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.
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.
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, firstname.lastname@example.org
For more on this topic, see "FDA Collaborates on Nanotechnology Research".