Characterization of Nanoparticles

It has become clear to most of those involved in research or development of potential nanotech-nology applications that it is only possible to assess the safety of nanomaterials when the material under study is adequately characterized. If two or more laboratories are working on what they think is the same material, then in order for the data from one laboratory to be compared with data from another laboratory, there needs to be some confirmation that in fact the nanomaterials being studied are actually identical. It has been mentioned by many that for nanomaterials, small differences in product characteristics (such as size, surface charge, hydrophobicity, or a number of other attributes) may impact product behavior and thus result in vastly different safety profiles. Published data show that slight modifications of a nanoparticle have resulted in different toxicity profiles. For example, several in vitro studies with Starburst® polyamidoamine (PAMAM) dendrimers and Caco-2 cells have shown decreased cytotoxicity of cationic dendrimers upon addition of lauroyl or polyethylene glycol (PEG) to the surface of the macromolecules.93-94 Similar findings of diminished toxicity were observed in J774 macrophages upon conjugation of polysaccharides to polymer nanoparticles and in fibroblasts and CHO cells with the addition of PEG-silica to the surface of CdSe and CdSe/ZnS nanocrystals.95-96

Although much less toxicity data is available in vivo, it is evident that surface chemistry is of similar importance to the toxico- and pharmacokinetics, toxico- and pharmacodynamics, and overall stability of the nanomaterials in vivo.97-99 When injected into rodents, several generations of dendrimers with different surface configurations displayed contrasting organ distribution patterns and plasma clearance profiles in vivo, typically depositing within the liver, kidney, and pancreas.98_100 PEG-conjugation to the dendrimer particle surface significantly increased the blood half-life and diminished the liver accumulation of dendrimer particles.99 Similarly, quantum dots coated with a complex polymer with carbon alkyl side chains demonstrated greater in vivo stability and less genotoxicity than those coated with a simpler polymer or lipid coating.101 Based on the findings of these studies and the collection of pulmonary inhalation data with environmental ultrafines and other in vitro cytotoxicity results obtained with different nanomaterials (e.g., quantum dots, fullerenes, and nanoshells, etc.), it appears that a thorough characterization of the nanomaterial is essential to the interpretation and understanding of toxicity data collected from in vitro and in vivo studies.

To summarize some of the ongoing discussions within CDER's nanotechnology working group, a list of questions has been put together regarding the characterization of nanomaterial-containing products. At this time, it appears that there are no adequate answers to these questions. However, it may be that in the future, to satisfy regulatory requirements for nanomaterial-containing products, the questions listed below will need to be addressed by product sponsors.

1. What are the forms in which particles are presented to the organism, the cells and the organelles? Are these particles soluble or insoluble, are the nanomaterials organic or inorganic molecules, are the nanomaterials described as nanoemulsions, nanocrystal colloid dispersions, liposomes, nanoparticles that are combination products (drug_ device, drug_biologic, drug_device_biologic), or something else? Does the product fall within the currently established definition of nanotechnology?

2. What are the tools that can be used to characterize the properties of the nanoparticles? Can standard tools that are used of other types of products (for example, spectroscopic tools) be used to characterize nanomaterial-containing products, or do these products require specialized tools that are not widely available for product characterization (atomic force microscopy, tunneling electron microscopy, or other specialized modalities)?

3. Are there validated assays to detect and quantify nanoparticles in the drug product and in tissues?

4. How can long- and short-term stability of nanomaterials be assessed? Specifically, how can the stability of nanomaterials be assessed in various environments (buffer, blood, plasma, and tissues)?

5. What are the critical physical and chemical properties of nanomaterials in a drug product and how do residual solvents, processing variables, impurities and excipients impact these properties?

6. How do physical characteristics impact product quality and performance? Within what range can these physical properties be modified without significantly affecting product quality and performance?

7. What are the critical steps in the scale-up and manufacturing process for nanotechnology products? How could manufacturing procedures for nanomaterials differ from those for other types of drugs?

8. How are issues concerning the characterization and manufacturing procedures for nano-technology products assessed, when considering the development of "personalized therapies"? In this context, personalized therapies refer to those multifunctional products that will be "custom made" for specific patients, depending on issues such as the expression of a certain receptor on a tumor or the response of the tumor to a particular chemotherapeutic agent. For these types of therapies, what should be the level of characterization of the nanomaterials? Does the preclinical testing need to be repeated for each modification of the multifunctional molecule, or can there be limited testing to cover certain aspects of the product behavior, such as the ADME, the toxicology (a bridging study for the acute and/or repeat dose toxicology studies)? What aspects of the chemistry, manufacturing and controls (CMC) studies need to be repeated and what should be the extent of physical characterization?

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