Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

More details are needed, but developers now have a better idea of what constitutes nanomaterials.

The naked eye cannot see particles that are a billionth of a meter, or a nanometer. Yet the FDA is trying to get its arms around them, so to speak, in hopes of defining for biotechnology companies and others whether FDA-regulated products contain nanomaterials or otherwise involve the application of nanotechnology.

FDA recently issued a draft guidance titled “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology” and has launched a 60-day comment period on it. “The guidance is intended to help industry identify when they should consider potential implications for regulatory status, safety, effectiveness, or public health impact that may arise with the application of nanotechnology in FDA-regulated products,” Jeff Ventura, an FDA spokesman, told GEN.

In the draft guidance, FDA stated that it will determine whether products contain nanomaterials or involve the application of nanotech by their properties and size. FDA will ask whether engineered materials or their end products have at least one dimension ranging from 1 to 100 nm. The agency will also check whether they exhibit physical or chemical properties or biological effects attributable to its dimensions, even if they fall outside the nanoscale range, going up to one micrometer.

The agency noted that it may issue further guidance to address considerations for specific products or classes of products. “The critical element is that size matters in biological systems,” Frank J. Malinoski, M.D., Ph.D., CMO for Liquidia Technologies, told GEN. “We need to know which sizes are important for which biological or chemical effects.”

The Push to Regulate

In May 2006, the International Center for Technology Assessment and Friends of the Earth presented the FDA with a citizen petition to require labeling of all nanomaterials in consumer products. Then on October 5, 2006, the Woodrow Wilson Center for International Scholars issued a report by former FDA deputy commissioner for policy Michael Taylor, which concluded the agency lacked the legal tools, let alone the resources, needed to regulate nanotech products, especially in cosmetics and dietary supplements. Taylor is now deputy commissioner for foods at the FDA.

Five days after Taylor’s report, FDA convened the first meeting of the the Nanotechnology Task Force, which had been set up earlier that year. It found that the agency needed to improve its scientific knowledge of nanotech and needed to evaluate current tools for describing and evaluating nanoscale materials. The task force, however, offered little in the way of guidance except for the meek conclusion stating that there was a need for “timely development of a transparent, consistent, and predictable regulatory pathway.”

FDA released its first “draft guidance” on June 9 of this year, the day three Obama administration agencies—the offices of Management and Budget, of Science and Technology Policy, and of the U.S. Trade Representative—put out a set of policy principles for regulating and overseeing nanotechnology and nanomaterials.

The heads of all three agencies included in the principles a subtle pitch for President Obama’s plan to boost spending for the National Nanotechnology Initiative (NNI), calling it “one of the Obama Administration’s top science and technology priorities.”

NNI coordinates the individual and cooperative nanotechnology-related activities of 25 federal agencies. Its budget is the sum of the R&D budgets of 15 agencies. It has spent $14 billion on nanotech R&D since the 2001 fiscal year. NNI saw funding dip under the FY 2011 budget agreement crafted in April to $1.76 billion from $1.9 billion in FY 2010.

President Obama has proposed $2.1 billion for NNI in his $3.8 trillion budget for the fiscal year starting Oct. 1. The prospects of that happening are uncertain at best; the budget won’t be decided until Congressional leaders hash out spending cuts to eliminate now-annual trillion-dollar deficits. So far, that process has yielded little more than Obama’s proposed budget, the Republican-approved deficit reduction plan unveiled by Rep. Paul Ryan (R-WI), and much partisan sniping.

Agency’s Definition of Nanotech

The draft stated, “A range of approximately 1 nm to 100 nm should be applied as a first reference point in considering whether an FDA-regulated product contains nanomaterials or otherwise involves application of nanotechnology.”

Nanomaterials could also be larger or combine into agglomerates that exceed 100 nm. FDA addressed that as well in the draft guidance: “The agency considers that an upper bound of up to one micrometer (i.e., 1,000 nm) would serve as a reasonable parameter for screening materials with dimensions beyond the nanoscale range for further examination to determine whether these materials exhibit properties or phenomena attributable to their dimension(s) and relevant to nanotechnology.”

“A lot of the products that the FDA would have jurisdiction under, a lot of those products have agglomerates of nanomaterials in the final product,” Todd Kuiken, Ph.D., research associate for the Project on Emerging Nanotechnologies at the Woodrow Wilson Center for International Scholars, pointed out to GEN.

James R. Baker Jr., M.D., CEO and founder of NanoBio®, offered this perspective to GEN: “Practically, it helps to clarify things by defining a little more broadly what they’re considering. But for a company like us, we have to go through standard toxicity testing, so it really doesn’t change the game.”

Founded in 2000 as a spin-out from the Center for Biologic Nanotechnology at the University of Michigan, NanoBio develops and commercializes dermatological products, anti-infective treatments, and intranasal vaccines, all based on its NanoStat™ platform.

Last month NanoBio reported the start of two Phase III multicenter trials evaluating its NB-001 as a topical treatment for cold sores, a step forward in the company’s OTC licensing agreement with GlaxoSmithKline Consumer Healthcare. The trials of NB-001 will be conducted in 1,700 subjects at 72 clinical sites and will evaluate the effectiveness of NB-001 to reduce cold sore healing time. The trials are expected to conclude next year.

Dr. Baker said the draft guidance’s acknowledgement that nanomaterials may be larger than 100 nm would prove helpful to many businesses. NanoBio’s NanoStat platform, for one, uses high-energy, oil-in-water emulsions manufactured at 150–400 nm and stabilized by surfactants.

More to Be Considered

“There is no one nanotechnology,” Dr. Baker asserted. “Thus nanomaterials, even in the same size range, act very differently. Essentially, they’re just going to have to consider these one-on-one and not make any blanket statements about them.”

Dr. Malinoski of Liquidia added: “One of the critical elements will be, ‘How well can we measure those? How reproducibly? What’s your distribution of particles, and what do different particle sizes do to affect the biological result you’re trying to achieve? How can you distinguish something 10 from something 20, 40, 60, 100 nanometers?”

Also very important, Liquidia chairman Seth Rudnick, M.D., added, is shape. FDA addressed this by saying “manufacturing changes alter the dimensions, properties, or effects of an FDA-regulated product or any of its components.”

Dr. Rudnick remarked, “all of us are trying to define what is a nanostructure that is biologically relevant and important. That probably will be dependent on both size and shape, something we think Liquidia is uniquely positioned to be able to explore but that other companies will be exploring with the agency over the next few years.”

Liquidia is a developer of vaccines based on engineered particles capable of delivering small molecule and biologic therapies to an intended target. Its platform technology is called Particle Replication in Non-Wetting Templates. Those particles can range from tens of nanometers to hundreds of microns.

Liquidia reportedly established a dialogue with agency regulators as it was developing its technologies, starting with lead candidate LIQ001, a seasonal flu vaccine. LIQ001 began Phase I testing last year. “Our first IND was submitted, went through without any regulatory stops, so that we got from concept into the clinic in 18 months,” Dr. Malinoski said. “And part of that was because we saw the need to be proactive and to help educate those reviewers at the agency who were looking at this nanotechnology for the first time.”

FDA hopes other companies follow suit, whether or not they are pursuing required premarket reviews. “Where products applying nanotechnology are not subject to premarket review, the agency urges manufacturers to consult with the agency early in the product development process. In this way, any questions related to the regulatory status, safety, effectiveness, or public health impact of these products can be appropriately and adequately addressed,” the draft guidance advised.

As FDA acknowledges, the draft guidance is just the beginning of its thinking on how to ensure that nanotech-based products are safe and effective. To the extent they address these two qualities, the guidance should provide a valuable roadmap for nanotech-based drug development.

A heavier-than-needed hand by FDA when it comes to regulation, however, creates potential for something else: as Dr. Malinoski put it, “getting so bogged down in guidances that we focus on guidance instead of bringing new products forward.”

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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