Many of the issues raised in the CTA petition have been under scrutiny at FDA for some time. Nanomaterials have been used in the R&D process for drugs and biologics for many years to enhance biological markers, probe DNA structures, purify biological molecules, enhance MRI imaging agents, and develop drug delivery mechanisms, explains Nakissa Sadrieh, associate director for research policy in the Office of Pharmaceutical Science of the Center for Drug Evaluation and Research (CDER). However, FDA has not detected any safety concerns related to particle size in drug products and believes that existing requirements for preclinical testing can uncover safety problems specific to nanomedicine.

At the same time, FDA recognizes that nanoparticles in drugs and cosmetics may gain access to tissues and cells more easily and that there is little information on how long nanoparticles remain in the body, how they are cleared from tissues and blood, and whether they have additional effects on cellular functions or on different cell types. The agency advises manufacturers to assess any differences in the absorption, distribution, metabolism, and excretion profile of nanoparticles compared with larger particles of the same drug, including whether they have accurate methods for measuring drug levels in the blood and eventual clearance.

FDA would like more research conducted on whether inhalation of nanoparticles raises specific safety issues, if local sensitization arises from subcutaneous injection of nanoproducts, and whether dermal applications could spread to local lymph nodes. To assist manufacturers in developing appropriate safety and quality control methods, and to ensure appropriate regulatory strategies, FDA is conducting in-house laboratory research to learn more about the ability of preclinical screening tests to identify potential risks and toxicities. CDER scientists are examining the impact of particle size on sunscreens, as well as issues related to manufacture of nanoformulations and characterization of physical and chemical properties. Tests are being conducted on whether excipients or different process and formulation variables may affect nanotech product characteristics, overall stability, and bioavail-ability. The Center for Biologics Evaluation and Research also is developing a nanoparticle-based assay for detecting blood born viruses and for testing blood cell compatibility of nanomaterials.

Efforts to ensure the safety of nanomaterials require manufacturers to fully assess how "nanosizing" of drugs affects dissolution rate, solubility, and onset of therapeutic action. Characterization of nanotechnology products may raise unique considerations. New tools may be needed to assess the critical physical and chemical properties of these products, including residual solvents, processing variables, impurities, and excipients.

A prime challenge for manufacturers is ensuring reproducibility and quality of nanotechnology products. Validated assays are important for detecting and quantifying nanoparticles in tissues and medical products and how physical characteristics may impact product quality and performance. All these issues are critical for demonstrating full control of a production process and for justifying drug release parameters and bioequivalence testing approaches, Sadrieh points out. Additional standard test methods may be needed to ensure appropriate formulation of nanoparticles for drugs and biologics.

At FDA's Science Forum, held in April 2006, a panel of scientists presented an overview of emerging applications of nanotechnology for biology, imaging, and medicine. They discussed a number of nanotechnology developments affecting drugs and medical products, including factors related to toxicity and preclinical characterization.

These issues are scheduled to be discussed at an FDA public meeting in October 2006 on scientific and regulatory issues related to products containing nanotechnology materials. The agency acknowledges that the small size and extremely high ratio of surface area to volume may alter chemical and physical properties of nanoproducts, compared with their larger counterparts. There may be differences in magnetic properties and electric, chemical, and biological activity. FDA hopes attendees will report on new nanotech drugs and other regulated products under development, what scientific issues FDA should address, and other regulatory concerns.

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