# Presentation: 485307

## NANOTECHNOLOGY: Regulatory Considerations for Drug Development

- Nakissa Sadrieh, Ph.D.
- Associate Director for Research Policy and Implementation
- Office of Pharmaceutical Science/CDER/FDA

## What is Nanotechnology?

- Research and technology development at the atomic or macromolecular levels, in the length scale of approximately 1-100 nm range.
- Creating and using structures, devices and systems that have novel properties and functions because of their small or intermediate size.
- Ability to control or manipulate on the atomic scale

**Notes:**
NNI is a federal R and D program established to coordinate the multiagency efforts in nanoscale science, engineering and technology

## The Scale of Things

| Object | Size |
| --- | --- |
| Width of hair | 50,000 nm |
| Red blood cell | 7,000 nm |
| Bacterium | 1,000 nm |
| Virus | 100 nm |
| Width of DNA | 2.5 nm |
| Aspirin molecule | 1 nm |

## Nanomaterials

- Multifunctional materials that interact with biological systems in well controlled ways
- Broad class of materials that feed into multiple industries.
- Exhibit unique properties and functions because of their small size.
- Include such structures as:
- Carbon nanostructures
- Dendrimers
- Metal oxides (FeO, TiO2, ZnO)
- Quantum dots (CdSe)
- Some liposomes

## Carbon Nanostructures

- Source of pure carbon (like graphite and diamond).
- Based on fullerene molecules which are closed and convex cage molecules containing only hexagonal and pentagonal faces.
- Examples of carbon nanostructures:
- Buckyballs
- Nanotubes
- Nanowires
- Nanowhiskers

## Carbon Nanotubes and Buckyballs

- Carbon nanotubes
- elongated fullerenes.
-  resemble graphite sheets wrapped into cylinders
- Length to width ratio is very high (few nm in diameter and up to 1 mm in length)
- Buckyballs
- spherical fullerenes (C60 is most stable and symmetrical and resembles a soccer ball).
- named after architect R. Buckminster Fuller .
- 1996 Nobel prize in Chemistry awarded for their discovery.

## Some Properties of Carbon Nanostructures

- High tensile strength
- Physically stable
- Chemically reactive with free radicals
- Derivatives can be formed
- More hydrophilic than fullerenes
-  New organic molecules can be generated
- Other atoms can be placed inside its “cage” (doping with alkali metals)
- Superconducting properties
- Optical properties (endohedral fullerenes)

## Several Nanocarbon Structures

## Dendrimers

- Spherical polymeric molecules
- Series of chemical shells built on a small core molecule (each shell is called a generation).
- Made from a core and alternating layers of 2 monomers: acrylic acid and diamine.
- Molecular structure has the form of a tree with many branches.
- Can serve as nano-devices for delivery of therapeutics.

## Dendrimer Structure

## Possible Applications in Drug Development

- Biologic nanodevices  based on dendrimers are being developed with the potential to :
- Recognize Cancer cells
- Diagnose cause of cancer
- Delivery of drug to target
- Report location of tumor
- Report outcome of therapy (cancer cell death)
- (_[http://](http://www.nano.med.umich.edu/)__[www.nano.med.umich.edu](http://www.nano.med.umich.edu/)_, James Baker, Univ. of Michigan)

## Nanomaterials are not new to FDA

- Many approved products currently on the market with components manufactured in the nanoscale range (drugs, sunscreens, cosmetics...).
- Most drugs act at their site of action as individual molecules that are in the nanosize range.

## Reasons for special consideration of nanotechnolgy products

- Rapidly growing area of science
- Anticipated to lead to the development of novel and sophisticated (possibly complex) applications in drug delivery systems
- Private sector, academic centers and federal agencies are developing substantial programs in nanotechnology
- Significant research dollars being invested in nanotechnology

## “Nanosizing” of Drugs

- Particle size reductions of drugs has the potential to:
- Increase surface area
- Enhance solubility
- Increase rate of dissolution
- Increase oral bioavailability
- More rapid onset of therapeutic action
- Decrease the dose needed
- Decrease fed/fasted variability
- Decrease patient to patient variability

## Nanosizing=Nanotechnology ?

- Not necessarily
- Potential nanotechnology applications: Novel drug delivery systems based on nanoparticle carriers (such as dendrimers, carbon nanotubes and buckyballs)

## CDER Activities in Nanotechnology

- Creation of a multidisciplinary CDER working group
- to identify regulatory challenges related to timely scientific assessment of drug and drug-device combination products
- To propose solutions to overcome challenges
- Participation in FDA Nanotechnology Interest Group and in NCI Cancer Nanotechnology Working Group

## Regulatory Considerations for Nanotechnology Drugs

- Nomenclature
- Quality
- Safety
- Environmental Impact

## Nomenclature

- Current NNI definition:
- Research and technology development at the atomic or macromolecular levels, in the length scale of approximately 1-100 nm range.
- Creating and using structures, devices and systems that have novel properties and functions because of their small and/or intermediate size.
- Ability to control or manipulate on the atomic scale
- Nomenclature may need to be tailored for CDER products
- Procedure:
- Identify potential nanotechnology drug applications
- Define nomenclature criteria
- Develop definition

## Quality Considerations

- Critical attributes of nanotechnology products might include:
- Particle size and size distribution
- Surface area, surface chemistry, surface coating, porosity
- Hydrophilicity, surface charge density
- Purity, sterility
- Stability (aggregation, protein adsorption)
- Does in vitro behavior reflect in vivo behavior
- Manufacturing and Controls
- Drug release parameters and bioequivalence testing considerations.

## Preclinical Safety Assessment

- Current required studies for drug applications generally include:
- In vivo short-term and long-term toxicity in rodent and non-rodent species, ADME, pharmacology, safety pharmacology, genotoxicity, developmental toxicity, irritation studies, immunotoxicology, carcinogenicity and other possible studies.
- Additional studies might be requested based on drug-specific considerations.

## Preclinical Safety Assessment (cont’d)

- Our current system is expected to identify possible hazard resulting from drug exposure, due to the extensive pre-clinical evaluation of new drugs.
- For nanotechnology drugs:
- Are current required studies adequate? YES
- Are new testing models needed?  MAYBE

## Examples of Preclinical Considerations for Nanotechnology Drugs

- Studies in In vitro models
- Target binding/receptor screens
- Cellular uptake
- Cytotoxicity
- Studies in In vivo models
- Efficacy/proof of concept
- Imaging studies
- Special toxicology studies (functional studies?)
- Mechanisms of tissue uptake and tissue clearance

## Environmental Considerations

- Depend on reported physical characteristics and biological effects of specific nanomaterials.
- 1.   Facility design considerations
- Limiting cross contamination between different products manufactured in the same facility.
- Limiting contamination by components of machinery used in the manufacturing process
- 2.   Impact of nanotechnology products on the 	environment
- Disposal of unused/expired products.
- Potential environmental impact of material entering the environment after administration.

## CDER Nanotechnology Working Group

- Goals and Objectives
- Definition and terminology
- Develop position papers (White Paper)
- Identify and propose development of regulatory guidance documents
- Identify training and research needs
- Coordination (between Centers/Agencies) and collaboration

## Parting Words...

- Maintain open dialogue between academic researchers and scientists/regulators within CDER.
- Timely communication of relevant scientific findings by the research community to regulatory agencies.
- Possible collaborations between academic researchers and CDER researchers.
- Sadriehn@CDER.FDA.GOV