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424 Herbal Pharmacopeia
immortalized abnormal cell lines. However, the use of donor- derived human cell lines such as
peripheral blood leukocytes resulted in inter- individual variations in immune responses during
immunotoxicity assessment (Tirumala etal., 2021). Relevant and suitable tests should be developed
and strategies adopted for proling the immune function of the whole organism after the administration of NP by the desired route of administration (Halamoda- Kenzaoui etal., 2019b).
Some recent trends and advancements in nanotoxicology assessment are discussed below.
20.3.3 UtIlIzAtIon of AdVAnced AnAlytIcAl tools
xCELLigence utilizes a low electrolyte impedance interface for real- time monitoring of the various
cellular processes. Since it does not use any dye or reagent, the risk of interference by NPs has been
minimized. Results obtained with several inorganic NPs from this in vitro, non- invasive technique
have been found to match with data obtained from conventional toxicity assays . The use of uorescent probes provides sensitive and accurate quantication of intracellular ROS levels. However, the
method involves irreversible oxidation of the cellular constituents, leading to permanent damage, and
thus cannot be adopted during clinical trials. Interference with the conventional COMET assay has
been overcome by incorporating NPs in a gel and the discovery of the COMET Chip. Development
and improvements in the Conventional FADU (Fluorimetric Detection of Alkaline DNA Unwinding)
method have been possible with the use of a robot for the handling of samples and the dispensing of reagents in a light- and temperature- protected controlled environment . The improvised technique utilizes fewer cells (Tirumala etal., 2021). Quartz crystal microbalance- dissipation monitoring
(QCM- D) shows promise in assessing the extent of binding and deposition of NP onto the cell surface
and subsequent losses in membrane integrity. The electrochemical technique is a high- throughput
technique that measures impedance behavior and enables real- time and in situ monitoring of phenomena occurring at the NP–membrane interface in cells, tissues, organs, fetuses, and whole body
of an organism (Qiu etal., 2018). The chemical reactivity of surface- coated NPs and biophysical
interactions can be investigated and monitored by electrochemical impedance spectroscopy (ECIS)
(Shinde etal., 2020). High- throughput screening (HTS) techniques facilitate the rapid detection of
analytes in small volumes of samples in a single shot, saving time, money, manpower, and resources.
Standard analytical methods can be transformed into HTS methods by automation and increasing
the sensitivity and efciency of existing methods, such as high- throughput ow cytometry, highthroughput micronucleus assay, high- throughput COMET assay, and H2AX assay. Large number
of samples can be analyzed through the integration of HTS techniques with high- content analysis or
high- content imaging. High- content image- based screening can be used for the training of predictive
models and to enhance the accuracy of toxicity predictions (Singh & Gauri, 2023; Forest, 2022).
20.3.4 In sIlIco ApproAch: nAno- QsAr
Prediction of Quantitative Structure- Activity Relationship of NPs (or nano- QSAR) is a highly
promising technique that saves time, money, and resources in comparison to the above- mentioned
conventional experimental nanotoxicity assessment techniques. In this approach, suitable, wellconceptualized molecular descriptors, data- driven articial intelligence, and machine learning- based
tools are employed to establish the cause- effect relationship between in vivo pharmacokinetics and
toxicity data with NP features, without performing any in vitro or in vivo experiments (Singh etal.,
2023; Tirumala etal., 2021; Pikula etal., 2020). The concept of nano- QSAR is built on the similarity between biological responses from nanomaterials and identical molecular structures. NanoQSAR has been successfully employed to explore the toxicity potential of several metallic oxide
NPs towards E. coli. The interpretation of outcomes of the models revealed NP composition to contribute signicantly to NP- induced toxicity with insignicant roles of size or shape, as discussed in
the previous sections. The results from studies on bacteria were validated with experiments on mammalian cells, the HaCaT cell lines. Similar nano- QSAR models have also been utilized to explore
Safety Proles and Potential Toxicological Concerns of Herbal Nanomedicine 425
and predict the uptake of metallic oxide NPs by pancreatic cancer cells (PaCa2). Nano- QSAR can
generate 1D, 2D, and 3D models. Limitation with highly efcient predictive tools is the need for
extensive reliable, and high- quality databases and datasets for the training and validation of models.
Missing data produce conicting results. Although sufcient data are available with nanomedicines,
most of them are heterogeneous which are unsuitable for model development. Another disadvantage
of the in silico approaches is that the data cannot be used for establishing in vitro–in vivo correlation.
Molecular descriptors used during model development are based on pristine NPs rather than on the
NPs in biological systems, where substantial alterations in their surface properties and characteristics occur (Verma etal., 2023; Forest, 2022). Data mining, which involves assembling data from
different sources and various studies involving different media, cells, and chemicals, can generate a
huge database that can be processed appropriately to extract useful information (Singh etal., 2023).
Improvements in prediction capacity and, hence, fabrication and characterization strategies have
been possible by the de- convolution of variables with a known tendency of interaction and interference, thereby facilitating the unraveling of the different types of interaction (Qiu etal., 2018).
Another advancement employs periodic table- based molecular descriptors in nano- QSAR, which
can bridge the current gap in nanotoxicity studies (Roy & Roy, 2023).
20.3.5 GroUpInG/reAd-Across technIQUe
In this approach, the prediction of adverse effects is carried out by the acquisition of data from substances identical to test substances (in this case, nanomaterials) under investigation with respect to
physicochemical and structural properties. For successful implementation, chemometric tools are
employed, namely hierarchical clustering (HC), principal component analysis (PCA), and random
forest variable selection (Forest, 2022).
20.3.6 GenetIc ApproAches
Since uorescent probes(dyes) employed for ROS quantication induce permanent oxidation, they
may be replaced by designing genetically encoded reporters or redox- sensitive uorescent protein
with the ability to target typical cellular compartments. This approach is likely to be a useful tool in
the future in determining the genetic susceptibility of vulnerable individuals to certain phenotypes
of nanotoxicity and will also form the foundation for personalized medicines. However, the strategy
involves technical expertise and is not always economically possible at present. Conventional genotoxic assessment methods have been replaced by GreenScreen HC, BlueScreen HC, and ToxTracker
reporter assays (Akcan etal., 2020; Tirumala etal., 2021).
20.3.7 UtIlIzAtIon of VAlIdAted hUMAn cell lInes In IMMUnotoxIcIty AssAys
To overcome the issues of inter- individual variation in immune responses from donors, recently
developed immunotoxicity assays utilize validated human cell lines such as human Jurkat T- cell,
human lymphoid T- cell (MOLT- 4) or B- cell (IM- 9), human acute myeloid leukemia HL- 60 cells,
human- based skin explant, and so on. For accurate prediction of delayed hypersensitivity reactions from engineered nanomaterials, tests like human cell line activation test (hCLAT) and myeloid
U937 skin (sensitization) test (MUSST) have been developed (Tirumala etal., 2021).
20.3.8 In VItro cArcInoGenIcIty AssessMent wIth trAnsforMed cells
In this approach, the European Union Reference Laboratory for Alternatives to Animal Testing and
other research groups have performed in vitro carcinogenicity assessment with transformed cellbased models such as in vitro Syrian hamster embryo cell transformation and the Balb/c3T3 A311-1 mouse model. The endpoints for toxicity identication in this technique have been recognized
426 Herbal Pharmacopeia
as changes in morphology, colony formation, and the growth and formation of criss- crossed cells or
the piling of cell foci (Tirumala etal., 2021).
20.3.9 dnA BArcodInG
DNA barcoding is an innovative technique employed for the simultaneous screening of whole
organisms for the biodistribution of innumerable NPs (size > 100nm) to target sites and off- target
accumulation, leading to organ toxicity. The data- intensive tool needs help from bioinformatics
methods such as the unbiased Euclidean clustering strategy. It has been established from several
studies that NPs interact with some specic categories of immune cells (Kantak etal., 2023). The
technique possesses a high potential for assessing immune- and genotoxicity accurately in in vivo
models (Lokugamage etal., 2018).
20.3.10 systeMs toxIcoloGy: ‘oMIcs’ technoloGy
Systems toxicology is a discipline that attempts to amalgamate conventional toxicity assessment
techniques for the better and realistic interpretation of data and to ensure the availability of safe
nanomedicinal formulation. ‘omics’ lies at the heart of systemic toxicology. The ‘omics’ technologies are versatile tools that enable the quantitative and qualitative description of complex, biological,
adaptive changes, and behaviors. They can assess cellular stress at multiple levels and cross- talk or
interactions among different levels in response to low doses of nanomedicines, applicable in clinical
settings. The methods reect and correlate genotypic and phenotypic experimental observations.
They provide molecular information for in- depth analysis of underlying mechanisms and cellular
pathways leading to toxic effects. ‘omics’ provides a functional readout of cellular state from all
aspects. Nanoparticle- induced interference observed in conventional cytotoxicity assays is absent
when ‘omics’ technologies are employed (Abdelkader et al., 2023). However, highly advanced
infrastructure and expertise are essential prerequisites to the adoption of ‘omics’ in nanotoxicity
assessment (Forest, 2022; Fröhlich, 2017).
Studies of ‘omics’ encompass proteomics, lipidomics, transcriptomics, genomics, metabolomics,
and toxicogenomics. Of these, metabolomics is unique since the metabolome of individuals is
generic, whereas protein, gene, or transcript varies with individuals. The integration of different
‘omics’ techniques across the multiple ‘omics’ layers, and the combination of integrated ‘omics’
with in vitro tests and advanced instrumentation techniques, such as mass spectrometry and articial
intelligence- and machine learning- enabled statistical tools, enhance sensitivity and facilitate the
detection and proling of several endogenous small molecules. The application of high- resolution
magic angle spinning (HR- MAS) NMR- based metabolomics study revealed that silver nanoparticleinduced oxidative stress led to the metabolic conversion of lactate and taurine to pyruvate (Mengying
et al., 2015). The intersection of metabolomics, mechanobiological tools, bioinformatics, and
machine learning algorithms revealed ROS production, alteration in glucose metabolism, and lower
ATP synthesis in HEK293 cells following treatment with a low dose of magnetic silica nanoparticles
containing Rhodamine B isothiocyanate ([MNPs@SiO2(RITC)) (Shin etal., 2021; Shim etal., 2012).
20.3.11 nAno- InforMAtIcs dAtABAse
European Union–United States Roadmap Nanoinformatics 2030 enlisted several databases related to
nanomaterials of both the European Union and the United States such as, eNano- Mapper, nanoHub,
DaNa, the Online Chemical Modeling Environment (OCHEM), the NanoExposure and Contextual
Information Database (NECID), the NanoDatabank, the Nanomaterials–Biological Interactions
Knowledgebase, Nanominer, NanoMILE, and ModNanoTox. These databases have organized,
stored, shared, analyzed, and ensured the application of data obtained from various sources and
laboratories on nanomaterials (Pikula etal., 2020).
Safety Proles and Potential Toxicological Concerns of Herbal Nanomedicine 427
20.3.12 MIscellAneoUs AdVAnced ApproAches In nAnotoxIcoloGy AssessMent
Approaches such as testing species sensitivity distribution can be employed to predict the maximum
concentration of NPs in the surrounding environment and enable band gap analysis to investigate the
effects of chronic exposure to metallic nanoparticles . Computational models have been designed
to fulll regulatory needs where potential risks from nano- formulations can be predicted before
preclinical and clinical studies in animals and humans. In compliance with this specic requirement, projects that came into the forefront are NanoTEST, NANoREG, and NANoREG2. The outcomes of these projects will provide a new direction to the taxonomy of NPs based on toxicity (Kad
etal., 2022). Several of the tools, techniques, and approaches employed in experimental toxicology,
advanced instrumentation techniques, and systems toxicological approaches have been combined
and incorporated into the framework of Adverse Outcome Pathways (AOPs). Some AOPs are relevant in the study and assessment of nanotoxicology, e.g., AOP 173, AOP 303, AOP 237, and AOP
302. These pathways helped in describing and elucidating hallmark features and endpoints of the
disease and nano- formulations under investigation (Forest, 2022). To minimize toxicity, a new paradigm in the synthesis and fabrication of NPs is the eco- friendly transition to green nanotechnology or the green synthesis of metallic NPs with the help of microbes and secondary metabolites
present in vegetable extracts (Anand etal., 2022; Hu etal., 2022; Martinez etal., 2021; Osman,
2019). Figure 20.2 highlights various techniques and tools used in the safety and risk assessment of
nanomedicines.
20.4 THE NANOTOXICOLOGICAL CLASSIFICATION SYSTEM:
A NEW HORIZON
A surge in the development of nano- formulations for herbal medicines has necessitated the systematic classication and categorization of nanomaterials based on their adverse effects, risks,
hazards, and toxicity. The DF4nanoGrouping has devised a functionality- driven scheme for the
categorization of NPs, starting from simple to complex events attributed to intrinsic characteristics, biological system- dependent properties, and toxicological manifestations. In this system, there
are four classes of nanomaterials, namely, soluble, biopersistent –high- aspect ratio, passive with
no biological effects and active formulations exhibiting adverse effects related to their surface
FIGURE 20.2 Techniques and tools for safety and risk assessment of nanomedicines.
428 Herbal Pharmacopeia
properties. For this classication, both in vitro and in vivo data have been utilized. In response to
the need to reduce the number of descriptors, DF4nanoGrouping has identied structural attributes
of nanomaterials and calculated property with quantum mechanical signicance. It has been previously reported by the National Nanotechnology Initiative that quantum effects are governed by size.
However, DF4nanoGrouping is not ideal for nano- formulations for drug delivery (Gajewicz etal.,
2018; Siegrist etal., 2019).
In the Nanotoxicological Classication System (NCS), nanomaterials have been classied into
four types based on their size and biodegradability, governed by route of administration and biocompatibility of the surface. Class I and Class II are nanomaterials with size greater than 100 nm and are
either biodegradable or non- bio- degradable, respectively. These NPs are not endocytosed. Class III
and Class IV are meant for biodegradable and non- biodegradable NP with size less than 100 nm and
hence are endocytosed and are more bioperistent, identical to Class II. These four classes can further
be subclassied, leading to eight classes in which physicochemical surface properties are also taken
into consideration. Other classication systems have integrated concepts of toxicology, risk assessment modeling, and the multi- criteria decision approach (Laloy, 2021; Keck & Müller, 2013).
A different system of classication of NPs can also be adopted based on the occupational hazards
associated with the production of these nanomaterials. In this system, the NPs are categorized into
three classes; namely, Class 1 for water- soluble NPs e.g. sucrose or siloxane NPs; Class 2 for synthetic, non- brous and persistent NPs as silver, gold, metal, and metallic oxide NPs; and, nally,
Class 3 for brous, non- soluble carbon nanotubes (Osman, 2019).
Based on hazard assessment as per the Hazard Evaluation Strategy (HES), there are four categories of NPs: Category I, with low cellular uptake and low intracellular persistence (PEGylated superparamagnetic iron oxide nanoparticles or SPIONs); Category II, with high cellular uptake and low
intracellular persistence (uncoated SPIONs); Category III, with low cellular uptake and high intracellular persistence (SPIONs coated with a layer of polyglucose sorbitol carboxymethylether); and
Category IV, with high cellular uptake and high intracellular persistence (in situ- coated lauric acid
ferrouid) (Siegrist etal., 2019).
20.5 INTERNATIONAL GUIDELINES ON THE SAFETY AND TOXICITY
ASSESSMENT OF HERBAL NANOMEDICINES
The domain of herbal nanomedicines is gradually expanding with more scope for development in
the near future. Quality control requirements for the establishment of monographs for herbal raw
materials, intermediates, and nished products and the subsequent validation of protocols and techniques can be found in different versions of guidelines from the European Medicines Agency, the
Pharmaceutical Inspection Co- operation Scheme, and in the WHO guidelines (EMA 2022; WHO
guidelines 2011). The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) issued guidelines for preclinical safety assessment, before conducting clinical trials for all medicinal products also including nano- formulations.
However, lacunae exist in the guidelines as they were initially developed for conventional formulations, bulk ingredients of macro- dimensions, and not for formulations of nano- dimensions. Data
obtained from such studies failed to represent the clinical situation in actual practice. In 2011, the
Food and Drug Administration (FDA) rst realized the need for developing guidelines for nanomedicines for regulatory control. The need was felt to make public aware about differences in properties between nanoparticles and the bulk chemical constituents of nanoparticles (Foulkes etal.,
2020). Later, in 2017, FDA proposed the consideration of nano- sized medicinal formulation on a
product- specic basis or a case- by- case basis, because of the unique features of each formulation,
which was attributed to nano- dimensions. The regulatory authority has advised manufacturers to
enter into consultation with the FDA in the development stage of nano- formulations, to avoid risk
of rejection on the grounds of being toxic or being unable to provide sufcient data and documents
in support of different phenotypes of nanotoxicity. Similarly, Medicines and Healthcare Products
Safety Proles and Potential Toxicological Concerns of Herbal Nanomedicine 429
Regulatory Agency (MHRA), the regulatory body for medicinal products in the UK also has no
single guideline, designed specically for nanomedicines, and proposes the manufacturers to consult with the MHRA Innovation Ofce. They also support case- by- case consideration of products
with respect to toxicity assessment. The EU and Canada adopt a similar approach; indeed, international regulatory authorities are constantly rening the guidelines with new inputs from highly
advanced techniques and novel strategies employed in nanotoxicological assessment to produce
reliable experimental data and to minimize inter- batch variation in quality and toxicity proles.
The HES is the rst- of- its- kind three- tier strategy, especially aimed at evaluating the toxicity of
injectable, engineered nanomedicines, based on exclusion criteria. The HES enables applicationoriented decision- making in an effective manner. HES is unique from several other toxicity control
approaches in that it has focussed on monitoring microbial contamination and contamination with
endotoxins in the case of nanotherapeutics. It has stressed that any attempt to minimize bioburden in
the nished product should not affect or alter NP characteristics, essential for their clinical applications (Siegrist etal., 2019). The European Nanomedicine Characterization Laboratory (EUNCL)
and the Regulatory Science Framework for Nano(bio)material- based Medical Products and Devices
(REFINE) are two projects funded by the Horizon 2020 Research and Innovation programme.
These projects are supported by the Decision Support System (Liu etal., 2022; Foulkes etal., 2020;
Halamoda- Kenzaoui etal., 2019b). In one development, ISO/TC 229 (ISO/TC 229 N 673) developed proposals specically for nanoparticles (Halamoda- Kenzaoui et al., 2019a). As mentioned
previously, nano- formulations differ from conventional formulations with respect to excipients.
International regulatory bodies should adopt consensus on the contribution of the excipient to the
production of nanoparticles as a whole and the regulatory aspects that should be devised to t the
purpose and objective (Hemmrich & McNeil, 2023). During the assessment of nanotoxicity, little
attention is paid to studying the eco- toxicological effects of the burgeoning development, use and
the disposal of nanoparticles (Halamoda- Kenzaoui etal., 2019b). Moreover, the heterogeneity of
nano- formulations, along with opportunities for administration by various routes for the amelioration of symptoms of different tissues, organs, and systems, create challenges in developing universal
guidelines for safety and toxicological assessment for all nanomedicines under a single umbrella
(Ramanathan, 2019). It has become obvious to show that the benets of nano- drug delivery systems
outweigh the risks. However, EMA has mandated the submission of data regarding environmental
risk assessment (ERA) of drug products for human use, as an essential component of marketing
authorization. Conventional methods for the estimation of the partition coefcient of materials in
the octanol- water system will provide inaccurate data with nanomaterials as the method is based
on the principle of equilibration. In the case of nanomaterials, interactions at the nanoparticle–cell
membrane interface are highly dynamic manifesting non- equilibrium behavior. The Organization
for Economic Co- operation and Development (OECD) test guidelines from 2006 are being revised
to incorporate suitable guidelines for nanomaterials so that reliable data can be obtained to ensure
safety and efcacy (OECD, 2017). For this, 91 reports on the safety of manufactured nanomaterials
have been submitted up to 2019, revealing the increased awareness and scope of nanotoxicological aspects. In 2019, the OECD drafted two guidelines on the physical- chemical decision framework for informed decisions and principles for measurements and the reporting of physicochemical
parameters for risk assessment of manufactured nanomaterials to assure relevance and reliability
(Pikula etal., 2020). Under the aegis of the Government of India’s Nano Mission, a Nanoregulatory
Task Force has been constituted, which has guided the Center for Knowledge Management of
Nanoscience and Technology to address the issues of occupational hazards associated with inadvertent exposure during the manufacture and quality control of nanomaterials in general, among
the industry personnel. Extensive research has been undertaken to collect pieces of evidence of signicant adverse effects of nanomaterials on human health. The draft guidelines aim to recommend
strategies for the safe production, handling, use, and disposal of nanomaterials and implement them
appropriately for societal benets in a wider context (DST Guidelines, n.d.). In India, an important
guideline for the evaluation of nanopharmaceuticals has been brought out by collaborative efforts
430 Herbal Pharmacopeia
from the Department of Biotechnology, the Ministry of Science and Technology, the Indian Council
of Medical Research and Central Drugs Standard Control Organization, the Ministry of Health and
Family Welfare (Gupta etal., 2019). Standardized genotoxicity assessment protocols have not yet
been developed (Tirumala et al., 2021). The issuance of formal regulatory guidelines regarding
safety and toxicity proling of nanomedicines is essential to prevent disinvestment in this highly
impactful technology (Mahapatra etal., 2018).
As discussed previously, personnel involved in manufacturing of nano- formulations may be inadvertently exposed to the same which may prove to be hazardous. Several authorities and organizations, such as the National Institute for Occupational Safety and Health (NIOSH), the Industrial
Technology Development Organization (NEDO), and the American Conference of Governmental
Industrial Hygienists (AGGIH), have recommended occupational exposure limits to nanomaterials
(Tirumala etal., 2021; Osman, 2019).
The preceding discussion reveals that considerable efforts have been made internationally to
formulate guidelines related to nanomaterials, and nanomedicines in general, but that very few have
been formulated with herbal nanomedicines in mind. It is to be noted that as yet no uniform internationally and universally accepted and harmonized guideline exists for nanomedicines. The unifying
concept of most of the guidelines is, however, to adopt a case- by- case approach for nanomedicines,
taking into consideration the signicant impact of nanomaterials on human health, industry personnel, non- target organisms in the surrounding environment, and, nally, on the abiotic components of
the ecosystem. Moreover, none of these guidelines should be implemented for natural and biological
nanomaterials or with conventional drug delivery systems with the insignicant and incidental presence of nanomaterials.
These guidelines will serve as useful documents for researchers, manufacturers, and stakeholders
to engage in innovative and novel products, pave the way for the optimization of current research in
the domain of development of nanopharmaceuticals in compliance with regulatory requirements,
the translation of nano- formulations from bench to bedside with minimum risk of toxicity to man
and environment and will promote ground- breaking advances for signicant societal and economic
impact.
One important aspect that needs to be strictly monitored by the regulatory bodies is the possible
availability of nano- size pharmaceutical nished products as future over- the- counter (OTC) products. Herbal products are available as OTC products in the unregulated market of several of the
world’s developing nations. Yet the same marketing strategy may prove to be harmful to end- users.
Nano- formulations are designed to provide controlled release over prolonged duration and if they
cannot be validated to be safe for prolonged use, they may precipitate serious toxic consequences.
Therefore, regulatory authorities should devise an appropriate framework to prevent the entry of
nano- formulations as OTC products into the market (Foulkes etal., 2020) Further consideration of
the durability of the complex formed between nanocarrier and the encapsulated payload in the environment is necessary as the drug, once released, may have undesirable effects on uptake by soil
bacteria or other animals. The OECD is revising guidelines for the assessment of the hazard potential of NPs in the aquatic environment (Mahapatra etal., 2018). One area where work needs to be
done is the framing of guidelines for the estimation of immunotoxic effects, especially for nanoformulations over and above ICH S8 guidelines (Halamoda- Kenzaoui etal., 2019b).
Recently, EU has adopted a “Green Deal”, in which the ultimate objective is to adopt safe and
sustainable practices in the design of nanomaterials with the ultimate goal of protecting the environment for future generations, giving birth to the concept of “Safe- and- sustainable- by- design” (SSbD),
which is identical to the concept of Quality- by- Design adopted for the manufacture of any medicinal
product and an improvement over earlier Safe- by- Design (SbD) frameworks. The GoNanoBioMat
SbD approach is the SbD concept, applicable for polymeric nanomaterials for pharmaceutical applications, ensuring the use of safe materials, products, production techniques, safe use (especially
with respect to suspensions, sunscreens, cosmetics, etc.), and the disposal of leftover products after
use. Implementation of this production strategy from the onset ensures the affordability and
Safety Proles and Potential Toxicological Concerns of Herbal Nanomedicine 431
availability of the product with minimal risk to humans, personnel in the manufacturing industry,
non- target organisms, environment, in all stages of the lifecycle of the product and not only the nal
product (Bhat etal., 2023; Furxhi etal., 2023; Soeteman- Hernandez etal., 2019). ICH and OECD
should incorporate the principles of SSbD in their revised guidelines for the complete nanotoxicological proling of nanomedicines (Schmutz etal., 2020).
20.6 CRITICAL CHALLENGES IN THE DEVELOPMENT OF HERBAL
NANOMEDICINES
No gold standard exists for the calculation and estimation of the dose, time, and duration of treatment
with herbal nanomedicines. There is a lack of literature and scientic reports on the dosimetry of
nanomedicines in general. Dosimetry should be clearly understood as biological response and toxic
effects are directly related to dose. A consensus should be adopted in dening and using various
terminologies associated with nanomedicine dosimetry. For conventional drug delivery platforms,
the dose is usually expressed as amount or as concentration. However, with nano- formulations, this
system may prove to be inefcient and incorrect. Since previous sections have repeatedly focussed
on the role of size and specic surface area of nanoparticles with regard to safety and efcacy, the
dose calculation should preferably be based on mass, surface area, or number of particles to avoid
inconsistency in dose and interpretation of outcomes and effects (Hussain etal., 2015).
20.7 CONCLUSION
Continuous involvement and endeavors of the scientic fraternity in the area of nanotechnology
have facilitated rapid and tremendous progress in enriching the knowledge base, resulted in innovative approaches in delivering herbal medicines, extracts, and phytoconstituents, enabled great strides
in the development of characterization techniques, and have driven the regulatory authorities to formulate effective guidelines in controlling and monitoring the safety and toxicity of nanopharmaceuticals. The collaborative efforts and expertise of academia, industry, government agencies, and other
stakeholders have contributed signicantly to these advancements. Although, several in vitro, in
vivo, and highly sophisticated instrumental techniques, in silico and computational predictive tools,
and nano- informatics databases are available , no single assay or technique can provide a comprehensive quality- efcacy- safety prole of herbal nanomedicines and can establish a causal relationship between physicochemical attributes and pharmacokinetic behavior of nanoparticles. Intrinsic
and extrinsic toxicity characteristics of herbal medicines, and existence of the “nano- paradox” are
the barriers to translating the effective products from laboratory to the bedside of the patient. In an
effort to overcome these formidable hurdles in the successful commercialization of nanomedicines,
the regulatory authorities should work round the clock to bridge the gap between existing guidelines and future needs and formulate and implement guidelines, specically for herbal nanomedicines, taking care not to overburden the manufacturers and investors with statutory prejudices and
provision. Special attention should be paid to standardizing dosimetry protocols to avoid over- or
under- estimating toxicity and efcacy. The dissemination of reports in the public domain should
be ensured. The ultimate goal of the pharmaceutical industry remains amelioration of pathological
conditions to enable mankind to lead a quality life, with minimal impact on Mother Nature. Safe
and sustainable practices should be adopted proactively from concept initiation through all stages
of the product lifecycle.
ACKNOWLEDGEMENT
The authors express their gratitude to NSHM Knowledge Campus, Kolkata – Group of Institutions,
Kolkata for offering the necessary facilities to conduct the data search for this chapter.
432 Herbal Pharmacopeia
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