17.8 Commentary on Hurdles in Clinical Translation of Various Nanotechnology Products
Research regarding nanoconstructs development in the cancer treatment field has witnessed a noticeable increase after discovery of the EPR effect. However, the number of anticancer drugs that actually reached the market was considered extremely low, as out of 200,000 anticancer drugs only 15 made it by 2017 (Greish et al., 2018). The reasons why most of the nanomedicines cannot even reach the market are the hardship or inability to maintain detailed characterization of these products, unsuccessful manufacturing on large scales, and issues in their safety and efficacy. These hurdles require many developmental processes to overcome them including a precise understanding of every component and all the possible interactions between them, determination of key characteristics to understand in which possible ways they affect performance, and the extent of it. If key characteristics can be replicated under manufacturing conditions (scaling up), the efficacy of targeting at the site of action and their stability and sterility can be enhanced and/or assessed (Desai, 2012). The majority of these hurdles are summarized in Table 17.5 (Tinkle et al., 2014).
Table 17.5. Major Hurdles That Face the Commercialization of Nanomedicine
Lack of standard nano nomenclature: imprecise definition for nanomedicines
Currently used compounds/components for nanodrug synthesis often pose problems for large-scale good manufacturing (cGMP) production
Lack of precise control over nanoparticle manufacturing parameters and control assays
Lack of quality control: issues pertaining to separation of undesired nanostructures (byproducts, catalysts, starting materials) during manufacturing
Reproducibility issues: control of particle size distribution and mass
Scalability complexities: enhancing the production rate to increase yield
High fabrication costs
Lack of rational preclinical characterization strategies via multiple techniques
Biocompatibility, biodistribution and toxicity issues: lack of knowledge regarding the interaction between nanoparticles and biosurfaces/tissues
Consumer confidence: the publics general reluctance to embrace innovative medical technologies without clearer safety or regulatory guidelines
The relative scarcity of venture funds
Ethical issues and societal issues are hyped up by the media
Big Pharmas continued reluctance to seriously invest in nanomedicine
Patent review delays, patent thickets, and issuance of invalid patents by the US Patent and Trademark Office
Regulatory uncertainty and confusion due to baby steps undertaken by US Food and Drug Administration: a lack of clear regulatory/safety guidelines
One of the major concerns related to NPs is their potential incompatibility and toxicity. Studies showed that inhaling NPs can cause pulmonary inflammation as well as inducing endothelial dysfunction that might lead to further complications in the cardiovascular system. A study for evaluation of iron oxide toxicity showed that monocyte-mediated dissolution and phagocytosis of the NPs have caused severe endothelial toxicity by initiating oxidative stress. Nanomaterials used in oral DDS have been shown to accumulate in hepatic cells, which might induce the immune response and eventually cause permanent damage to the liver. The accumulation of NPs in cells has been found to cause cancer by transforming cells into the tumorous state (Jain et al., 2018; Riehemann et al., 2009). Thus, handling these nanosystems requires special equipment and caution, which increases the cost of the production process and requires further investigations of the safety of nanomaterials to have a better understanding and optimize safety during manufacturing (Hammed et al., 2016). Production of NPs in the laboratory often requires complex, multistep synthesis processes to yield the nanomaterials with the required properties. Aside from the complexity of the process, controlling conditions such as temperature and concentrations precisely is significant to achieve homogeneity of NPs in terms of desired characteristics. However, retaining temperature and concentration in large systems is harder to achieve resulting in NPs with different characteristics (Gomez et al., 2014).
NPs tend to aggregate forming clusters with several microns in size. Aggregation of NPs alters their characteristics such as reactivity, transport, toxicity, and risk in the environment. Dissolution reduces when aggregation occurs due to the decrease in available surface area that will eventually reduce the activity of NPs. For example, dechlorination rate of CT (carbon tetrachloride) by magnetite NPs has shown to decrease when aggregation of the NPs increases resulting in an inverse relationship between dechlorination rate of carbon tetrachloride and aggregation of magnetite NPs (Hotze et al., 2010; Hou and Jafvert, 2009).
All these requirements are extremely important because the majority of the nanomedicines have failed to reach the commercialization step even though their efficacy in animal models was considerably high. Due consideration must be given regarding the several difficulties such as their low targeting, low safety, low efficacy, heterogeneity of disease between individuals, inability to scale-up successfully, and unavailability in determining a convenient characterization methods (Agrahari and Agrahari, 2018; Hare et al., 2017; Kaur et al., 2014). These hurdles that face the research process of accelerated translation are summarized in Fig. 17.8 (Satalkar et al., 2016).
Figure 17.8. Major issues that face accelerated translation process of nanoparticles.
Therefore, more understanding in all aspects of nanomedicine production, characterization, and clinical processes must be fulfilled to control and improve the development processes, and increase the efficacy of the translational methods. Other significant hurdles hindering clinical translation are the insignificant incentives regarding technology transfer, as well as socioeconomic uncertainties along with the safety problems faced. In the majority of cases, consideration of commercialization aspects in early stages of development is hardly even considered thus eliminating the market-oriented development (Rsslein et al., 2017).
Nanomedicines face tough, challenging concerns when it comes to determining the applicable analytical tests in terms of chemical, physical, or biological characterization. This is mainly achieved due to their complex nature in comparison with other pharmaceutical products. Hence, there is a need for more complex and advanced levels of testing to ensure a full accurate characterization of nanomedicine products. Quantification of each component of nanomedicine is considered essential alongside the identification and evaluation of interactions between them. For more possibility in achieving successful manufacturing processes with reproducibility, these products should be investigated and understood more during the early developmental stages to identify their key characteristics. The challenges for nanomedicine during scale-up and manufacturing are considered relatively unique because other pharmaceutical manufacturing processes systems are not three-dimensional multicomponent in nature on the nanometer scale. Therefore, a certain series of obstacles in the scale-up process is required. To reach the desired safety, pharmacokinetic and pharmacodynamic parameters to produce the therapeutic effect are needed. These are further determined by the proper selections of the essential components, determination of the critical manufacturing steps, and key characteristics identification. Several methods of orthogonal analysis are essential for in-process quality controls of nanoparticle products and any deviations from key parameters could result in a significant negative impact on both the safety and efficacy of nanomedicines (Desai, 2012).
Each step in the manufacturing process of NPs must be understood extensively with the need of experienced technicians. The development process also requires more enhancements in both complexity and cost. Inadequate data regarding scaling-up processes of nanomedicine products is a major concern in the commercialization step as there are only a few reports supporting scaling-up developments. Many formulation methods have been developed for manufacturing nanomedicine products. The most common methods are nanoprecipitation and emulsion-based approaches. Generally, formulations are prepared either by precipitating the dissolved molecules (bottom-up method) or by reducing the size of larger drug particles (top-down method). Removal of the solvent in the bottom-up method is not an easy process and it cannot be controlled well either, thus explaining why this method is less often applied in industrial manufacturing (Agrahari and Agrahari, 2018; Vauthier and Bouchemal, 2009). Investments in innovative projects face several issues with the major one being the knowledge that should be obtained from the innovation. Its confidentiality is easily breached when a company uses that knowledge as it cannot prevent other companies from using it. Thus, investors are not attracted to this type of project because the total return on the investment cannot be easily appropriated (Morigi et al., 2012).
The complexities in formulating nanoproducts on large scales are due to the inability of optimization of formulation processes and achieving reproducibility. Whereas formulation steps including size reduction, homogenization, centrifugation, sonication, solvent evaporation, lyophilization, extrusion, and sterilization can be easily optimized on small-scales, its still a challenging process on large-scales. Accordingly, variations between batches cannot be controlled sufficiently thereby limiting the possibility of nanomedicine to get through commercial translation (Anselmo et al., 2017; Desai, 2012).
Another problem is that even slight changes in either the formulation or the manufacturing process can have a significant effect on the nanomedicine physiochemical properties (crystallinity, size, surface charge, release profile), which will ultimately influence the therapeutic outcome. Most of the pharmaceutical industrial facilities cannot manufacture nanomedicines because of the lack of the right equipment for the process. As nanomedicine manufacturing usually involves the use of organic solvents, the ability to correctly process and handle nanoproducts is crucial to control their safety and sterility (Anselmo et al., 2017; Desai, 2012; Kaur et al., 2014). These steps require an expensive and complicated equipment, well-trained staff, and precise control to get the required product in the right quality (Desai, 2012; Kaur et al., 2014; Ragelle et al., 2017).
To date, only 58 nanoformulations are approved based on their clinical efficacy but only a quarter of them are meant for cancer treatment. Majority of the nanoformulations could not even be reproduced successfully due to several factors including the study design, overall analysis, protocols, data collection, and the quality and purity of materials used. Besides, the poor establishment of the correlation and prediction of safety and efficacy of the nanomedicine on patients hinders the successful DDS. Targeting and drug accumulation of anticancer drugs in the site of action is considered relatively poor in mouse models. Many nanoformulations were faced with failure in different clinical trial phases. Some of them got approved but then withdrawn from the market such as peginesatide. Unfortunately, the increased failures will most probably affect the development movement in the pharmaceutical industry (Greish et al., 2018).
At the present time, regulatory agencies such as the FDA and EMEA are examining every new nanomedicine on a product-by-product basis. They are considered a unique category due to the fact that there are no true standards in their examination process (Desai, 2012). Two of the major regulatory issues that emerged at the start of nanomedicine is the lack of scientific experts in the FDA and the difficulty in classifying the product (Morigi et al., 2012). The unique characteristics of nanomedicines are directly related to their regulation hurdles, which is the same as other pharmaceutical systems such as liposomes and polymeric systems (Sainz et al., 2015).
Researchers keep investigating nanomedicines when attached to prodrugs, drugs, tracking entities, and targeting molecules. Development of robust methods and assays in quality control of nanomedicines are required for more effective monitoring and characterizations. Also, estimation of their overall performance in releasing drugs, binding to proteins, and the specificity in cellular uptake must be considered (Sainz et al., 2015; Tinkle et al., 2014).
Nanomedicine products are both complex and diverse requiring explanation of challenges to have a clear definition and an effective regulation. The lack of regulatory guidelines for these products hinders their clinical potential. Drug regulatory authorities must keep up with the rapid pace of the knowledge and technological development as they play a major role translating nanomedicines towards the market. The European Medicines Agency (EMEA) and the FDA have different requirements in evaluating new nanomedicines as well as different definitions regarding nanomedicine. Agreeing on specific regulatory procedures internationally is very important to ease the translational researches of nanomedicines. Also, better long-term monitoring of toxicity should be achieved by prolonging postmarketing surveillance especially for a patient with chronic diseases (Sainz et al., 2015; Tinkle et al., 2014).
Nanomedicines just like any other pharmaceutical formulations must offer higher value to patients to become commercially successful, and have better efficacy and safety. New nanomedicine products follow the same steps in clinical trials as other drugs. It starts with preclinical tests, then be submitted to get the IND (investigational new drug) approval and following that it enters the three stages of clinical trials, one after another to evaluate safety and efficacy of the new drug (Agrahari and Agrahari, 2018).
In recent years, toxicities caused by nanomedicines have drawn attention and been recognized to be unique to nanoparticulate systems. Hence, a minimum set of measurements for the nanoparticle like surface charge, size, and solubility are monitored so as to predict the possible toxicity of NPs. Besides, NPs can stimulate the immune system by acting as an antigen. Immunogenicity is mainly affected by the size of the nanoparticle, its surface characteristics, hydrophobicity, charge, and solubility. Hematologic safety concerns have also been observed such as hemolysis and thrombogenicity (Desai, 2012).
In vivo and in vitro studies provide the proper characterization of the interactions between the product and the biological system. The problem is that the data attained from current toxicity tests are not from clinical trials and it cannot always be extrapolated to humans. Monolayers of cell cultures are currently used to characterize immunogenicity, drug release, cellular uptake, and toxicity. However, the cellular uptake process of nanoformulations is majorly influenced by physicochemical characteristics. Thus, 3D cell systems will probably provide better outcomes (Gupta et al., 2016). More caution should be given when handling any nanosized powder due to the ability of such particles to penetrate the skin and because it can also show pulmonary toxicity (Agrahari and Hiremath, 2017; Nel et al., 2006).
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