FDA Panel Can't Decide Whether Agency Should Issue Nanotechnology Guidance

Do nanotechnology-derived drugs merit their own GMPs? That remains an open question, say FDA advisors, unsure whether nanoguidance is warranted.

FDA's request for advice from its Pharmaceutical Science and Clinical Pharmacology Subcommittee on whether to issue guidance on nanotechnology-derived drugs resulted in an evenly split vote.

FDA was given mixed signals by its Pharmaceutical Science and Clinical Pharmacology Advisory Committee as to whether the agency should issue a guidance on nanotechnology-derived drugs. Half of the advisory panel members voted against the idea and the other half voted for it.

Most of the members who voted against the guidance at the July 22 meeting said that not enough information about the characteristics of these drugs, how they respond in humans and how they are manufactured is known for the agency to issue guidance. And a few who voted against the guidance said that existing regulations governing drug safety, efficacy and quality are sufficient and that a new regulatory framework is not necessary.

In the meantime, two industry representatives explained to panel members how they have developed - or are developing - two nanomedicines under existing regulations. The different uses and manufacturing approaches to nanotechnology-derived drugs, ranging from a drug delivery system to a therapeutic, were also explained to panel members.

Nanotechnology Impasse

The split vote by the committee is indicative of the uncertainty that has persisted for years as to exactly how nanotechnology derived products are different from conventional products and whether they should be regulated any differently.

Part of the problem, agency officials acknowledge, is that the agency does not yet have enough regulatory experience in dealing with these products because there are so few of them. For example, they point out that the agency still does not yet have a formal definition of what constitutes a nanotechnology drug.

In the absence of a formal definition, the agency generally defers to the National Nanotechnology Initiative definition, which defines these products as between one and 100 nanometers in scale.

Officials estimate that there are roughly 12 to 15 nanotechnology-derived products on the market, but that without a standard definition it is hard to pinpoint an exact number. These marketed products include both prescription and over-the-counter drugs, and include cancer drugs, sunscreens and contrast agents used for imaging, based on nanoscale particles.

Another problem pointed out in a 2006 report issued by the Woodrow Wilson International Center for Scholars is that FDA lacks the necessary resources to build its own expertise to evaluate new nanotechnology products. The report, "Regulating the Products of Nanotechnology: Does FDA Have the Tools it Needs?" was written by Michael Taylor, who was a deputy commissioner of policy at FDA during the Clinton administration.

A subsequent report released by the FDA Nanotechnology Task Force in July 2007 acknow­ledged the lack of information about nanotechnology as a barrier for moving forward with regulations. The task force, comprised of FDA officials, was formed in August 2006 to determine the appropriate regulatory framework for these products.

The task force noted that "nanoscale materials present regulatory challenges similar to those posed by products using other emerging technologies. However, these challenges may be magnified both because nanotechnology can be used in, or to make, any FDA-regulated product, and because, at this scale, properties of a material relevant to the safety and (as applicable) effectiveness of FDA-regulated products might change repeatedly as size enters into or varies within the nanoscale range."

Despite these challenges, FDA is forging ahead in its attempts to get some examples from manufacturers on how they are developing their products and what type of guidance they need from FDA in this nascent field.

CDER's Office of Pharmaceutical Science (OPS) Director Helen Winkle announced at the outset of the meeting that "CDER continues to grapple with how best to regulate these nanomaterial-containing products and whether our current regulatory requirements are adequate for the evaluation of such products now and in the future. The presentations will provide information on state-of-the-art applications in the field of drug delivery, pharmaceutical product development and manufacturing. The discussion will focus on issues that need to be addressed by the FDA regarding nanomaterial-containing products, their safety, their manufacturing, and the regulatory procedures involved in the approval of such products."

The panel was asked to consider whether CDER guidance was needed for the development of nanotechnology derived drug applications.

Keith Webber, deputy director of OPS, observed that "some of the challenges we have in dealing with these products is related to product quality assessment. How do you characterize what technologies are needed to characterize nanotechnology products? What are the relevant characteristics of nanotechnology products? For drug manufacturing how do you ensure the quality of those products to ensure consistent lot-to-lot quality? And then what is the bet way to manufacture these products?"

Webber noted that FDA was going to hold a public meeting on Sept. 8 as a next step to getting guidance on center-specific nanotechnology issues. CDER, however, will focus mainly on characterization, instrumentation and manufacturing.

Current GMP Requirements Seen As Adequate

Two industry presenters that have developed and are developing nanotechnology derived products told panel members that the current regulatory framework for assessing safety, efficacy, quality and purity is adequate for nanoparticles.

Stephen Ruddy, senior director of pharmaceutical development for Elan NanoSystems, which has developed and patented the use of NanoCrystal technology in four FDA-approved drugs, explained that nanoparticle-derived drug products are promising new therapies because they offer an alternative to poorly water-soluble drugs.

Ruddy estimates that about 40 percent of all new drug compounds fail in development because they are insoluble, and "many of these drugs suffer from poor bioavailability."

He noted that "nanoparticle engineering offers significant potential to improve the delivery performance of poorly water-soluble drugs, and hence the treatment outcomes of patients who will benefit from these novel drug products… for readily permeable compounds a reduction in particle size can translate to substantial improvement in the rate and extent of oral absorption."

Elan NanoSystems has manufactured four nano­medicines for pharmaceutical companies. These approved drugs include Wyeth's Rapamune , Merck's Emend , Par Pharmaceuticals' Megace , and Abbott's Tricor .

The NanoCrystal technology transforms drugs into nanometer-sized particles that can be used to create tablets, capsules, liquids and powders. The technology uses a wet-milling technique to reduce the drug crystal size to 1,000 nanometers. At this small size, the greater surface area of the crystals increases the solubility of the drug.

He explained that engineered nanoparticles are produced through spray freezing into liquid (SPL), emulsification, precipitation with a compressed fluid antisolvent, rapid expansion from a liquefied-gas solution, evaporative precipitation into aqueous solution, high-pressure homogenization, microfluidization and high-energy wet milling.

Ruddy said that "I am pleased that Dr. Webber in one of his earlier slides showed the spectrum of nanotechnologies currently in development. …We have a very broad spectrum of technologies in nanomedicine ranging at one end of the spectrum from technologies that involve highly complex structural particles. In many cases these particles are truly insoluble and in many cases they have broad-based functionalities such as passive or active drug targeting and the ability to get into the cell body itself."

Ruddy acknowledged, however, that "there are potential challenges to developing nanoparticle products." These include particle agglomeration, or oversize particles; controlling particle size growth, changes in particle morphology, changes in polymorphic forms, process-related impurities as well as media attrition. There is a lack of a universal particle counting method across all the sites.

In order to properly characterize nanoparticles, manufacturers need to evaluate particle size distribution, solid-state properties, dissolution behavior, microbial limits testing for aqueous products or product intermediates, application specific methods including route of administration and technology specific methods that are unique to the formulation.

Despite the different nature of these products compared to macroparticles, Ruddy told the panel that "FDA's current requirements for assessing safety, quality and efficacy appear adequate for evaluating nanotechnology-derived products. Future evolution of more complex nanotechnologies, however, will likely drive the need for periodic evaluation of FDA policy and procedures for regulating nanotechnology based drug products."

Bottoms-Up or Top Down?

Lawrence Tamarkin, the CEO of CytImmune, explained how the nanotechnology drug being developed by his company is different from the NanoCrystal system in that it works more like a drug delivery system while NanoCrystal is designed to make a therapeutic drug, just in a smaller form.

Yet despite these differences, he agreed with Ruddy that FDA should use the same regulatory framework for nanomaterials as it uses for conventional drugs.

Tamarkin explained that the company just completed phase I animal studies for its nanomedicine Auroimmune , a cancer drug. The phase I studies conducted in the spring showed positive results in shrinking cancer tumors in dogs. Phase II human studies are expected to start shortly.

The drug, which is a protein tumor necrosis factor, is attached to gold nanoparticles that are carried through the bloodstream to target cancer cells.

He explained that while "there is nothing new here…colloidal nanoparticles have been around for many years, particularly for the treatment of rheumatoid arthritis." The difference is that with the new use, the colloidal drug will be used more like a drug delivery systems to deliver the tumor necrosis factor to the tumor. Past uses of colloidal gold involved its direct use for treating rheumatoid arthritis.

Tamarkin noted that "in manufacturing these nanomedicines each particle has to be constructed the same way so when it is injected systemically into the body the particles need to be small enough to traverse the body to avoid detection but big enough so that they can enter the systems through healthy normal blood vessels and then exit the system….This is the core of what the nanomedicine is all about."

Tamarkin also drew a distinction between the ways Aurimmune and NanoCrystals are manufactured.

Aurimmune uses a bottoms-up approach as it involves the assembly of gold and drug nanoparticles in the vessel, the binding of the two components, the bulk final product and the lyophilization; whereas the technology employed by NanoSystems uses a top-down approach because the process involves the breaking down of large particles into smaller components.

Tamarkin further noted that "in our case we need to understand the amount of gold because the ratio of gold is absolutely critical to make sure that we have a properly manufactured product…We also have to make sure that we understand our immune-avoiding particle, in this case polyethylene glycol, and what's happening with that."

The company contracted in April 2008 with the University of Maryland's Biotechnology Institute to manufacture these products.

FDA Nanomedicine Safety Standard Suggested

One presenter, Darin Furgeson, assistant professor of Pharmaceutical Sciences at the University of Wisconsin at Madison, addressed some of the preclinical issues associated with nanomedicines.

He said that current FDA requirements governing preclinical assessment are "insufficient" for these products. He drew from his research in nanotoxicity showing abnormalities in zebrafish after exposure to small amounts of nanoparticles.

Furgeson noted that "part of the problem is the exponential growth in nanotechnology coupled with the lack of concomitant screening assays. There is a lack of an in vitro model correlative to in vivo systems for predicting nanotoxicity. "

Despite these concerns, Furgeson urged the panel to move ahead quickly and adopt a new regulatory framework for nanomedicine.

"People working in nanotechnology are so far ahead and there are people trying to catch up with respect to development issues. We're years behind….there is increasing political and economic pressure to deliver nanotechnology to the marketplace…nanomedicines are on the horizon and substantial investment and time is needed to bring drugs to the market. FDA hesitance will stifle commercialization of these products."

Committee Split on Whether Guidance Needed

In response to these presentations, the committee had a split 5-5 vote, with one abstention, as to whether FDA CDER guidance is needed for the development of nanotechnology-derived drug applications.

Most of the members who voted against developing a guidance said that there is still not enough good information out there in terms of how nanotechnology is covered under the existing regulations and that there is still a lack of adequate information on nanotechnology.

Elizabeth Topp, a professor in the department of pharmaceutical chemistry at the University of Kansas, said that "one of these questions that you have to ask is if nanosize materials are so unique that they do not all under the existing regulatory considerations. Are there unique characteristics that are not being captured if we submit them through existing pathways? I don't know the answer to that question."

Marvin Myer, professor emeritus of the department of pharmaceutical sciences at the University of Tennessee College of Pharmacy concurred that "I try not to vote on something I have no information on. What does FDA already do? I don't know how many of these problems are already covered by FDA."

Myer further observed that "in my opinion [Ruddy's] presentation really sounded like a dosage form that is already covered. It is smaller but it is more conventional than the first presentation, which sounded like a more complex dosage form."

Ken Morris, professor of pharmaceutics at the College of Pharmacy at the University of Hawaii, concurred that "a premature guidance does more harm than good."

A few members voted against the guidance on the grounds that existing regulations cover nanomedicine, so a new guidance is unnecessary.

Arthur Kibbe, the pharmaceutical sciences chair at the Nesbitt School of Pharmacy at Wilkes University, said that he voted against guidance because in his view, current GMPs testing and evaluations already cover nanoparticles.

"There is nothing dramatic in my mind how we do anything any different from GMPs and evaluation that are not already codified and if you follow a good science process…Companies that take a unique or have a novel approach will know far more about their approach than any regulator…I don't think you need a new guidance to get people to come in and do this."

- Joanne S. Eglovitch ([email protected])