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The NanoAssemblr™ Platform : Microfluidics-Based Manufacture of
siRNA Nanoparticles Colin Walsh, Ph.D.
University of British Columbia
Controlled Release Society 2013 Annual Meeting
July 23, 2013
Conceptual Drug
Product Scale-up Formulation Process Manufacturability Final
Drug Product
Nanoparticle Drug Development Process
Current nanoparticle manufacturing techniques limit innovation
• Poorly controlled processes • Limited application for biologics (nucleic acids,
proteins, peptides)
2
Microfluidics Enables Exquisite Process Control
Molecular Self-Assembly
• Control: laminar flow
• Nanoliter reaction volumes
• Rapid mixing: Timemix < Timeppt
• Low energy input
• Readily scalable
Solvent + Nanoparticle Components
Aqueous + Drug
Rapid & Controlled Mixing
Mixer design by: Stroock et al., Science 2002
Channel Dimensions: ~100 µm
3
The NanoAssemblr™: Microfluidics Enables Smarter Nanoparticles
ü Enable rapid nanoparticle
prototyping
ü Remove process variability
ü Robustly manipulate single
variables
ü Remove operator variability
ü Enable seamless scale-up
4
NanoAssemblr™
Microfluidic Cartridge
The NanoAssemblr™ : Rapidly Screen Formulation and Process
Parameters
5
Simple Technology Transfer Between Users and Sites
6
siRNA-LNP (Cationic Lipid:DSPC:Cholesterol:PEG)
Automated instrumentation removes operator variability
Dia
me
ter
(nm
)
Sample
20
40
1 40
60
2 3 5 6
PD
I
0.04
0.12
0.00
0.16
0.08
7
Nanoparticle Drug Development Using the NanoAssemblr™
Rapid formulation and process development
Conceptual Drug
Product Scale-up Formulation Process Manufacturability Final
Drug Product
Small Scale Formulation Development
8
• Removal of process variability allows for rational formulation optimization • Robustly manipulate single variables in nanoparticle composition
Changing Composition siRNA-LNP (Cationic Lipid:DSPC:Cholesterol:PEG)
Dia
me
ter
(nm
)
PEG-Lipid Content (mol %)
10
20
30
1.0 2.5 5.00
40
50
60
PD
I
0.02
0.04
0.08
0.00
0.10
0.06
9
• Removal of process variability allows for rational process optimization • Robustly manipulate single variables in process
Small Scale Process Development Changing Process
siRNA-LNP (Cationic Lipid:DSPC:Cholesterol:PEG) D
iam
ete
r (n
m)
Flow Rate (mL / min)
20
40
0 120
60
80
100
4 8 16 20 24
Formulation & Process Manufacturability Assessment
10
Stable Results = Robust Process = Scalable Process
Design of Experiment (DoE) variables
– Lipid Concentration – Flow Rate – Mixing Conditions – Lipid:siRNA Ratio
11
Nanoparticle Drug Development Using the NanoAssemblr™
Seamless process scalability makes small scale results more relevant
Conceptual Drug
Product Scale-up Formulation Process Manufacturability Final
Drug Product
Continuous Flow NanoAssemblr™ Enables Seamless Scale-Up
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Continuous flow system: ü Rapidly achieves steady state ü Maintains particle quality with scale ü siRNA encapsulation efficiency > 94% in all fractions
PD
ID
iam
ete
r (n
m)
NanoAssemblrTM Scale-upCumulative Fraction (mL)
NanoAssemblr
TM
10
20
30
15
Primin
g (5m
L) 2535
4555
6575
8595
1000
40
50
60
0.020.04
0.08
0.00
0.10
0.12
0.06
0.14
Microfluidics as a Scalable Manufacturing Platform
Parallelization facilitates large volume production with identical reactor conditions
13
6x Mixer
1x Mixer
Processing Final Drug Product
14
Final RNA Concentration = 0.96 mg/mL siRNA Encapsulation Efficiency = 96%
15
Nanoparticle Drug Development Using the NanoAssemblr Platform
Conceptual Drug
Product Scale-up Formulation Process Manufacturability Final
Drug Product
Acknowledgements
University of British Columbia
Prof. Pieter Cullis Prof. Carl Hansen Igor Zhigaltzev Chris Tam Genc Basha Paulo Lin
Chen Wan Alex Leung Justin Lee Sam Chen Ismail Hafez
16
Precision NanoSystems
Euan Ramsay James Taylor
Nathan Belliveau Andre Wild Tim Leaver
Kevin Ou Aysha Ansari
David Zwaenepoel
The NanoAssemblr™ Platform ü Microfluidics-based nanoparticle manufacturing process ü Rationally engineered nanoparticle systems ü Automated instrumentation, precise process control, rapid prototyping ü Seamless scale-up
Come see the NanoAssemblr™ at BOOTH # 307 WE’RE HIRING Contact James Taylor Colin Walsh [email protected] [email protected]
www.nanoassemblr.com
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Microfluidics Enables Manufacture of Potent LNP siRNA Systems
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