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

Introduction to Nanomaterials Biological nanomaterials are not monolithic-- compositions span organic chemistry, inorganic chemistry, polymer chemistry and biology While all nanomaterials share a 1-100 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

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

Nanomaterials: Efficacy Issues & Potential Benefits

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 1-100 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.

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)

Nanomaterials: Regulatory Issues & Potential Risks

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

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

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

Regulation of Nanomaterials: Conclusions & Recommendation

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)

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.

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)

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.