A Comparison of Dry Powder Inhalation Setups
Used in Preclinical Testing
Mark C. Freke, André Viau. Charles River Montreal, Quebec, Canada
1
ABS TRACT
Although it is not critical to use the intended clinical device when generating aerosols as part of a
nonclinical testing program, it is crucial that a suitable setup be selected. The generation system has to
tick multiple boxes; it has to have the ability to generate not only a range of aerosols sufficient enough to
expose the Test System to the multiples of the clinical dose required to prove safety; it has to be able to
sustain a stable aerosol at these concentrations for at least the intended duration of dosing; and it has to
generate an aerosol that is respirable to the Test System. With the therapeutic agent often being in
limited supply during these initial trials, all of these criteria must be met using the most efficient setup
and the least amount of material possible.
The purpose of this investigation was to directly compare key performance indicators of several routinely
used aerosol generation setups and exposure chamber types, namely their ability to achieve a target
aerosol, the spatial and temporal homogeneity of the generated aerosol and the mass transfer efficiency
(calculated by comparing the amount of powder consumed per minute versus the aerosol concentration
generated).
2
MATERIALS AND METHO DS
Two dry powder aerosol generation devices were selected, the commercially available PALAS® Rotating
Brush Generator (RBG) series 1000 using either 10 mm or 28 mm canisters, and a device developed at
Charles River Montreal, referred to internally as the Extended Duration Powder Delivery System, or
EDPDS (Figure 1).
3
Aerosols were generated on multiple occasions using Sodium Bicarbonate, USP (Fisher Scientific, lot
No. 125296) into cylindrical flow-through or flow-past chambers through a feed line (Bev-A-Line)
supplied with pre-dried compressed air.
The chambers themselves were of modular design and configured as follows (see Figure 2):
The flow-past chamber consisted of an inner and outer plenum that provided
12 separate ports. The aerosol was generated into the central plenum and fed out under slight positive
pressure (0.3 L/min) to each port through horizontal delivery branches before being exhausted through
the external plenum.
The flow-through chamber was effectively a hollow cylinder providing 20 separate ports and was
operated under slight negative pressure.
Target total aerosol concentrations were achieved by varying the rate of powder introduction into the
feed line such that concentrations ranging from 0.1 to 1.0 mg/L could be achieved. Gravimetric sampling
techniques (using 25 mm glass fiber filters) were employed to determine the achieved aerosol
concentration. Each flow-past and flow-through chamber was sampled over a period of at least
60 minutes, with aerosol concentration means, standard deviations and correlation coefficients
calculated along with mass transfer efficiency (MTE) for each.
Exhaust rates were sufficient to maintain at least 12 air changes per hour and a chamber environment of
19-25°C, 30-70% RH and at least 19% O2. Monitored as a differential across a constriction in the
exhaust line using a Magnehelic® gauge, the exhaust from each chamber was driven by a vacuum
pump, drawing contaminated air through a purifying system consisting of a series of filters before
expelling the remaining air from the Facility.
RE S ULTS
4
CO NCLUSIO NS
All setups/combinations had the ability to achieve a homogeneous aerosol concentration at or around
0.1 mg/L, with the EDPDS proving the most efficient dry powder aerosol generation system regardless of
chamber type (flow-through versus flow-past) at this concentration (5 to 8% MTE, versus 3 to 4% for the
RBG). The RBG, regardless of chamber type, was either not able to achieve, or was not able to
maintain, a stable aerosol concentration at the targeted 1.0 mg/L (whereas the EDPDS was).
The low mass transfer efficiencies noted during these trials were likely due to the choice of powder used,
as it is not uncommon to obtain MTE values of upwards of 70% when using other dry powders such as
Lactose Monohydrate, USP using comparable aerosol concentrations and similar equipment setups.
Although these values maybe somewhat atypical, they do still allow for a direct comparison within the
confines of the investigation.
Based on the physical characteristics of the powder being used, careful consideration should be given
when selecting a suitable chamber and dry powder aerosol generation system combination for use on
preclinical inhalation toxicology programs. Further work is needed to fully understand the relationship
between efficiency and aerosol concentration, but under the conditions of this experiment, using Sodium
Bicarbonate, USP as test material, it can be concluded that any of the combinations tested are suitable
for use when targeting a total dry powder aerosol at or around 0.1 mg/L; with the EDPDS, in combination
with either the flow-through or flow-past chamber types, provided the best results (i.e., stable and closest
to target) at the higher target aerosol concentration of
1.0 mg/L.
Chamber Type
Aerosol
Generation
System
EDPDS
Flow-through
RBG
EDPDS
Flow-past
RBG
Figure 1. Left: A PALAS® Rotating Brush Generator (RBG) series 1000 feeding into a flow-past chamber
Right: The Charles River-developed/manufactured ‘EDPDS’
Figure 2. Left: Top view of a 12-port flow-past chamber (lid removed). Note sampling line at 10 o’clock
Right: A flow-through chamber (note that only one, not three [pictured], exposure levels were used)
Target
Aerosol
conc’n
(mg/L)
Mean
achieved
Standard
Aerosol
Deviation
conc’n (mg/L)
Correlation
Coefficient
(%)
Variance
Mass Transfer
from target
Efficiency (%)
(%)
0.100
0.101
0.0105
10.4
1
5
1.00
0.950
0.1330
14.0
-5
8
0.100
0.091
0.0075
8.2
-9
3
1.00
0.546
0.1401
25.7
-45
3
0.100
0.109
0.0040
3.7
9
8
1.00
0.857
0.1160
13.5
-14
12
0.100
0.099
0.0104
10.5
-1
4
1.00
1.449
0.4732
32.7
45
27
Table 1. Achieved aerosol conditions for each chamber type and powder aerosol generation system combination