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  1. CDER Small Business & Industry Assistance (SBIA)

Considerations for Drug Products that Contain Nanomaterials

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Nanomaterial is a term describing material that has been engineered to have one or more dimension within the nanoscale range, typically to control size-dependent properties or phenomena. Normally, this range is considered to be up to 100 nm. However, FDA has not established a regulatory definition for “nanomaterial.” For drug products that contain nanomaterials, if the size is engineered to exhibit specific properties or phenomena, the FDA may consider products having one or more dimensions up to 1,000 nm (or 1 micron) to be nanomaterials.

 Andrei Ponta, Ph.D., Review Chemist, Division of Product Quality Assessment VIII | Office of Product Quality Assessment II | Office of Pharmaceutical Quality | CDER | FDA
Andrei Ponta, Ph.D., Review Chemist, Division of Product Quality Assessment VIII | Office of Product Quality Assessment II | Office of Pharmaceutical Quality | CDER | FDA

FDA recently released the guidance for industry, "Drug Products, Including Biological Products, that Contain Nanomaterials," describing considerations for drug products that contain nanomaterials. This guidance focuses on identifying and managing risks that are present when nanomaterials are part of a product. While the same standards of safety, efficacy, and quality apply to products containing nanomaterial as to other drug products, nanotechnology is relatively new in the field of medicine, and this guidance is intended to help FDA and industry think through any unknowns that may arise. It considers the characterization, controls, testing, and qualification of nanomaterial components and applies to drug products that are engineered to have nanoscale dimensions. Therefore, some products that have dimensions naturally in the nanoscale, such as proteins, nucleic acids, and other biological materials, are not explicitly considered nanomaterials per the guidance. This guidance also does not pertain to products that have incidental nanoscale particles due to conventional manufacture or storage.

The products that may fall under the auspices of this guidance 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 administration. In fact, a 2017 study of over 350 drug products that contained nanomaterials and were submitted to FDA found that while the majority of them 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 nm. 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!

Due to their small size, characterization of nanomaterials can be challenging. For example, because these materials are so small, the signal cannot be adequately characterized with a standard light microscope. The diffraction limit governs how small an object can be resolved with a microscopic system and is dependent on the wavelength of light used as well as the objective lenses being used. Standard microscopes can resolve objects as small as roughly 250 nm. This means to adequately characterize nanomaterials, specialized techniques must be used. One of the reasons adequate characterization of materials is critical is that particle size distribution may affect the desired properties of the product.

It is also important that the 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 product, tying everything back to the patient. While new technologies and materials are often neither intrinsically benign nor harmful, they do come with unknowns. Bridging the changes in properties such as size and size distribution to desired clinical outcomes is a way that product developers and manufacturers can minimize risk to patients.

The guidance also acknowledges another important point: nanomaterials may also be present as inactive ingredients, or excipients. Excipients may ensure or enhance desired attributes, although they do not themselves have therapeutic, prophylactic, or diagnostic effects. Control of the nanomaterial excipient may be critical for structure or function of the final product. The guidance discusses how, for example, the purity of the lipids in a liposome or the molecular weight of polymers in a nanomaterial drug delivery system may be critical.

Nanomaterials may be sensitive to process conditions and scale-up. Thus, it is important to understand the desired clinical and therapeutic outcomes and which properties, or critical quality attributes (CQAs), affect such products. Early identification of CQAs can help manufacturers develop and implement appropriate in-process controls.

Manufacturers of drug products that may contain nanomaterials must also follow stability and testing processes that apply to premarket applications. For products containing nanomaterials, common stability issues may include changes to nanomaterial size and/or size distribution, changes to morphology or solid state, or aggregation/agglomeration, to name a few.

The use of nanomaterials in drug products does carry unknowns and challenges. However, as for any other drug product, developers and manufacturers of products containing nanomaterial must follow current good manufacturing practice (CGMP), fully describe the CQAs, and rigorously evaluate their safety, efficacy, and quality. The 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.



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