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Nanobiotechnology: Therapeutic Approaches and Legal Regulation

The prefix nano derives from the Greek word for dwarf. One nanometer (nm) is equal to one-billionth of a meter, or about the width of 6 carbon atoms or 10 water molecules.
A human hair is approximately 7000-nm wide. Atoms are smaller than 1 nm, whereas many molecules including some proteins range between 1 nm and larger[1]. Most accounts of the history and origins of nanotechnology begin with Richard Feynman's historic 1959 lecture at the California Institute of Technology titled There is Plenty of Room at the Bottom, in which he outlined the idea of building objects from the bottom up.

This brilliant suggestion did not gain much traction until the mid-1980s, when Eric Drexler published Engines of Creation in 1986, a popular treatment of the promises and potentials of nanotechnology. Drexler envisioned a molecular nanotechnology discipline that would allow manufactures to fabricate products from the bottom up with precise molecular control[2].

The National Nanotechnology Initiative (NNI) defines nanotechnology as research and development at the atomic, molecular, or macromolecular levels in the sub-100 nm range to create structures, devices, and systems that have novel functional properties.

At this scale, scientists can manipulate atoms to create stronger, lighter, and more efficient materials with
tailored properties. Given the inherent nanoscale functions for the biological components of living cells, it was inevitable that nanotechnology would be applied to the life sciences. Such applications give rise to the term nanobiotechnology.[3]

Nanobiotechnology is a recently coined term describing the convergence of the two existing, however distant, worlds between engineering and molecular biology. Engineers have been working for the past three decades on shrinking the dimensions of fabricated structures to enable faster and higher density electronic chips, which have reached feature sizes as small as 20 nm.

In parallel, molecular biologists have been operating for many years in the domain of molecular and cellular dimensions ranging from nanometers to micrometers. It is believed that a combination of these disciplines will result in a new class of multifunctional devices and systems for biological and chemical analysis characterized by better sensitivity and specificity and higher rates of recognition compared with current solutions[4].

Analyses of signaling pathways by nanobiotechnology techniques might provide new insight into disease processes, thus identifying more efficient biomarkers and understanding the mechanisms of action of drugs. Advances in the manipulation of the nanomaterials permit the binding of different biomolecules, such as bacteria, toxins, proteins, and nucleic acids[5]. Nanotechnology is relatively new and although the full scope of contributions to these technological advances in the field of human health care remains unexplored, recent advances suggest that nanobiotechnology will have a profound impact on disease prevention, diagnosis, and treatment.

Statement Of Problem
Nanotechnology is a very vast field which includes a range of technologies at the nano scale, such as pharmaceuticals, biotechnology, genomics, neuroscience, robotics and information technologies. Nanotechnology is the latest technological innovation in global debates on risk regulation and international cooperation. Regulatory bodies have started dealing with the potential risks posed by nanoparticles. Currently, specific provisions on nanomaterials have been introduced for biocides, cosmetics, food additives, food labelling and materials in contact with foodstuff. The statement that nanotechnologies do inevitably imply ethical questions. The main problems are public trust, potential risks, and issues of environmental impact, transparency of information, responsible nanosciences and nanotechnologies research. The aim of this article is to analysis the main problems regulating nanobiotechnology.

Review Of Literature
The strictly established time span for the beginning of nanotechnology development is explained by the fact that nanotechnology has its backgrounds in the distant past when people used it without knowledge of it (Tolochko). The difference between these ancient examples of nanotechnology and the current situation is the ability to understand or at least embark on a path towards understanding—the .fundamental principles underlying nanotechnological behavior, the ability to assess the current state of knowledge, and the ability to systematically plan for the future based on that knowledge (USEPA, 2007).

The word nanotechnology was introduced for the first time by Norio Taniguchi at the International Conference on Industrial Production in Tokyo in 1974 in order to describe the super thin processing of materials with nanometer accuracy and the creation of nano-sized mechanisms. Ideas of nanotechnological strategy, which were put forward by Richard Feynman (known as Father of Nanotechnology) in his lecture delivered in 1959 at the session of the American Physical Society, were developed by Eric Drexler in 1986.

Nanotechnology and nanoscience got a boost in the early 1980s with two major developments: the birth of cluster science and the invention of the Scanning Tunneling Microscope (STM) in 1981. These developments led to the discovery of Fullerenes in 1985 and the structural assignment of Carbon Nanotubes in 1991.

A confluence of nanotechnology and biology can address several biomedical problems, and can revolutionize the field of health and medicine (Curtis and Wilkinson, 2001). Nanotechnology is currently employed as a tool to explore the darkest avenues of medical sciences in several ways like imaging (Waren and Nie, 1998) sensing (Vaseashta and Malinovska, 2005), targeted drug delivery (Langer, 2001) and gene delivery systems (Roy et al., 1999) and artificial implants (Sachlos et al., 2006).

Hence, nanosized organic and inorganic particles are finding increasing attention in medical applications (Xu et al., 2006) due to their amenability to biological functionalization. Based on enhanced effectiveness, the new age drugs are nanoparticles of polymers, metals or ceramics, which can combat conditions like cancer (Farokhzad et al., 2006) and fight human pathogens like bacteria (Stoimenov et al., 2002; Sondi and Sondi, 2004; Panacek et al., 2006; Morones et al., 2005; Baker et al., 2005).

Many nanoparticles like silver are useful as therapeutics due to their antimicrobial properties. Polyisohexylcyanoacrylate nanoparticles, poly(lactic-co-glycolic acid) (PLGA) nanoparticles, Gold nanoparticles, Chitosan nanoparticles, Cetyl alcohol/polysorbate nanoparticles, Lipid nanocapsules, P (4-vinylpyridine) particles, Chitosan-alginate nanoparticles, Poly (3-hydroxybutyrate-co-3 hydroxyoctanoate) nanoparticles are some of the nanoparticles that can be effectively used for therapeutics (Barraud et al., 2005; Cheng et al., 2010; Chithrani et al., 2010; Hee-Dong et al., 2010; Koziara et al., 2004; Lamprecht et al., 2006; Ozay et al., 2010; Parveen et al., 2010; Zhang et al., 2010). Nanoparticles has also been modified for early detection of Alzheimer's disease biomarkers in biological fluids as well as delivery of bioactive molecules directly to brain.Although nanotechnology is expected to have a huge impact on the development of smart drug delivery and devices against Alzheimer's disease, a crucial gap still to be filled concerns the elucidation of its etiology, for which a great deal of effort is required (Brambilla et al., 2011).

Research Objectives
  1. To understand nanotherapeutics with regard to its safety and efficacy.
  2. To align nanobiotechnology with public health under the current legal system.

Research Question
  1. Can the safety and efficacy of complex follow-on nanotherapeutics ever be assured?
  2. Can nanomedicine, as applied to public health, be solely regulated under existing regulations and laws?

Research Methodology
The researcher mainly conducted a doctrinal research due to paucity of time and resources.

Role Of Nanobiotechnology In Biological Therapies
Biological therapies mean the application of molecular biology in therapeutics. Broadly speaking, biological therapies include vaccines, cell therapy, gene therapy, antisense therapy and RNA interference. Some of these involve use of nucleic acids and proteins, whereas others involve genetic manipulation. Biological therapies, particularly their delivery, can be refined by use of nanobiotechnology. Uses of nanobiotechnology-based biological therapies are briefly described under various therapeutic areas.
  1. Nanomedicine
    Nanobiotechnology has applications in practically every branch of medicine and surgery. Some important therapeutic areas will be described briefly here and detailed descriptions are given in the Handbook of Nanomedicine[6] . Although nanomaterials have been available for a number of years and several structures in molecular biology were measured on nanoscale, further research on the systematic application of this knowledge to life sciences and particularly in healthcare is being vigorously pursued in recent years. This parallels advances in other biotechnologies. Historically new technologies are slowly absorbed into mainstream medical practice. Decision to use a new technology depends on the clinical judgment of the physicians taking care of their patients. Many of the new technologies are applied in challenging areas, where either no satisfactory treatments are available or nanobiotechnology-based methods have been shown to be more effective than the conventional approaches. Cancer is one area where rapid advances have been made in the application of nanobiotechnology.

    1. Nanooncology
      Application of nanotechnology in cancer can be termed nanooncology. This includes both diagnostics and therapeutics. Two nanotechnology-based products are already approved for the treatment of cancer – Doxil (a liposome preparation of doxorubicin) and Abraxane (paclitaxel in nanoparticle formulation). Nanoparticles can deliver chemotherapy drugs directly to tumor cells and then give off a signal after the cells are destroyed.

      Efficient conversion of strongly absorbed light by plasmonic gold nanoparticles to heat energy and their easy bioconjugation suggest their use as selective photothermal agents in molecular cancer cell targeting[7]. Two oral squamous carcinoma cell lines and one benign epithelial cell line were incubated with antiepithelial growth factor receptor (EGFR) antibody conjugated gold nanoparticles and then exposed to continuous visible argon ion laser at 514 nm.

      Malignant cells required less than half the laser energy to be killed than the benign cells after incubation with anti-EGFR antibody conjugated Au nanoparticles. In the absence of nanoparticles, no photothermal destruction was observed for all types of cells at four times the energy required to kill the malignant cells bonded with anti-EGFR/Au conjugates. Au nanoparticles thus offer a novel class of selective photothermal agents using a CW laser at low powers.

      The ability of gold nanoparticles to detect cancer was demonstrated previously. Now it will be possible to design an all-in-one active agent that can be used to find cancer noninvasively and then destroy it. This selective technique has a potential in molecularly targeted photothermal therapy in vivo.
       
    2. Nanoneurology
      Nanobiotechnology will have an impact on improving our understanding of the nervous system and developing new treatments, both medical and surgical, for disorders of the nervous system[8] . Working with platinum nanowires and using blood vessels as conduits to guide the wires, researchers have successfully detected the activity of individual neurons lying adjacent to the blood vessels[9]. Use of nonintrusive, biocompatible and biodegradable nanoprobes improves our understanding of the brain at the neuron-to-neuron interaction level.

      Delivery of drugs to the central nervous system is a challenge and various strategies based on nanobiotechnology are discussed elsewhere[10]. Most of these are directed at overcoming the blood-brain barrier, which is a major hurdle in drug delivery to the brain.

      Nanobiotechnology can facilitate neuroprotection. Water-soluble derivatives of buckminsterfullerene C60 derivatives are a unique class of nanoparticle compounds with potent antioxidant properties. Robust neuroprotection against excitotoxic, apoptotic and metabolic insults in cortical cell cultures has been demonstrated by use of carboxyfullerenes. Ongoing studies in animal models of neurodegenerative disorders suggest that these novel antioxidants are potential neuroprotective agents.

      One of the major challenges of treating neurological disorders, particularly central nervous system damage resulting from trauma, is repair and regeneration. At nanoscale, there is little difference between basic building blocks of neuronal structures whether they are created artificially or occur in nature. Nanoelectronics, by improving cell-to-cell communication, may enable the creation of a bridge between severed nerves and muscles up to a meter away. This opens up the possibilities of repairing severed spinal cords and rehabilitation of stroke victims.
       
    3. Nanocardiology
      Perfluorocarbon nanoparticles provide an opportunity for combining molecular imaging and local drug delivery in cardiovascular disorders. The utility of targeted perfluorocarbon nanoparticles has been demonstrated for a variety of applications in animal models including and antiangiogenic treatment of atherosclerotic plaque and the localization and delivery of antirestenotic therapy following angioplasty[11].

      Nanoscale particles can be synthetically designed to potentially intervene in lipoprotein matrix retention and lipoprotein uptake in cells – processes central to atherosclerosis. Nanoengineered molecules called nanolipoblockers can be used to attack atherosclerotic plaques due to raised levels of lowdensity lipoproteins[12].

      An experimental study in rats using injectable self-assembling peptide nanofiber bound to platelet-derived growth factor demonstrated sustained delivery to the myocardium resulting in decreased cardiomyocyte death and preserved systolic function after myocardial infarction[13]. In studies on rats, cell therapy with insulin-like growth factor 1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction[14]. This nanobiotechnology approach has the potential to improve the results of cell therapy for myocardial infarction, which is on clinical trials currently.

      Nanobiotechnology may facilitate repair and replacement of blood vessels, myocardium and myocardial valves. It may also be used to stimulate regenerative processes such as therapeutic angiogenesis for ischemic heart disease.
       
    4. Nanoorthopedics
      A new method of repairing bones using nanotechnology is based on bone scaffold material (nano-HA/collagen/PLA composite) produced by biomimetic synthesis. The scaffolds or 'nanobones' have been successfully implanted in patients in China for repair of bone defects after fractures or tumor removal and also for spinal fusion. Bone cells can grow and proliferate on a scaffold of carbon nanotubes, because they are not biodegradable,and behave like an inert matrix on which cells can proliferate and deposit new living material, which becomes functional, normal bone[15].

      Several methods are being developed to encourage the regeneration of cartilage defects, particularly after knee injuries. Nanotechnology and cell therapy are being used as refinements of procedures to replace the torn knee cartilage. The fine structure of an electrospun poly (l-lactide)- scaffold makes it an ideal material for tissue engineering, in particular for cartilage repair. Implanted cells showed a clear preference for growth along the nanofibers, which are both biocompatible and biodegradable[16].

      Nanotechnology-based scaffolds are capable of promoting the growth of mesenchymal stem cells, and differentiate these cells into viable structural and functional tissue for replacement of the medial meniscus of the knee.
       
    5. Role of Nanobiotechnology in the Treatment of Infections
      Nanobiotechnology is used not only for the diagnosis of infections but as a basis of microbicidal agents as well. Certain formulations of nanoscale powders possess antimicrobial properties. These formulations are made of simple, nontoxic metal oxides such as magnesium oxide (MgO) and calcium oxide (CaO, lime) in nanocrystalline form, carrying active forms of halogens, e.g. MgO _ Cl 2 and MgO _ Br 2 .

      When these ultrafine powders contact vegetative cells of Escherichia coli , Bacillus cereus , or Bacillus globigii , over 90% are killed within a few minutes. A simple molecule synthesized from a hydrocarbon and an ammonium compound can produce a unique nanotube structure with antimicrobial capability[17]. The quaternary ammonium compound is known for its ability to disrupt cell membranes and causes cell death whereas the hydrocarbon diacetylene can change colors when appropriately formulated; the resulting molecule would have the desired properties of both a biosensor and a biocide.

      Silver nanoparticles have been incorporated in preparations for wound care to prevent infection. Acticoat bandages (Smith & Nephew) contain nanocrystal silver, which is highly toxic to pathogens in wounds. Nanoviricides, which are nanomedicines that destroy viruses, are in development. A nanoviricide is an agent that recognizes a specific virus particle, binds to it at multiple points, neutralizes and then dismantles it. Targets for this approach include influenzas, HIV, hepatitis C and rabies.
       
    6. Nanoophthalmology
      Approximately 90% of all ophthalmic drug formulations are applied as eye drops. While eye drops are convenient, about 95% of the drug contained in the drops is lost through tear drainage, a mechanism for protecting the eye against exposure to noxious substances. Moreover, the very tight epithelium of the cornea compromises the permeation of drug molecules. Nanocarriers, such as nanoparticles, liposomes and dendrimers, are used to enhance ocular drug delivery[18].

      Easily administered as eye drops, these systems provide a prolonged residence time at the ocular surface after instillation, thus avoiding the clearance mechanisms of the eye. In combination with a controlled drug delivery, it should be possible to develop ocular formulations that provide therapeutic concentrations for a long period of time at the site of action, thereby reducing the dose administered as well as the instillation frequency. In intraocular drug delivery, the same systems can be used to protect and release the drug in a controlled way, reducing the number of injections required. Another potential advantage is the targeting of the drug to the site of action, leading to a decrease in the dose required and a decrease in side effects.

      Nanoparticles have also been investigated to provide controlled drug release, protect the drug against enzymatic degradation and to direct the drug to the site of action in the eye. Subconjunctivally administered 200-nm and larger polylactide nanoparticles can be almost completely retained at the site of injection. Poly(lactic acidglycolic acid nanospheres encapsulating pigment epithelium- derived factor have been shown to have neuroprotective effects in experimentally induced retinal ischemic injury[19].

The Rationale Behind The Use Of Nanomedicines
Nanoparticles have tremendous potential to increase the bioavailability of the drug by improving its pharmacokinetic and pharmacodynamic profile[20]. Their high surface-to-volume ratio attracts the researchers to do several surface modifications like PEGylation, ligand binding, etc. for better drug targeting. Nanoparticles can be administered parentally conveying better drug circulation, drug protection, and a sustained release[21].

These can also be applied topically, but there may be a chance for dose dumping which can lead to drug toxicity. Active drug targeting, can be achieved by employing ligands such as peptides, antibodies, etc., to the surface of the nanoparticles which upon systemic circulation reach the active site where the ligand will bind to the receptor and engulf the nanoparticle loaded with the drug through endocytosis.[22]

Safety Issues Of Nanomedicine
The first generation of nanomedicines were approved more than a decade ago before a real awareness existed about a number of issues related to safety concerns of nanomaterials. These products have been used for the treatment of cancer without any toxicity of nanoparticles. However, nanomaterials such as phospholipids or biodegradable polymers, are of a completely different nature from other anticipated materials that will be produced in the near future from the research pipeline.

Although in vitro use of nanoparticles in diagnostics does not pose any risk, concern has been expressed about the introduction of nanoparticles into the human body for therapeutic purposes and possible toxic effects. The small size of particles, particularly those below 50 nm, makes them versatile therapeutic tools for drug delivery and treatment of cancer but they may have undesirable effects. This topic is discussed in more detail elsewhere with review of studies on the toxic potential of nanoparticles [23].

The biological effects of various nanoparticles vary according to size, chemical composition, surface structure, solubility, shape, and aggregation. QDs may release potentiallytoxic cadmium and zinc ions into cells. However, because of their protective coating, QDs have minimal impact on cells. Studies using 2-nm core gold nanoparticles have shown that cationic particles are moderately toxic, whereas anionic particles are quite nontoxic[24].

A study has shown that naturally occurring gum arabic can be used as a nontoxic phytochemical excipient in the production of readily administrable biocompatible gold nanoparticles for diagnostic and therapeutic applications in nanomedicine[25]. Because several nanoparticle formulations are designed for systemic administration, the compatibility of these with blood and blood cells can be tested with a particular focus on hemolytic activity, platelet function, and blood coagulation[26]. This is no different from the requirements for testing of nonnanoparticulate formulations for systemic administration.

Nanomaterials are likely to receive closer attention from regulatory bodies for toxicological potential in a number of different applications. It has been suggested that existing nanopharmaceuticals, when administered for the same or new therapeutic indications making use of different administration routes (e.g. pulmonary), should not receive waiver of a full assessment of their potential toxicology[27].

Impact of Nanomedicine on Public Health
Nanomedicine significantly affects various aspects of public health like promotes general health, improves quality of life, increases lifespan, prevents and treats disease conditions and can cure life-threatening disorders. It can also imply for community-based or social health issues including vaccination, infection control, civic sanitization, environmental infection control, early detection and prevention of infectious disease[28].

The association of school of public health categorized public health into five different core areas including:
  1. epidemiology,
  2. biostatistics,
  3. health policy management,
  4. community and social behavior and lastly
  5. environmental health science.
Epidemiology is concerned with the elements and social distribution of disease while biostatistics deals with the quantitative analysis of factors, frequency, and distribution of disease in society. Subsequently, health policy management prepares guidelines and laws on the basis of a community survey to maintain the health of society and improve community health. Environmental health is based on the effect of the social and physical atmosphere on public health and vice versa.

Technological advancements in the medical field always significantly affect public health. The development and implementation of vaccines is the most popular example of advanced medication, which is continuously modified according to the need, and response of the society[29].

Similarly, now nanomedicines represent an emerging technology, which has the potential to treat untreated chronic disorders like neurodegenerative disorders, cancer, and cardiovascular diseases as well as improve the potency of various drugs. Due to the benefits over conventional therapies such as effective targeting, high performance, prolonged action, and reduced side effects, FDA approved various nanomedicines for the treatment of cancer. Numerous research efforts utilize nanotechnology to improve community health[30].

Existing And Emerging Regulation For Nanomedicine In India
As discussed earlier, nanomedicine is an application of nanotechnology in the field of healthcare and, therefore, inevitably shares overlapping issues with nanotechnology.
Thus, a regulatory framework for nanotechnology in many instances can provide useful insights to address governance challenges presented by nanomedicine.

Notably,
nanomedicine is delineable from the other fields of nanotechnology on the basis of intentional human exposure, as it is meant for diagnosis, prevention and treatment of diseases. Keeping this in view, the authors in the present section have critically assessed the initiatives and studies on regulation of nanotechnology and nanomedicine that may influence the governance of nanomedicine in India.

Currently, India does not have any nanospecific regulation in place[31]. Lately, initiatives for regulation of nanotechnology in India have been taken up. The Department
of Science and Technology (DST), Government of India, created a working group for regulation of nanotechnology[32]. Nanomission, a program of DST, announced establishment of a National Regulatory Authority Framework Roadmap for Nanotechnology[33].

Nanomission has also framed draft guidelines and best practices for safe handling of nanomaterials[34]. The Council for Scientific and Industrial Research (CSIR) initiated a project Nano- SHE that is Nanomaterials: Application and Impact on Safety, Health and Environment for toxicological evaluation of nano structured materials[35].

The Department of Pharmaceuticals (DOP), Government of India, in the year 2006 had assigned the task of framing regulations for nanomedicine to the National Institute of Pharmaceutical Education and Research (NIPER) Mohali, which was later given to NIPER Kolkata in the year 2012. A national center for pharmaceutical nanotechnology has been proposed by DOP to be instituted at NIPER Kolkata that will be responsible for nanotoxicology assessment and regulation of nanodrugs and devices[36].

Notably, nanotechnology poses complex challenges that also need immediate attention due to potential commercialization of products. Most researchers have emphasized the need for a regulatory body responsible for governing development and commercialization of nanotechnology products[37].

The studies discussed above emphasize the need for risk assessment and generation of data but fail to provide solutions for effective enforcement to enhance growth of nanomedicine in India. The regulatory framework that may be suitable for India is debatable[38]. As nanomedicine is evolving and it is too early to comment on the possible amendments, we propose a regulatory framework to govern nanomedicine from different angles.

The authors propose establishment of a separate national regulatory authority independent of any funding agency that can have separate divisions for each thematic area. Further, for state-level implementation, state regulatory authorities can coordinate and report to the national regulatory authority. The authors elucidate a multi-tier regulatory framework considering India as a case study. The next section discusses the governance framework proposed for regulation of nanomedicine in India and its components. The presented framework intends to promote an efficient ecosystem for nanomedicine innovation and policy development.

Multi-level governance framework for India
A multi-level national governance system to regulate nanomedicine at the level of research, premarket and post market that involves regulatory space, policy regime, site of governance and lifecycle can be proposed. The framework will aim to (i) promote responsible research and innovation, (ii) enhance public and social acceptability of the products as well as research and (iii) ensure safety of human beings and environment.

Nanotoxicology
Because of their small size, a large proportion of the atoms that make up a nanoparticle are exposed to the exterior of the particle and would be free to participate in many chemical process[39]. Although the benefits of nanotechnology are widely publicized, discussion of the potential effects of their widespread use in consumer and industrial products is just beginning[40].

Concerns over safety issues are heightened by the fact that the nanotechnology workforce is growing rapidly, projected to reach 2 million workers by 2015. Both pioneers of nanotechnology and its opponents are finding it extremely hard to argue their case because of the limited information available to support one side or the other. Although some concerns may be ill-founded, it remains true that the toxicology of many nanomaterials has notcyet been fully evaluated.

Because of the huge diversity of materials used and the wide range in sizes of nanoparticles, these effects will vary a lot. It is conceivable that particular sizes of some materials might turn out to have toxic effects and further investigations will be needed[41].

Future Perspectives On Nanomedicine Translation And Commercialization And Recommendations
The application of nanomedicines in healthcare is changing current diagnosis and therapy concepts. Despite their therapeutic significance, only a few products have reached the market. A comprehensive preclinical assessment of nanomedicines includes physicochemical characterization, efficacy, pharmacology, and toxicology evaluations.

In summary:
  1. the challenges in physicochemical characterization include the unavailability of appropriate and sensitive methods;
  2. the challenges in determining the efficacy include selection of the appropriate models, drug encapsulation and release, stability, and evaluation of biological activity;
  3. the challenges in pharmacology and toxicology evaluations are related to the drug bio distribution, availability of relevant animal models, determining the mechanisms of toxicity and the in-vitro–in-vivo correlation between toxicity assays
Other technical challenges include sterilization and endotoxin removal of nanomedicines. Thus, a better understanding of crucial physicochemical characteristics, in vivo behaviour as well as the in-vitro–in-vivo characterization cascade of safety and efficacy testing is needed to accelerate nanomedicine translation[42].

The development of nanomedicines requires that the product quality must satisfy manufacturing, industry, the patient or customer and the regulatory demands. In this regard, the implementation of a robust quality control system is the key to ensuring successful manufacturing and quality of nanomedicines[43]. Identification of the product critical quality attributes [CQAs] helps in determining whether a batch meets or fails the standard requirements.

Thus, identifying the essential process conditions is crucial to attain key attributes of a product. Incorporating a quality-by-design (QbD) approach in product development can contribute to gaining thorough product and process knowledge and enabling cost-effective manufacturing. The QbD concept is strongly recommended by regulatory agencies to ensure a high-quality product.

In the QbD approach, the formulation and process are designed to consistently deliver a product that meets the CQAs necessary for clinical performance. This necessitates the understanding of the influence of raw materials and process parameters on the product quality. In pharmaceutical manufacturing, QbD identifies CQAs and investigates the effects of factors based on scientific design and risk assessment.

In addition, QbD helps construct a comprehensive understanding of relations between manufacturing conditions and final product characteristics to facilitate the scale-up of the nano manufacturing process. Although promising, more systemic studies employing the QbD concept need to be conducted. Training programs are needed for the scientists for a better understanding of the QbD terminologies such as design space, CQAs, among others, and application software.

Nanomedicine manufacturing and its characteristics are difficult to predict or measure because the formulation processes are sensitive to raw material attributes and any subtle changes in the processing conditions. Hence, the development of process analytical technology (PAT) is encouraging to monitor the product quality[44].

The FDA has encouraged the use of PAT to obtain process data in real-time and build quality assurance into the manufacturing process. PAT techniques can provide valuable insight and understanding for process scaleup/optimization and help accommodate the inherent process variability and improve control. PAT provides information of CQAs with the goal of improving the final product quality as well as reducing the manufacturing cost[45].

In summary, the strategies that could significantly enhance the therapeutic efficacy of nanomedicine products can include:
  • Defining key physicochemical parameters influencing the drug efficacy and safety.
  • Understanding robust characterization methods.
  • Application of QbD, PAT and microfluidics approaches in the manufacturing, scale up and evaluation.
  • Development of adequate in vitro, ex vivo and in vivo models.
  • Understanding product interactions with the biological environment.
  • Development of validated stability, safety and efficacy assays.
  • Development of specific regulatory guidelines for manufacturing and characterization
  • Focus on selecting the right patients and patient preselection criteria to develop strategies on patient-focused product design
  • Identifying a suitable biomarker profile that is predictive of therapeutic outcomes.
  • Employing clinically applicable imaging techniques that can be correlated to the fate of the drug and delivery system in vivo.
  • Clinical trials focused on well-defined outcomes and under-standing disease and patient-specific pathophysiology
Overall, to bridge the gap of nanomedicine's lab research to industrial development, effective collaboration among academics, scientists, industry, regulatory agencies, consortia, investors, and clinicians is required to develop comprehensive approaches to ensure reproducibility and precise control for an effective, safe and cost-effective nanomedicine product.

Conclusion
Nanotechnology is a global business enterprise impacting universities, industry, and regulation agents. Nanobiotechnology is still at its early stages of expansion; however, the development is multi-directional and fast-paced. Nanobiotechnology will provide opportunities for developing new materials and methods that will enhance our ability to develop faster, more reliable and more sensitive analytical systems.

Although there are many exciting potential biological applications of nanomaterials, one needs to discern genuine scientific promises from hype and to constantly improve the fundamental understanding of the interactions of nanomaterials with intracellular structures, the process, and the environment.

End-Notes:
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