Nanotechnology-based medicine is still in its infancy, but to date, the Food & Drug Administration has received more than 150 applications for new drugs that contain nanomaterials. The types of nanomaterials, the diseases they are designed to treat, and the way they are administered vary widely.
FDA’s information about nanomaterials in drugs also varies considerably. Drug applications do not contain consistent data, particularly with respect to characterization of nanoparticles, and FDA has found several gaps in the data. In some cases, data are insufficient for FDA to even determine whether a product contains nanomaterials.
To get a clear picture of the current landscape of nanotech drugs, FDA’s Center for Drug Evaluation & Research (CDER) is building a database using information collected from drug applications. FDA scientists are also performing research to better understand the characteristics of drug products that contain nanomaterials, and they are conducting an in-depth risk assessment to optimize the drug review process for nanotech products.
FDA staff presented preliminary results of those efforts last month at a meeting of FDA’s Pharmaceutical Science & Clinical Pharmacology Advisory Committee.
“In general, drugs that use nanotechnology are either new molecular entities that are formulated with components in the nanoscale, or they are reformulations of already approved products,” said Nakissa K. Sadrieh, associate director for research policy and implementation at CDER. Decreasing the size of particles in a drug formulation can enable targeted delivery, improve absorption or distribution of the drug, provide a more convenient dosage form, and ultimately lead to better patient compliance, Sadrieh pointed out to the committee.
Thus far, FDA’s database of nanotech drug products lists several different types of nanomaterials including liposomes, nanoparticles, nanocrystals, micelles, supermagnetic iron oxide, nanoemulsions, colloidal metals, and dendrimers. But that list does not include every nanomaterial that can be used in drugs, Sadrieh stressed. To create the database, FDA searched its drug applications for keywords, which were identified through a literature search of nanomaterials associated with drug particles, she explained.
The database currently contains information from 158 drug applications. Of those, 128 are Investigational New Drug Applications, which are typically filed before clinical testing, and 30 are New Drug Applications for candidates that have been through clinical testing.
Most of the drugs in the database are intended to treat cancer. “This mirrors what we’ve seen in the literature,” Sadrieh noted. Other nanotech drugs in the FDA’s database are designed for pain, infections, magnetic resonance imaging, anemia, diabetes, and immunosuppression.
The majority of the drugs in FDA’s nanotech database are administered intravenously. “The only category where that is not the case is nanocrystals,” Sadrieh noted. Nanocrystals are designed to turn a nonoral formulation into an oral formulation, she said. Nearly a quarter of products in the database are administered orally.
Because nanomaterials can be characterized by several different methods, data are often reported differently from one nanotech product to the next. “Since there are no requirements, there isn’t really a consistent fashion for reporting the data,” Sadrieh said.
Even the size of nanoparticles is reported differently, Sadrieh emphasized. Drug manufacturers provide a mean particle size, a mean range, a mean plus or minus a standard deviation, or no data at all, she noted.
Overall, 98% of the nanotech drug products in FDA’s database have some information about the size of nanoparticles, Sadrieh noted. But more than half of them do not have information about the method used to determine particle size, she said. Dynamic light scattering was used to measure particle size for nearly 25% of the products, and laser diffraction was used for about 10%. Ideally, more than one method should be used to measure particle size so that impurities can be distinguished from other particles of interest, Sadrieh commented.
Information about the size of particles is important because a change in particle size can affect product performance. “We want to have a better understanding of the effects of particle size on bioavailability and dissolution,” noted Elaine Morefield, deputy office director for review and administration at CDER. “This is especially important if you have low-solubility drugs,” she said. Typically, the smaller the particle size, the faster the rate of dissolution.
Another important property of nanomaterials is the ability to cluster or form aggregates of nanoparticles that are chemically bound to each other. Aggregates can also join together through physical forces to form micrometer-sized agglomerates. When nanoparticles self-associate and form large superstructures, their biodistribution changes, warned Katherine M. Tyner, a chemist in FDA’s Division of Drug Safety Research.
Tyner and colleagues studied the biodistribution of nanostructures administered to laboratory animals. They found that different structures went to different organs, different cells within organs, and different places within cells. The biodistribution varied “down to the subcellular level simply by changing the agglomeration/aggregation status of these materials,” Tyner said.
FDA scientists are examining the potential for interactions between nanomaterials in a drug formulation and excipients—inactive substances typically used as carriers of active pharmaceutical ingredients. They are also investigating the potential risks of nanosized excipients themselves.
So far, FDA has found that the risks of nanosized excipients are similar to those for a nanosized active ingredient. “However, we don’t always monitor the particle size of excipients,” Morefield said. “We may not know that there is a nanosized excipient. Not knowing causes difficulty in evaluating.”
Meanwhile, CDER scientists have begun a detailed assessment of FDA’s drug review process to determine whether it is suitable for products that contain nanomaterials. “We feel that current review practices are adequate,” particularly when a nanomaterial is included in a formulation early in the drug development stage, Morefield told the committee. But when a drug is reformulated to contain nanomaterials after Phase III clinical trials, there are potential problems with risk, she said.
FDA staff have already identified a few areas in the review process that could be improved for drugs containing nanomaterials. For example, they discovered that traditional analytical methods may not be adequate to identify or properly characterize nanomaterials. “This is especially true in physical testing and in vitro dissolution methods,” Morefield pointed out. “Filtration is frequently used in the dissolution test to keep particles out of the bath. However, most filters currently used in dissolution methods would not be capable of removing nanosized particles.”
Other potential areas for improvement include clarifying what data are needed for safety evaluations, understanding the effects of nanoparticles on bioequivalency and dissolution testing, and training FDA reviewers to raise awareness of potential risks of nanomaterials, Morefield said.
For its part, FDA acknowledges that its review process for drugs containing nanomaterials isn’t perfect, but for now it says the process is sufficient. The products FDA is seeing are ones the agency knows how to regulate, Sadrieh noted. “The problem is, we don’t know what to expect in the future.”
FDA is planning to hold a public workshop in the coming months to get input from stakeholders on ways it can improve its review process to be better prepared for the onslaught of nanotech drugs coming down the pike.