate protein propensity for agitation-induced aggregation. Vial shaking in horizontal orientation has been widely recommended to maximize the air-liquid interface area while ensuring solution contact with the stopper. We evaluated the impact of shaking orbit diameter and frequency, and glass vial orientation (horizontal versus vertical) on the aggregation of three proteins prepared in surfactant-free formulation buffers. As soon as an orbit-specific frequency threshold was reached, an increase in turbidity was observed for the three proteins in vertical orientation only when using a 3 mm agitation orbit, and in horizontal orientation only when using a 30 mm agitation orbit. Orthogonal analyses confirmed turbidity was linked to protein aggregation. The most turbid samples had a visually more homogeneous appearance in vertical than in horizontal orientation, in line with the predicted dispersion of air and liquid phases obtained from computational fluid dynamics agitation simulations. Both shaking orbits were used to assess the performance of nonionic surfactants. We show that the propensity of a protein to aggregate in a vial agitated in horizontal or vertical orientation depends on the shaking orbit, and confirm that Brij® 58 and FM1000 prevent proteins from agitation-induced aggregation at lower concentrations than polysorbate 80. [Display omitted] • Protein propensity for aggregation in a vial agitated in horizontal or vertical orientation depends on the shaking orbit. • Computational fluid dynamics agitation simulations reflect the visual homogeneity of aggregated samples. • Brij® 58 and FM1000 prevent proteins from agitation-induced aggregation at lower concentrations than polysorbate 80. [ABSTRACT FROM AUTHOR]

Aflibercept is a recombinant fusion protein that is commercially available for several ocular diseases impacting millions of people worldwide. Here, we use a case study approach to examine alternative liquid formulations for aflibercept for ocular delivery, utilizing different stabilizers, buffering agents, and surfactants with the goal of improving the thermostability to allow for limited storage outside the cold chain. The formulations were developed by studying the effects of pH changes, substituting amino acids for sucrose and salt, and using polysorbate 80 or poloxamer 188 instead of polysorbate 20. A formulation containing acetate, proline, and poloxamer 188 had lower rates of aggregate formation at 4, 30, and 40°C when compared to the marketed commercial formulation containing phosphate, sucrose, sodium chloride, and polysorbate 20. Further studies examining subvisible particles after exposure to a transport stress and long-term stability at 4°C, post-translational modifications by multi-attribute method, purity by reduced and non-reduced capillary electrophoresis, and potency by cell proliferation also demonstrated a comparable or improved stability for the enhanced formulation of acetate, proline, and poloxamer 188. This enhanced stability could enable limited storage outside of the cold chain, allowing for easier distribution in low to middle income countries. [ABSTRACT FROM AUTHOR]

Therapeutic biology encompasses different modalities, and their manufacturing processes may be vastly different. However, there are many similarities that run across the different modalities during the drug product (DP) development process and manufacturing. Similarities include the need for Quality Target Product Profile (QTTP), analytical development, formulation development, container/closure studies, drug product process development, manufacturing and technical requirements set out by numerous regulatory documents such as the FDA, EMA, and ICH for pharmaceuticals for human use and other country specific requirements. While there is a plethora of knowledge on studies needed for development of a drug product, there is no specific guidance set out in a phase dependent manner delineating what studies should be completed in alignment with the different phases of clinical development from pre-clinical through commercialization. Because of this reason, we assembled a high-level drug product development and manufacturing roadmap. The roadmap is applicable across the different modalities with the intention of providing a unified framework from early phase development to commercialization of biologic drug products. [ABSTRACT FROM AUTHOR]

Aluminum hydroxide adjuvants are widely used in human vaccines, such as diphtheria, tetanus, hepatitis A and hepatitis B vaccines. The adsorption of antigens on aluminum hydroxide adjuvants determines the immune boosting effect of vaccines, but it is not clear how changes in physicochemical properties resulting from the production and formulation processes affect the adsorption of aluminum hydroxide adjuvants with antigens. In this study, the commercial aluminum hydroxide adjuvant Alhydrogel® was pretreated by commonly used processes such as autoclaving and calcination, and the changes of aluminum hydroxide adjuvant in physicochemical properties during the treatment were then comprehensively characterized. The adsorption of ovalbumin (OVA) with treated Alhydrogel®, was also investigated, it was found that the decrease in specific surface area caused by the autoclaving process reduced the adsorptive capacity of the antigen, and the adsorptive strength of antigen was decreased only when the surface hydroxyl groups and chemically bound water of adjuvant were reduced by calcination. These findings help to optimize the production and formulation process of adjuvants for the rational regulation of antigen adsorption in vaccines. [Display omitted] • Autoclaved Alhydrogel® exhibits crystal growth and dehydration. • The decreased surface area of Alhydrogel® reduces adsorptive capacity of OVA. • Alhydrogel® loses surface hydroxyl group when calcined to 350 °C. • The loss of hydroxyl groups of Alhydrogel® reduces adsorptive strength of OVA. [ABSTRACT FROM AUTHOR]

Athletes are incredibly motivated and perpetually pursuing dominance in skill, strength, endurance, and execution–often while balancing many additional responsibilities. Despite the appearance of living fun, luxurious, care-free lifestyles, they are vulnerable to exceptional stressors and the same mental health challenges as the general population. The use of screening tools and assessment guided by a biopsychosocial framework can assist in understanding the factors that contribute to the athlete's mental health status. This can facilitate the development of a targeted management approach to mental health challenges. [ABSTRACT FROM AUTHOR]

Though ferulic acid presents great hypoglycemic potential, it possesses limited aqueous solubility, and low oral bioavailability. When associated with metformin, the first-choice drug in Type 2 diabetes treatment, FA demonstrates synergistic hypoglycemic effects, however, it also causes certain undesirable dose-related effects. This study aimed to develop a new ferulic acid - metformin multicomponent system, and incorporate it into a solid dosage form with improved biopharmaceutical parameters. A novel metformin: ferulate (1:1) salt (MFS) was produced, which was properly characterized using differing analytical techniques, including single crystal analysis. Also during the course of the study, a new polymorph of the metformin free base was observed. The MFS was obtained using solvent evaporation methods, which achieved high yields in reproducible process, as well as a 740-fold increase in ferulic acid aqueous solubility. The MFS tablets developed met quality control requirements for this dosage form, as well as revealing excellent performance in vitro dissolution tests, presenting dissolution efficiency values of 95.4 ± 0.5%. Additionally, physicochemical instability was not observed in a study at 40 °C for 3 months for both MFS powder and its tablet form. The MFS product developed is a promising candidate for further Type 2 diabetes clinical study. [Display omitted] • A salt formation increases the aqueous solubility of the ferulic acid. • A new metformin free base polymorph is found. • Study of powder flow properties and formulation development are highlighted. • In vitro dissolution tests can provide the performance of metformin tablets. [ABSTRACT FROM AUTHOR]

[Display omitted] This study discusses the lubricant properties of magnesium stearate solid lipid nanoparticles (MgSt-SLN) and their effect on the tabletability, mechanical properties, disintegration, and acetaminophen-model dissolution time of microcrystalline cellulose (MCC) tablets prepared by direct compression. The behavior of MgSt-SLN was compared to reference material (RM) to identify advantages and drawbacks. The nanoprecipitation/ion exchange method was employed to prepare the MgSt-SLN. Particle size, zeta potential, specific surface area, morphology, and true density were measured to characterize the nanosystem. The MgSt-SLN particle sizes obtained were 240 ± 5 nm with a specific surface area of 12.2 m2/g. The MCC tablets with MgSt-SLN presented a reduction greater than 20 % in their ejection force, good tabletability, higher tensile strength, lower disintegration delay, and marked differences in acetaminophen dissolution when compared to the RM. The reduced particle size of the magnesium stearate seems to offer a promising technological advantage as an efficient lubricant process that does not affect the properties of tablets. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is a highly prevalent ocular surface disease that affects life quality and reduces productivity at work. The purpose of this study is to improve the efficacy of tacrolimus (FK506) in the treatment of DED using the special eye surface retention properties of cationic nanoemulsion (CNE) modified by thermosensitive in-situ gel (ISG) (CNE-ISG). The precorneal retention of CNE-ISG containing 0.05% FK506 (50 min) was longer than that of CNE containing 0.05% FK506 (25 min) and commercial suspension containing 0.1% FK506 (Talymus®) (10 min). Successfully modeled dry-eye rabbits were treated with 0.05% CNE-ISG (twice/day), 0.05% CNE and 0.1% suspension (Talymus®) (thrice/day). Schirmer's tear secretion test showed no significant difference between the CNE-ISG group and the healthy group after 5 days of treatment (p > 0.05). The results of a tear ferning test (TFT) showed that the tear-fern-like crystal branches in the CNE-ISG group returned to normal after 5 days of treatment. Histological analysis showed that the number of goblet cells in the CNE-ISG group significantly increased. HET-CAM stimulation test showed that the CNE-ISG group had no ocular irritation. The above results indicated that CNE-ISG might be a promising delivery system and as an effective dosage form was employed for FK506 in the treatment of DED. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of safe and effective second-generation COVID-19 vaccines to improve affordability and storage stability requirements remains a high priority to expand global coverage. In this report, we describe formulation development and comparability studies with a self-assembled SARS-CoV-2 spike ferritin nanoparticle vaccine antigen (called DCFHP), when produced in two different cell lines and formulated with an aluminum-salt adjuvant (Alhydrogel, AH). Varying levels of phosphate buffer altered the extent and strength of antigen-adjuvant interactions, and these formulations were evaluated for their (1) in vivo performance in mice and (2) in vitro stability profiles. Unadjuvanted DCFHP produced minimal immune responses while AH-adjuvanted formulations elicited greatly enhanced pseudovirus neutralization titers independent of ∼100%, ∼40% or ∼10% of the DCFHP antigen adsorbed to AH. These formulations differed, however, in their in vitro stability properties as determined by biophysical studies and a competitive ELISA for measuring ACE2 receptor binding of AH-bound antigen. Interestingly, after one month of 4°C storage, small increases in antigenicity with concomitant decreases in the ability to desorb the antigen from the AH were observed. Finally, we performed a comparability assessment of DCFHP antigen produced in Expi293 and CHO cells, which displayed expected differences in their N-linked oligosaccharide profiles. Despite consisting of different DCFHP glycoforms, these two preparations were highly similar in their key quality attributes including molecular size, structural integrity, conformational stability, binding to ACE2 receptor and mouse immunogenicity profiles. Taken together, these studies support future preclinical and clinical development of an AH-adjuvanted DCFHP vaccine candidate produced in CHO cells. [ABSTRACT FROM AUTHOR]

• This is the first report to include ultrasonic lactic acid extraction of active compounds from Populus nigra buds. • Contribution to the evaluation of antioxidant and anti-inflammatory activity in vitro and formulation based on particles with a photoprotective effect. • Novel phenolic compounds and organic acids identified for the first time in Populus nigra buds. • The extract of populus buds could be used as a photoprotective agent in the preparation of sun creams in the pharmaceutical industry and can be considered as a natural source of antioxidants. Many studies have been conducted on the biological potential of medicinal plant extracts; the present study looked into the use of antioxidant extracts from P.nigra buds in cosmetic formulations to boost photoprotection potential, with a particular emphasis on green extraction and the biological activities of these compounds. Extraction of phenolic compounds using ultrasonically assisted lactic acid reported content of 42.64 ± 0.16 mg GAE/g dw with an antioxidant potential of 72.20 ± 1.05 mmol TE/100g dw and 72.73 ± 2.59 mg AAE/g dw for DPPH • and OH • scavenging activities, respectively. Furthermore, a significant iron chelation capacity of the extract was recorded (104.45 ± 1.66 mg EDTA E/g dw). In addition, a strong anti-inflammatory activity of the extract was demonstrated (IC 50 : 0.122 and 0.1788%) for the inhibition of the mono-nitrogen oxide radical and cyclooxygenase respectively. The evaluation of the photoprotective effect expressed a high protection factor (34.81) and no irritant effects. Chemical analysis of the crude extracts was carried out by FTIR, LC-MS and GC-MS. The FTIR spectral study revealed the presence of different functional groups such as alcohols, ketones and amines, indicating the richness of the extract in various metabolites. GC-MS and LC-MS studies revealed the presence of 15 bioactive compounds, of which 9 phenolics and 6 organic acid components were identified for the first time in P.nigra buds. This approach using lactic acid as an ecological solvent and ultrasound as an alternative energy source represents a good choice for the design of an extraction system of bioactive compounds with antioxidant, anti-inflammatory and photoprotective properties. Further studies are needed to extend the screening approach anti-irritancy to develop antioxidant-enriched. [ABSTRACT FROM AUTHOR]

Cell therapy uses living cells as a drug to treat diseases. To develop a cell therapy drug product (DP), cryopreservation plays a central role in extending the shelf life of these living medicines by pausing their biological activities, especially preventing degradation, at a temperature as low as liquid nitrogen. This helps overcome the temporal and geographical gaps between centralized manufacturing and clinical administration, as well as allowing sufficient time for full release testing and flexibility in scheduling patients for administration. Cryopreservation determines or influences several key manufacturing, logistical, or clinical in-use processes, including formulation, filling, controlled rate freezing, cryogenic storage and transportation, thawing, and dose preparation. This article overviews the key technical aspects of cell therapy DP development and elucidates fundamental principles of cryobiology that should be considered when we design and optimize the relevant processes. This article also discusses the challenges that motivate continued innovation for cell therapy drug product development. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are small membrane-bound vesicles released by cells. EVs are emerging as a promising class of therapeutic entity that could be adapted in formulation due to their lack of immunogenicity and targeting capabilities. EVs have been shown to have similar regenerative and therapeutic effects to their parental cells and also have potential in disease diagnosis. To improve the therapeutic potential of EVs, researchers have developed various strategies for modifying them, including genetic engineering and chemical modifications which have been examined to confer target specificity and prevent rapid clearance after systematic injection. Formulation efforts have focused on utilising hydrogel and nano-formulation strategies to increase the persistence of EV localisation in a specific tissue or organ. Researchers have also used biomaterials or bioscaffolds to deliver EVs directly to disease sites and prolong EV release and exposure. This review provides an in-depth examination of the material design of EV delivery systems, highlighting the impact of the material properties on the molecular interactions and the maintenance of EV stability and function. The various characteristics of materials designed to regulate the stability, release rate and biodistribution of EVs are described. Other aspects of material design, including modification methods to improve the targeting of EVs, are also discussed. This review aims to offer an understanding of the strategies for designing EV delivery systems, and how they can be formulated to make the transition from laboratory research to clinical use. [Display omitted] [ABSTRACT FROM AUTHOR]

The specifications of excipients are important to pharmaceutical manufacturers to ensure that the final product can be manufactured robustly over the entire lifecycle of a drug product. Particle size specifications are key for dry powder inhalation excipients and they should be agreed between users and suppliers. The current paper evaluates two development strategies to set particle size specifications. It is shown that the application of quality-by-design principles to specification setting could result in broader specifications, while it guarantees that efficacy, safety and manufacturing of the medication is not affected. A multitude of reasons exist to keep specifications broader than the production capability range, including improved risk-mitigation and potentially reduced regulatory challenges during and after registration. [ABSTRACT FROM AUTHOR]

Co-processing of APIs, the practice of creating multi-component APIs directly in chemical processing facilities used to make drug substance, is gaining increased attention with a view to streamlining manufacturing, improving supply chain robustness and accessing enhanced product attributes in terms of stability and bioavailability. Direct co-precipitation of amorphous solid dispersions (ASDs) at the final step of chemical processing is one such example of co-processing. The purpose of this work was to investigate the application of different advanced solvent-based processing techniques - direct co-precipitation (CP) and the benchmark well-established spray-drying (SD) process - to the production of ASDs comprised of a drug with a high T g (hydrochlorothiazide, HCTZ) or a low T g (simvastatin, SIM) molecularly dispersed in a PVP/VA 64 or Soluplus® matrix. ASDs of the same composition were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Both methods produced ASDs that were PXRD amorphous, with some differences, depending on the process used, in glass transition temperature and particle size distribution. Irrespective of manufacturing method used, all ASDs remained PXRD amorphous when subjected to high relative humidity conditions (75% RH, 25°C) for four weeks, although changes in the colour and physical characteristics were observed on storage for spray-dried systems with SIM and PVP/VA 64 copolymer. The particle morphology differed for co-precipitated compared to spray dried systems, with powder generated by the former process being comprised of more irregularly shaped particles of larger particle size when compared to the equivalent spray-dried systems which may enable more streamlined drug product processes to be used for CP materials. These differences may have implications in downstream drug product processing. A limitation identified when applying the solvent/anti-solvent co-precipitation method to SIM was the high antisolvent to solvent ratios required to effect the precipitation process. Thus, while similar outcomes may arise for both co-precipitation and spray drying processes in terms of ASD critical quality attributes, practical implications of applying the co-precipitation method and downstream processability of the resulting ASDs should be considered when choosing one solvent-based ASD production process over another. [ABSTRACT FROM AUTHOR]

The addition of non-active components at the point of active pharmaceutical ingredient (API) isolation by means of co-processing is an attractive approach for improving the material properties of APIs. Simultaneously, there is increased interest in the pharmaceutical industry in continuous manufacturing processes. These often consist of liquid feeds which maintain materials in solution and mean that solids handling is avoided until the final step. Such techniques enable new forms of APIs to be used in final dosage forms which have been overlooked due to unfavourable material properties. API-based ionic liquids (API-ILs) are an example of a class of compounds that exhibit exceptional solubility and stability qualities at the cost of their physical characteristics. API-ILs could benefit from isolation-free manufacturing in combination with co-processing approaches to circumvent handling issues and make them viable routes to formulating poorly soluble APIs. However, API-ILs are most commonly synthesised via a batch reaction that produces an insoluble solid by-product. To avoid this, an ion exchange resin protocol was developed to enable the API-IL to be synthesised and purified in a single step, and also produce it in a liquid effluent that can be integrated with other unit operations. Confined agitated bed crystallisation and spray drying are examples of processes that have been adapted to produce or consume liquid feeds and were combined with the ion exchange process to incorporate the API-IL synthesis into isolation-free frameworks and continuous manufacturing streams. This combination of isolation-free and co-processing techniques paves the way towards end-to-end continuous manufacturing of API-IL drug products. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets. [ABSTRACT FROM AUTHOR]

Continuous direct compression (CDC) of solid oral dosage forms requires materials exhibiting acceptable flow and compression properties. The desired active pharmaceutical ingredient (API) powder properties can be difficult to achieve through conventional particle engineering approaches, such as particle size and habit modification during crystallization. Co-processing of API with excipients can significantly improve the powder properties to overcome these difficulties. In this manuscript, performance of a co-processed API was evaluated in a continuous feeding and blending process using GEA ConsiGma® Continuous Dosing and Blending Unit (CDB1). The co-processed theophylline was generated via a methodology in which polymer was precipitated and coated the crystalline theophylline particles resulting in nearly spherical agglomerates. A range of drug loads (1-25% w/w), flow rates (15-40 kg/h) and blender speeds (220-400 rpm) were studied. The results demonstrated that the co-processed API can be successfully fed through a loss-in-weight feeder and blended with other excipients in a high shear blender to generate tablets with acceptable content uniformity at 1-25% w/w drug loads. This study supports that using co-processed API with enhanced powder properties is a promising approach to enable continuous manufacturing for APIs with challenging properties. [ABSTRACT FROM AUTHOR]

• Orf virus degradation study shows high robustness against common process conditions. • Recombinant human serum albumin increases Orf virus stability. • Freeze-thawing of Orf virus shows no infectivity reduction, but aggregation. • NH 4 Cl reduces Orf virus infectivity significantly. A promising new vaccine platform is based on the Orf virus, a viral vector of the genus Parapoxvirus , which is currently being tested in phase I clinical trials. The application as a vaccine platform mandates a well-characterised, robust, and efficient production process. To identify critical process parameters in the production process affecting the virus' infectivity, the Orf virus was subjected to forced degradation studies, including thermal, pH, chemical, and mechanical stress conditions. The tests indicated a robust virus infectivity within a pH range of 5–7.4 and in the presence of the tested buffering substances (TRIS, HEPES, PBS). The ionic strength up to 0.5 M had no influence on the Orf virus' infectivity stability for NaCl and MgCl 2 , while NH 4 Cl destabilized significantly. Furthermore, short-term thermal stress of 2 d up to 37 °C and repeated freeze-thaw cycles (20 cycles) did not affect the virus' infectivity. The addition of recombinant human serum albumin was found to reduce virus inactivation. Last, the Orf virus showed a low shear sensitivity induced by peristaltic pumps and mixing, but was sensitive to ultrasonication. The isoelectric point of the applied Orf virus genotype D1707-V was determined at pH 3.5. The broad picture of the Orf virus' infectivity stability against environmental parameters is an important contribution for the identification of critical process parameters for the production process, and supports the development of a stable pharmaceutical formulation. The work is specifically relevant for enveloped (large DNA) viruses, like the Orf virus and like most vectored vaccine approaches. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) is a common cause for diarrheal infections in children in low- and middle-income countries (LMICs). To date, no ETEC vaccine candidates have been approved. Passive immunization with low-cost, oral formulations of secretory IgA (sIgA) against ETEC is an alternative approach to protect high-risk populations in LMICs. Using a model sIgA monoclonal antibody (anti-LT sIgA2-mAb), the stability profiles of different formulations were assessed during storage and in in vitro digestion models (mimicking in vivo oral delivery). First, by employing various physicochemical techniques and a LT-antigen binding assay, three formulations with varying acid-neutralizing capacity (ANC) were evaluated to stabilize sIgA2-mAb during stress studies (freeze-thaw, agitation, elevated temperature) and during exposure to gastric phase digestion. Next, a low-volume, in vitro intestinal digestion model was developed to screen various additives to stabilize sIgA2-mAb in the intestinal phase. Finally, combinations of high ANC buffers and decoy proteins were assessed to collectively protect sIgA2-mAb during in vitro sequential (stomach to intestine) digestion. Based on the results, we demonstrate the feasibility of low-cost, 'single-vial', liquid formulations of sIgA-mAbs delivered orally after infant feeding for passive immunization, and we suggest future work based on a combination of in vitro and in vivo stability considerations. [ABSTRACT FROM AUTHOR]

It has been nearly four decades since the first therapeutic monoclonal antibodies were approved and made available for widespread human use. Herein, US and EU approved antibody formulations are reviewed, and their nature and compositions are evaluated over time. From 1986 through Jan 2023, significant formulation trends have occurred and to represent this, 165 commercial antibody therapeutic formulations were binned into 5 different periods of time. Overall, we have observed the following: 1) The average formulation pH has decreased in recent years by over 0.5 units along with a decrease in variability that is largely driven by non-high concentration liquid in vial presentations for IV administration, 2) The use of certain excipients and buffers such as histidine, sucrose, metal chelators, arginine and methionine has become significantly more common, whereas formulations that contain phosphate, salt, no sugar or no surfactant have fallen out of favor, 3) Overall formulation space has increasingly become more homogenous and has converged in terms of formulation pH and excipient preferences regardless of formulation concentration, drug product presentation, and route of administration, 4) The average calculated isoelectric point (pI) has decreased 0.26 units, and 5) Overall, the average formulation pH and calculated pI for all commercial antibodies surveyed was 6.0 and 8.4, respectively. These trends and formulation convergence may be driven by multiple factors such as advancements in high-throughput computational and analytical technologies, the increased emphasis and understanding of certain developability attributes and formulation principles during lead selection and formulation development, and the adoption of low-risk development platform approaches. [ABSTRACT FROM AUTHOR]

The degradation kinetics of the glycopeptide antibiotic dalbavancin in solution are systematically evaluated over the pH range 1–12 at 70°C. The decomposition rate of dalbavancin was measured as a function of pH, buffer composition, temperature, ionic strength, and drug concentration. A pH-rate profile was constructed using pseudo first-order kinetics at 70°C after correcting for buffer effects; the observed pH-rate profile could be fitted with standard pseudo first order rate laws. The degradation reactions of dalbavancin were found to be strongly dependent on pH and were catalyzed by protons or hydroxyl groups at extreme pH values. Dalbavancin shows maximum stability in the pH region 4–5. Based on the Arrhenius equation, dalbavancin solution at pH 4.5 is predicted to have a maximum stability of thirteen years under refrigerated conditions, eight months at room temperature and one month at 40°C. Mannosyl Aglycone (MAG), the major thermal and acid degradation product, and DB-R6, an additional acid degradation product, were formed in dalbavancin solutions at 70°C due to hydrolytic cleavage at the anomeric carbons of the sugars. Through deamination and hydrolytic cleavage of dalbavancin, a small amount of DB-Iso-DP2 (RRT-1.22) degradation product was also formed under thermal stress at 70°C. A greater amount of the base degradation product DB-R2 forms under basic conditions at 70°C due to epimerization of the alpha carbon of phenylglycine residue 3. [ABSTRACT FROM AUTHOR]

Phosphate buffer is predominantly used instead of the more physiological bicarbonate buffer, as the latter requires a technical solution of adequate gas mixing. Recent pioneering work on how bicarbonate buffer affected drug supersaturation revealed interesting effects that call for more mechanistic understanding. Therefore, this study used hydroxypropyl cellulose as a model precipitation inhibitor and real-time desupersaturation testing was conducted with the drugs bifonazole, ezetimibe, tolfenamic acid and triclabendazole. Specific buffer effects for the different compounds were noted and overall, statistical significance was found for the precipitation induction time (p = 0.0088). Interestingly, molecular dynamics simulation revealed a conformational effect of the polymer in the presence of the different buffer types. Subsequent molecular docking trials suggested a stronger interaction energy of drug and polymer in the presence of phosphate compared to bicarbonate buffer (p =0.0010). In conclusion, a better mechanistic understanding of how different buffers affect drug-polymer interactions regarding drug supersaturation was achieved. Further mechanisms may account for the overall buffer effects and additional research on drug supersaturation is certainly needed, but it can already be concluded that bicarbonate buffering should be used more often for in vitro testing in drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

The integration of product-based learning strategies in Materials in Chemical Engineering education is crucial for students to gain the skills and competencies required to thrive in the emerging circular bioeconomy. Traditional materials engineering education has often relied on a transmission teaching approach, in which students are expected to passively receive information from instructors. However, this approach has shown to be inadequate under the current circumstances, in which information is readily available and innovative tools such as artificial intelligence and virtual reality environments are becoming widespread (e.g., metaverse). Instead, we consider that a critical goal of education should be to develop aptitudes and abilities that enable students to generate solutions and products that address societal demands. In this work, we propose innovative strategies, such as product-based learning methods and GPT (Generative Pre-trained Transformer) artificial intelligence text generation models, to modify the focus of a Materials in Chemical Engineering course from non-sustainable materials to sustainable ones, aiming to address the critical challenges of our society. This approach aims to achieve two objectives: first to enable students to actively engage with raw materials and solve real-world challenges, and second, to foster creativity and entrepreneurship skills by providing them with the necessary tools to conduct brainstorming sessions and develop procedures following scientific methods. The incorporation of circular bioeconomy concepts, such as renewable resources, waste reduction, and resource efficiency into the curriculum provides a framework for students to understand the environmental, social, and economic implications in Chemical Engineering. It also allows them to make informed decisions within the circular bioeconomy framework, benefiting society by promoting the development and adoption of sustainable technologies and practices. [Display omitted] • Integrating sustainability into Chemical Engineering education is a significant challenge. • Alternatives to improve teaching in Chemical Engineering shifting to a cognitive, constructivist, product-based approach. • Integrating new technologies such as digital platforms and AI platforms fosters learning and collaboration in experiential courses. • GPT models and AI image generators can help students interact and visualize to acquire knowledge in biobased materials courses. [ABSTRACT FROM AUTHOR]

• Chromatography and spectroscopy techniques have been progressively used in quality-based standardization or authentication of medicinal plants and their derived traditional formulations for their regulatory purpose. • Insights on current scenario, LC-MS/MS and NMR are the most preferred analytical techniques for validating quality standards of medicinal plants and their derived formulations. • PCA is the most frequent chemometric techniques used for data acquisition and integration of a large data set and establish relationship between object and variable based on their symmetrical pattern with future insights. Authentication of medicinal plants and their derived formulations are contributed to the quality, safety, and efficacy as well as to their regulatory purpose. Chromatography and their hyphenation with spectroscopic techniques are the most used analytical methods for quality assessment and authentication of medicinal plants and their derived products, also. The present study is aimed to explore the quality aspects of the authentication of medicinal plants and their derived formulation with a comprehensive explanation of analytical techniques used in authentication, current scenario, and future perspectives. The data was gathered from different online data bases such as Science Direct, Google Scholar, Elsevier, Wiley, Springer, PubMed, etc. The finding of the review suggested that targeted and non-targeted metabolites-based quality assessment of medicinal plants depends on authentication of medicinal plants belong to the same species, collection of quality raw material, extraction method, and the acting solvents for more suitability in applied process. Many cutting-edge chromatographic and analytical approaches such as HPTLC-MS, HPLC-MS, LC-MS, GC–MS, etc are familiarized for complete metabolomic profiling. Moreover, chemometric techniques better contributed to mining essential chemical information from a wide diversity of original data. Among the chemometrics analysis, principal component analysis (PCA) is the most commonly used method that represents the large dimensionality of data sets based on metabolites for authenticity, efficacy and consistency. Hence, this review comprehended the in-sights into the current scenario and the future perspectives for quality-based standardization of medicinal plants and their derived formulations and to validate the scientific evidence for their regulatory purpose. [ABSTRACT FROM AUTHOR]

Standard freezing protocols of clinically relevant cell lines commonly employ agents such as fetal bovine serum and dimethyl sulfoxide, which are a potential concern from both a regulatory and a patient safety perspective. The aim of this work was to develop formulations with safe and well tolerated excipients for the (cryo-) preservation of cell therapy products. We evaluated the cryoprotective capabilities of urea and glucose through measurements of cell metabolic activity. Freezing of clinically relevant human mesenchymal stromal/stem cells and human dermal fibroblasts at ≤ - 65°C at equimolar ratios of urea and glucose resulted in comparable viabilities to established dimethyl sulfoxide. Pre-incubation of human mesenchymal stromal/stem cells in trehalose and addition of mannitol and sucrose to the formulation further enhanced cell viability after freeze-thaw stress. Other cell types assessed (A549 and SK-N-AS) could not satisfactorily be preserved with urea and glucose, highlighting the need for tailored formulations to sustain acceptable cryopreservation. [ABSTRACT FROM AUTHOR]

[Display omitted] The objective of this investigation was to study the effect of induced vibrations on adhesive mixtures containing budesonide and salbutamol sulphate as active pharmaceutical ingredients (APIs) and InhaLac 70 as carrier. A series of adhesive mixtures with varied API concentration (1–4%) was prepared for each API. Half of the adhesive mixture was stressed on a vibrating sieve under conditions resembling hopper flow. Based on scanning electron micrographs, it was concluded that InhaLac 70 contains particles of two distinct shapes, one irregular with groves and valleys and the other more regular with well defined edges. The dispersibility of the control and stressed mixtures was studied using a next generation impactor. The stressed mixtures containing 1 and 1.5% API displayed a significant reduction in fine particle dose (FPD) compared to the control. The reduction in FPD resulted from a loss of API from the adhesive mixture during vibration and as a consequence of restructuring and self agglomeration resulting in reduced dispersibility. However, no significant difference was observed for mixtures with larger weight fractions of API (2 and 4% API) but these have a drawback of reduced fine particle fraction (FPF). It is concluded that vibrations induced on the adhesive mixtures during handling potentially have a significant effect on the dispersibility of the API and the total amount of drug delivered to the lungs. [ABSTRACT FROM AUTHOR]

The encapsulation efficiency (EE) of hydrophobic drug into cubosomes was high by conventional methods, while poor for the hydrophilic drug. In this study, a remote loading method based on transmembrane pH-gradient was applied to prepare hydrophilic drug loaded cubosomes. Several hydrophilic drugs were selected and studied. Results showed just part of the investigated drugs were successfully loaded into cubosomes by the remote loading method, whereas all the drugs failed to be encapsulated by the high-pressure homogenization method. The EE based on remote loading method was affected by the solubility, LogP, number of rings, and polarizability of the drug independent of the number of hydrogen acceptor and hydrogen donor. And the drugs that had high EE by remote loading method were BCS class 1 or 2. In addition, the EE base on remote loading method was significantly affected by the external water pH of cubosomes and drug concentration. The size of drug-loaded cubosomes by remote loading method mainly depended on the pre-formed blank cubosomes, which was bigger than that by high-pressure homogenization method. The preparation method affected the liquid crystalline structure of acidic drug loaded cubosomes, while showed no obvious effect on that of basic drug loaded cubosomes. The release of drug was susceptible to the pH of release medium independent of the preparation method. The drug-loaded cubosomes prepared by different method all showed favorable stability during storage. The remote loading method was a promising approach for the efficient encapsulation of hydrophilic drug into cubosomes. This study laid a foundation for the application of remote loading method on the preparation of hydrophilic drug loaded cubosomes. [Display omitted] • A remote loading method based on transmembrane pH-gradient was applied to prepare hydrophilic drug-loaded cubosomes. • The encapsulation efficiency of hydrophilic drugs in cubosomes was significantly improved using the remote loading method compared with the conventional method. • This study clarified the fact that the EE based on remote loading method was significantly affected by the solubility, LogP, number of rings, polarizability, and and BCS information of the drug independent of the number of hydrogen acceptor and hydrogen donor. • The remote loading method based on transmembrane pH-gradient was simple, rapid, and efficient, which was a promising approach for the efficient encapsulation of hydrophilic drugs into cubosomes. This study laid a foundation for the application of remote loading method on the preparation of hydrophilic drug loaded cubosomes. [ABSTRACT FROM AUTHOR]