Manufacturing challenges
Efforts to ensure the safety of nanomaterials also require manufacturers to assess fully how nano-sizing drugs affects their
dissolution rate, solubility, and onset of therapeutic action. Although these features may permit lower dosages and simplify
administration, they also can raise concerns about safety and product quality.
A prime challenge for manufacturers is to ensure reproducibility and quality of nanotechnology products. Critical quality
attributes include:
- particle size and size distribution;
- surface area, surface chemistry, porosity;
- hydrophilicity, surface-change density;
- purity and sterility;
- stability (aggregation, protein interactions).
Issues to consider during nanotechnology product characterization
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Characterization of nanotechnology products may raise unique considerations (see sidebar, "Issues to consider during nanotechnology
product characterization"). Manufacturers must identify available tools for assessing the critical physical and chemical properties
of the products, including residual solvents, processing variables, impurities, and excipients. Validated assays are important
for detecting and quantifying nanoparticles in tissues and medical products and for determining how physical characteristics
may affect product quality and performance.
All of these issues are important in demonstrating full control of a production process and justifying drug-release parameters
and bioequivalence-testing approaches, Sadrieh points out. The process of developing test methods and specifications that
clearly can control product and process to scale up to mass production may be complicated by a lack of reference materials
and standards. Additional standard test methods may be needed to develop nanoparticles for drugs and biologics.
To assist manufacturers in developing appropriate safety and quality-control methods and to ensure appropriate regulatory
strategies, FDA is conducting laboratory research to understand better the ability of preclinical screening tests to identify
potential risks and toxicities. CDER scientists are examining the effect of particle size on sunscreens that contain zinc
oxide and titanium dioxide nanoparticles, as well as issues related to the manufacture of nanoformulations and the characterization
of physical and chemical properties. Tests are being conducted to determine whether excipients or different process and formulation
variables may affect nanotechnology product characteristics, overall stability, and bioavailability. The Center for Biologics
Evaluation and Research is developing a nanoparticle-based assay for detecting blood-borne viruses and for testing blood-cell
compatibility of nanomaterials. Additional FDA research is evaluating skin penetration (in humans and animals) of nanoparticles
in sunscreens.
The future of nanotechnology
At FDA's Science Forum in April, a panel of scientists discussed various nanotechnology developments affecting drugs and medical
products. The researchers addressed factors related to toxicity and preclinical characterization of nanomaterials as part
of an overview of emerging applications of nanotechnology for biology, imaging, and medicine.
FDA expects that nanotechnology will yield more combination products with multiple components, including a delivery system,
therapy, imaging agent, and targeting agent. Such complex products will create challenges for FDA's Office of Combination
Products in determining the primary mode of action, which is the basis for assigning products to a lead Center for application
review.
In addition to the cancer agent Abraxane, FDA has approved nanoscale liposomes and microemulsions as well as MRI imaging agents
and targeting agents. One antibacterial wound dressing incorporates silver nanoparticles, and a nano-based dental restorative
has been created. FDA anticipates more nano-based new drugs and imaging agents will be on the way soon. Its Office of Science
and Health Coordination oversees nanotechnology activities throughout the agency, including its participation on government-wide
nanotechnology committees. CDER also has established a Nanotechnology Working Group to develop position papers and identify
regulatory concerns in this area.
These issues are slated to be discussed in October at an FDA public meeting about scientific and regulatory issues related
to products containing nanotechnological materials. The meeting will fit FDA's Critical Path Initiative, which aims to identify
scientific hurdles that may inhibit the use of nanotechnology in medical product development. FDA hopes attendees will report
on new nanotech drugs, on what scientific issues FDA should address, and on other regulatory concerns.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634,
jwechsler@advanstar.com
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