Nanotechnology Challenges FDA and Manufacturers

In the past three years, nanotechnology has gained prominence on the US Food and Drug Administration's regulatory and research agenda. The prospect that tiny materials may form effective, targeted medicines and improved versions of many FDA-regulated products has generated great enthusiasm among scientists and manufacturers. Some drugs that incorporate nanomaterials are already on the market, along with many over-the-counter sunscreens, cosmetics, dietary supplements, and food products.

Jill Wechsler

Nanotechnology will be used in many products that come across FDA's threshold, according to the agency's senior scientist Richard Canady. FDA's challenge, Canady explained at a public meeting on nanotechnology in September 2008, is to determine whether products incorporating small 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 more analysis of possible toxicities and more scrutiny of unanticipated effects. Sunscreens with nanoparticles appear to offer better protection from harmful rays, but raise concerns about particle absorption into the body, as well as emission of nanomaterials into the air and water. And little is known about whether ingestion of dietary supplements, food products, and medicines made or packaged with nanomaterials will affect individuals.

Although scientific evidence does not indicate that nanoscale particles are inherently toxic, most experts don't assume a product is safe based on evidence from conventional versions of a material. FDA has been grappling with these safety issues for several years and continues to weigh whether nanotechnology can be regulated under existing rules and authorities. A related question is whether new requirements are needed for all nanomaterials or for certain subgroups of products using this technology.

FDA moved to address these concerns formally when the International Center for Technology Assessment and a consumer coalition filed a petition in 2006 that cited the agency's failure to regulate health threats from nanomaterials, particularly from the rising number of nanosunscreens then proliferating on the market. The agency formed a task force and held a public meeting in October 2006 to discuss the need for stricter nanotechnology-product regulation. This led to a report in July 2007 that outlined the scientific and regulatory challenges for FDA oversight of the expanding nanotechnology world.

The report recommended that FDA evaluate the adequacy of testing approaches to ensure the safety, efficacy, and quality of nanoscale materials in regulated products. The task force said that FDA should weigh the need for new data-characterization methods, standards for nanoscale materials, and for a better understanding of how nanomaterials relate to one another. The panel also emphasized that FDA should build its in-house expertise to ensure it can keep up with new scientific developments in this field. And manufacturers should better inform FDA reviewers about what is known about a nanoproduct and what analysis has been performed, the panel said.

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No new regulations

The report stopped short, however, of recommending new regulatory action, citing little evidence that nanoscale materials are inherently hazardous. Instead of requiring companies to submit manufacturing and safety information for all products with nanomaterials to the agency and to disclose the presence of such materials on product labels, as advocated by some experts and consumer groups, the report recommended addressing disclosure and data issues on a product-by-product basis.

FDA officials explained that the agency may not need added authority to ensure the safety of nanomaterials in drugs and other medical products that already require premarket review. Instead, the agency should issue guidance recommending how and when sponsors should identify particle size in submissions. For products with varying premarket-data submission requirements, such as medical devices, dietary supplements, and over-the-counter drugs, new guidance could clarify when FDA should request particle-size data. Manufacturers are responsible for the safety of these products, noted Canady, but the presence of nanoscale materials in such products, he said, "may in fact change regulatory status."

Former FDA official Michael Taylor, who works with the Project on Emerging Nanotechnologies at the Woodrow Wilson International Center (Washington, DC), says that FDA may need additional authority to obtain safety information about products that include nanomaterials, particularly cosmetics and dietary supplements not normally reviewed by the agency before entering the market. He also urges lawmakers to provide the agency with added resources to support research on nanomaterials and to build up agency expertise to make FDA "nanoready."

At a nanotechnology conference in February 2008, sponsored by the Food and Drug Law Institute (FDLI), Taylor warned that a safety problem involving a product with nanotechnological materials not subject to premarket review "will set back public confidence and acceptance of nanotech products generally." And public fears about nanoproducts, along with unresolved scientific and safety issues, "will slow or block market access for innovative products," he predicted.

At the same time, Taylor and other experts raise concerns that overregulation could discourage innovation that might lead to valuable advances in biomedical research and development. At the July 2008 meeting of FDA's Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, Keith Webber, deputy director of the Office of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER), noted a need to "filter out the hype" about the safety of products containing nanoparticles so that FDA can establish an appropriate regulatory process. The hope is, Webber commented, that nanoscale materials may lead to targeted therapies with reduced systemic exposure in patients, to novel dosage forms with sustained release, and to products less likely to degrade over time.

More guidance

A lead recommendation from the nanotechnology task force is that FDA develop guidance to help manufacturers understand what testing and disclosure is appropriate for nanotechnological products. Because nanomaterials have different physical, chemical, and biological properties 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 FDA is to define nanotechnology for the purposes of medical-product regulation. FDA needs to clarify what it considers nanoscale and how manufacturers should identify particle size.

Guidance should further explain what kind of data is needed to ensure product safety. Such an assessment can clarify when products that use nanotechnology require premarket notification. And guidance can explain whether FDA needs a specific regulatory framework to deal with nanotechnology or can oversee these products with its current rules and authority.

Another 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. Deliberations about testing requirements involve the assessment of what might be missed in the current range of animal and early human studies, which endpoints to measure with added tests, and how specific tests would be to nanotechnology products.

A third topic is the extent to which product labeling should be revised to include nanotechnology information to be truthful and not misleading. So far, FDA has not required manufacturers to revise labels to list nanomaterials. Food companies, in particular, oppose such policies for fear that nanofoods would be rejected like genetically modified and irradiated foods. But the current tendency toward "stealth" nanotechnology bothers many scientists and consumer advocates who believe that proper safety testing and access to nanosafety data will reduce public concerns.

A related controversy is whether an approved drug that is reformulated to contain nanomaterials should be retested and re-evaluated as a new product. FDA has not imposed such requirements on new drug formulations such as the many sunscreens with nanoemulsions and nanoscale versions of titanium oxide and zinc oxide that make the creams clean on the skin. But some experts believe that adding nanomaterials to a product makes it so different as to warrant more extensive regulatory review.

Manufacturing challenges

At its September public meeting, FDA heard comments from biomedical companies and scientists about what factors should be considered in crafting guidance for developing safe and effective drugs containing nanoscale materials. Of particular interest to FDA is whether the manufacturing process for drugs with nanomaterials is unique or different from that for other drugs, whether added parameters should be measured, whether nanoscale materials raise new concerns during production scale-up, and how such materials might alter product standards and specifications. The underlying question is 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 nanodrugs poses new challenges. Manufacturers need appropriate tools and methodologies to assess product chemistry and unique characteristics such as primary particle size, aggregation or agglomeration state, two-dimensional 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, and that product-quality measures relate to product performance.

David Hobson of nanoTox (Austin, TX) explained that nanomaterials have a much higher surface-area-to-weight ratio than conventional materials, and this property can affect mechanisms of action, biodistribution, and pharmacokinetics. Stability testing for nanomaterials should follow international guidelines, but more extensive stability assessment may be necessary because nanomaterials can change under different storage and handling conditions, he noted. In assessing product safety, manufacturers should consider whether parameters and storage temperatures may need to be adjusted based on particle size, shape, surface area, and potential for forming aggregates.

Webber acknowledged at the July 2008 advisory-committee meeting that characterization and quality control of nanotechnology products raise unique concerns. Traditional safety studies for biodistribution, clearance, metabolism, and toxicology may be affected by pro-ducts that remain in the body longer and behave differently. FDA wants to discuss the safety and efficacy of nanoproducts early in development and is encouraging manufacturers to meet with staff to address these issues. CDER is developing a database of approved products and those under review that use nanotechnology to better assess what data are available and what are needed. The agency also is establishing a process that will allow reviewers of new drug applications to detect and track nanotechnological information.

Spurring innovation

The enthusiasm for nanotechnology stems from its potential to create new medicines that are safer, more effective, and less expensive than traditional therapies.

Now researchers hope to discover new cancer therapies that are more soluble, more targeted, and less toxic than current drugs, explains Larry Tamarkin, CEO of CytImmune Sciences, which is conducting research on anticancer drugs that use colloidal-gold nanoparticles. élan (Dublin) is developing nanocrystal technology that allows the formulation of highly soluble drug ingredients for oral, parenteral, and inhaled drug products. FDA approved a nanoenabled molecular diagnostic platform for warfarin sensitivity testing last year. Nanomaterials are being tested as possible vectors for delivering gene therapies to patients, and nano tissue engineering combines stem cells and nanolattices.

The emergence of nanotechnological drugs fits the broader shift toward personalized medicine, which would offer treatments tailored to reach specific targets and patients most likely to respond positively. Drug-delivery applications using nanoparticle platforms and nanotechnological diagnostics that quantify disease-related biomarkers are important for identifying precise medicines to fit patient needs, said Nakissa Sadrieh, OPS's deputy director for science who monitors nanotechnology drug-development issues at CDER. The hope is that targeted drugs may require less frequent dosing, enhance safety profiles, and improve patient compliance, Sadrieh explained. Manufacturers, moreover, may be able to extend the life of existing drugs and enhance patent protection by reformulating drugs to incorporate nanomaterials.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com

For more on this topic, see "FDA Collaborates on Nanotechnology Research".