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Testing inhalers

This article investigates how the industry can test inhalers


in a way that is most representative of typical use.

ne of the longstanding challenges facing the People who suffer from these aforementioned illnesses David Harris
O United States Pharmacopeia (USP) is the necessity
to provide guidance for testing standards that are
will not necessarily have impaired lung function. The
current test point of a 4 kPa pressure drop across the
representative of typical use. The USP maintains DPI is unlikely to be representative of what will be
a formal revision process, which is reliant upon achieved in typical use.
‘substantial interaction’ between their stakeholders As engineers and scientists responsible for the
(the public, and scientific and technical groups) and development of DPIs to treat a range of conditions,
their Council of Experts. As engineers and scientists we should believe that an in-depth understanding of
working within the field of respiratory drug delivery, the nature of the lung power of the target therapeutic
it is up to us, therefore, to challenge existing testing group is prerequisite to achieving a successful inhaler
methodologies, and strive to constantly reduce the gap design. Only once armed with this information can we
between results produced within the laboratory to expect to achieve clinical results that marry well to
those acquired in clinical studies. those generated within the laboratory.
Passive dry powder inhalers (DPIs) rely solely upon
the inspiratory effort provided by the patient to Usefully measuring lung power
produce a respirable aerosol. Historically, DPIs have There is little published literature available on the
been used to administer medication for the direct measurement of lung power — most research has been
treatment or relief of chronic obstructive pulmonary conducted using inhaler devices with fixed resistances,
disease (COPD) and asthma. People who suffer from each inhaler representing just a single datum on a lung
either of these, characteristically, have impaired lung power profile. Also to be considered is the relatively short
function and are less able to inhale forcefully through duration of an inspiratory manoeuvre — usually less than
an aerodynamically resistive DPI. Studies researching 2 s; half that of the prescribed test duration by the USP
the lung power of these groups report that a flow for a medium resistance inhaler.3 Of course, this is
rate of 60 L/min can typically be achieved through a
medium resistance device (corresponding to a
pressure drop across the device of 4 kPa).1 I However,
a new generation of DPIs is under development to
cover a range of diseases and illnesses, including the
systemic delivery of a wide range of molecules to
treat conditions such as diabetes, pain management,
allergic reactions and sexual dysfunction. In addition,
numerous pharmaceutical companies are developing
inhalable vaccines to overcome problems associated
with parenteral administration, such as needle-stick
injury and the requirement for refrigeration of the
vaccines throughout the shipping cycle. There are
two distinct advantages of delivering drugs directly
into the lungs:2
● There is a high rate of absorption into the

bloodstream, resulting in a fast onset of relief.


● A reduced chance of drug metabolism occurring,

meaning delicate molecules can be delivered that


would normally be administered parenterally.

I. A ‘medium’ resistance inhaler device requires a pressure drop of 4 kPa to draw an airflow rate of 60 L/min.
through it. As the resistance is given by the ratio of the square root of pressure drop to airflow rate, medium
resistance is 0.105 √cm H2O/(L/min) (conventional units).

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Harris

considerably shorter as far as the drug is milliseconds, all data above 80% of
concerned as it will have typically exited the peak datum value were averaged
the inhaler within 100–300 ms. In terms (i.e., the top 20%), and this mean value
of developing a testing methodology, taken to be the peak flow rate (or
this means that a fast response time of pressure) for that particular resistance.
Figure 1 Schematic illustration of equipment to the measurement instrumentation is An example is illustrated by the purple
measure lung power. required to capture the dynamic nature triangles overlaid on the profile of
of the inhalation event. Orifice 5 (Ø7.4 mm) (Figure 3). This
Q Orifice plate(s) A similar technique, albeit on a larger was believed to be a more
(various resistances) scale, is used to measure the power representative measure as it rules out
Mouthpiece
response of in-line centrifugal fan spikes in the profile and is effectively
motors.4 I adapted this technique to the average peak period of the
Airwatts work on a much smaller scale, to inhalation. The mean peak flow rate
box measure the pressure/flow temporal achieved by our example volunteer
profiles of 16 healthy, adult volunteers through Orifice 5 was 158.3 L/min,
(Figure 1). A low volume (200 cm3) which is 94% of the absolute peak
‘airwatts’box was designed to minimize value, 168.7 L/min. It is accepted that
P capacitance effects and, using nine this method will slightly under predict
orifice plates, a wide range of inhaler the power of our volunteers’ lungs.
(Courtesy of Virginia Commonwealth University)
resistances could be represented. Each Several parameters are captured
orifice was pressure-mapped to simultaneously, including; pressure III
determine its discharge coefficient, Cd, airflow rate, power and airflow
Figure 2 Example of flow rate profiles acquired for according to Equation 1, thus allowing velocity IV, which was used to
one volunteer. flow rate to be accurately deduced from measure the power response of
350 static pressure data. II human lungs.
Ø15.0 mm The first order derivative of these
Equation 1
300 Ø12.9 mm four parameters has been calculated
Ø11.0 mm using a straightforward linear
250 Ø9.0 mm  regression of the data falling
Flow rate (L/min)

Ø7.4 mm between 10% and 80% of the


200 Ø5.6 mm absolute peak datum on the positive
Ø4.1 mm slope of the profiles. An example is
150 Ø2.6 mm shown by the red diamonds, together
Ø1.3 mm
Q  flow rate (m3/s)
A  area (m2) with the dashed trend line, overlaid
100 on the profile shown in Figure 3. The
ΔP  pressure drop (Pa)
  local air density (kg/m3) slope of this trend line is taken to be
50 the peak rate of change for all of the
measured parameters.
0
Each volunteer was asked to “breathe Once we have calculated peak
0 500 1000 1500 2000 2500 3000
out gently, as far as is comfortable”, pressure and peak airflow rate from
Elapsed time (ms)
then inhale through the airwatts box each of the nine resistance profiles,
as “quickly, hard and deeply” as we can derive airflow power,
possible. This produces nine pressure according to Equation 2. V
Figure 3 Illustration of profile dissection; and flow rate temporal profiles per A known measure for inspiratory
Orifice 5, Ø7.4 mm. volunteer (Figure 2). muscle strength is the maximal
180 To construct a power-flow rate inspiratory mouth pressure, which is
profile, the peak flow rate must be achieved against a closed shutter
160 Peak flow rate calculated from each profile. Rather (zero airflow rate). Conversely, the
140 than simply take the absolute peak peak inspiratory flow rate is reached
Flow rate (L/min)

data, which may only last a few with no additional resistance to the
120
100
II. 200 cm3 is 5–10% of a normal adult’s lung capacity. There must be sufficient
80
volume to remove the dynamic head component of the airflow through the
60 box, to measure static pressure accurately — but this must be traded off
against having too high a volume, which reduces the responsiveness of the
40 Linear regression
system to measure high rates of change in pressure or airflow rate.
20 III. Specifically ‘mouth pressure’. The airwatts box method effectively measures
0 the pressure drop that would be achieved within the mouth at any point
0 200 400 600 800 1000 1200 1400 1600 during the inhalation event, and the subsequent airflow rate that will result
Elapsed time (ms) through the resistance that is providing that pressure drop.

30 SEPTEMBER 2007 PHARMACEUTICAL TECHNOLOGY EUROPE


Harris

Power (airwatts)  Airflow rate (Ls-1)  Pressure drop (kPa) Figure 4 Pressure profile of healthy human lungs.

Equation 2 14

Mean mouth pressure (kPa)


12
inhalation (zero pressure) (Figure 4). aerosol performance characteristics
In accordance with Equation 2, the of virtually all DPIs. This is because the Increasing airflow resistance
10
airflow power peaks somewhere majority of DPIs release their
between the extremes of pressure formulation within 100–300 ms, 8
and airflow rate (Figure 5). hence, any available energy beyond
A key finding here is that the mean this time point will have no 6
mouth pressure achieved by our opportunity to do work on the drug
4
group of healthy volunteers through formulation. A Malvern Spraytech laser
a medium resistance device is diffractometer was used to
2
approximately 8 kPa, resulting in a demonstrate this effect (Figure 6).
Error bars show standard deviation
flow rate of 90 L/min and a power of Airflow acceleration in particular is 0
12 airwatts (Figure 5). This is double likely to influence the aerosolization 0 50 100 150 200 250 300 350 400
the pressure drop and triple the of drug formulation within the DPI. Flow rate (L/min)
recommended power prescribed as This is because the powder is initially (Courtesy of Virginia Commonwealth University)
the nominal test point for a medium at rest, and, therefore, the differential
resistance DPI by the USP. Further, an velocity (between the airflow and the
inhaler with a significantly lower powder) is maximum. The quicker the
resistance could run at almost airflow can be brought up to peak Figure 5 Power profile of healthy human lungs.
200 L/min, receiving 17 airwatts velocity, the greater the differential
of power.7 VI velocity (because of the inertial lag of 20
Important parameters the powder), and thus, the larger the 18
The USP instructs us to draw four litres aerodynamic drag force exerted Mean power (airwatts) 16
of air through the DPI under upon the particles. There is a strong
14
evaluation at a flow rate (Qout) that correlation between airflow resistance
produces a pressure drop of 4 kPa and peak airflow acceleration 12
across the device, using a solenoid (Figure 7). This immediately suggests 10
valve to start and stop the airflow.3 It is that if the residence time of the drug 8
widely known (and accepted) within formulation within the DPI is likely to
6
the industry that this method gives be short, it will be beneficial to have
Power consumption of
rise to a steep ramp-up in the flow as high a resistance inhaler as 4 medium resistance DPI
profile through the inhaler, which is possible. It must be remembered, 2
unlikely to be representative of patient however, that airflow power was
0
use (Figure 6). Our healthy volunteers found to peak with an extremely low 0 50 100 150 200 250 300 350 400
took approximately half a second to resistance (Figure 8). Without Flow rate (L/min)
reach their peak inspiratory flow rate adequate power, the momentum of
through the medium resistance orifice. the airflow will be insufficient to
A powerful vacuum pump, coupled to aerosolize the formulation.
the inhaler with a low volume circuit Figure 6 Mean flow profile through Orifice 6
and using a solenoid valve to trigger So what does it all mean? (Ø5.6 mm). Orifice 6 has a resistance of 0.09 √cm
the airflow would have an almost Many factors contribute towards the H2O/(L/min), which was the closest resistance
instantaneous rise in the flow performance of a passive DPI. During (of the nine orifices) to a medium resistance DPI.
profile — clearly unrepresentative this pilot study evaluating a novel 100
Error bars show standard deviation
of typical use. methodology to characterize human
90
Mean flow rate with n16 (L/min)

The ramp-up of the profile lung power response, it became


(pressure, flow rate and ultimately apparent that these parameters are 80
airflow velocity within the inhaler) is often in conflict with one another. For 70
likely to have a strong influence on the example, it may be advantageous for a
60
50
IV. The estimated peak velocity through the orifice, calculated as the ratio of 40 Relative mass
the volumetric flow rate to the open cross-sectional area. emitted from a
30 conventional DPI
V. Airflow power is a reasonable approximation of airflow power in the
measurement of human lung power as it assumes the air in incompressible. As 20
the pressure drops are typically less than 10% of atmospheric, the changes in 10
the density of the air can be considered negligible. As the air expands and
0
contracts, there are small additional losses because of the energy lost in the 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5
process of heat exchange between the air and the surroundings. Inhalation event time (s)

32 SEPTEMBER 2007 PHARMACEUTICAL TECHNOLOGY EUROPE


Harris

particular DPI design to have to establish the relative influence of


extended inhalation event duration — these measured parameters upon the
yet this would limit the airflow power DPI under development, such that
available. Similarly, an inhaler with informed decisions can be made to
high perceived user comfort (in our pursue the optimal usage of the
tests the users indicated a preference energy available.
for low resistance) may have There is clearly dissimilarity between
insufficient airflow velocity or the way in which the airflow develops
acceleration to produce the required through a passive DPI in laboratory
aerosol performance. testing to typical patient use: patients,
The design of an optimal passive DPI at least those who do not suffer from
represents a balance of multiple trade impaired lung function, may well
offs (Figure 9). The most important achieve higher driving pressures than
conclusion we reached was that the 4 kPa recommended by the USP.
building an in-depth understanding of However, they are unlikely to be able to
the energy available in the target match the steep ramp-ups produced by
therapeutic market is essential for the the vacuum pump/solenoid valve
successful development of a passive combination in vitro method. It is our
DPI. This should include in vitro studies intention, and indeed a strong

Figure 7 Effect of airflow resistance upon peak airflow


acceleration.

800
Mean peak airflow acceleration (m/s2) Smallest hole not included

700

600

500
y = 128.57Ln(x) + 855.96
400 R2 = 0.9032

300

200

100

0
0.01 0.10 1.00
Airflow resistance (√cm H2O/(L/min))

Figure 8 Effect of airflow resistance upon peak


airflow power.

25
Smallest hole not included
Mean peak power (airwatts)

20

15

10

0
0.10 0.10 1.00
Airflow resistance (√cm H2O/(L/min))
Harris

recommendation for other interested Prescribing and Use,” Chapter 1:


parties, such as pharmaceutical or Introduction to Inhalation Therapy with
device development companies, to Dry Powder Inhalers, Thesis, University of
extend this study to cover a broader Groningen, Groningen, The Netherlands
range of people, and to a statistically (2001), Section 1.8.
Figure 9 Summary of pressure and power
significant scale. An extensive data set 7. J.P. de Koning, “Dry Powder Inhalation:
characteristics of healthy human lungs.
would enable us to characterize the Technical and Physiological Aspects, 20 10
effect of these dissimilarities upon DPI Prescribing and Use,” ‘Chapter 3: Medium resistance DPI
18 9

Mean mouth pressure (kPa)


performance and potentially improve Relationship between Inspiratory Flow
the methodologies prescribed by Through Simulated Dry Powder Inhalers 16 8

Mean power (airwatts)


the USP. and Peak Maximal Inspiratory 14 7
Pressure,Thesis, University of Groningen, 12 6
References Groningen, The Netherlands (2001),
10 5
1. A.R. Clarke and A.M. Hollingworth, Section 3.1, 2001. PTE

J. Aerosol Med., 6, 99–110 (1993).


8 4
Increasing consistency
2. R. Uchenna et al., Respiratory Research, 2, David Harris 6 3
198–209 (2001). is a senior consultant at Cambridge 4 Increasing user comfort 2
3. United States Pharmacopeia 29, Consultants and works in the drug delivery
2 Increasing acceleration 1
Physical Tests/<601>, Aerosols, products group. He specializes in aerosol
0 0
pp 2620–2621. science, including fluid dynamics,
0 50 100 150 200 250 300 350 400
4. BS EN 60312:1998, Vacuum cleaners for electrostatics and their applications to
Flow rate (L/min)
household use — Methods of measuring the inhaler technology.
performance, Sections 2.8 and 5.2.8, pp 18,
37–38, 50–52.
5. D. Harris, Respiratory Drug Delivery, VI. An inhaler requiring a pressure drop of only 0.6 kPa to draw 60 L/min through it would actually
537–540 (2006). run at almost 200 L/min, at a pressure drop of just over 5 kPa — consuming 17 airwatts. This is a
6. J.P. de Koning, “Dry Powder Inhalation: very low resistance inhaler, with R0.04 √cm H2O/(L/min. The only marketed inhaler with a
Technical and Physiological Aspects, resistance close to this value is the Rotahaler at R0.046 √cm H2O/(L/min).

Key points
● For the new generation of DPIs customized solutions
the current test point of a 4 kPa
is unlikely to be representative
of what will be achieved in
typical use. The mean mouth
pressure achieved by our group
of healthy volunteers through a
medium resistance device is
tailor-made specialty chemicals
approximately 8 kPa —
equivalent to triple the nominal
power prescribed by the USP.
● Airflow acceleration in
particular is likely to influence proven track record in specific industries
the aerosolization of drug
formulation within the DPI:
The instantaneous rise in
airflow rate achieved in almost our focus, your success
all in vitro test apparatus is As a specialist in custom additives and auxiliaries, high-
clearly unrepresentative of the manufacturing, Saltigo provi- tech monomers, electronic
half a second our volunteers des tailormade solutions for chemicals, dyes, pigments,
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