Applicability of Existing Regulations to the Development of a Dendrimer NanotechnologyBased Pharmace

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Applicability of Existing Regulations to the
Development of a Dendrimer Nanotechnology-Based
PharmaceuticalPresentation to Advisory
Committee for Pharmaceutical Sciences
Jeremy Paull, PhD October 6, 2006
www.starpharma.com
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Key Messages

• Nanotechnologies are enabling technologies
• Dendrimer-based API developed as a preventive
  product
• Developed in context of existing regulatory
  framework
• Possible challenges now and in the future?

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Defining Regulation and Nanotechnology

• Regulation aims to set standards that ensure
  balance between risk and benefit
• Specific regulations for nanotechnology?
• Nanotechnology is
• Research and technology development at the
  atomic, molecular or macromolecular levels, in
  the length scale of approximately 1 - 100
  nanometer 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.
• Isnt it? But!
• Specific regulation of non-specific technology
  challenging, inappropriate?

i-Pod Nano
Nano Cash
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Dendrimers Nanoscale Chemical Diversity

• Dendrimers
• Precise, defined nanostructures, with significant
  potential for structural diversity
• It is difficult to generalize about properties
  and applications of dendrimers because of the
  extreme diversity possible

• It is difficult to generalize about properties
  and applications of dendrimers because of the
  extreme diversity possible

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Dendrimer Nanotechnology Applications

• Pharmaceuticals
• Polyvalent presentation of surface molecules
  covalently bound to the underlying dendrimer
  architecture, resulting in unique properties
  compared with single presentation.
• Drug Delivery
• Small molecules bound on the surface or carried
  within dendrimer architecture, not bound to the
  dendrimer, then released.
• In vitro Diagnostics
• Detection of biomarkers in assays.
• In vivo Diagnostics
• Imaging agents bound to the surface of
  dendrimers, with improved resolution, targeting.
• Combinations?

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Dendrimer Synthesis Small Molecule Techniques
Amide bond formation
Deprotection of reactive groups
Amide bond formation
Deprotection of reactive groups
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Dendrimer Synthesis Large Molecule Techniques

• Ultrafiltration a technique used in the
  purification of biopharmaceuticals
• Purification and analytical techniques vary with
  dendrimer generation (size) and surface polarity

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Dendrimer Synthesis Surface Group
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Dendrimers a Platform for Polyvalent Interactions
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Dendrimers Controlled Topologies

• Precise, controlled placement of surface groups
  to provide specific properties
• Quality by design

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Dendrimers Drug Delivery Capability

• Dendrimers as functional excipients
• Delivery of covalently bound or encapsulated drug
  direct to a target

Adapted from Dendrimers Dendrons Facets of
Pharmaceutical Nanotechnology Sakthivel and
Florence, Drug Delivery Technology,
www.drugdeliverytech.com, accessed 10/02/2006
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Regulatory Challenge

• All forms of nanotechnology carry unique
  properties because of their size
• Particles of a finished drug product or other
  material may provide better or more favorable
  solubility or function if they are nanoscale
• Dendrimers are not different because they are
  small, they are different because the individual
  molecules are big compared with small molecules
• Can you regulate such different types of
  nanotechnology as a single technology?

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Classification of Dendrimer Products

• Star Rx
• Existing regulatory framework allows for proper
  classification and oversight of development
• Cosmetic, Drug, Device, Biologic?
• NOT Cosmetic, NOT Biologic
• Drug? Device? Drug-Device Combination?
• Claims made and primary mode of action?
• Prevention of HIV / HSV-2, pharmaceutical /
  antiviral mode of action potential clinical
  utility as vaginal microbicide.
• Opportunity / Challenge
• Topical administration, not absorbed, barrier to
  virus possibility of device classification?
• Drug delivery? Regulation of a molecule as device?

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Manufacturing and Characterization of Dendrimers

• Star Rx
• Existing industry manufacturing norms and
  expectations apply
• ICH Q7A, 21 CFR Parts 210 / 211
• Identity, strength, purity, quality
• Quality by design
• Risk management
• Control of inputs
• Monitoring of reaction
• Opportunity / Challenge
• Combination of small molecule and large molecule
  processes required
• Lack of commercial availability of API starting
  materials and intermediates does strict cGMP
  compliance apply?

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Manufacturing and Characterization of Dendrimers

• Star Rx
• Characterization of dendrimers in order to
  monitor and confirm identity, strength, purity,
  and quality provides the biggest challenge
• How much characterization required if QbD,
  process understanding (PAT)?

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Manufacturing and Characterization of Dendrimers

• Star Rx
• Achieving purities expected of small molecule
  synthesis?
• Minor impurity in dendrimer capping material can
  lead to significantly undercapped or miscapped,
  related API
• Characterize related species in terms of identity
  as well as qualify in terms of safety and
  efficacy adequate characterization of
  impurities?

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ADME of Dendrimers

• Star Rx
• Topical (vaginal) administration
• Due to size and polarity of molecule, not
  expected to be absorbed
• Not detected systemically following repeated
  vaginal administration in animals and humans
• Bioanalytical assay limit of quantitation
  0.5µg/mL 30nM
• Opportunity / Challenge
• Application of small molecule expectations in
  terms of bioanalytical assay limits to large
  molecules?
• Absorption below 0.5µg/mL qualified?
• Full characterization of metabolites, degradation
  required?
• Opportunity for analytical lab!

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Safety and Efficacy of Dendrimers

• Star Rx
• Intensive battery of toxicology studies
  conducted, as required for development of a
  topical, vaginal product
• Genotoxicity
• Hypersensitivity (topical)
• Acute, Single-Dose (oral, intravenous, vaginal)
• Sub-Chronic, Repeat-Dose (vaginal)
• Reproductive and Developmental
• Intensive battery of toxicology studies ongoing
  or planned
• Chronic, Repeat-Dose (vaginal)
• Further Reproductive and Developmental
• Carcinogenicity
• Intensive battery of in vitro and in vivo
  pharmacology studies
• In vitro HIV and HSV anti-viral activity / mode
  of action
• In vivo HIV and HSV anti-viral activity

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Safety and Efficacy of Dendrimers

• Star Rx
• Nonclinical safety and efficacy profile
  acceptable for use in human clinical studies
• Phase 1 study
• Confinement to a Phase 1 unit for intensive
  monitoring of volunteers
• Escalating doses
• Intensive monitoring of safety endpoints
• Ongoing assessment of safety
• Safety profile acceptable for use in further
  human clinical studies
• No special safety or efficacy study
  considerations for dendrimer-based Star Rx

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Regulatory Interaction on Dendrimer Development

• Star Rx
• Human studies conducted under US IND
• Fast Track designation
• Opportunities for frequent (more frequent!)
  informal and formal interaction on most advanced
  dendrimer nanotech product
• Engagement of industry by regulator, and of
  regulator by industry important to ensure
  efficient development of new products based on
  novel technologies

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Environmental Considerations

• Star Rx
• Exempt at this stage of development under 21 CFR
  Part 25.24(c)(4)
• Ongoing nonclinical and clinical safety
  assessment in controlled environment
• Environmental impact of lysine-based dendrimer
  molecule? Case-by-case consideration required

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Occupational Health and Safety Considerations

• Star Rx
• Treated as an uncertain risk
• Suitable precautions taken during manufacturing,
  analysis, transportation and handling
• No special nanotechnology requirements

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Other Nanotechnology-Based Products

• Can other products be consistently manufactured?
• Are other products well characterized?
• Does the safety profile of other products support
  intended use?
• Do other products perform as required and
  expected?
• FDA regulation should be applied to new materials
  as they are incorporated into products regulated
  by FDA
• Consumer products containing nanotech materials
  should be overseen by FDA if they present public
  health issues

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Summary

• Existing regulations have adequately addressed
  development of a dendrimer nanotechnology-based
  pharmaceutical
• Development challenges come from science, not
  from regulation
• Starpharma is developing dendrimer employing
  risk-based approach and quality-by-design

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Thank you

• Email jeremy.paull_at_starpharma.com
• Web www.starpharma.com
• Tel [phone]