Xiaoming Xu, Ph.D., Senior Staff Fellow, Office of Testing and Research, Office of Pharmaceutical Quality, CDER

The use of nanotechnology in products regulated by the FDA has been ongoing for several decades and has included foods, cosmetics, medical devices and drugs. Within the purview of FDA’s Center for Drug Evaluation and Research (CDER), there is great diversity in drug products containing nanomaterials.

There has been a steady increase in the number of approved drug products containing nanomaterials, including investigational new drugs, new drug applications, and abbreviated new drug applications (commonly known as generics). More than 60 applications have been approved since the early 1970s, and interest continues to rise.

Drug products containing nanomaterials are unique in several ways because they may take on different chemical, physical, or biological properties compared to other types of drugs. In some instances, this may impact the quality, safety, or efficacy of the product. For example, drug products containing nanomaterials may follow a different pathway in the body compared to a small molecule drug. After a drug product formulated as a nanomaterial enters the bloodstream, it could interact with specialized immune cells called macrophages, which engulf and transport a drug to the location for which it has been programmed, such as where bacteria, fungi, or viruses reside. These areas are typically difficult to reach for a small molecule.

In another example, a drug formulated as a nanomaterial may have a special “coating” that prevents it from interacting with immune cells so that the drug can circulate in the bloodstream for prolonged periods of time until it reaches tumor tissues. The ability to target areas of the body and bypass others can significantly reduce the risk of side effects, such as toxicity to nontarget organs, and potentially increase the effectiveness of the treatment. For these reasons, nanomaterials are most frequently used in the treatment of cancer or infections. Formulations like liposomes, nanocrystals and nano-emulsions are among the most common types of drug products containing nanomaterials being approved.

Research to Address Challenges Related to Nanotechnology

For the last decade, the Office of Testing and Research (OTR) in CDER’s Office of Pharmaceutical Quality has been conducting research to better understand the manufacturing and quality issues associated with drug products containing nanomaterials with the aim to inform agency guidances and regulatory review. OTR is addressing challenges associated with developing new drugs using nanotechnology, and is establishing clear standards to pave the way for approval of future generics containing nanomaterials.

Current studies are focused on identifying the critical processes and material properties that can impact quality, and understanding quality within the context of efficacy and safety. For instance, if the manufacturing process is changed in some way, what impact will that have on drug quality? How does particle size, surface charge, and the amount of drug that is carried affect product quality? How stable is a nanomaterial like a liposome, and how does its stability affect quality? To what extent can manufacturing deviations, such as temperature changes or drying, impact particle size, distribution within the body, and overall stability? Manufacturers must select and implement the right quality control measures so that any variability can be captured and accounted for.

OTR studies also focus on evaluating the drug’s performance using advanced analytical methods, both inside the body (in vivo) and outside the body (in vitro) to determine how the drug is released from the nano carriers, and to establish the relationship between in vivo and in vitro measurements. By better characterizing how the drug is released when it gets to its target location, we can better evaluate product quality and its impact on safety and efficacy.

Another critical component of our nanotechnology research is to encourage the use of advanced manufacturing techniques to produce liposomes and other nanomaterials in a way that reduces variations in product quality. For the last five years, OTR has been collaborating with scientists at the University of Connecticut (grant numbers HHSF223201310117C, HHSF223201610121C and 1U01FD005773-01) to develop a platform for continuous manufacturing of nanomaterials, which should afford better control over the manufacturing and quality control process, and potentially lead to higher quality products.

Additionally, we are beginning to look at characterizing excipients (inactive ingredients) in some complex formulations. In nanomaterial formulations, excipients may play a more significant role compared to traditional pharmaceuticals, but their critical attributes are not yet well understood. We are collaborating with CDER’s Office of Generic Drugs to determine if current characterization tools and standards for excipients are sufficient to support generic product development, or if different ones are needed. This research is funded in part by the Generic Drug User Fee Amendments (known as GDUFA II). Currently, very few nanomaterial-containing drug products have generic versions on the market.

Providing Nanotechnology Guidance and Information

In 2014, the Nanotechnology Risk Assessment Working Group was convened to assess the potential impact of nanotechnology on drug products. The working group, which includes expertise from across CDER, is helping to develop standards for nanomaterials used in drug development and facilitate advancement of the technology. The working group determined that in most cases, current assessment practices are adequate for evaluating drugs that include nanomaterials, provided the drug applicant conducts appropriate studies early in the development process and implements a formulation control strategy to ensure consistent clinical results. 

In December 2017, CDER issued a draft guidance for industry, Drug Products, including Biological Products, that Contain Nanomaterials. More information about nanotechnology research at CDER is available here.

The Spotlight series presents generalized perspectives on ongoing research and science-based activities within CDER. Spotlight articles should not be construed to represent FDA’s views or policies.