Regulatory Approach to Novel Nanomaterials: Unique Benefits Versus Unique Risks

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

1. Biological nanomaterials are not monolithic--
   compositions span organic chemistry, inorganic
   chemistry, polymer chemistry and biology
2. 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
3. From a regulatory perspective, size is easy to
   addresscomplexity and heterodispersity are not

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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

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Nanomaterials Efficacy Issues Potential
Benefits
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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.

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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)

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Nanomaterials Regulatory Issues Potential
Risks
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Evolution of Biological Materials in Drugs,
Biomaterials and Diagnostics
Generation 1
Generation 2
Generation 3
Synthetic Biologicals
Synthetic Nanomaterials
Conventional Biomaterials

• 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
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Nanotechnology Products Can Fit Into Existing
Classes of FDA-Approved Therapeutic Drugs,
Devices and Biologicals
Metabolite
Characterization
Class
Example
Characterization
PK
Tox
PD
Small Molecule Drugs Most approved drugs Pure species Complete structural determination GMP manufacturing X X X Complete
Biologicals (Biomers) Hormones Targeted therapies Mostly pure species, Complete backbone structure GMP manufacturing X X X Complete
Carriers/ Delivery Agents Excipients, Liposomes, Patches Generally mixture of pure species Complete structural determination GMP X X X Yes- For each component
Physical Agents EMR, Acoustic Complete determination of wavelengths and energies. Maintenance mandated X ? N/A
Electro-Bio Mechanical Agents Catheters, Stents, Pacemakers Complete specification of components and manufacturing processes GMP X N/A Yes for any drug/bio components
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Nanotechnology Products Can Fit Into Existing
Classes of FDA-Approved Diagnostic Agents/Devices
Metabolite
Characterization
Class
Example
Characterization
PK
Tox
PD
Small Molecule Agents Xray/CT, MRI contrast agents Pure species Complete structural determination GMP manufacturing X X X Complete
Biologicals/ Targeted diagnostics Targeted contrast and bio detectors Mostly pure species, Complete backbone structure GMP manufacturing X X X Complete
Carriers/ Delivery Agents Multifunction Particles, Liposomes, Generally mixture of pure species Complete structural determination GMP X X X 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 X N/A Yes for any drug/bio components
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Regulation of Nanomaterials Conclusions
Recommendation
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Conclusions (1)

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

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Conclusions (2)

1. Complexity of nanoparticles presents new
   challenges with respect to characterization of
   size, orientation and isomerization states
2. 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.
3. There will need to be a shift in emphasis towards
   characterizing complex isomeric states and
   supramolecular aggregation states as new
   nanomaterials are introduced.
4. 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.

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Recommendations

1. 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).
2. Regulation of low and intermediate complexity
   products should closely follow guidelines already
   set for small molecules and biologicals,
   respectively
3. 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)

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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.