FDA Releases Guidance On Drug Products Containing Nanomaterials

Nanomedicine has advanced considerably in the past five years (as per the OECD nanotechnology R&D intensity measure).¹ Nanomedicine is a broad term, defined as using nanoscale materials, including biocompatible nanoparticles and nanorobots for disease diagnosis, drug delivery, physiological sensing, or for actuation purposes.² The innovations in nanomedicine with the greatest potential are in the treatment of cancers.³ The level of regulatory oversight required for these advancements has led to the FDA issuing a guidance for industry document, Drug Products, Including Biological Products, that Contain Nanomaterials.⁴

For the FDA, “nanomedicine” refers to a drug product that contains at least one component with a dimension in the size range of approximately 1 nanometer (nm) up to 100 nm.⁵ The definition extends to one of function in that the nanocomponent needs to be capable of exerting different chemical or physical properties or biological effects, when compared to larger-scale counterparts. The guidance sets out the current challenges in nanomedicine development and the likely future directions in the field.

As to what nanomaterials are used for, the focus of the guidance document is that the dimension-dependent properties or phenomena lead to one or more of:

increased bioavailability
decreased dosage
increased potency
decreased toxicity
better detection (such as of pathogens).

These functions are dependent upon altered chemical, biological, or magnetic properties, altered electrical or optical activity, increased structural integrity, or another unique characteristic. The reason specific guidance is required is that the resultant drug product’s attributes differ from those of conventionally manufactured products.

There is an evident theme within the guidance that the FDA places its strongest focus for matters of drug efficacy and safety upon biotechnologies that lead to the deliberate and purposeful manipulation or control of dimensions designed to produce components with specific properties. That concern is less with “natural” components that exist in the nanoscale and more with the development of new material properties (whether embedded within or attached to other materials) and the impact of these upon the safety, effectiveness, performance, quality, or wider public health impact of the drug product.

Risk-Based Regulatory Strategy

The most important point within the FDA guidance is the requirement to develop a regulatory strategy and for this to be risk-based. To put together such a strategy, the following considerations are required:

Product Matrix Risks

The foremost risk is with bioavailability, in that the nanotechnology may alter the bioavailability of the active substance. This concerns whether the drug will reach its intended target or whether it will be prevented from doing so or inactivated by the body (such as by the immune system or through interactions with blood proteins). The information required by the FDA to make a suitable evaluation will need to include:

Characterization of the nanomaterial (physicochemical properties and biological interactions).
Understanding of a nanomaterial’s intended use and application (physical and chemical stability and the release mechanisms).
How each nanomaterial attribute relates to product quality, safety, and efficacy, including the route of administration. An important safety consideration with nanomedicines is immunogenicity (an immune response triggered by a foreign substance).
How the nanomaterial breaks down and is removed from the body (the properties of dissolution, risk of accumulation, and the process of biodegradation). This needs to be assessed first through animal studies.
Excipients used must be well characterized, especially given the potential impact upon drug absorbency at the nano-level.

Quality Assessment

Definitions are required of the nanocomponents, including their size, charge, morphology, composition, and complexation.

Critical quality attributes (CQAs) require defining, especially those based on drug function and potential impact on product performance, covering quality, safety, and efficacy. Examples include chemical composition, particle size distribution (plus shape and size, together with structural and surface attributes), physical and chemical stability, and presence of impurities.
Assay methods need to be developed and evaluated. As well as chemical and physical methods (such as to assess the particle size range and structure), nanomedicines require testing for sterility and pyrogenic levels (including bacterial endotoxin). Manufacturing controls should reduce the potential for microbial contaminants to enter the process. Assay methods should be suitable, qualified, and the samples evaluated need to be representative of the process stage. Care also needs to be given to sample preparation, especially to any part of the methodology that could render the particle size characteristics incorrect.

Clinical Studies

The manufacturer must ensure it collects sufficient data to cover the steps from early development batches to late-stage clinical trial material and to the point where commercial material could be manufactured (pending approval).

Manufacturing Control Strategy

This includes understanding the potential impact of manufacturing robustness and changes (including media, agitation/rotation speed, pH, surfactant type, and concentration); the assessment of manufacturing stability through in-process controls; and demonstrating the robustness of the control strategy through the review and trending of CQAs. Measures also need to be in place to prevent cross-contamination from other processes.

Release Testing

An important aspect of release testing, in addition to verification of CQAs, is through demonstrating bioequivalency. This concerns demonstrating the biochemical similarity of commercial drugs with those approved at the clinical stage, such as equivalency of active ingredient(s) and particle dimensions. A pivotal data assessment will be with the drug release profile, which is a factor of time as well as one of quantity. Release testing will need to be supported by an appropriate stability program.

Environmental Impact

The firm will need to perform an environmental impact given the potential for nanomaterials to contaminate soil or migrate into surface and ground waters. Controls pertaining to particles in solid wastes and wastewater effluents are particularly important.

Epigenetic modifications represent another risk area, although this is not afforded attention in the FDA guidance; nonetheless, nanomedicine exposure and epigenetic deregulation is an area that also needs to be considered from the drug safety perspective.⁶

Evolution

Unlike other guidance documents that are more exacting in terms of their scope and an understanding of risk, the guidance document acknowledges that both industry and regulatory understanding is at an early point on the learning curve and there remains much more to understand about the potential role and importance of dimensions in the physical and chemical characteristics and biological effects exhibited by nanomedicines. For these reasons, the FDA advises that companies alert the agency early in the product development process. This will enable both the firm and FDA to work through the regulatory status, safety, effectiveness, or public health impact of the medicine. Given the novel nature of nanomedicines, the FDA will be keen to ensure that process and clinical knowledge is developed and captured.

Nanomedicine promises a health revolution, but its effectiveness and safety need to be considered through progressive evolution.

References

OECD. Nanotechnology R&D intensity, 2022: https://www.oecd.org/sti/emerging-tech/nanotechnology-indicators.htm
Etheridge ML, Campbell SA, Erdman AG, et al. The big picture on nanomedicine: the state of investigational and approved nanomedicine products. Nanomedicine: Nanotechnology, Biology, and Medicine 9:1-14, 2013
Sandle, T. How Can Nanomedicine Innovations Combat Cancer?, Cell and Gene, 2022: https://www.cellandgene.com/doc/how-can-nanomedicine-innovations-combat-cancer-0001
U.S. FDA, Drug Products, Including Biological Products, that Contain Nanomaterials: Guidance for Industry, U.S. Department of Health and Human Services, April 2022: https://www.fda.gov/media/157812/download
U.S. FDA Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, U.S. Department of Health and Human Services, June 2014: https://www.fda.gov/media/88423/download
Smolkova, B., Dusinska, M., Gabelova, A. Nanomedicine and epigenome. Possible health risks, Food and Chemical Toxicology, 2017, 109 (1): 780-796

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.