Search Results (247)

Background/Objectives: A robust and scalable manufacturing framework for lipid-based nanocarriers remains a critical challenge, particularly for labile phytochemicals such as curcuminoids in turmeric. This study presents an integrated Quality by Design (QbD)-driven and Outcome-Based Design (ObD) strategy to establish a scalable, resource-efficient manufacturing process for curcuminoids-loaded nanostructured lipid carriers (NLCs). Methods: To overcome the limitations of conventional multivariate design of experiments (DOE), which require extensive experimental runs, a risk-based, knowledge-driven single-factor screening approach was employed. Guided by risk assessment tools, including Ishikawa diagrams and failure mode considerations, 12 representative processing conditions were selected to define the design space. Critical quality attributes (CQAs), namely, particle size, polydispersity index (PDI), and zeta potential, were predefined to establish a robust control strategy. A two-step homogenization process—high-shear homogenization (HSH) for pre-emulsification followed by high-pressure homogenization (HPH) for nanoscale refinement—was systematically optimized. Results: Multivariate data analysis using principal component analysis (PCA) and hierarchical cluster analysis (HCA) identified key critical process parameters (CPPs), particularly HSH speed, processing time, and HPH cycles, as dominant factors influencing nanoparticle characteristics. The optimized 1-h process enabled successful scale-up of NLCs from 100 g to 5000 g, demonstrating the capability to generate nanosized particles within 100–500 nm. The combined HSH–HPH approach produced smaller, more uniform nanoparticles with high encapsulation efficiency and physical stability, outperforming HSH alone. Conclusions: Overall, this study establishes a practical and industrially viable framework that integrates QbD principles with data-driven optimization tools, for enabling reliable translation from laboratories to semi-industrial production. Full article

Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery platform, revolutionizing the development of nucleic acid-based medicines for gene delivery and gene therapy. This review provides an insightful industrial perspective on the production process of LNPs, focusing on cutting-edge manufacturing equipment, downstream processing and the crucial transition from laboratory to large scale. While LNP production in the discovery phase relies on a small scale (µL to mL) for screening various LNP formulation candidates, transferring to preclinical (up to hundreds of mL) and clinical/commercial scales (up to liters) requires a robust and reproducible manufacturing process. Thus, mixing technologies throughout these scales must be carefully selected and require precision, scalability and high reproducibility to meet the target quality of the LNP drug product. Key mixing technologies in mRNA-LNP production primarily include microfluidic systems and impinging jet mixers (IJMs). In this review, we discuss key critical process parameters (CPPs) in LNP preparation, including flow rate ratio (FRR) or total flow rate (TFR), in relation to associated critical quality attributes (CQAs) across multiple manufacturing scales. We further assess the impact of downstream processing, specifically tangential flow filtration (TFF), on the formulation’s CQAs. In particular, the review highlights the importance of maintaining CQAs along each step of the process and emphasizes the role of robust analytical methods in ensuring product quality and safety. Additionally, we touch on current challenges associated with these advanced delivery vehicles, such as their long-term stability, and introduce the readership to innovative stabilization strategies aimed to extent LNP shelf-life. Full article

Virus-like particles (VLPs), nanoscale self-assembled structures lacking viral genetic material, have emerged as a versatile platform for vaccines, targeted delivery systems, and gene-editing applications owing to their strong immunogenicity, favorable biosafety profile, and high engineerability. However, the complex architecture of VLPs, their significant size heterogeneity, and the diversity of process- and product-related impurities generated in different expression systems make downstream purification a major bottleneck limiting product quality, yield, and manufacturability. This review systematically discusses advanced downstream purification strategies for VLPs from the perspective of three major objectives: preservation of structure and biological activity, control of product heterogeneity, and assurance of viral safety. First, strategies for maintaining VLP integrity and function are examined, including optimization of solution conditions, adoption of gentle yet efficient separation operations, and integration of process analytical technology (PAT) to reduce process-induced damage. Second, the review summarizes multi-step purification approaches—spanning clarification, ultrafiltration/diafiltration (UF/DF), chromatography, and disassembly/reassembly—to remove host cell proteins, host cell DNA, and product-related impurities while improving particle homogeneity and stability. Third, viral safety is discussed primarily from the perspective of downstream virus clearance under host-dependent risk, with particular attention to orthogonal clearance steps tailored to VLP properties and expression systems such as CHO cells and insect cell–baculovirus platforms. Overall, this review provides a CQA-oriented framework and practical guidance for the development of robust, scalable, and GMP-compliant downstream purification processes for VLP-based products. Full article

A dual-mode electrical–optical nanocomposite hydrogel is developed by integrating carboxyl-modified upconversion nanoparticles (UCNPs-COOH) and quaternized chitosan (CQAS) into a polyacrylamide (PAAm) covalent network. The hydrogel exhibits high optical transparency (>90% in the visible region), excellent mechanical properties (fracture strain of 1742%, tensile strength of 0.85 MPa, toughness of 6.57 MJ/m³), and robust adhesion to various substrates. The synergistic covalent–noncovalent hybrid network enables efficient energy dissipation, while CQAS-enhanced dispersion of UCNPs significantly improves upconversion luminescence intensity and stability, as evidenced by prolonged fluorescence lifetime from 0.564 ms to 0.691 ms at 539 nm. Leveraging distinct electrical and optical signal transduction pathways, the hydrogel functions as a highly sensitive resistive strain sensor with multistage gauge factors up to 13.85 and excellent cyclic stability over 1200 loading–unloading cycles at 100% strain for human motion monitoring. It also serves as a ratiometric optical pH sensor over a broad range (pH 1–13) based on phenolphthalein-sensitized upconversion luminescence, with excellent repeatability. By integrating real-time resistance responses with optical readouts within a single soft material, this work demonstrates a reliable dual-mode sensing strategy for simultaneous mechanical and chemical monitoring, holding promise for wearable electronics, smart healthcare, and environment-responsive sensing systems. Full article

Sustainable nanotechnologies derived from renewable resources are increasingly being positioned at the interface of green chemistry, advanced drug delivery, and translational pharmaceutics. Over the past decade, lignocellulosic nanomaterials, chitin/chitosan platforms, polysaccharide-based nanogels and nano-enabled hydrogels, lignin- and polyphenol-derived nanostructures, and bio-based lipid nanocarriers have been engineered through progressively eco-efficient routes, including solvent-minimized self-assembly, nanoprecipitation, spray drying, hot-melt extrusion, and microfluidic-assisted fabrication. This work provides a structured evidence map of nano-enabled drug delivery and therapeutic platforms derived from renewable biological resources. Specifically, we aim to (i) identify and classify nanoplatform classes and renewable feedstocks; (ii) summarize reported pharmaceutical critical quality attributes (CQAs) and performance and safety endpoints; and (iii) appraise how “renewability” and “green” claims are evidenced (feedstock origin vs. process sustainability) and how frequently translational readiness factors (scalability, quality control, regulatory alignment) are addressed. We critically compare renewable and conventional nanomaterial platforms across key translational dimensions, including carbon footprint, batch consistency, biodegradability, functional tunability, safety/persistence, and scale-up maturity. Finally, we delineate a practical translational pathway—from biomass sourcing and fractionation to nanoformulation, characterization/stability, and GMP scale-up—highlighting cross-cutting enablers such as lifecycle assessment, EHS/toxicology risk assessment, quality-by-design, and regulatory alignment. Collectively, the evidence supports renewable nanomaterials as viable, scalable candidates for next-generation therapeutics, provided that variability control, standardized characterization, and safety-by-design principles are embedded early in development. Full article

This study aimed to develop a 100 mg immediate-release (IR) tablet containing dasatinib monohydrate, a tyrosine kinase inhibitor, using a Quality by Design (QbD) framework at laboratory scale. The development strategy focused on systematic identification and control of critical process parameters (CPPs) affecting tablet quality during wet granulation. Preformulation studies were conducted to evaluate key physicochemical properties of the active pharmaceutical ingredient (API), including solubility, particle size distribution, and crystallinity, which may influence dissolution behavior. A risk assessment approach based on preliminary hazard analysis (PHA) and failure mode and effects analysis (FMEA) was applied to identify high-risk process variables. Based on the risk assessment results, chopper speed during wet granulation and compression force during tableting were identified as critical process parameters. These factors were further investigated using a Design of Experiments (DoE) approach based on Define Custom Design (DCD) and response surface methodology (RSM) to evaluate their effects on critical quality attributes (CQAs), including dissolution performance, disintegration time, and tablet friability. Response surface analysis established a design space in which chopper speed ranged from approximately 2300–2500 rpm and compression force ranged from 11 to 13 kN, ensuring consistent tablet quality within the investigated operating range. The optimized process conditions produced tablets that satisfied predefined quality targets. Comparative dissolution studies demonstrated dissolution profiles comparable to the reference product across pH 1.2, 4.0, and 6.8 media, with similarity factor (f₂) values ranging from 51.18 to 85.23. The experimentally established design space demonstrated reproducible in vitro performance and physicochemical stability under accelerated storage conditions. Overall, this study demonstrates the practical application of a QbD-based development strategy integrating risk assessment and response surface optimization to improve process understanding and manufacturing robustness in wet granulation-based tablet production. Full article

Background: Advanced therapy medicinal products (ATMPs) require strict control of critical process parameters (CPPs) to ensure manufacturing efficiency. The relative impact of donor systemic factors, such as vitamin D status, versus technical process parameters on dental pulp-derived stem cell (DPSC) production remains unclear. Methods: In this prospective observational study, 250 adults undergoing extraction of impacted mandibular third molars were included. Dental pulp was processed under a standardized SOP using different preparation methods and enzyme conditions. Primary endpoints were serum 25(OH)D concentration and cell yield; secondary endpoints included number of passages and cryovials. Results: Mean 25(OH)D concentration was 30.1 ± 14.5 ng/mL and was higher in supplemented individuals (38.2 ± 14.0 vs. 25.6 ± 12.7 ng/mL; p < 0.0001) but was not associated with cell yield (ρ = 0.14, p = 0.168) or passages (ρ = 0.07, p = 0.406). In contrast, process parameters showed strong effects: scissor preparation resulted in a substantially higher yield than mechanical methods (median 5.00 vs. 1.00 million cells; p = 3.6 × 10⁻¹³), and type II collagenase was independently associated with a higher yield (+2.04 million cells; p = 0.026). The number of passages was the strongest predictor of yield (β = 2.28 million per passage; p < 10⁻²⁶). Post-thaw viability remained high (mean 90.1% and range 81–98%). Conclusions: Manufacturing efficiency of DPSCs is primarily determined by critical process parameters, particularly preparation method, enzyme selection, and passage control, whereas donor vitamin D status did not significantly influence outcomes under the studied SOP. These findings highlight process standardization as the key driver of reproducible ATMP manufacturing. Full article

Deciphering the coupling mechanisms between post-harvest precursor shaping and roasting thermochemistry is pivotal for precise coffee flavor modulation. This study aimed to investigate the regulation mechanisms of in vitro biomimetic fermentation (BF) on the precursor-roasting reaction network. Integrated multi-omics characterization and sensory evaluation reveal that the BF protocol achieves targeted substrate enrichment, notably amplifying free amino acids—particularly leucine and phenylalanine—by 1.89-fold while accumulating lactate and succinate buffering salt systems. This reconfiguration constructs a matrix with superior thermal buffering capacity (ΔpH 0.17), which optimizes the thermal reaction kinetic window during roasting. Consequently, BF drives a 3.08-fold surge in esterification flux, significantly increasing the abundance of key fruity markers such as ethyl acetate and ethyl isovalerate. It also enhances the diversity of Maillard products, specifically elevating nutty-associated alkylpyrazines (e.g., 2,3,5-trimethylpyrazine). Concurrently, BF improves the thermal stability of bioactive compounds, including 5-caffeoylquinic acid (5-CQA) and trigonelline. Multi-scale molecular dynamics and quantum chemical calculations elucidate that BF-derived organic acid–salt complexes exert a ‘pseudo-catalytic effect,’ lowering activation free energy barriers for critical aroma-generating reactions by approximately 8.5 kcal/mol. This study demonstrates high sensory predictability (predictive model R² = 0.98) and provides a quantitative theoretical framework to advance coffee processing from empirical observation to rational flavor design. Full article

Background/Objectives: Clonazepam (CLZ), a BCS Class II drug, presents significant oral delivery challenges due to its low aqueous solubility. This study explores the systematic development of solid self-emulsifying drug delivery systems (S-SEDDS) using Quality by Design (QbD). The primary objective was to evaluate and compare advanced mathematical optimization frameworks, specifically Derringer’s Desirability Function (D) and Weighted Goal Programming (WGP), to identify a robust formulation that enhances drug solubilization while ensuring superior processability and flowability. Methods: Liquid SEDDS were solidified by adsorption onto a porous matrix (Aerosil^® 200/Lactose). A multi-objective optimization was conducted to define a robust Design Space (DS), comparing D against WGP. The trade-offs between competing Critical Quality Attributes (CQAs), specifically powder flowability (angle of repose, AR), blending efficiency (BE), and CLZ recovery (CR), were evaluated. Characterization included morphology from Environmental Scanning Electron Microscopy (ESEM), droplet size analysis, and pH-dependent dissolution studies. Results: D provided a highly robust baseline, yielding constant optimal coordinates (F2, F3 = +1; F4 = 0) across all sensitivity levels, with a predicted AR of 40.46°, BE of 0.12 and CR of 90.0%. However, WGP successfully refined this solution by allowing a more flexible weighting of goals, achieving a more favorable compromise with an AR of 38.96°, a BE of 0.11, and a CR of 90.23%. The optimized system maintained nanometric droplet sizes (<200 nm) and showed a controlled, pH-independent release profile, reaching 80% drug solubilization at 6 h. Conclusions: Integrating WGP into the QbD framework offers a more versatile and precise optimization than the traditional D for complex pharmaceutical systems. This approach ensures the production of high-quality S-SEDDS, bridging the gap between mathematical modeling and the stringent requirements of industrial solid dosage manufacturing. Full article

Background: The oral delivery of biopharmaceuticals remains a major challenge for researchers and the pharmaceutical industry. Therefore, extensive research is ongoing to develop a viable delivery method, hence self-emulsifying drug delivery systems (SEDDSs) are being investigated because of their ability to protect the carried macromolecules in the gastrointestinal environment and facilitate absorption through the intestinal barrier. Objectives: To systematically investigate this promising method for the oral delivery of lysozyme (LYZ) and to model oral peptide/protein administration. Methods: LYZ/sodium dodecyl sulfate (SDS) hydrophobic ion pairs (HIPs) were prepared to enhance protein solubility and stability in SEDDSs. Different surfactants (Tween^® 20 and 80) and as co-surfactants (Span^® 20 and 80) were combined for the preparation of liquid SEDDSs according to a 2² full factorial design and samples of each combination were formulated based on a three-factor-constrained mixture design. The critical quality attributes (CQAs), droplet size, polydispersity index (PDI), and zeta potential were measured by dynamic light scattering (DLS). The process design space was determined by response surface methodology (RSM) and two-dimensional ternary contour plots. An in vitro release test was performed using the sample-and-separate approach. Results: Emulsions of SEDDSs with the optimal properties of droplet size < 200 nm, PDI < 0.4 and zeta potential < −10 mV were prepared. Consequently, a HIP load of 10 mg/g was achievable, exhibiting apparent first-order kinetics, with approximately 80% of the loaded LYZ released within 6 h. Conclusions: This study may contribute to better understanding of the effects and interactions of formulating materials for SEDDSs and their possible role in the oral delivery of biopharmaceuticals. Full article

Caffeoylquinic acids (CQAs) are polyphenolic compounds widely present in daily diets, but their bioactivities are limited by poor intestinal absorption, the mechanisms of which remain incompletely understood for various isomers. This study investigated the transepithelial transport of three mono-CQAs and three di-CQAs using Caco-2 monolayers. Concurrently, the potential of five dietary flavonoids to enhance intestinal absorption by modulating efflux transporters was evaluated. Results suggest that CQAs were mainly transported via passive paracellular diffusion. The apparent permeability coefficients (P_app) of mono-CQAs were (1.49 ± 0.22) × 10⁻⁶, (1.49 ± 0.25) × 10⁻⁶, and (2.15 ± 0.57) × 10⁻⁶ cm/s, which were significantly higher than those of di-CQAs. And the efflux of 5-CQA, 3,4-diCQA, and 3,5-diCQA was primarily mediated by P-gp. Among the five dietary flavonoids tested for their potential to inhibit this efflux, quercetin and kaempferol exhibited the most potent enhancing CQA uptake. They increased the P_app of 5-CQA from (2.15 ± 0.21) × 10⁻⁶ to (3.05 ± 0.08) × 10⁻⁶ cm/s and (2.57 ± 0.17) × 10⁻⁶ cm/s, respectively. Similar promoting trends were observed for 3,4-diCQA and 3,5-diCQAs. Molecular docking revealed that CQAs and these effective flavonoids share common binding residues within the P-gp pocket, providing a structural basis for the inhibition of efflux. These findings provide insights into the intestinal transport of structurally diverse CQAs and highlight the potential of dietary flavonoids to improve the oral bioavailability of CQAs. Full article

Background/Objectives: Manual preparation of semisolid formulations (creams, ointments, gels) is prone to variability in mixing energy and time, which may compromise uniform API distribution. This study aimed to evaluate an Electronic Mortar and Pestle (EMP; Unguator™) as a standardized compounding tool, with objectives to: (i) validate stability-indicating UHPLC methods; (ii) assess content uniformity across jar strata; (iii) quantify the impact of mixing time and rotation speed via design of experiments (DOE); and (iv) verify cleaning effectiveness and cross-contamination risk. Methods: Five representative formulations were compounded: urea 40%, clobetasol 0.05%, diclofenac 2.5% in hyaluronic acid 3% gel, urea 10% + salicylic acid 1%, and hydroquinone 5%. UHPLC methods were validated per ICH Q2(R2) and stress-tested under acid, base, oxidative, thermal, and UV conditions. Homogeneity was assessed by stratified sampling (top/middle/bottom). A 3² factorial DOE (time: 2/6/10 min; speed: 600/1500/2400 rpm) modeled effects on % label claim and RSD. Cleaning validation employed hydroquinone as a tracer, with swab sampling pre-/post-use and post-sanitization analyzed by HPLC. Results: All UHPLC methods met specificity, linearity, precision, accuracy, and sensitivity criteria and were stability-indicating (Rs ≥ 1.5). Formulations achieved 90–110% label claim with strata CV ≤ 5%. DOE revealed speed as the dominant factor for clobetasol, urea, and diclofenac, while time was more influential for salicylic acid; gels exhibited curvature, indicating diminishing returns at high rpm. Model-predicted optima were implementable on the Unguator™ with minor rounding of rpm/time. Cleaning validation confirmed post-sanitization residues below LOQ and <10 ppm acceptance. Conclusions: The Unguator™ provides a practical, parameter-controlled route for compounding pharmacies to standardize semisolid preparations, achieving reproducible layer-to-layer content uniformity within predefined criteria under the evaluated conditions through programmable set-points and validated cycles. DOE-derived rpm–time relationships define an operational design space within the studied ranges and support selection of implementable device settings and set-points. Importantly, the DOE-derived “optima” in this study are optimized for assay-based content uniformity (mean % label claim and strata variability). Cleaning validation supports a closed, low-cross-contamination workflow, facilitating consistent routines for both routine and complex formulations. Overall, the work implements selected QbD elements (QTPP—Quality Target Product Profile; CQA—Critical Quality Attribute definition; CPP—Critical Process Parameter identification; operational design space; and a proposed control strategy) and should be viewed as a step toward broader lifecycle QbD implementation in compounding. Full article

Background: Liposomes are attractive topical carriers, yet translating laboratory fabrication to scalable, well-controlled processes remains challenging. Objectives: We compared three manufacturing methods for diclofenac-loaded liposomes: probe sonication, microfluidic mixing, and a high-turbulence microreactor, under a Quality-by-Design framework. Methods: Differential scanning calorimetry (DSC) was used to define a processing-relevant liquid-crystalline temperature window for the lipid excipients. For sonication scale-up, a Plackett-Burman screening design identified key process factors and supported an energy-density (W·s·L⁻¹) control approach. For microfluidics, the effects of flow-rate ratio (FRR) and total flow rate (TFR) were mapped and optimized using a desirability function. Microreactor trials were performed at elevated throughput. Residual ethanol during post-processing was monitored at-line by Raman spectroscopy calibrated against gas chromatography (GC). Particle size and dispersity were measured by DLS and morphology assessed by cryo-TEM. Results: DSC supported a 70–85 °C processing window. Sonication scale-up using an energy-density target (~11,000 W·s·L⁻¹) reproduced lab-scale quality at 8 L (Z-average ~87–92 nm; PDI 0.16–0.23; %EE 86–94%). Microfluidics optimization selected FRR 3:1/TFR 4 mL·min⁻¹, yielding ~64 nm liposomes with PDI ~0.13 and %EE ~93%. The microreactor achieved ~50 nm liposomes with %EE ~95% at 50 mL·min⁻¹. Cryo-TEM corroborated size trends and showed no evident aggregates. Conclusions: All three routes met topical CQAs (~50–100 nm; PDI ≤ 0.30; high %EE). Method selection should be guided by target size/dispersity and operational constraints: sonication enables energy-based scale-up, microfluidics offers precise size control, and microreactors provide higher throughput. Full article

N-glycans represent the most common and abundant post-translational modification (PTM) in therapeutic antibodies, playing crucial roles in key functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Consequently, glycan profiling is regarded as a critical quality attribute (CQA) and is routinely performed to ensure antibody quality and consistency. The Rapi-Fluor method is a conventional standard for detailed glycan profiling, while intact mass analysis serves as a parallel CQA. However, the Rapi-Fluor method is a multi-step, time-consuming process that can limit high-throughput monitoring. In this study, we conducted a rigorous comparative validation of the Rapi-Fluor method and intact mass analysis for determining the glycan composition of ten therapeutic antibodies, comprising five original products and their biosimilars. Consistent with established findings, the biosimilars exhibited glycan compositions highly similar to their original counterparts. Furthermore, major glycans constituted over 85% of the total glycans across all samples. Crucially, the analytical comparison revealed highly congruent results between the Rapi-Fluor method and intact mass analysis, with quantitative differences in glycan composition being less than 10% across all ten therapeutic antibodies. This successfully demonstrates that intact mass analysis is a highly feasible, reliable, and significantly time-efficient alternative for rapidly and reliably assessing glycan composition, thereby accelerating quality control and process monitoring. Full article

Community Question-Answering (cQA) sites have an urgent need to be increasingly efficient at (a) offering contextualized/personalized content and (b) linking open questions to people willing to answer. Most recent ideas with respect to attaining this goal combine demographic factors (i.e., gender) with deep neural networks. In essence, recent studies have shown that high gender classification rates are perfectly viable by independently modeling profile images or textual interactions. This paper advances this body of knowledge by leveraging bimodal transformers that fuse gender signals from text and images. Qualitative results suggest that (a) profile avatars reinforce one of the genders manifested across textual inputs, (b) their positive contribution grows in tandem with the number of community fellows that provide this picture, and (c) their use might be detrimental if the goal is distinguishing throwaway/fake profiles. From a quantitative standpoint, ViLT proved to be a better alternative when coping with sparse datasets such as Stack Exchange, whereas CLIP and FLAVA excel with a large-scale collection—namely, Yahoo! answers and Reddit. Full article