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A Collaborative Study by the European Pharmaceutical Aerosol Group (EPAG)

to Assess Applicability of a Leak Rate Method and Typical Leak Rate Data for
Different Cascade Impactor Ty...

Conference Paper · December 2007

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A Collaborative Study by the European Pharmaceutical Aerosol Group (EPAG) to Assess Applicability of
a Leak Rate Method and Typical Leak Rate Data for Different Cascade Impactor Types

R Greguletz*
with
Lars Asking, Chris Blatchford, Frank Chambers, Mark Copley, James Hurst, David Lewis, Jolyon Mitchell, Hlack
Mohammed, Steve Nichols, Daryl Roberts, David Russell-Graham, Christopher Shelton, Dilraj Singh, Mårten
Svensson, Maria Chiara Taverna

(on behalf of EPAG)

*Almirall Sofotec, Benzstr. 1-3, D-61352 Bad Homburg, Germany

Summary

A leak rate study was designed and performed by the EPAG ‘Impactor’ sub-team. The study focussed on
assessing methodology to determine leakage in cascade impactors (Andersen 8-stage and Next Generation
Impactor). The objectives were to define a test method and test conditions for determination of leakage, to
assess the applicability of the test method and to generate typical leak rate data for the cascade impactor types
used. The applied test method was based on measurement of the differential pressure decay for one minute,
after a suitable pre-evacuation of the impactor. The results showed that the test method is quick, straightforward,
sensitive, and precise. The test method is useful and a recommended verification test during the operating life of
cascade impactors.

Introduction

Cascade impactors are designed to operate under defined and steady airflow conditions. The effective cut-off
diameter (ECD) of an impactor stage determines the collection characteristic for airborne particles. The ECD of a
round-jet impactor stage depends on impactor geometry and is a function of airflow rate through the device.
Therefore, deviations in operational flow rate can affect the particle size characterisation. Leakage can be
considered as an interfering bypass airflow varying the operational airflow through the impactor (Figure 1). This
change of the operational flow through impactor stages affects the ECD of the respective stages.

Figure 1. Effect of leakage on impactor operational flow.

Qinlet where
Q : Flow rate, e.g. in L/min

Q1 For leakage:
Leak
flow Q1 ≠ Q2
Qinlet ≠ Qoutlet
Q2

Qoutlet Vacuum
pump

If only the inlet flow rate is measured and if a leak is present, the real operational flow rate within the impactor is
unknown and can vary from test to test. Additional measurement of outlet flow rate would be necessary to detect
leakage. But even if outlet flow rate (between impactor and vacuum pump) and inlet flow rate are measured,
leakage cannot be certainly excluded due to limited accuracy of available flow meters. Typically, accuracy of flow
meters is within 1-5% of the reading. Thus, it is only possible for significant leakage (>5% of operational flow) to
differentiate between uncertainty of flow rate measurement and real leakage. Furthermore, the flow rate through
the adapted inhaler device could be reduced by leakage, and with this, the fine particle output as well as the total
dose delivery could be affected, depending on the inhaler device characteristics. Thus, leakage should be noticed
as one significant disturbance source, and an appropriate leak test method should be used for detection of
leakage in cascade impactors.

To assess the criticality of impactor leakage in general and to define approximately tolerable levels for impactor
leakage, the deviation in operational flow rate can be considered and combined with the ideal gas law. Assuming
that a flow rate deviation of approx. 1% of the total flow is not relevant for an impactor measurement due to only
slightest influence on ECD (Table 1), the following mole flows can be derived for typical operational flow rates
through an impactor. From these mole flows, the corresponding pressure-related, tolerable leak rates can be
calculated for typical impactor setups (Table 2).
Table 1. Effect of flow rate deviations on cut-off diameter.
Flow rate deviation [%] Resulting deviation in effective cut-off diameter [%]
1 0.5
2 1.0
5 2.4
10 4.7

Table 2. Tolerable leak rates for different impactor setups.

Impactor type Operational Mole flow* at 1% Internal impactor Corresponding
flow of operational flow volume according to [3] leak rate*
NGI with UIP 15 L/min 0.0062 moles/min 1245 mL 12 kPa/min
NGI with UIP + pre-separator 30 L/min 0.0125 moles/min 2025 mL 15 kPa/min
ACI with UIP 28.3 L/min 0.0118 moles/min 975 mL 29 kPa/min
ACI with UIP + pre-separator 30 L/min 0.0125 moles/min 1155 mL 26 kPa/min
*at ambient conditions: T=293.15 K (=20°C), p=101.3 kPa (=atmospheric pressure).

A number of impactor types are listed in the Ph. Eur. [1] and in the USP [2]. However, the Andersen 8-stage
cascade impactor (ACI) and the Next Generation Impactor (NGI) are the most commonly used cascade
impactors for aerodynamic particle size characterisation of inhalation products. Therefore, the leak rate study
focussed on assessing methodology to determine leakage in both cascade impactor types, ACI and NGI. The
objectives and the study design were set by the EPAG ‘Impactor’ sub-team, as follows:
- Define a test method and test conditions for determination of leakage
- Assess the applicability of the test method for determination of leakage
- Generate typical leak rate data for the two different cascade impactor types used

In addition, a survey was included where the participants of the study were asked to provide additional
information of the tested impactors to allow assessment of the leakage regarding different impactor types,
impactor materials, and impactor age.

Experimental design

Method description
Leakage can be described by a pressure-related leak rate. In short, the test method was based on the
measurement of the differential pressure decay after impactor pre-evacuation during one minute. The following
equation was used to calculate a pressure-related leak rate:

Leak rate = P0 – P1
t
where
P0 : Initial differential pressure (between impactor and atmosphere), e.g. in kPa
P1 : Differential pressure after dwell time (t=1 min), e.g. in kPa
t : Dwell time for measurement of the vacuum decay, e.g. in min
Leak rate : Vacuum decay (P0-P1) within the dwell time (t), e.g. in kPa/min

Study design
The participating companies were asked to use as many individual impactors as possible. If possible six different
impactors of each type (ACI, NGI) should have been investigated. If this was not possible, the available
impactors were disassembled and reassembled between the leakage measurements. Impactors after
disassembly and reassembly were assessed as a new impactor. Disassembly includes the removal of all seals
and single parts. For each single impactor run, a triplicate measurement of the leakage without disassembly of
the respective impactor was done to show repeatability of the measurement as well as to show leakage
variations. This triplicate measurement was done respectively at low (P0=2 kPa), at medium (P0=5 kPa), as well
as at high initial differential pressure (P0=20 kPa) without intermediate disassembly of the impactor. The mean,
the standard deviation, and the span of the triplicate measurement (difference between Min and Max value) were
calculated separately for each level of initial differential pressure. The experimental setup was that shown in
Figure 2.

Figure 2. Schematic diagram of the experimental setup.

 1 1 Rubber bung for blocking the test impactor
2 Test impactor (blocked against atmosphere)
3 Differential pressure meter indicating
P0 (= Patm - Ptest), in kPa
4 Closure valve
5 Needle valve
6 Vacuum pump
dP Patm

Ptest

2 3 4 5 6
Testing procedure
The leak rate of the respective test impactor was determined by the following procedure:
- The test impactor is blocked tightly against atmosphere at its induction port inlet with a suitable rubber bung
(1). The test impactor outlet (2) is connected in accordance with the experimental setup diagram (Figure 2).
- The closure valve (4) is opened, and the vacuum pump (6) is switched on.
- The respective initial differential pressure P0 (e.g. P0 = 2 kPa ± 0.5 kPa) is applied to the test system by
adjusting the needle valve (5) and using the connected differential pressure meter (3). The differential
pressure between test system and atmosphere is measured by connecting the differential pressure meter at
its negative pressure port to the test system.
- After P0 ± 0.5 kPa is achieved and displayed at the differential pressure meter (3), the closure valve (4) is
fully closed to enclose the test vacuum. The vacuum pump can be switched off.
- The initial differential pressure (P0) is determined exactly and is documented for the calculation of the leak
rate. The stop watch is started simultaneously.
- After a dwell time of t = 1.0 min indicated by the stop watch, the decay of vacuum is measured by
determining the differential pressure again. This is differential pressure P1.
- The connector tube or the rubber bung can be removed from the test impactor (2) to bring the entire test
system back to atmospheric pressure conditions. Next test run is done as described above, but at medium
initial differential pressure P0 = 5 kPa ± 0.5 kPa, and after this, at high initial differential pressure
P0 = 20 kPa ± 0.5 kPa.
The above-mentioned measurement was repeated two more times for the same impactor (without disassembly of
the impactor) to have a total set of n=3 leakage results for each initial differential pressure level (P0 = 2, 5, and
20 kPa). Afterwards, the next test impactor was measured accordingly.

Results

Ten companies participated in measuring leak rate data for the different cascade impactor types and
configurations, different materials, and a broad distribution of impactor ages, providing an overview of leakage
behaviour. In total 60 different impactors were tested for leakage, 101 impactor leak tests were performed and
with this, a total number of 909 individual leak rate values were determined. Test conditions using different initial
differential pressures (pre-evacuation at P0 = 2 kPa, 5 kPa, and 20 kPa) were investigated for each impactor. All
mean leak rate values were in the range of approximately 0 - 10 kPa/min (Figure 3), and 99% of the mean leak
rates were <7 kPa/min (Figure 4). The ACI and the NGI showed very similar mean leak rates.

Figure 3.
Obtained mean leak rates at different initial differential pressures P0
(no. of impactor runs: 101; 3 series per impactor run at P0=2, 5, and 20 kPa; total mean no.: 303)

11
Error indicator: Standard deviation
10

8
Leak rate [kPa/min]

0
1

11

21

31

41

51

61

71

81

91

101

Impactor test no.

Leak test at P0=2 kPa Leak test at P0=5 kPa Leak test at P0=20 kPa
 Figure 4.
Frequency distribution of all obtained mean leak rates
(no. of impactor runs: 101; 3 series per impactor run at P0=2, 5, and 20 kPa; total mean no.: 303)

50

45

40

35
Relative frequency [%]

30

25

20

15 28.7
27.1
22.8
10

5 9.2 8.6
2.3 0.7 0.3 0.3
0
<=0 >0 - 0.1 >0.1 - 0.5 >0.5 - 1 >1 - 2.5 >2.5 - 5 >5 - 7.5 >7.5 - 10 >10
Leak rate [kPa/min]
mean leak rates

The variability of the method was verified by assessment of the span (difference between Min and Max) and the
standard deviation. Ninety percent of the span values and of the standard deviations were found to be less than
approximately 0.1 kPa/min. Thus, the differences within each test series under the same leakage conditions
typically were small. Higher leak rates were correlated with increasing applied differential pressure, indicating that
leakage sensitivity is higher for higher pre-evacuation levels.

Conclusion

In summary, the results of the impactor leakage study showed:

- The leak rate determination used in this study is a very sensitive method, able to detect even very small
ingresses of air via leakage pathways.
- The initial differential pressure should be close to the pressure conditions during impactor usage, for
example, a value within the range of 5-20 kPa.
- Variability of the investigated leak rate method is typically small and of no practical relevance, confirming that
the precision of the method is sufficiently high.
- Typical leak rates of impactors during operating life are found in the range of 0-10 kPa/min, significantly
below the critical level of leakage derived from theoretical considerations based on gas mole flow
calculations.

It can be concluded that the described test method is suitable for measuring the impactor leak rate. The leak rate
test method is quick, straightforward, sensitive, and precise. Thus, the leak rate test method is useful and a
recommended verification test during the operating life of the cascade impactor or as a rapid system suitability
test directly before use of the impactor.

References

[1] Ph. Eur Edition 5, Section 2.9.18, 2005.

[2] USP 27 Section <601>, 2004.
[3] Copley, M., Smurthwaite, M., Roberts, D. L., Mitchell, J.P. 2005. Revised Internal Volumes of Cascade
Impactors to Those Provided by Mitchell and Nagel. J. Aerosol Med., 18(3): 364-366.

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