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.

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".