Dr. Mino-Olivares: Welcome to the CDER Small Business and Industry Assistance (SBIA) Chronicles Podcast.
Today’s topic: Considerations for Drug Products that Contain Nanomaterials.
My name is Dr. Alexa Mino-Olivares and today we are joined by Dr. Andrei Ponta, a chemist in the Office of Pharmaceutical Quality, or OPQ, within FDA’s Center for Drug Evaluation and Research. Dr. Ponta will be discussing FDA’s recent guidance on Drug Products Including Biological Products That Contain Nanomaterials.
Thank you for joining us Dr. Ponta!
Dr. Ponta: Glad to be here. Thanks for having me!
Dr. Mino-Olivares: For those not familiar with nanomaterials, could you offer a brief overview of what this term means?
Dr. Ponta: Sure. Nanomaterials fall under the umbrella of “nanotechnology” which basically means a material that has one or more external dimension, or an internal or surface structure, within the nanoscale range. A nanometer is one billionth of a meter, and the nanoscale range is approximately 1 nanometer to 100 nanometers. Think of a few atoms together, for example three gold atoms. Most “nano” materials are a little bigger – in fact many organizations consider anything to be a nanomaterial if it has one or more dimensions under 100 nanometers. However, for regulatory purposes, the FDA considers a drug to contain nanomaterials if it is engineered for sizes up to a micron, or one thousand nanometers, as outlined in our recent guidance for industry, “Drug Products, Including Biological Products, that Contain Nanomaterials”.
Dr. Mino-Olivares: Why would a manufacturer be interested in developing products with nanomaterials?
Dr. Ponta: Nanomaterials may have different physical and chemical properties that change with their size, and nanomaterials may provide benefits with respect to safety or efficacy of a drug product.
For example, nanomaterials can serve as drug delivery systems. One type of nanomaterial we see is something called a liposome. Liposomes are essentially small spheres with sizes of around 100 nanometers, though different sizes have been manufactured. They are generally made of some sort of lipid such as cholesterol or other phospholipids. The middle of the sphere can contain a drug, which can be fully encapsulated by the liposome. Liposomes may carry small molecules, gene therapies, oligonucleotides, or can even be used for transdermal drug delivery. Depending on the design, they can offer a way to get drugs directly to the target with high efficiency. Other drug products may be engineered to contain nanomaterials because the smaller size may increase the safety or efficacy, or even be needed to deliver the desired therapeutic result.
Dr. Mino-Olivares: This is a challenging scientific area but one that presents with many opportunities. Can you tell us about some of the challenges with using nanomaterials in drugs?
Dr. Ponta: Yes, there are many challenges I’d like to mention - and note that these are not exhaustive, nor are they ranked in any order. As with any advances, there are many unknowns, and of course this is something we think about at the FDA a lot. We are always thinking about the patient first, and we must consider the risk-benefit profile for each product, including those that use nanomaterials.
Controlling and characterizing matter at the scales we’re talking about has only been successful in the past few decades. Characterization of a property, such as particle size, is tied back to the overall drug product quality and how these property or properties in turn impact the safety and efficacy of the drug product is key. While new technologies and materials are often neither intrinsically benign nor harmful, they do come with unknowns. Understanding how changes in properties such as size and distribution can have an impact on desired clinical outcomes is a way that product developers and manufacturers can minimize risk to patients. It may be challenging for the industry to make the bridge among material size, drug product quality, the final product, and the connection to the patient. We encourage drug developers to really understand how modifying physical properties changes the safety, efficacy, and quality of the drug products they are developing. If you set out with a goal to treat a particular condition, always keep that in mind and tailor the product to accomplish this and try to characterize any risks to the highest degree possible.
Dr. Mino-Olivares: This is important advice for drug developers. Are there additional challenges you’d like to highlight?
Dr. Ponta: A couple more if we have time. One parameter with nanomaterials we think about is the size and the size distribution. This often is a critical quality attribute, or CQA, that will affect the performance of the product. The manufacturing process can directly impact the nanomaterial size; therefore, process parameters in manufacturing are tightly controlled at the nanoscale to produce the desired size. Differences in the number of atoms may affect the size by several percent at the nanoscale. Characterizing nanomaterials is another challenge. If you think about a microscope in a high school science lab, you may be able to resolve objects of about 250 nanometers. So, what do we do if our liposome is 50 nanometers? How do we measure that? There are ways, but some of them require specialized equipment such as electron microscopes and light diffraction equipment. Thankfully, in the Office of Pharmaceutical Quality we have several scientists who really understand nanotechnology and develop methods using the types of equipment I mentioned to better characterize drugs that may contain nanomaterials.
Dr. Mino-Olivares: With challenges though, there always come opportunities.
Dr. Ponta: Nanoscale drug delivery systems have really been a game changer for targeted delivery. An example of this would be nanomaterials where the surface is modified with ligands, enabling targeted delivery. Nanomaterials can be used for modified release of the active pharmaceutical ingredient, allowing for patients to have extended release over the course of a day, rather than rely on taking multiple doses throughout the day. I think that really this is the opportunity; using these technologies to either make existing drugs better, or to modify to treat diseases that have few options on the market currently.
Dr. Mino-Olivares: You mentioned CQAs—how exactly does a manufacturer go about determining what is actually a critical quality attribute?
Dr. Ponta: Well, because CQAs are specific to the finished drug product, I’ll keep my answer fairly general, although I encourage those interested to look into our guidance. The CQAs should be determined on the basis of the function and potential impact on drug product performance. For nanomaterials, we expect to see the chemical composition, the average particle size along with the particle size distribution, the general shape and morphology, and physical and chemical stability data. This last point will include whether the product aggregates or agglomerates. There may be additional CQAs such as distribution of the active pharmaceutical ingredient with respect to the nanomaterials, the particle concentration, if it’s coated or not. At the end of the day, we really care a lot about the properties that will impact the final function of the product. Early identification of CQAs can help manufacturers develop and implement appropriate in-process controls.
Dr. Mino-Olivares: Can you share some examples of applications of nanomaterials?
Dr. Ponta: The drug products that may fall under nanotechnology are incredibly diverse. They are indicated to treat a wide range of conditions from anemia to cancer, and they are delivered via many routes of administrations. In fact, a 2017 study of over 350 drug products that contained nanomaterials and were submitted to the FDA found that while the majority of the products were indicated for cancer treatment, many were also used to treat inflammation and pain, infection, and systemic disorders. This study also concluded that the majority of size-engineered materials were under 300 nanometers. For reference, a strand of human hair is normally between 80,000 and 100,000 nanometers, so these materials are less than 0.05% as long as the width of a human hair!
Dr. Mino-Olivares: That’s so interesting! We have a provided a link on the Episode webpage, which you can also access via fda.gov/cdersbiachronicles. Where can drug manufacturers or even consumers go to learn more about drugs that are manufactured using these nanomaterials?
Dr. Ponta: I’m glad you asked that question! We have a lot of resources to help manufacturers, or even to inform interested consumers. As previously mentioned, we recently published the guidance for industry: Drugs Products, Including Biological Products, that Contain Nanomaterials in 2022, so it’s still pretty new. This guidance covers potential risk factors for products containing nanomaterials, quality recommendations, nonclinical studies for drug products, the clinical studies, and environmental impact considerations. In OPQ, our work focuses on understanding quality and the risk factors that may impact drug product quality. The guidance makes recommendations on considerations for the CQAs—which are product specific—but should include things such as particle size distribution and physical stability.
Dr. Mino-Olivares: And this guidance is located on our website on the “Search for Guidance Documents” webpage. Dr. Ponta, are there other resources you’d like to highlight?
Dr. Ponta: Yes, industry may also be interested in the FDA’s product specific guidance documents, or PSGs. These are often developed with our colleagues in the Office of Generic Drugs based on scientific studies conducted in FDA’s labs and offer advice on considerations such as what characterization and other studies should completed between innovator and generic drugs to ensure they are just as safe and as effective as the innovator product. Once again, we have a link to the PSGs on our webpage.
Additionally, as I mentioned, we have a number of scientists and subject matter experts who regularly publish in the peer reviewed literature about studies on drug products containing nanomaterials.
And lastly, FDA experts regularly present at regional and national conferences. For the past few years, the Agency has also hosted the FDA NanoDay Symposium with SBIA and looks forward to hosting it again in October 2024.
Dr. Mino-Olivares: And one last question: are drugs containing nanomaterials regulated differently than those that don’t contain nanomaterials?
Dr. Ponta: No, and that’s great news. We regulate all drugs, regardless of the size of their active pharmaceutical ingredient or any of the other ingredients in the same way. We have exactly the same expectations for safety, efficacy, and quality across the board. We expect manufacturers to follow current good manufacturing practice requirements and to provide adequate characterization and testing for the FDA to make an informed decision on any regulated product marketed in the U.S.
Dr. Mino-Olivares: Dr. Ponta, thank you for your time today and for sharing this information with our audience!
Dr. Ponta: Thanks for the opportunity to discuss this emerging science. FDA is committed to working with industry to advance our shared understanding of nanomaterials in medicine and harnessing their potential to save lives of patients and consumers.
Dr. Mino-Olivares: You can find a link to the full SBIA Chronicles article at fda.gov/cdersbiachronicles. Also visit fda.gov/cdersbia to stay connected with upcoming webinars and conferences, sign up for SBIA email updates, and follow SBIA on LinkedIn. Thanks for tuning in!
