applicability of existing regulations to the development of a dendrimer nanotechnology-based...
TRANSCRIPT
Applicability of Existing Regulations to the Development of a Dendrimer Nanotechnology-Based Pharmaceutical
Presentation to
Advisory Committee for Pharmaceutical Sciences
www.starpharma.com
Jeremy Paull, PhD
October 6, 2006
2
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?
3
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.
• Isn’t it? But!
• Specific regulation of non-specific technology challenging, inappropriate?
i-Pod Nano Nano Cash
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Dendrimers: Nanoscale Chemical Diversity
Core molecule
Surface molecules
Branching molecules
Dendrimer Synthesis
1 nm
Approximate size range:
10 nm 100 nm
• 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
5
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
HNHN
O
NH
NH2
O
ONH2
NH2
NH2
HNHN
O
Ph
Ph
NH
NHBoc
O
ONHBoc
NHBoc
NHBoc
NH2HN
O
NH2
HNHN
O
Ph
PhNH
HN
O
ONH
HN
NHBoc
NH
O
O
NHBoc
NHBoc
NHBoc
BocHN
O
O
NHBoc
NHBoc
NHBoc
HNHN
O
NH
HN
O
O
NH
HN
HNH2N
NH2
NH2
O
O
O
O
NH2
NH2
NH2
NH2
NH2
Amide bond formation
Amide bond formation
Deprotection of reactive groups
Deprotection of reactive groups
7
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
HNHN
O
NH
HN
O
O
NH
HN
HNH2N
NH2
NH2
O
O
O
O
NH2
NH2
NH2
NH2
H2N
SO3Na
SO3Na
NaO3SNaO3S
NaO3S
SO3Na
SO3Na
SO3Na
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Dendrimers: a Platform for Polyvalent Interactions
HNHN
O
NH
HN
O
O
NH
HN
HNHN
HN
NH
O
O
O
O
NH
HN
HN
HN
HN
HN
SSO3Na
SNH
S
HN S
HN
SO3Na
NaO3SNaO3S
NH
S
NaO3S
S
HN
SO3Na
S NH
SO3Na
S
HN
SO3Na
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Dendrimers: Controlled Topologies
N
N
N
N
N
N
N
N
N
N
N
N N
N N NN
N
NN
N
N N N N
N
N
N
N
N
N
N
N
NN
N
N
N
N
N
N
N N
N N NN
N
NN
N
N N N N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N N
N N NN
N
NN
N
N N N N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N N
N N NN
N
NN
N
N N N N
N
N
N
N
N
• 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?
15
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)?
Minutes
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
AU
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
AU
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08PDA - 214nmPk1-78
PDA - 214nm104119.dat
PDA - 214nmpK1-36
PDA - 214nm103794
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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’
20
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
21
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
22
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
