Timothy Shelbourn is a member of the Joint Subcommittee of the United States Pharmacopeia Expert Committees on Dosage Forms, Chemical Analysis, Physical Analysis, and Excipients

Timothy Shelbourn

A version of this article was published in 

APIs, Excipients, and Manufacturing 2019 Supplement

The current interest in nanotechnology and its application to the medical field has historical precedent. Initial products employed general physical chemistry of colloids to produce stable drug suspensions and improve bioavailability. The later introduction of liposomes began the evolution to today’s more sophisticated, and potentially revolutionary, new technologies accompanying the rapid growth in biotechnology product opportunities, notably including targeted drug delivery products.

	The term ‘nanomaterials’ describes materials that have features or structures that exist on the nanoscale in any of the three spatial dimensions. The large numbers of formulations containing nanomaterials that are currently under development, under review, or have already received approval from the US FDA emphasizes the need to identify important properties of these formulations and methods of measurement of their properties to ensure quality and performance. FDA has offered guidance to nanomaterials (1). The document emphasizes the need to evaluate materials with any dimension in the nanoscale (1–100 nm) as well as products showing size-dependent properties with dimensions up to 1000 nm.

	Nanomaterials may be added to the dosage form to confer a desired physicochemical or mechanical properties; for example, colloidal silicon dioxide (i.e., fumed silica), which acts as a glidant in tablet manufacture. Despite achieving the desirable properties, undesirable effects of excipients should also be considered. A guidance for industry from FDA addresses the needs of this class of nanomaterials (2).

	When considering the composition of specific nanomaterial formulations a variety of structures can be considered including: carbon nanotubes (3,4); dendrimers (5); drug (6) and inorganic (7) nanoparticles; liposomes (8), micelles (9,10), nanobubbles (11); nanoemulsions (12), nanofibers (13–15), polymeric (16,17) (natural and synthetic); and solid-lipid nanoparticles (18). Characterization of nanomaterial is presented below.

	Products may initially contain nanomaterials, or this state of matter might result from post-market changes to existing products through processes to create nanostructures. Over a period of 10 years, spanning the turn of the Millennium, products for cancer (doxorubicin and paclitaxel), anemia (sodium ferric gluconate complex), macular degeneration (pegaptanib sodium), tear production (cyclosporine), aspergillosis (amphotericin B), acromegaly (lanreotide acetate), and hypercholesterolaemia (fenofibrate) as liposomes, inorganic, and polymeric (natural and synthetic, nanotubes, nanocrystal emulsions, and micelles (19) were prepared. Many of the aforementioned formulations have yet to be translated to commercialized products. However, it should be anticipated that many will find their way onto the market.

	Nanotechnology can be employed to modify the biopharmaceutical disposition, bioavailability, and biodistribution, of a drug substance. Desired characteristics such as solubility and the route of administration of the drug substance dictate how critical the size and structure of nanomaterials are to their function. 

	Rapidly degrading/dissolving nanoparticles exhibit near instantaneous loss of morphology and release drug substance for absorption and distribution, whereas nanoparticles that remain intact for extended time periods may play a role in the pharmacological effect of the drug in the central compartment due to their size and/or structure. Following oral administration, a rapidly dissolving, readily bioavailable nanocrystal drug substance/formulation is known to exhibit different pharmacokinetics compared to that exhibited by a formulation containing the drug substance of larger particle size. Similarly, differences in integrity of nanoparticles, rapid or slow dissolution, will influence systems administered by the parenteral route. Hydrophobic systems are routinely used for intravenous injection and inhalation. Synthetic and natural polymeric nanoparticles forming rigid structures have been used primarily for intramuscular depot delivery. Nanocrystals have been delivered in oral solid dosage forms for gastro-intestinal (GI) absorption. 

	Generalizing critical quality attributes from one product to the next to accommodate the needs of quality by design is difficult (19). Nevertheless, key variables should be identified, and their impact characterized and controlled to support quality metrics. Considerations with respect to products containing nanomaterials have been reviewed (20) and risk has been characterized (21). 

	General texts on the safety of nanomaterials exist (22). Specific considerations for drug products containing nanomaterials relate to the kinetics of dissolution and disposition following administration and the fate of components of the materials. Safety considerations for pharmaceutical nanomaterials in a regulatory context have been described (13,16,20,22). 

	The risk associated with the drug alone exposure is a baseline consideration for a nanoparticle formulation. It can be assumed that rapidly dissolving nanoparticles carry the same risk as molecular drug presentation, because the existence of the nanomaterial is transient. Long residence-time nanoparticles potentially modulate the risk. Limiting the release rate of the drug may reduce the risk of adverse effects. In contrast, the risk may be elevated beyond that of the drug and components alone if accumulation or concentration in specific physiological compartments occurs. Parenterally administered inorganic particles (e.g., gold and silver), micelles, and liposomes are among the drug nanomaterial combinations that might present an elevated risk. Oral administration of nanoparticles may affect the residence time of nanoparticles in the GI tract as a desirable drug delivery function but may also raise the potential for elevated risk.

	Every drug product requires the assessment of quality parameters to grant safety and efficacy to be released for human and veterinary use. Yet, nanomaterials add an additional layer of complexity to the formulation steps. For example, the processes of mixing/blending, filling (solid and liquid), compression, and lypophilization require consideration of the nanomaterial state and its preservation throughout manufacturing. Performance quality tests follow the dosage form characterization and route of administration considerations set forth in the 

) and regulatory guidance. If the nanomaterial is essential to the function of the dosage form, additional specific tests may be requested.

	A comprehensive approach to the measurement of physicochemical characteristics includes the following: 

		Aerodynamic particle size distribution using 

<601> for micro-aggregated nanoparticles and <1601> nebulized particles or low-pressure impactor for nanoparticle aerosols (23) 

		Composition and structure using atomic absorption spectroscopy and photon-correlation spectroscopy 

release using microdialysis (24), fiber optic probe (25), infrared (26) and Raman (27) spectroscopy 

		Particle size using scanning and transmission electron microscopy (SEM and TEM) and atomic force microscopy (AFM)

		Particle distribution using photon correlation spectroscopy, small angle X-ray and neutron scattering (SAXS and SANS); 

		Purity, shape using SEM, TEM, AFM, SAXS and SANS, and solubility 

		Surface area using gas adsorption, surface properties using X-ray photoelectron spectroscopy, secondary ion mass spectroscopy, zeta potential, and freeze fracture SEM

Critical quality attributes (CQA) and regulatory considerations. 

It should be noted that FDA and the European Medicines Agency (EMA) do not formally use the term ‘nanomedicines’ and EMA has only recently acknowledged it.

	Nanomedicines in combination products are subject to the overarching FDA guidance and then assessed on a case-by-case basis. There are no combinations in the EMA lexicon so it is important to meet with the regulatory agency early to address requirements.

	FDA has guidance that is overarching, class-specific, and product-specific. The International Pharmaceutical Regulators Forum is developing a map of relevant guidance and regulations.

Methods and specific product considerations. 

An example of specific consideration is the use of an oral formulation with and without nanomaterial. In this case, FDA would conduct a risk assessment and track this information over time as it would for products not containing nanomaterials. Each product would be managed on a case-by-case basis, and the complete package would be evaluated regarding the materials and their physicochemical properties, and how they impact quality. This approach ensures that methods are appropriate to the way the product is characterized. This approach necessitates that CQAs are defined and have adequate characterization methods, stability testing, and a risk management plan.

	As bioequivalence implies drug bioavailability from the drug product, the extent to which the unique contribution of nanomaterials as a subcomponent should be evaluated depends on the dosage form. For example, drug release information from drug products containing nanomaterials may be required by FDA. Consequently, dissolution testing may be a tool that can be used for evaluation. The analysis of dimers (or other polymers) may require a different method and gel electrophoresis has been considered.

	There may be subtle differences in the way in which dynamic light scattering (DLS) measures particles based on their material properties, hard versus soft, for example. FDA is also working with the International Organization for Standardization (ISO), American Society for Testing and Materials (ASTM) International, and USP to develop and disseminate DLS standards. It is important to recognize which materials DLS would appropriately characterize. Complementary methods to DLS seem to focus on microscopy.

An informatics strategy for the collection and collation of data is required to characterize CQAs of the nanomaterial in the product. It is difficult to identify biological endpoints attributable to the nanomaterial. Measures of efficacy and safety should be derived from the studies of the drug product. 

	The most prominent drug formulations comprising nanoparticles are liposomes, drug nanocrystals, and iron colloids as illustrated by the earlier mentioned extensive description. The most frequently measured characteristic-particle size distribution-and the DLS and high-resolution imaging techniques employed will be the initial focus of the USP in preparing general chapters to address these topics. 

	A strategy will then be adopted to continue to introduce general chapters as new delivery systems come to market and to increase the compendium of important physicochemical properties measured. In this regard zeta-potential measurement has been identified as an important method for which a general chapter should be developed. In addition, the expert committee with the most relevant expertise to prepare these chapters will be alerted to the need and tasked with generating the document (e.g., physical analysis, dosage forms or excipients).

	There is a need for clarity on CQAs, their measurement and impact on product quality, safety, and efficacy.

	1. FDA, Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology (Rockville, MD, June 2014).
	2. FDA, Guidance for Industry, Non-Clinical Studies for the Safety Evaluation Of Pharmaceutical Excipients (Rockville, MD, May 2005).
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Handbook of Nanosafety: Measurement, Exposure and Toxicology 

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	Supplement: APIs, Excipients, and Manufacturing
	October 2019
	Pages: s12–s15

	When referring to this article, please cite it as A. Hickey, et al., "Perspectives on Quality Attributes of Drug Profucts Containing Nanomaterials," 

Pharmaceutical Technology APIs, Excipients, and Manufacturing

Articles

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