Abstract
Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and reduced adverse effects. Hence, nanomedicines can be used to achieve the same therapeutic effect at smaller doses than their conventional counterparts. Three types of nanomedicines are described: nanocarriers used in drug delivery, nanosuspensions used in the improvement of drug solubility, and nanoparticles used in bioimaging. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Furthermore, there are currently no regulatory guidelines developed specifically for nanomedicines due to limitations including inadequate knowledge regarding nanoparticle behavior, the absence of standardized nomenclature, test methods, and characterization of nanoparticles, as well as difficulty in determining primary jurisdiction for combination products. In addition, a shortage of trained personnel, a lack of a nanomedicine-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and the establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities.
LAY ABSTRACT: Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and better side effect profile. Hence, smaller doses of nanomedicines are needed to achieve the same therapeutic effect. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Standardized test methods and characterization of nanoparticles are lacking. In addition, a shortage of trained personnel, a lack of a nanomedicines-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities.
Introduction
Nanomedicines are an emerging group of drugs, medical devices, and health products which makes use of novel properties displayed by particles in the nanoscale to achieve breakthroughs in disease diagnosis and treatment (1). However, these novel properties of nanoparticles have also triggered debates on their actual clinical significance versus their potential harm—issues which have yet to be resolved due to inadequate data available (2). A clear and globally acceptable regulatory framework is required to ensure the safety and quality of nanomedicines and to facilitate their development and public acceptance in the future (3).
This paper is a scientific literature review that addresses the above-mentioned concerns. It comprises three sections. The first section aims to provide a better understanding of nanomedicines with respect to their unique advantages, types of nanomedicines, and their uses in the diagnosis and treatment of diseases. In particular, nanocarrier systems, nanosuspensions, and nanoparticles used for bioimaging will be highlighted. The second section will analyze the distinctive properties of nanoparticles, namely their size, shape, agglomeration/aggregation potential, and surface chemistry, and their possible effects on the safety and the quality of nanoformulations. The third and last section will examine the current regulatory framework and good manufacturing practice (GMP) requirements and their limitations in controlling nanomedicines. Challenges faced in the control of their manufacturing processes, product quality and safety, as well as ongoing efforts made by established regulatory authorities to resolve them will also be discussed. The adequacy of nanomedicine regulation will be discussed and improvements to the existing regulatory framework will be proposed.
An Overview of Nanomedicines
Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology (4,5) with the aim of diagnosing, monitoring, or treating (6) diseases at the molecular level (4,7). Nanomedicines employ particles and devices with dimensions that lie within the nanometer scale (about 100 nm or less) so that they are small enough to interact with biomolecules, such as enzymes and receptors, at the cellular level to detect and treat pathologic problems even before the expression of disease symptoms (8,9).
(a) Advantages of Nanoparticles/Nanomedicines
Due to their small size, nanomedicines offer three advantages over conventional medicines as described below:
(i) Effective Targeting of Difficult-To-Reach Sites:
Nanoparticles are small enough to sneak past the immune system (10,11) and enter certain sites in the human body that are less accessible to conventional medicines, which employ micron-sized drug particles (12). Thus, they are intensively researched to develop therapies that target specific diseases (8), 13–16) such as cancer tumors, which generally have a more permeable vasculature and an impaired lymphatic drainage (17,18). With a size of only 10–100 nm, nanoparticles can exploit these tumoric features to passively diffuse and accumulate within the tumor (18,19). They can also undergo surface modifications with antibodies and other ligands to achieve specific targeting with tumor cells or tumor-bearing organs (20). As a result, many nanomedicine techniques are directed towards cancer treatment due to their potential in delivering highly potent and toxic drugs to tumors, while minimizing non-specific damage and toxicity (19). The ability of nanoparticles to traverse the blood–brain barrier has also been utilized to develop therapies for diseases of the brain (18,21,22).
(ii) Improved Solubility, Bioavailability, and Reduced Side Effects:
Many potential drug candidates fail clinical tests due to their inherently poor solubility with consequences of low bioavailability (23), poor delivery to target sites (24), and unpredictable toxicity (23,25). These issues can be resolved by sizing the drug particles to the nano level (19,26,27) so that their interface with the surrounding liquid medium is drastically increased (19), with a resultant steep rise in dissolution rate and saturation solubility (16,17,20). The consequent improvement in solubility enhances the drug's bioavailability (16,17), side effect profile (3,18,21), and dose homogeneity (2,28) to achieve better therapeutic outcomes (29).
(iii) Achieving the Same Therapeutic Effect with Smaller Doses:
The chemical (30) and biological reactivity (31,32) of nanoparticles are greatly enhanced due to their decreased size (33) and increased specific surface area (34). As such, a smaller number of nanoparticles can achieve the same therapeutic effect as compared to microparticles of the same mass dose due to the former's greater interaction with biological components (35). A smaller overall dose could reduce the need for frequent administration of drugs and its associated inconvenience. The larger specific surface area and higher reactivity of nano-sized drugs also confer upon them the advantage of a faster onset of drug action (36).
(b) Types of Nanomedicines
Nanomedicines include biopharmaceuticals intended for drug delivery, implantable materials and devices for tissue repair and replacement, surgical tools for operation, and diagnostic tools for disease detection (29,37,38). This paper will highlight in detail three commonly used types of nanomedicines: nanocarrier systems, nanosuspensions, and nanoparticles used for bioimaging.
(i) Nanocarrier Systems:
Nanocarrier systems consist of a biodegradable (18) and biocompatible casing that encapsulates or conjugates therapeutic (19,20,29,39) and diagnostic agents (7,40) to protect them against degradation in the body (5,41,42). Often, functionalized moieties (17,24) are attached to the nanocarriers to improve the solubility of these agents in the bloodstream (21,29) and guide them to specific locations (5,43). Once delivered to the target site, the active ingredient is released either via erosion of the casing due to pH changes, heat, light or magnetic fields (18,44), or direct diffusion of the active ingredient through the casing into the tissues or cells (18,27). Examples of nanocarriers are liposomes and polymeric micelles.
Liposomes
A liposome is a sphere of amphiphilic bilayer membranes composed of natural or synthetic lipids surrounding an aqueous core which contains the active ingredient (Figure 1) (18,27). Liposomes are particularly useful for the protection and transport of biotechnological drugs that are unstable in the bloodstream (42,45,46). Due to their small size and similar constituency as that of biological membranes (15,17), liposomes can escape opsonization and reside long enough (15,17,27) to transport their cargo across the cell membrane successfully (18). An example of an approved liposome nanocarrier system is Doxil®, which contains doxorubicin used to treat Kaposi's sarcoma (KS) (47). Studies have shown that Doxil® remained in the circulation with a half-life of 40–60 h as compared to the half-life of doxorubicin, which is less than 10 min (48). This is because the liposomes in Doxil® are coated with polyethylene-glycol to evade interception by the immune system through the reduction of interactions between the lipid bilayer membrane and plasma components (49). As such, the resultant long circulation time increases the likelihood of liposomes reaching and accumulating in cutaneous KS lesions (50).
Polymeric Micelles
Polymeric micelles (5–100 nm) are generally smaller than liposomes (20–1000 nm) (18,51) and consist of several hundred block copolymers (Figure 2) (52,53). These copolymers comprise a hydrophobic core and hydrophilic shell (17,45) for encapsulating the drug and ensuring micelle solubility, respectively (53). The hydrophilic shell is usually made of poly(ethylene) oxide which prevents protein adsorption and cellular adhesion (52). Sometimes, the drug may also be covalently linked to the micellar surface (20). Currently, no micelle-based drugs are available in the market, but studies have shown their potential for future commercialization (54–56).
(ii) Nanosuspensions:
As mentioned previously, drug solubility and stability can be improved through the use of nanocarriers. However, many nanocarriers face challenges in their manufacture due to low encapsulation rates (15,17,27). Nanosuspensions provide an alternative means for enhancing drug solubility and stability via a reduction of the drug particles to the sub-micron range (16,21). This is followed by coating with a stabilizing agent (24,29) to form nanocrystals suspended in a liquid medium (21,57). Nanocrystals are small enough to be injected intravenously, thereby achieving a 100% bioavailabilty (24) without the need for specific solubilizing agents, which may be toxic if administered in high concentrations (20,21).
Abraxane® is a well-known example of a nanosuspension used for breast cancer treatment (8). The original product Taxol® contains the active ingredient paclitaxel, a water-sensitive molecule that can only be solubilized by Cremophor EL in ethanol (58,59). However, as Cremophor EL is a toxic solvent, it cannot be infused directly; hence, dilution of the ethanolic solution with an isotonic solution must be done prior to infusion (24). This greatly limits therapeutic doses and treatment options (17,54). With Abraxane®, paclitaxel is added to an aqueous solution of albumin using low-speed homogenization. High-pressure homogenization is then applied to reduce the size of the paclitaxel particles before they are attached to the albumin coating via disulfide bonds, leaving an aqueous suspension of nanoparticles of approximately 130 nm in diameter (60,61). This does away with the need for using Cremophor EL and eliminates the hypersensitivity reaction associated with it (20). With a longer shelf-life, Abraxane® is also more stable compared to Taxol® (24).
Being a nanosuspension, Abraxane® also has a faster onset and improved bioavailability. Small particles have an increased tendency to adhere to mucosal surfaces at the absorption site over a longer period as compared to larger particles, resulting in enhanced permeation and uptake (26). This, coupled with transendothelial transport via the albumin binding protein, enables paclitaxel to accumulate sufficiently in the tumor to exert its therapeutic effect (27). The high specific surface area of nanoparticles also facilitates faster drug release and action (29). Clinical studies have shown that Abraxane® doubles the therapeutic response rate, delays metastatic progression, and increases overall survival in breast cancer patients (62).
(iii) Nanoparticles Used in Bioimaging:
Bioimaging refers to a variety of non-invasive methods used to visualize biological processes in real time (63). It is achieved through the generation of colorimetric contrast between different cells (64), tissues, and organs (65). Examples of nanoparticles used in bioimaging include quantum dots (30), 66–68), iron oxide nanocrystals (69,70), and gold nanoparticles (64,71). Nanoparticles are deemed promising imaging tools (18,29) due to several useful properties as described below.
Quantum dots (QDs) are inorganic semiconductor crystals with dimensions of 1–10 nm. They are typically made of binary alloys, such as cadmium selenide, and emit different colors based on their size. They possess broad excitation spectra that enable the use of a single excitation wavelength to excite QDs of different colors (66). QDs can produce multi-colored images of a greater resolution than conventional fluorescent dyes (20).
Affinity ligands (65) (e.g., tumor-specific peptides/antibodies) may be attached to enable nano-sized imaging agents in targeting specific sites of interest with minimal accumulation in proximate healthy tissues (8,18). They also allow for the detection of disease biomarkers (18,72) at an early stage (8,21). An example is Combidex®, a formulation of iron oxide nanoparticles which has been proven to be significantly more sensitive in detecting prostate cancer metastasis as compared to conventional magnetic resonance imaging (MRI) (27). Therapeutic agents may also be affixed to them to provide simultaneous cell imaging and drug delivery (20,73).
Photobleaching refers to the chemical destruction of fluorescence after a certain number of excitation–emission cycles. Inorganic nanoparticles were found to be able to resist photobleaching for a much longer time as compared to conventional organic dyes (18,21,65). This allows longer imaging in both in vitro and in vivo applications (74) and simplifies analysis and interpretation of data (75).
(c) The Future of Nanomedicines
Currently, nanomedicines are only a prelude to a truly innovative future technology (21). Nanomedicines are constantly evolving in terms of their intricacy in structure and function such as nanorobots (6,76,77) and pulsatile delivery systems (20,78). However, advanced nanomedicines are likely to enter the market decades later due to the complexity of clinical tests and conservatism in adapting revolutionary technology (21).
Properties of Nanoparticles and Their Effects on the Safety and Quality of Nanomedicines
While nanomedicines offer promising possibilities, there are concerns that they might also cause adverse effects not encountered with conventional medicines (24). To verify the certainty of these claims, the principal properties of nanoparticles—their size, shape, agglomeration/aggregation potential, and surface chemistry—have been tested in laboratories to gain insights into their behavior. Each of these properties will be discussed and deductions made as to whether they could cause harm to individuals exposed to high concentrations of nanoparticles over the longer term.
(a) Size
Nanoparticles are small enough to be distributed to sites previously inaccessible to microparticles (31,79,80), including cells (81,82), erythrocytes (79), lungs (83,84), spleen (85,86), liver (85,87), heart (88), and brain (88,89). Their ease of accumulation in organs (83), coupled with their large specific surface area and high reactivity, may enhance intrinsic toxicity (90) due to greater contact with biological components (79). However, toxicity usually occurs only after the absorption and accumulation of a massive amount in the body (30). Thus, manufacturing personnel who are adequately protected are unlikely to experience any toxicity associated with nanoparticles.
The concerns regarding inflammatory responses evoked by nanoparticles may be overhyped. Kobayashi and colleagues instilled titanium dioxide nanoparticles in rats and observed only transient induction of inflammatory responses. This may reflect the effects of bolus administration and not necessarily indicate toxicity of the instilled particles (86). Other studies also showed similar results regarding transient inflammatory effects (91–94).
(b) Shape and Agglomeration/Aggregation Potential
Studies have shown that the shape of nanoparticles may play a role in toxicity, but findings are varied and the exact mechanism of toxicity is still unknown, though several hypotheses have been made (81), 95–98). One study in particular suggested that shape may influence the agglomeration/aggregation of nanoparticles (99). This study compared rod-shaped and spherical-shaped silica nanoparticles and postulated that the interaction force between the two rods is twice that of two spheres. The shape of nanoparticles may also confer their potential to cause the agglomeration/aggregation of biological components. A study found higher platelet aggregation and thrombosis rates in rats with nanotubes as opposed to nanospheres due to greater cell–cell contact by nanotubes, which are believed to mimic molecular bridges involved in platelet–platelet interactions (100).
The shape of nanoparticles can be influenced by factors related to their manufacture and biological environment (101). Thus, validated tests should be performed to ensure that the shape of nanoparticles in nanomedicines does not pose any safety concerns.
(c) Surface Chemistry
Surface chemistry is an important factor in determining the extent of organ and cellular uptake as well as intracellular interactions (2), 53–55). For instance, surface charges of nanoparticles can disrupt cell membranes (102) and cause possible adverse effects (54–56). Surface characteristics may also determine the opsonization and clearance kinetics (29) of nanoparticles, which affect their biopersistence. In cases of inorganic nanoparticles, studies have demonstrated that uncoated QDs have the ability to release toxic ions (65,103,104).
Besides the influence of shape, uncoated nanoparticles also have a high tendency to agglomerate/aggregate (82–84), affecting their redispersibility (105) in formulations. These agglomerates/aggregates may also be too large to be internalized by macrophages (106), evoking a chronic immunological response (99). Fortunately, this agglomeration and aggregation propensity may be prevented through the use of appropriate coatings or functional groups to stabilize particle–particle interactions through electrostatic or steric means (107–109).
Appropriate coatings or functional moieties can also be applied/attached to nanoparticles to enhance their biocompatibility in the body (110,111). The coatings should be evaluated for their possible wear and tear over time (90) and under certain environmental conditions (68,112). Otherwise, free nanoparticles in the form of wear debris may be released which can cause adverse health effects (20). Nanoparticles coated by polymers may de-coat when the polymer degrades. For example, those coated by alginates may de-coat under conditions where monovalent cations are present in abundance.
Current Regulations and GMP Requirements Governing Nanomedicines and Challenges in the Control of Their Manufacturing Processes, Product Quality, and Safety
The properties of nanoparticles mentioned above are known to affect the safety and quality of nanomedicines. However, the harmful effects of nanoparticles can be prevented through the implementation of protective measures such as the wearing of personal protective equipment to prevent entry of nanoparticles into the body during manufacture, and the application of appropriate and durable coatings on the surfaces of nanoparticles to ensure their release at the intended site. In addition, current research on nanoformulations concentrates on particle size within 200 nm to prevent the induction of inflammatory responses. Certain nanoparticle properties such as shape and agglomeration/aggregation potential can also be tested for their effects on the safety of nanomedicines.
Like other pharmaceutical products, nanomedicines have to undergo an approval process by regulatory authorities to establish their safety, efficacy, and quality before entry into the market. Their manufacturing processes are also required to adhere to GMP requirements to ensure consistency in production and control and, ultimately, to achieve quality standards. The issues surrounding the regulation of nanomedicines are discussed below.
(a) Regulations Pertaining to the Safety of Nanomedicines
There are currently no specific regulations for nanomedicines. The U.S. Food and Drug Administration (FDA), the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA), the Australia Therapeutic Goods Administration (TGA), the Canada Health Products and Food Branch (HPFB), and the European Medicines Agency (EMA) have not found evidence to prove that medicinal products with incorporated nanotechnology pose a higher risk as compared to conventional medicines (113–116). As such, the regulatory framework that governs conventional medicines has also been extended to nanomedicines because it is deemed to be adequate in handling any risk(s) associated with them (115).
Under existing regulations, nanomedicines are approved through a risk/benefit assessment (2,117) based on efficacy, quality, and safety data submitted by the manufacturer (2), 117–119). If a nanoparticulate formulation of a previously approved drug has resulted in the creation of a new chemical entity, it is treated as a new product and will have to undergo the full evaluation process.
Challenges Faced and Ongoing Improvements
Although there are currently no regulatory policies designed specifically for nanomedicines, authorities foresee a possible need (2) in the future due to the increasing complexity of nanomedicines. Some challenges anticipated by authorities worldwide are described below:
(i) Paucity of Adequate Knowledge on the Behavior and Safety of Nanoparticles/Nanomedicines To Allow for Development of Systematic Guidelines:
Currently, there is insufficient information on nanoparticles to allow the accurate determination of any potential hazards associated with nanomedicines. An analysis in 2005 showed that the U.S. government invested only 1% of the total U.S. $1.2 billion budget allocated to occupational health and safety research on nanomedicines (120). An adequate knowledge of the possible implications of nanoparticles/nanomedicines is critical for the implementation of appropriate control procedures and risk management steps to ensure the safety of nanomedicines to both manufacturing personnel and consumers in the long term (121). Authorities have taken an active approach by establishing ad-hoc research groups in the hope that the insights gained will be useful in improving regulatory guidelines. Table I lists some of the activities that have been undertaken by the respective regulatory authorities/countries.
(ii) Non-Standardization of Nomenclature, Test Methods, and Characterization of Nanoparticles:
The nomenclature of nanoparticles is not globally standardized (130,131). This may lead to divergent interpretations and ineffective communication of information across the world (132). For instance, the National Nanotechnology Institute defines the term nanoscale as “dimensions between 1 and 100 nm” (133). However, nano-sized ingredients in certain nanomedicines are known to exceed 100 nm in size (60), and these may be unwittingly excluded from research and scientific studies although they may be potentially harmful (20). A common and harmonized nomenclature is required to prevent any confusion and to allow for proper assessment of scientific and regulatory implications posed by nanoparticles.
There are also no validated methods for measuring the exposure level of nanoparticles in manufacturing facilities, which can help immensely in the collection of safety data (134,135) for risk assessment and management (116,131,136). Due to the diverse chemical nature of nanoparticles (137), the characterization of nanoparticles has not been completed (114). The FDA is also uncertain whether there is the possibility that once a few members of a class have been characterized, other members of the same class would be deemed to share the same characteristics and need not be subjected to additional testing to justify their use (113). More efforts would need to be spent in nanoparticle characterization to prepare for regulation of more complex nanomedicines in the future.
The International Organization for Standardization Technical Committee 229 and the American National Standards Institute's Nanotechnology Standards Panel (ANSI-NSP) have been established to facilitate the development of standards in the nanotechnology field, including their nomenclature/terminology, characterization procedures, and testing methods (138,139). The U.S. Nanotechnology Characterization Lab is also attempting to establish a set of standards and assays for the characterization of nanoparticles and their behavior in the body (123). The European Commission (EC) has funded two research projects entitled “Nanosafe 1” and “Nanosafe 2” to develop a protocol for assessing the level of risks in individuals exposed to nanoparticles (140,141).
(iii) Difficulty in Regulating Combination Products:
Regulators face the challenge of regulating nanomedicines due to their increasing complexity (113). The ability to operate at the nano level has enabled manufacturers to incorporate various components to produce a single therapy such that the final product can be a combination of (1) a drug and a device, (2) a drug and a biological agent, (3) a device and a biological agent, or (4) a combination of all three. An example of a combination product is the carbon nanotube-based biosensor attached to a hip implant that detects new bone growth and delivers drugs as appropriate (142). This is likely to cause confusion and disputes during assignment of the product to respective agency centers (which evaluate different types of medical products) for primary evaluation (62,69,71,72).
The U.S. FDA's Office of Combination Products has declared that it would assign the product to an agency center based on its primary mode of action (143), defined as “the single mode of action … that provides the most important therapeutic action at the time a request is submitted” (144). However, some combination products might have two modes of action, neither of which is subordinate to the other. There may also be disputes between the regulatory agency centers and the manufacturer regarding the primary mode of action (145). The problem of assignment and the possibility of transferring the product among agency centers for assessment of its individual components might lengthen the approval process for nanomedicines (145). This might present a problem to certain regulatory authorities like the TGA, which took up recent obligations in a trade agreement to accelerate the commercialization of innovative pharmaceuticals (146). Manufacturing companies may also suffer a loss of investments due to delays in obtaining regulatory approvals (130), and patients would be deprived of early access to novel therapies.
Hence, an algorithm was created by the FDA in 2005 to determine the primary jurisdiction for a combination product in cases where neither the FDA nor the sponsor can agree on the primary mode of action. This algorithm will assign the product to the regulatory agency center that is the most proficient in evaluating the most important safety and effectiveness questions related to the product, or to the center with prior experience in evaluating other combination products raising similar types of safety and effectiveness questions (143). In certain cases, single or separate marketing applications for the individual constituents may be submitted depending on the product (113). To coordinate regulations, a Nanotechnology Interest Group has been set up where representatives from all agency centers would meet regularly to ensure effective communication (113).
Evaluation of Current Proposed Regulations and Improvements
Apparently, the most pressing problem with nanomedicines is the lack of understanding of nanoparticles. Thus, the aggressive pursuit of nano-related research work and nanoparticle characterization may be a good step towards improving the existing regulatory framework. The standardization of nanotechnology nomenclature and the development of validated test methods can also harmonize the methods of risk assessment and management. Additional improvements are proposed below:
(i) Modification and Extension of Current Regulatory Framework to Nanoparticles/Nanomedicines:
As nanomedicines become increasingly complex, their current regulatory framework may not adequately address the specific risks and challenges posed by them. Once validated test methods have been established, relevant data on the nanoparticle properties discussed previously should be submitted to the regulatory authority for evaluation. For instance, because the extent of nanoparticles' interaction with biological components is dependent on the surface area and surface particle number (87), these properties may be better parameters than mass when expressing doses in terms of exposure (58,85,86). Thus, the submission of safety information to regulatory authorities for approval should include surface area as the unit of dose measurement.
(ii) Other Nanoparticle-Containing Products Should Also Be Regulated for Consumers' Safety:
Besides nanomedicines, other emerging nanoparticle-containing products such as cosmetics and dietary supplements (147), which are currently not required for premarket approval (113,122,148), should be regulated as well. This is to prevent any adverse effects being discovered only after their entry into the market. Cosmetic products and dietary supplements are used on a regular basis, and the toxicity of any nanoformulation has not been adequately studied. Regulatory authorities should make it compulsory for safety data to be submitted, with specific information requirements to ensure that risks commonly associated with nanoparticles are absent. More human and financial resources should also be assigned to conduct regular checks on manufacturing facilities producing nanoformulations of all health products.
(iii) Collective Database To Facilitate Retrieval of Information by Regulatory Authorities:
Many studies have been carried out to investigate the properties of nanoparticles, with several theories proposed regarding certain phenomena expressed. Information retrieval could prove to be a challenge for scientists and regulatory authorities, as the various international data sources are not organized. A common online database can be established, into which relevant scientific findings and results are uploaded and archived within a single platform for easy access by users. Current regulatory practices, conference papers, meetings, and the latest updates of movements within the nanomedicines arena in various countries can also be documented for sharing by regulatory authorities and interested stakeholders. This one-stop portal could act as a convenient interface to facilitate regulatory authorities in obtaining the required information on areas of interest. Categories and sub-sections that are more specifically targeted to the various fields in nanomedicines can also be added from time to time.
(b)GMP Requirements Pertaining to the Quality of Nanomedicines and the Safety of Manufacturing Personnel
No information has been found on GMP requirements that are specific to the manufacture of nanomedicines. Since nanomedicines and conventional medicines are regulated under the same regulatory framework, it is likely that they are subject to the same GMP requirements. Issues in the manufacturing processes that challenge the quality of nanomedicines and the safety of manufacturing personnel will be discussed below. Improvements to resolve them will also be proposed.
Challenges Faced and Improvements Proposed
(i) Lack of Trained Personnel To Operate Manufacturing Processes:
GMP requires that manufacturing plants have sufficient qualified trained and experienced personnel to assure the production of safe, efficacious, and good quality nanomedicines (149). However, due to the infancy of this field, there is currently a dearth of sufficiently trained personnel in the nanomedicines industry (2). As nanotechnology develops, new knowledge regarding nanoparticles would be gained. Manufacturing personnel should undergo training to be updated with the essential skills in managing and controlling the manufacture of nanomedicines so that quality standards are met. Continued training tailored to the context of their operation processes should also be conducted. Thus, manufacturing companies must be prepared to invest heavily in both time and money to ensure that their manufacturing processes meet the minimum GMP requirements (2).
(ii) Lack of Safety Protocol for Manufacturing Personnel:
In general, the processes generating nanomaterials in aerosols or powders pose the greatest risk for releasing nanoparticles. Sanitization of production equipment can also release deposited nanoparticles into the manufacturing environment (150). These free nanoparticles have been shown to demonstrate potential health hazards (90,111,151). However, there are currently no standardized methods to characterize their toxicology, which could be used to predict risks and propose safety measures for operation personnel to undertake during the manufacture of nanomedicines.
The safety of manufacturing personnel should also be ensured. For instance, studies have shown that certain nanoparticles are more likely to trigger or exacerbate attacks in people with impaired respiratory function (152). They may also produce free radicals in the body when penetrated through the skin (125).
Therefore, there is a need for validated steps in the assessment and management of risks in the workplace. Minimal characterization of nanomedicines should include acute toxicity and predictive modeling as well as physicochemical characterization (153). To avoid misleading conclusions during hazard assessments, both short- and long-term responses should be thoroughly evaluated (86).
With respect to the safety of manufacturing personnel, a detailed protocol should be drawn up to stipulate prerequisites to protect workers' personal health. For example, all manufacturing personnel should be examined for medical conditions of the skin and respiratory system before they are employed. They should also be adequately protected to prevent the entry of nanoparticles through the oral, nasal, and dermal routes during the manufacture of nanomedicines. Personal protective equipment should be cleaned using a suction device to prevent the release of free nanoparticles into the manufacturing environment during cleaning. Manufacturing methods should exclude or minimize the formation of aerosols to avoid intake of nanoparticles by inhalation.
(iii) Challenges in Controlling for Nanoparticle Contamination in the Workplace:
There may be a greater level of contamination at the nano level due to unexpected interactions of drug molecules with contaminant molecules (2). The control of nanoparticle contamination is crucial because ineffective cleaning of equipment is a common source of cross-contamination (149) that may adversely alter the quality of subsequent batches (154).
To ensure the quality and purity of the products, manufacturing companies should only use starting materials that have been assessed for their safety and quality. In Australia, the TGA is currently working with the National Industrial Notification & Assessment Scheme, which assesses industrial chemicals for their health and environmental safety, to develop a regulatory system that ensures only safe therapies including nanomedicines enter the market (117). Novel methods of contamination control used by other industries employing nanomaterials (155,156) could also be adopted for the nanomedicines industry. Protocols for proper handling and storing of nanomaterials by manufacturing personnel should also be developed to reduce contamination caused by human factors. Essentially, manufacturing companies must be prepared to invest more time and money in sanitizing production equipment (2).
Conclusion
Nanomedicines offer promising breakthroughs in the health care industry due to several advantages over conventional medicines. These advantages include a more effective targeting of difficult-to-reach sites, improved bioavailability and side effect profile, as well as a smaller dose needed to achieve the same therapeutic effect. Although nanomedicines have several applications in health care, attention has also been drawn towards the safety of nanoparticles and the challenges in controlling the quality of nanoformulations. Even though regulatory authorities recognize these concerns, they are not yet able to develop regulatory guidelines specifically tailored for nanomedicines due to inadequate knowledge about nanoparticles in general. As nanomedicines are expected to become more complex in terms of their structure and function, regulatory authorities will have to work closely with the industry, research institutions, and other stakeholders to come up with an appropriate regulatory framework for nanomedicines.
Declaration
The authors declare that they have no conflict of interests and are agreeable to the publication of this paper.
- ©PDA, Inc. 2011
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