## 3 Results
### Challenges and Future Directions
#### 3.6.2 Cost and Scalability  
Cost considerations play a decisive role in the selection of production methods for nanomedicines. Advanced technologies such as supercritical fluid processing or microfluidization offer significant technical advantages in controlling particle size and homogeneity. However, these methods require substantial investments in equipment, consume high energy, and involve the use of large volumes of CO2, which limits their industrial applicability.  
In contrast, techniques such as nanoprecipitation or emulsion-diffusion are more easily adaptable to large-scale production and significantly reduce processing time. For example, studies have shown that nanoprecipitation can shorten processing time by approximately one-third compared to emulsion-based methods, thus contributing to reduced operational costs [95].  
Methods based on sonication or milling introduce additional challenges, as they may cause contamination due to equipment wear. This contamination increases expenditures related to quality control. Moreover, losses of active pharmaceutical ingredients and the need for extensive washing steps negatively affect economic efficiency [96].  
The absence of standardized quality control methods, coupled with difficulties in establishing in vitro-in vivo correlations, leads to additional costs during development and regulatory approval phases. Manufacturers are therefore required to constantly balance technological performance, economic feasibility, and market demands [97].  
Batch-to-batch reproducibility continues to represent a major hurdle in the clinical application of nanotechnology-based therapies for hepatocellular carcinoma. Maintaining therapeutic efficacy requires strict control over essential parameters such as particle size, surface charge, drug distribution, and physicochemical stability.  
Modern technologies, such as microfluidics or soft lithography-based templating, allow precise control over nanoparticle size, composition, and properties, thus enhancing batch consistency [98]. Nevertheless, both laboratory-scale and industrial-scale synthesis processes frequently generate significant variability. This variability affects crucial characteristics--such as size, morphology, porosity, crystallinity, colloidal stability, and surface chemistry--which directly influence the interaction of nanoparticles with biological systems.  
Even when researchers use large batches of the same material, dispersion instability may result in property degradation over a few months, whereas in vivo studies may span several years. Furthermore, a single batch does not necessarily reflect the full complexity and variability of the entire manufacturing process, thereby limiting the accuracy and clinical relevance of the data.  
To address these limitations, it has been argued that batch-to-batch reproducibility must be actively integrated into the synthesis process, rather than treated as a secondary outcome. Proposed solutions include continuous flow synthesis, the implementation of stringent quality control measures, and the adoption of standardized characterization protocols using complementary analytical techniques [96]. Without such measures, batch variability risks compromising the interpretation of biological data and undermining trust in the safety assessments of nanomaterials.  
To make nanotechnology-based therapies accessible to a broader population, manufacturing processes must be optimized to ensure consistency, reproducibility, and economic efficiency. Therefore, the development of standardized protocols for nanoparticle synthesis and characterization is essential to overcoming these challenges [95].