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The FDA and other regulatory authorities are evaluating new regulations to ensure the safety and quality of nanomaterials in biomedical products.
Over the past three years, nanotechnology has gained prominence on the US Food and Drug Administration's regulatory agenda. The prospect that very tiny materials may yield more effective, less toxic, high-quality medicines has generated great enthusiasm among scientists and manufacturers. Some drugs that incorporate nanomaterials are already on the market.
Nanotechnology will be used in many products that come across the FDA's door, according to FDA Senior Scientist Richard Canady. The agency's challenge, Canady explained at an FDA public meeting on nanotechnology in September, is to determine whether products incorporating small-size particles pose new hazards and thus require new regulatory and testing policies. Uncertainties about how nanoscale materials may affect the human body and the environment has prompted calls for added analysis of possible toxicities and scrutiny of unanticipated effects. A related issue is whether new requirements are needed for all nanomaterials, or for certain subgroups of products using this technology.
An FDA task force was formed in 2006 to address the need for stricter nanotech product regulation and held a public meeting on the issue that year. This led to a task force report in July 2007 outlining the scientific and regulatory challenges for FDA oversight of the expanding nanotech world. The report recommended that the FDA evaluate the adequacy of testing approaches to ensure the safety, efficacy, and quality of nanoscale materials in regulated products. The task force noted the need for new data characterization methods, standards for nanoscale materials, and a better understanding of how nanomaterials relate to one another. The panel also emphasized that the FDA should build its in-house expertise to ensure it can keep up with new scientific developments in this field, and that FDA reviewers should be better informed by manufacturers on what is known about a nanoproduct and what analysis has been done.
The report stopped short, however, of recommending new regulatory action—instead it supported efforts to address disclosure and data issues on a product-by-product basis. The FDA may not need added authority to ensure the safety of nanomaterials in drugs, biologics, and other medical products that already require premarket review; here it may suffice for the agency to issue guidance on how and when sponsors should identify particle size in submissions.
Former FDA Official Michael Taylor, working with the Project on Emerging Nanotechnologies at the Woodrow Wilson International Center, says that the agency may need added legislative authority to obtain safety information on products with nanomaterials that receive less FDA oversight. At a nanotechnology conference in February sponsored by the Food and Drug Law Institute, Taylor warned that a safety problem involving a product with nanotech material not subject to premarket review "will set back public confidence and acceptance of nanotech products" and block market access for other products.
The nanotechnology task force's main recommendation is that the FDA develop guidance to help manufacturers understand what testing and disclosure is appropriate for nanotech products. Because nanomaterials have physical, chemical, and biological properties that differ from conventional substances, different biological activity may result, and new testing procedures may be required. Nanotechnology may open the door to new therapies with enhanced absorption and distribution, but these properties also raise the prospect of increased harm from toxic reactions.
The first order of business for the FDA is to define nanotechnology for the purposes of medical product regulation. The FDA needs to clarify what it considers nanoscale, how manufacturers should identify particle size in regulated products, and what kind of data are needed to ensure product safety. Such assessment can indicate when the FDA may need to mandate premarket notification for products using nanotechnology and whether the agency needs a specific regulatory framework to deal with nanotechnology. A related issue is whether additional preclinical safety assessment is needed to evaluate toxicities in experimental drugs with nanomaterials to predict injury to organ systems or other safety problems.
Another important topic is to what extent labeling should be revised to include nanotech information to be truthful and not misleading. So far, the FDA has not required manufacturers to revise product labels to reference nanomaterials. Nor has the agency regarded products that are reformulated to contain nanomaterials as new products that need to be retested and re-evaluated.
At its September public meeting, the FDA heard comments from industry representatives and scientists on what manufacturing and product characterization issues should be considered in crafting guidance for developing safe and effective products containing nanoscale materials. Of particular interest to the FDA is whether using nanomaterials changes the manufacturing process for drugs and biologics, what added parameters should be measured, if nanoscale materials raise new issues in production scale-up, and how such materials might alter product standards and specifications. The bottom line is to determine to what extent the size, shape, and surface charge of a nanoscale material affects the quality, safety, and effectiveness of an excipient or drug formulated with such ingredients.
Characterization of nanomaterials in medicines also poses new challenges. There is a need for appropriate tools to assess product chemistry and unique characteristics, including primary particle size; aggregation and agglomeration state; two- and three-dimensional distribution; and particle size distribution. Chemical composition should consider element distribution, crystal form, surface composition, and reactivity. Full product characterization may require enhanced quality control measures and evidence that a manufacturer can produce consistent formulations with low batch-to-batch variability.
David Hobson of nanoTox, Inc. (Austin, TX) explained that because nanomaterials have a much higher surface-area-to-weight ratio than conventional materials, this can affect mechanisms of action, biodistribution, and pharmacokinetics. Whereas stability testing for nanomaterials should follow international guidelines, more extensive stability assessment may be necessary because nanomaterials can change under different storage and handling conditions.
A goal for manufacturers and the FDA is to avoid regulatory requirements likely to block development of new products incorporating nanomaterials. Researchers are developing new cancer therapies that are more soluble and targeted and less toxic: anti-cancer drugs from CytImmune Sciences (Rockville, MD) use colloidal gold nanoparticles, and Elan (Dublin, Ireland) finds that nanocrystal technology can produce highly soluble ingredients. Nanomaterials are being tested as possible vectors for delivering gene therapies to patients, and nano tissue engineering combines stem cells and nano-lattices. Researchers at the University of Michigan recently announced progress in developing a nanoemulsion hepatitis B vaccine that doesn't need sterile syringes, refrigeration, or repeated booster shots.
Nanotech drugs, moreover, may be less vulnerable to enzymatic and chemical degradation and provide enhanced bioavailability. Another benefit may be the ability of nanoparticles to serve as effective platforms or carriers for insoluble or poorly soluble drugs and as scaffolding to attach chemical moieties in ways to increase solubility or decrease clearance. Reformulation of old or obsolete compounds to incorporate nanomaterials may also allow manufacturers to extend the life of existing drugs and enhance patent protection.
The emergence of nanotech drugs fits the broader shift to personalized medicine. Nanotech diagnostics able to quantify disease-related biomarkers may identify precise medicines to fit patient needs. The hope is that more targeted drugs may require less frequent dosing, enhance safety profiles, and improve patient compliance.
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org