Regulatory Beat: Nanotechnology Presents Opportunities and Challenges for FDA and Manufacturers

Nanotechnology is a highly promising approach to improving the design and manufacture of more targeted and less toxic therapies. Nanomaterials—any material that is less than 100-millionths of a millimeter in size—are being used in many consumer and industry products, including a growing number of drugs and diagnostics. Such tiny particles can increase product stability and enhance absorption and elimination. Most important, the ability of nanoparticles to pass more easily through cellular membranes and tissues is raising high hopes for developing cancer therapies capable of delivering drugs to targeted tumor cells, with less damage to healthy tissues and fewer toxic side effects.

Jill Wechsler

As part of its Critical Path Initiative, launched in 2004, the US Food and Drug Administration is encouraging public-private collaborations to more fully explore the physical and chemical characteristics of nanoparticles. The goal is to develop new test methods, characterization protocols, and standards that will help manufacturers move nanoproducts from preclinical testing to commercialization.

GREAT POTENTIAL

The federal government spends more than $1 billion a year on its National Nanotechnology Initiative, established in 2001. Some of this funding supports the National Institutes of Health Roadmap Initiative, launched in September 2003, to discover how nanotechnology can enhance our basic understanding of biological concepts and cellular processes. National Cancer Institute officials are particularly enthusiastic about the great potential of nanotechnology to detect cancer at very early stages. Such methods could enable clinical trials to assess efficacy in anticancer therapies much earlier. And "smart" nanotherapeutics could time the release of a drug or deliver multiple drugs sequentially, as well as provide sustained therapy for chronic cancers.

Biomedical nanoscience strategies may facilitate gene therapy development, which has been stymied by difficulties in finding suitable transport agents to carry nucleic acid to the diseased target cell. New nanoscale structures designed to bind and neutralize anthrax toxins may protect people from infectious diseases. Researchers at Montana State University are using disarmed viruses and protein "cage" technology to deliver therapeutic and imaging agents to specific tissues, an approach that may have multiple applications for carrying antibodies, peptides, and other therapies to cells.

FDA has approved nanoscale liposomes and microemulsions, as well as magnetic resonance imaging agents and targeting agents. A treatment for metastatic breast cancer, Abraxane, (Abraxis BioScience, www.abraxisbio.com) uses human albumin to create nanoparticles of Taxol (paclitaxel); the resulting injectable suspension does not require any solvent and thus reduces serious side effects and permits a higher doses for patients. Similarly, Cell Therapeutics of Seattle, WA (www.celltherapeutics.com) is testing a nanotherapy for lung cancer (Xyotax) that binds Taxol to a polyglutamate polymer, to more efficiently deliver the drug to tumor cells.

REGULATORY CONCERNS

These developments are expected to yield more combination products with multiple components, including a delivery system, therapy, and imaging agent. Such complex therapies will challenge FDA's Office of Combination Products in determining the primary mode of action, of which the FDA center has primary regulatory oversight. FDA's Office of Science and Health Coordination oversees nanotechnology activities throughout the agency, including its participation on government-wide nanotechnology committees.

As more nanotherapies and diagnostics move from laboratories to commercial development, FDA officials recognize the need for more guidance for manufacturers and added scrutiny of related safety issues. Such concerns have emerged with the appearance of multiple sunscreen products featuring nanoformulations that render them transparent and more easily absorbed by the skin.

Call for papers

A coalition of environmental and health organizations, led by Center for Technology Assessment, considers these products to be dangerous. The group filed a petition with FDA in May 2006, calling for the agency to pull all over-the-counter nanosunscreens off the market until manufacturers can prove they are safe. The petition seeks new regulations for drugs containing nanoparticles, along with changes in FDA's 1999 sunscreen monograph to require additional analysis of nanoparticles in these products and labeling all nanoingredients.

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.

MANUFACTURING CHALLENGES

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