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IPAC-RS 2011 Conference
Equipment Options for
AIM and Beyond
Jolyon P. Mitchell Ph.D., FRSC(UK), C.Chem., C.Sci.
Scientific Director, Trudell Medical International,
and
Adviser to IPAC-RS
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IPAC-RS 2011 Conference
SUMMARY
1. Background to the AIM Concept
2. AIM Equipment derived from the Andersen Cascade
Impactor (ACI)
3. AIM Equipment derived from the Next Generation
Pharmaceutical Impactor (NGI)
• Fast Screening Impactor (FSI)
• Modifications to the NGI itself
4. Other possibilities
5. Future needs
6. Approach to introducing AIM into the compendia
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IPAC-RS 2011 Conference
1: BACKGROUND
• AIM: Abbreviated Impactor Measurement(measurement techniques are the focus of this talk)
• EDA: Efficient Data Analysis(already covered in previous presentations)
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The two concepts are closely linked with the
focus of AIM being on the measurement
equipment, and EDA on data handling
IPAC-RS 2011 Conference
UNDERLYING PRINCIPLE OF AIM
• The cascade impactor is NOT a lung simulator
• However, it DOES determine APSD from which pertinent size sub-fractions may be obtained.
• The handling of these sub-fractions is at the heart of EDA
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ICRP-66 lung deposition sub-fractions
compared with stage collection efficiency
curves for the Andersen 8-stage CI:
Mitchell & Dunbar JAM 2005;18(4):439-51.
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A REMINDER: AIM-EDA GOALS
1. Investigate alternative methods that are better able to detect changes in APSD for Quality Control (QC) purposes
2. Develop standardized, robust methodologies that can be incorporated into the pharmacopeias in a fully harmonized way:
• Offer more than one alternative, as different inhaler classes are likely to need different AIM-based approaches
IPAC-RS 2011 Conference
AIM HAS 2 DISTINCT PATHWAYS
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AIM
MEASUREMENTS
FULL RESOLUTION CI
MEASUREMENTS
MMAD, SPM, LPM
REFERENCE
TECHNIQUE
PRODUCT
QC
SPM, LPM
EDA METRICS
Better decision making
tool than grouped CI stages
HRT-RELEVANT
APPLICATIONS
EPM, FPM, CPM
HRT METRICS
Appropriate in
support of IVIVRs:
Likely use
anatomically correct
inletFocus of today’s talk will be on AIM-QC systems
IPAC-RS 2011 Conference
2: AIM EQUIPMENT FROM THE
ANDERSEN CASCADE IMPACTOR (ACI)
• Two campaigns at Trudell Medical International:
1. 2008: Assess viability of approach with two abbreviated ACI designs
• Copley FSA (C-FSA)
• In-house FSA with inactive stage ‘0’ (T-FSA)
2. 2009: Undertake a designed experiment on behalf of IPAC-RS to assess precision and accuracy of two ACI designs
• ‘QC’ impactor
• ‘HRT’ impactor
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IPAC-RS 2011 Conference
CAMPAIGN 1: C-FSA
• C-FSA is two-stage stack
that divides the incoming
dose into coarse, fine and
extra fine fractions (CPF,
FPF and EPF, respectively)
• The C-FSA was operated
with stage cut-off diameters
of 4.7 and 1.0 microns at
28.3 L/min
• Other cut-off combinations
are possible
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IPAC-RS 2011 Conference
CAMPAIGN 1: T-FSA
• T-FSA was developed at TMI, and has stage cut-off diameters of 4.7 and 1.1 microns at 28.3 L/min, for direct comparison with stages 2 and 5 of the full resolution ACI
• It also includes a non-operable (collection surface removed) ACI stage 0 to provide functional dead space before the first size separating stage
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IPAC-RS 2011 Conference
CAMPAIGN 1: Methods
• STUDY 1 – 125 μg/actuation pMDI delivering ‘dry’
fluticasone propionate particles in HFA- 134
propellant:
• Mitchell, JP et al. AAPS PharmSciTechnol., 2009, 10(1),
243-251.
• STUDY 2 – 100 μg/actuation pMDI delivering
beclomethasone dipropionate particles with ethanol
co-solvent (8% v/v) in HFA- 134 propellant:
• Mitchell et al. AAPS PharmSciTechnol., 2009, 10(1), 252-
257.
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IPAC-RS 2011 Conference
CAMPAIGN 1 STUDY 1: - LEARNINGS
1. It was essential to coat
collection surfaces with an
agent to prevent particle
bounce and re-
entrainment biasing FPF to
larger values
2. Brij-35 polyoxyethylene 23
lauryl ether surfactant was
used, but alternatives are
likely to be equally as good
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uncoated surfaces
Brij-35 coated surfaces
IPAC-RS 2011 Conference
CAMPAIGN 1 STUDY 2: LEARNINGS
3. The additional functional
space afforded by the
inactive stage ‘0’ was
needed to match ethanol
evaporation with full
resolution ACI
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Closer agreement between FPF
from full resolution ACI when
Inactive stage ‘0’ was present
Liquid ethanol-sensitive paper showing
presence of liquid phase on upper stage
when inactive stage ‘0’ was NOT present
IPAC-RS 2011 Conference
CAMPAIGN 2: IPAC-RS EXPERIMENT
• To be covered in
the following
presentation
• The experiment
was a success,
demonstrating
consistent
variability
between the
abbreviated and
full systems
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IPAC-RS 2011 Conference
FOLLOW-ON STUDY:
PARTICLE BOUNCE IN AIM-pHRT
Learnings:
• Brij-35 surfactant layer on
collection plate of lower
stage displaced radially by
flow from upper stage
• Saturating glass fiber filter
created a soft surface
resisting lateral
displacement of surfactant
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STATISTICS COMPARING MODIFIED WITH
UN-MODIFIED AIM-pHRT
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LEARNING: Bias eliminated by use of surfactant-saturated filter
IPAC-RS 2011 Conference
3: AIM EQUIPMENT RELATED TO THE NGI
• Almost all other work has been undertaken with
either the FSI or modified versions of the NGI itself
• Although initial data were on the FSI were presented
by Russell-Graham et al. at DDL20 in December
2009, the EPAG-sponsored Workshop on AIM at
DDL21 last December contained an update
• 6 presentations represent the current state-of-the-
art with respect to these systems
• Copies are available in the public area of the EPAG website
at www.epag.co.uk
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IPAC-RS 2011 Conference
Background
• On December 8th, 2010, EPAG organized a half-day
workshop focusing on experimental aspects relating
to the AIM concept in relation to the more efficient
testing of oral inhaled products (OIPs)
• About 70 participants heard seven presentations
(see Table)
• The complete transcript of the Workshop, together
with each presentation are available on the EPAG
website at www.epag.co.uk
IPAC-RS 2011 Conference
FSI = Fast Screening Impactor (MSP Corp., St. Paul, MN, USA);
NGI = Next Generation Pharmaceutical Impactor (MSP Corp.)
Presentation OIP Type(s) Equipment
Russell-Graham et al. DPI FSI
Tservistas et al. Nebulizer FSI
Svensson and Berg pMDI, DPI Modified NGI configurations (2)
Després-Gnis DPI FSI
Sheng and Watanabe pMDI, nebulizer FSI
Rogueda et al. DPI, nebulizer FSI
AIM WORKSHOP PRESENTATIONS
• Snap-shot summaries of key points from these presentations follow
IPAC-RS 2011 Conference
FSI ANATOMY
• Use of modified pre-separator with
a single cut-point at 5 µm
aerodynamic diameter
• Filter collects particles < 5µm (Fine
Particle Fraction)
• Reduced number of stages should
greatly improve experiment time
• LEARNING: Coating the base of the
coarse particle collector in the FSI
with silicone oil was needed to
mitigate particle bounce
(5 µm)
(0.2 µm)
Courtesy: Russell-Graham, D et al.
Insert with
5 µm* cut-
off
Filter
holder
IPAC-RS 2011 Conference
RESULTS
DPI Product 1:two dosage strengths
DPI Product 2:combination
product
DPI Product 4:higher flow rate
dependency DPI
• FSI slightly, but detectably over-estimated FPF
Courtesy: Russell-Graham, D et al.
IPAC-RS 2011 Conference
TWO POSSIBLE CAUSES
• Differences in internal dead-space
between the FSI and NGI :
• FSI @ 960mL
• NGI @ 2000mL
• Pressure drop profiles at start-up
differ for the abbreviated and full
resolution systems
• LEARNING: The DPI test method,
involving start-up of the impactor
from zero flow rate, is a more
stringent test to achieve replication in
performance between abbreviated
and full resolution systems
(a) at start-up
(b) completemeasurement
Flow-time profiles
Courtesy: Russell-Graham, D et al.
IPAC-RS 2011 Conference
MORE DPI-BASED EXPERIENCES WITH FSI
• FSI-measured total emitted
mass compared well with
that obtained by DUSA
apparatus
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AptarDPI
LEARNING:Internal losses within the FSIare very small
Courtesy: Desprez-Gnis, F. et al.
IPAC-RS 2011 Conference
FSI FOR NEBULIZER TESTING: 1
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PARI e-Flow® nebulizer
Courtesy: Tservistas, M. et al.
LEARNINGS:1.Cooling the FSI had little
effect on FPF2.Agreement between FPF
for FSI and NGI was good3.These meaurements were made
at constant flow rate (15 L/min)
IPAC-RS 2011 Conference
FSI FOR NEBULIZER TESTING: 2
• Aeroneb Go® vibrating
mesh nebulizer
• Higher flow rates (28.3 and
30 L/min)
• Screening of 8 different
formulations
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LEARNING:
• Excellent agreement between FSI and NGI operated at constant flow rate for these aqueous systems
Courtesy: Sheng,G. et al.
IPAC-RS 2011 Conference
REDUCED NGI CONFIGURATIONS
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Flow to
vacuum
pump
Configuration 1: Particles collected on internal filter
= fine particle mass on filter MOC nozzle
NGI
body
Flow direct to
vacuum pump
MOC nozzle
Configuration 2: Particles collected on external filter
= fine particle mass on filter or return
flow via NGI
NGI
body
air flow
pathway
Courtesy Svensson, M. et al.
IPAC-RS 2011 Conference
REDUCED NGI: RESULTS
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Configuration 1 Configuration 2
Configuration 2 Configuration 2
Courtesy Svensson, M. et al.
LEARNING:• Excellent agreement for both pMDI and DPI formats with either configuration
IPAC-RS 2011 Conference
4: OTHER POSSIBILITIES: THE TWIN IMPINGER
• The Twin Impinger could be
developed as an AIM
apparatus.
• It has a single cut-point size
(6.4 μm at 60 L/min), and
eliminates bounce and re-
entrainment by collecting
the particles under a fluid.
• Recovery of active
pharmaceutical ingredient
from this fluid can in some
cases be achieved without
further analytical work-up.
Twin Impinger
IPAC-RS 2011 Conference
TWIN IMPINGER
• Unfortunately, validation data are not available
• The cut-point size also needs to be reduced closer to
5 μm at flow rates appropriate for the various OIP
classes:
• This would be a relatively easy change to make
• The use of more robust materials than glass may also be
worthwhile considering
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IPAC-RS 2011 Conference
COMBINED AIM-DUSA
• There are benefits to be
gained in terms of the
decision-making power by the
elimination of confounding
variables intrinsic to separate
measurements
• IPAC-RS intends to make the
detailed design of the
apparatus available once it
has been optimised, so that
the community involved in
OIP in vitro testing can
evaluate its usefulness
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IPAC-RS 2011 Conference
5: FUTURE NEEDS
1. Confirmation that the FSI performance can be
matched with that of the NGI for DPI testing
2. Evaluation of the Twin Impinger as a potential AIM-
based apparatus avoiding bias from particle bounce
3. Published calibration data for archival versions of
each short-runner AIM apparatus:
a. FSI with cut-point at 5 μm
b. C-FSA and variants with cut-points at 4.7 and 5 μm
(reduced NGI variants already have NGI archival data)
4. More published data demonstrating robustness of
AIM approach, especially when linked to EDA30
IPAC-RS 2011 Conference
6: AIM INTO THE COMPENDIA
• Evidence:
• Are AIM techniques sufficiently robust?
• Can they be applied across all classes of OINDP?
• One common cut-point (5 μm) or more than one?
• Is a ‘Quality’ benefit available beyond that currently
available from existing apparatuses and data analysis?
• Does AIM-EDA have the discriminating ability to identify
‘good’ from ‘OOS’ batches at least as good as at present?
• Are there published AIM calibration data, preferably with
‘archival’ apparatuses?
• Performance at different flow rates – especially important
for DPI testing
31THE WHOLE PROCESS WILL LIKELY TAKE SEVERAL YEARS
IPAC-RS 2011 Conference
Acknowledgements
• I wish to acknowledge the support of my colleagues
in the Cascade Impactor Working Group of IPAC-RS
as well as participants in the EPAG-sponsored
Workshop on AIM methods
• I also wish to acknowledge the support of the
Aerosol Laboratory team at Trudell Medical
International in the execution and interpretation of
the data from measurements undertaken there
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