1. Regulatory Approach to Novel Nanomaterials: Unique Benefits Versus Unique Risks
Russ Lebovitz, MD, PhD
SUMA Partners
October 6, 2006

2. Introduction to Nanomaterials
Biological nanomaterials are not monolithic-- compositions span organic chemistry, inorganic chemistry, polymer chemistry and biology
While all nanomaterials share a nm size range, the complexity of composition and structure range from ultrapure/single species to heterodispersity of both composition and structure
From a regulatory perspective, size is easy to address…complexity and heterodispersity are not

3. How Is Nanotechnology Relevant to Drug and Device Approval Processes?
New Atomic Elements– Certainly NOT
New Types of Molecules– Very RARELY
Closed 3D Polymers
“Caged” Atoms & Molecules
Novel Supramolecular Aggregation Properties–
Nanometer-Scale Crystalline Forms
Highly Novel Crystalline Packing
Multiple Covalently Linked Functional Groups–
Multifunctional Nano-particles
Relative orientation of functional groups may be key to benefits vs. risks

4. Nanomaterials: Efficacy Issues & Potential Benefits

5. Why Do Nanomaterials Tend to Have Unusual & Unexpected Properties?
Nanomaterials in the life-sciences area are most likely to represent supramolecular aggregates of active and non-active atoms/molecules where the overall particulate size is nm.
Due to the increased surface area of nanoparticles, even well-characterized nanomaterials may have unique physical and chemical properties compared with larger particulate aggregates of the same materials
Since the size of nanoparticles is on the order of that of medically useful EMR, the opticoelectomagnetic properties of nanoparticles tend to differ from those of the same material in a larger aggregate form.
Nanoparticles may differ substantially from larger aggregates in their biodistribution.

6. Examples
Liposomes- Size and surface components determine both stability and ability to elude reticuloendothelial sequestration.
Quantum dots- size of crystals determines wavelengths of light emitted
Carbon nanotubes- Axis of “rolling” up graphene sheet has profound effects on physical properties (conductivity)

8. Nanomaterials: Regulatory Issues & Potential Risks

9. Evolution of Biological Materials in Drugs, Biomaterials and Diagnostics
Generation 1
Generation 2
Generation 3
Conventional Biomaterials
Synthetic Biologicals
Synthetic Nanomaterials
Recombinant proteins/peptides
Humanized antibodies
Synthetic Nucleic Acids
Multifunction Nanoparticles
Carbon/Metallic Nanotubes
Nano shells/crystals/wires
Small Molecules
“Regular” Polymers
Simple Metal Alloys
Purity
Uniformity
Regularity of structure
Purity of backbone
Microheterogeneity of backbone modifiers
Heterogeneity of folding
Size heterogeneity
Isomer heterogeneity
Orientation heterogeneity
Structural Complexity
THE KEY REGULATORY CHALLENGE IS ADDRESSING THE INHERENT COMPLEXITY OF NANOMATERIALS ….NOT SIZE

10. Nanotechnology Products Can Fit Into Existing Classes of FDA-Approved Therapeutic Drugs, Devices and Biologicals
Metabolite
Class
Example
Characterization PK
Tox PD
Characterization
Small Molecule Drugs
Most approved drugs
Pure species; Complete structural determination; GMP manufacturing X
Complete
Biologicals (Biomers)
Hormones; Targeted therapies
Mostly pure species, Complete backbone structure; GMP manufacturing
Carriers/ Delivery Agents
Excipients, Liposomes, Patches
Generally mixture of pure species; Complete structural determination; GMP
Yes- For each component
Physical Agents
EMR, Acoustic
Complete determination of wavelengths and energies. Maintenance mandated ?
N/A
Electro-Bio
Mechanical Agents
Catheters, Stents, Pacemakers
Complete specification of components and manufacturing processes; GMP
N/A; Yes for any drug/bio components

11. Nanotechnology Products Can Fit Into Existing Classes of FDA-Approved Diagnostic Agents/Devices
Metabolite
Class
Example
Characterization PK
Tox PD
Characterization
Small Molecule Agents
Xray/CT, MRI contrast agents
Pure species; Complete structural determination; GMP manufacturing X
Complete
Biologicals/ Targeted diagnostics
Targeted contrast and bio detectors
Mostly pure species, Complete backbone structure; GMP manufacturing
Carriers/ Delivery Agents
Multifunction Particles, Liposomes,
Generally mixture of pure species; Complete structural determination; GMP
Yes- For each component
Ex-Vivo Sample Analysis
Blood, urine, stool testing
Consistent results within pre-determined tolerance; GMP
N/A
Electro-
Mechanical Agents
Catheters, Fiberoptics, Detectors
Complete specification of components and manufacturing processes; GMP
N/A; Yes for any drug/bio components

12. Regulation of Nanomaterials: Conclusions & Recommendation

13. Conclusions (1)
Nanomaterials are generally composed of well-characterized atoms and molecules in novel aggregation states
The nanometer scale of nano-biomaterials is similar to that of existing drugs and biologicals.
Nanoparticles are likely to have different biodistribution, toxicity and pharmacokinetics profiles than larger aggregates of the same materials.
Composition and structure of nanomaterials can be assessed using existing analytic tools (elemental analysis, MS, NMR, Xray Crystallography, spectroscopy)

14. Conclusions (2)
Complexity of nanoparticles presents new challenges with respect to characterization of size, orientation and isomerization states
Existing agency protocols, guidelines and requirements for drugs, biologicals, devices, diagnostics, etc. are directly applicable to most known and anticipated instances of nanoparticles and nanomaterials.
There will need to be a shift in emphasis towards characterizing complex isomeric states and supramolecular aggregation states as new nanomaterials are introduced.
Development of appropriate analysis tools by applicants should be part of the pre-clinical approval process. IP issues are likely to arise in this context.

15. Recommendations
Classify nanomaterials by structural complexity and inherent heterogeneity rather than by size: low complexity (similar to small molecule drugs); intermediate complexity (similar to biologicals); high complexity (new category).
Regulation of low and intermediate complexity products should closely follow guidelines already set for small molecules and biologicals, respectively
Regulation of high complexity products will require considerable modification to preclinical data requirements (CMC, PK, metabolism, PD) to ensure consistency and reproducibility of product and to understand how minor changes in supramolecular structure effects clinical parameters (efficacy toxicity, PK, PD)

16. Summation
As drugs, biologicals and nanoparticles become more inherently complex and heterogeneous, the ability to assess and control the reproducibility and uniformity of manufacturing represents the single greatest risk and challenge. Subtle changes in complex structures and compositions may have dramatic effects on safety and efficacy.