Nanomedicine: Current Regulatory Scenario and Prophylactic Regulatory Strategies

Posted 31 January 2012 By Aastha Kohli and Shrenik Desai

"According to Global Industry Analysts Inc. report on nanomedicine, commercialization of this tiny technology is surging at a steady rate and is expected to exceed $160 billion by 2015."1

What is Nanomedicine?

In simple terms, nanomedicine (NM) is nanotechnology-enabled medicine.2 It is the science and technology of diagnosing, curing and preventing a disease, repairing damaged tissues and preserving human health using molecular tools and molecular knowledge of the human body.3

Our bodies are made of nanostructures like DNA (~10 nm) and red blood cells (~10,000 nm). Compared to the conventional therapies and diagnostic practices, NM offers an opportunity to operate on the same scale as these body nanostructures. Thus, NM enables targeted drug delivery, improved solubility, increased dissolution rate, improved bioavailability and more rapid onset of action.

NM is a promising avenue for life-threatening disorders like cancer. Moreover, with major patents soon to expire, the healthcare industry needs innovative products and has enough reasons to invest in NM. The pipeline of NM products is presented in Table 1.4,5

Table 1: Big Promise of Tiny Technology in the Field of Medicine
In-Vitro Diagnostics
Cantilever arrays
(Nanomechanical arrays)
Improved diagnostic and analytical capacities for detecting diabetes mellitus, cancer, viruses, bacteria and fungi
NanosensorsDetect wide range of biomolecules and disease markers
Optical sensorsHighly effective noninvasive glucose monitoring via eye in diabetic patients
Nanoparticle (NP) sensors and detectorsSingle nanoparticles, e.g., gold, iron oxide or silica functionalized with poly/monoclonal antibodies can detect pathogenic biochemical markers or individual bacteria
Quantum dotsUnique optical and electronic properties
Applications in imaging and biophotonic devices which will enable diagnosis at local and specific sites in the body
NanowiresSemiconducting silicon-based nanowires exhibit promising detection of viruses in solution
Carbon-based nanomaterials, carbon nanotubesMay be used as actuators or sensors in various medical devices due to their property to elongate or contract in suitable electrolytes under very low voltages
DendrimersIn vitro diagnostics as carriers for contrast agents and drugs
Light sensitive carriers, which cause less physical damage to tissues
Surgery and Implants
Nanocoated needlesImproved ductility, strength and corrosion resistance
Optical tweezers and nanoscissorsEnable cellular-level surgeries through cell manipulation and immobilization
Nanocoated implant surfacesImproved wear characteristics, fixation and biocompatibility of surgical implants
Nanocoated surgical bladesExtremely sharp and low friction
Highly useful in optical and neurosurgery
Wound managementSilver NPs have shown improved wound dressing with antibacterial properties.
Therapeutic and Targeted drug delivery
Nanoporous materialsCarbon-, silicon-, ceramic- or polymer-based nanoporous materials can have extremely useful catalytic, adsorbent and absorbent properties
May have valuable applications in implant technology or drug delivery
NanorobotsWould travel throughout the human body using molecular robots, store and transport molecules, perform various operations and communicate with physicians
Would be able to eliminate cancer and HIV, reverse trauma and burn injuries, enhance mental and physical abilities and slow aging
Regenerative Medicine
Nanoscaffolds for tissue engineeringMimic cellular matrices to guide tissue repair and replacement

NM could become the future of medicine. However, there are a range of scientific, regulatory, financial, patent and ethical challenges (see Table 26) that restrict the commercialization of NM. Venture capitalists list regulatory uncertainty as a major reason for not investing in the technology.

Table 2: Types, Advantages, Risks and Range of Challenges of Nanomedicine
  • Scientific challenges
  • Applicability and relevance of current methods
  • Interactions with biological systems
  • Impact on immune system
  • Impact of intracellular or interstitial persistence
  • Regulatory uncertainty
  • Classification of converging technologies
  • Tools for characterization of risks
  • Comparability of existing nano-formulations
  • Financial uncertainty
  • Huge investments
  • Reimbursement issues
  • Patent challenges
  • Duplication of patents
  • Ethical issues
  • Informed choice of the patients vs. benefit:risk-based labeling

Regulatory Recommendations While Developing Nanomedicine

Owing to its newness in the field of medicine, there are a lot of unknowns pertaining to the safety of NM. The US Food and Drug Administration (FDA) is concerned about these unknowns, as is apparent from its 2011 Regulatory Science Research Project Categories that include the establishment of physicochemical characterization, nonclinical modeling, risk characterization and risk assessment of nanoparticles (NPs).7

Hence, it is prudent to understand the agency's perspective and also acknowledge the inadequacy of NM subject matter experts (SMEs).8 Failure to back up NM advances with a scientific rationale based on FDA's concerns can cause delay in the review process.

Providing such extensive data in regulatory submissions will not only shorten the agency's application review period, but will also help attract investors or partners and aid in product reimbursement.

Establish a Complete Physico-chemical Profile of Nanoparticles

The physicochemical profile of a drug substance (or product) forms the basis for assessing its biosolubility, structure-function relationships, biocompatibility, safety, toxicology and hazards. Compared to their larger counterparts, nanoparticles (NP) have significantly different physical, chemical, biological, magnetic and electric properties as well as different optical activity.

This is why their characterization is challenging as well as a critical aspect in product development. Du Pont and Environmental Defence proposed a nano risk framework that includes a good example of physicochemical profiling of NPs (see Table 3).9

Table 3: Physicochemical Profile of Nanoparticles
  • Technical name
  • Commercial name
  • Common form
  • Chemical composition
  • Surface chemistry (including surface coating)
  • Molecular structure
  • Crystal structure
  • Uniformity and regularity of structure (isomeric/orientation heterogeneity for target drug delivery)
  • Physical form/shape (at room temperature and pressure)
  • Particle size, size distribution and surface area
  • Particle density
  • Solubility (in water and biologically relevant fluids)
  • Dispersability (in general, polydisperse)
  • Bulk density
  • Agglomeration state
  • Porosity
  • Surface charge
  • Surface reactivity

Additionally, physicochemical profiling of NPs would help in defining storage, stability and purity conditions for NPs early in product development.

Categorize Your Nanoparticle

[media:1208] Categorizing NPs facilitates identification of relevant routes of exposure, hazard identification and effective risk management procedures.

NPs can be categorized based on their location in a system. This is described in Figure 1.10

  • bulk-one type of nanomaterial in three dimensions (e.g., nanocrystalline copper)
  • multiphase-two or more different nanomaterials in three dimensions (e.g., ceramic zeolites)
  • structured surface-surface of a material is structured on the nanoscale (e.g., nanostructured surface of implants)
  • film surface-nanoscale-thick film on a substrate of different material.(e.g., anti-reflective coating of glasses)
  • structured film surface - film on a substrate (e.g., nano cantilever integrated in a metal oxide semiconductor)
  • surface-bound-NPs bound to the surface of another solid structure. (e.g., nanometer-sized catalyst on inert surface)
  • suspension in liquids-NPs suspended in liquid (e.g., nanoparticles inside T cells for targeted drug delivery)
  • suspension in solids-NPs suspended in solid (e.g., carbon nanotubes mixed in solids to increase strength of materials)
  • airborne-NPs suspended in air (e.g., carbon nanotubes in air or gas)

Through correlating the category of NPs with their inherent physicochemical properties, hazards associated with each class could be identified. This is explained in Table 4.11

Table 4: Hazard Identification Scheme for Nanomaterial
Structured surfaceII.a+++-++-++
Structured filmII.c+++--+-++
Surface-bound NPsIII.a+++++++++
NPs suspended in liquidsIII.b+++++++++
NPs suspended in solidsIII.c+++++++++
Airborn NPsIII.d+++++++++

+ : Property expected to be relevant for hazard identification of the nanomaterial;
- : Property not expected to be relevant for hazard identification of the nanomaterial;
/ : Not possible to determine the property for this type of nanomaterial. NPs = nanoparticles.


Understand General NP and Product-specific Manufacturing Challenges

Commonly used methods for manufacturing NPs are size reduction, precipitation or emulsification, supercritical fluid technology, spray-drying and polymerization.12

Potential quality problems are associated with each of these procedures. Thus, all possible issues related to the procedure of interest should be identified and addressed.

Size reduction, besides being time-consuming, is associated with milling challenges like erosion of the milling material and the requirement of high amounts of excipients to balance the high surface free energy of NPs. Process challenges related to microfluidization include high amounts of input energy requirement, clogging of pistons, heavy metal contamination and high pressure homogenization.13

Liquid filtration is associated with the release of fibers, and the smallest filtration level currently available is approximately 15 nm when the nanodrugs could be as small as 5 to 6 nm.14 Precipitation or emulsification cause variability of mixing processes, giving rise to different particle size distribution.

Supercritical fluid technology faces the challenge of selecting polymers because most polymers display little or no solubility in supercritical fluids. Polymerization-related challenges include low pH (around 2), residual solvents, toxicity of monomers and cytotoxicity.15

Critical process control measures for NPs should include monitoring the presence of particles, powder size and distribution data.

NPs interact with assay constituents and disturb routine endpoints. Thus, inclusion of positive and negative controls while performing assay is crucial.

Vehicles influence the surface properties, aggregation and agglomeration of NPs and thus result in poor dispersion, which interferes with NP safety testing. Evaluation of the role of vehicles in the design phase is therefore recommended.

Owing to the lack of knowledge about the behavior of NPs under different storage and handling conditions, developers should collect extensive stability data for NPs as per international guidelines.

Address the Potential Good Manufacturing Practice Pitfalls

Developers should recognize and resolve NM-related Good Manufacturing Practice (GMP) challenges. There is a considerable shortage of trained personnel in this field.16

As per both 21 CFR 211.25 and 21 CFR 820.25, "Each person engaged in manufacturing….of…..shall have education, training and experience."

Under current Good Manufacturing Practices (CGMPs), training should be conducted only by qualified individuals. In addition, there is a lack of NM-specific safety protocols, maintenance of sanitary equipment and ineffective control of NP contamination.17

Address the Potential for Occupational Hazards

Occupational hazards associated with the use of NPs are hot button issues. Animal studies conducted with some types of engineered NPs have found NPs to cause adverse lung effects (e.g., pulmonary inflammation and progressive fibrosis), cardiovascular effects (e.g., inflammation, blood platelet activation, plaque formation and thrombosis) and translocation of NPs from lungs to the bloodstream.

A small survey of 78 companies found that companies working with NPs are not yet sure about the correct way to protect the people handling these materials and how to dispose of the byproducts.18 Some companies use methods such as sweeping or vacuuming to prevent contamination that are more likely to disperse NPs into the air than they are to clean them up.19

Protocols should be developed for proper handling and storage of nanomaterials by manufacturing personnel.

Other manufacturing challenges include a lack of quality control, scalability issues, enhancing the production rate, reproducibility from batch to batch with respect to particle size distribution, charge, porosity and mass and high fabrication costs.20


Preclinical Studies

Preclinical absorption, distribution, metabolism and excretion (ADME) studies should be designed in a manner such that enables the information obtained from these studies to be extrapolated to establish the in vivo fate of nanomaterials.

Our literature review revealed that in vitro assays used for NPs provide information on acute toxicity, but there are no validated methods for extrapolating these results to predict their chronic in vivo effects.21 Further, dose-response relationships should be established for NPs and not assumed to be similar to their larger counterparts.

Conventionally, NP mass or NP number is used to correlate in vivo and in vitro results. However, research shows that using NP surface area as a dose metric while expressing the response metric gives more authentic correlation between in vitro and in vivo studies.22

Due to the unknowns of this technology, evaluating the extent to which size, shape and surface charge of a nanoscale material affects the quality, safety and effectiveness of an excipient or drug formulated with such ingredients is strongly recommended, and may be vital.

NPs are non-biodegradable and accumulative in nature. To add to the problem, not enough is known about their physiochemical character to make some derivations on pharmacokinetic (PK) patterns. In that case, obtaining substantial PK data becomes more crucial from FDA's point of view. So far, little PK data are available for understanding the excretion pattern of NPs from the body. These concerns should be kept in mind while designing in vitro studies.


Nanomedicines, owing to their physicochemical parameters, promise to impart cutting-edge developments and improvements to the healthcare industry and especially to the field of cancer treatment.

At the same time, there are concerns related to the unknowns of NPs that bring their safety into question. Regulatory agencies are trying to address these concerns. Yet, due to the complexity of the technology and lack of scientific expertise within the agencies, they have not been able to develop specific regulatory guidelines for NMs.

As the field of NM grows more complex, regulatory bodies will have to work more closely with research organizations, industry and other stakeholders to tailor an appropriate regulatory framework for nanomedicines. Until there is a more appropriate regulatory framework, the aforementioned regulatory cautions can be adopted as prophylactic measures.

A regulatory submission containing complete risk-characterization and risk-assessment information is likely to pass smoothly and quickly through agency review.


  1. Nanomedicine Market to Surpass $160 Billion by 2015. Occupational Health and Safety website. Accessed 21 October 2011.
  2. Boisseau P, Loubaton B. Nanomedicine, nanotechnology in medicine. C. R. Physique. 2011; 12: 620-636.
  3. Oberdorster G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. Journal of Internal Medicine. 2010; 267(1): 89-105.
  4. Teli MK, Mutalik S and Rajanikant GK. Nanotechnology and Nanomedicine: Going Small Means Aiming Big. Current Pharmaceutical Design. 2010; 16(16): 1882-1892.
  5. Innovations in Medical technology- Nanotechnology. Eucomed Medical Technology website. Accessed 25 October 2011.
  6. Workshop on Nanomedicines Session 3: Nanomedicines on the market and in clinical development. European Medicines Agency website. Accessed 9 November 2011.
  7. FDA/Science and Research resources page. Food and Drug Administration website. Accessed 10 November 2011.
  8. Nijhara R, Balakrishnan K. Bringing nanomedicines to market: regulatory challenges, opportunities, and uncertainties. Nanomedicine: Nanotechnology, Biology and Medicine. 2006; 2(2): 127-136
  9. Environmental Defense-DuPont Nano Partnership. NANO Risk Framework website. Accessed 20 October 2011.
  10. Hansen S, Larsen B, Olsen S, Baun A. Categorization framework to aid hazard identification of nanomaterials. Nanotoxicology-Informa Healthcare. 2007; November 20: 1-8.
  11. Ibid.
  12. M.M. de Villiers, et al. (eds.), Nanotechnology in Drug Delivery. In: Shah RB, Khan MA. Nanopharmaceuticals: Challenges and Regulatory Perspective: American Association of Pharmaceutical Scientists; 2009: 621-646
  13. Ibid.
  14. Op cit 8.
  15. Op cit 12.
  16. Op cit 8.
  17. Ibid.
  18. Shaw G. Survey Shows Confusion On Protecting Nano Workers. New Haven Independent website. Accessed 20 October 2011.
  19. Ibid.
  20. Bawa R. Nanoparticle-based Therapeutics in Humans: A Survey. Nanotechnology Law and Business. 2008; 5(2): 135-155.
  21. Op cit 3.
  22. Ibid.


The authors sincerely thank Mukesh Kumar, Richard Morroney, Chas Burr and Harsha Jattani for their review and comments. Earnest gratitude is also acknowledged for the regulatory affairs faculty, College of Professional Studies, Northeastern University for their encouragement and cooperation while writing this article.

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Categories: Technology, Features

Tags: Prophylactic, Molecular, Nanostructures, Nanoparticles, Nanomedicine, nanotechnology, medicine, disease, regulatory

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