Stuck in the swinging sixties

Perhaps the first question should be “Why do we test inhalers at all?” The aim of regulators such as the FDA is to protect patients who receive medication — including respiratory therapies. Before conducting a Phase 1 clinical study, the applicant must demonstrate that their candidate drug product produces results in vitro that meet the target specification and with acceptable consistency. This, combined with satisfactory toxicology data, means in principle that a Phase 1 clinical study can be conducted. The primary aim of the in vitro evaluation prior to the clinical study is to ensure that the subjects receive a dose that is in line with expectations and, most importantly, safe.

With simple drug forms such, as tablets, this is reasonably straightforward. A number of tablets are dissolved, and each sample assayed for active drug content to determine the quantity that a patient can receive as a dose. Inhalers, on the other hand, are more complicated. Most dry powder inhalers (DPIs) have a delivered dose that is dependent upon the level of inspiratory effort provided by the user. If one user inhales more forcefully than another they will receive a higher dose and as a result, the challenge of defining the most suitable in vitro test point for an inhaler has plagued the industry for decades.

Current practices

The FDA recommends testing at three flowrates, the ‘reference labelled flowrate’ and ±50% of this rate1. If a DPI has a reference flowrate of 60 litres per minute (L/min), then the other recommended test points are 30 and 90 L/min. There is some historic reasoning behind these test flowrates. In the 1960s Fisons was developing the first commercially successful DPI — the Spinhaler® — and the scientists working on what was then an entirely novel product were also having to develop their testing methodologies as there were no standards or practices available to follow for dry powder inhaled therapies. There was also no information available about the likely flowrates that could be achieved through the Spinhaler, so the team conducted a clinical study of asthmatics and found that most could achieve a flowrate of 1 L/s for just half a second — i.e. only 500 ml of air2. As a result, 60 L/min became the standard DPI testing flowrate for many years after, although just half a litre of inhaled volume soon became four litres — mainly to ensure that sufficient chase air followed the drug aerosol through the test apparatus.

The state of the art particle sizing apparatus at the time was the Andersen Cascade Impactor (ACI). Originally developed in 1956, this inertial impactor had been designed “for the specific purpose of determining the size distribution of viable airborne particles”3. Whilst the development team at Fisons worked on its own liquid multi-stage impinger, based upon May’s 1966 design, others working in this rapidly progressing field continued to improve the ACI whilst developing early DPIs:

– 1965
Preseparator added to remove considerable quantities of larger particles (the lactose carrier fraction).
– 1966
Collecting petri dishes replaced with stainless steel impaction plates.
– 1970
MkI version now eight-stages (instead of six).
– 1977
MkII version with modified top two stages.

As the ACI was developed for monitoring airborne particulates in the field (literally) it was designed to run at a single flowrate — 1 ACFM (actual cubic feet per minute.) The ‘actual’ term simply means that it must be a true volumetric measurement (as the cut-points of the various stages within any impactor depend upon their air jet velocities) directly related to the true volumetric flowrate. One ACFM is equal to 28.3 L/min, which is fine for testing pressurised metered dose inhalers (pMDIs), as these devices are intended to be used with a ‘gentle’ inhalation, and are in no way reliant upon the inspiratory effort required to create a fine particle aerosol. Early DPIs, on the other hand, generally had low airflow resistance; they were easy to inhale through, and 28.3 L/min didn’t produce a realistic pressure drop across such devices which led to the development of additional stage sets that enabled the ACI to run at 60 and 90 L/min. So, perhaps unsurprisingly, 28.3, 60 and 90 L/min became the standard test flowrates for all DPIs, irrespective of their resistance or the target patient group.

What actually happens?

If the inspiratory flow characteristics of people inhaling through different airflow resistances are analysed, pressure-flow curves can be plotted as shown in Figure 14. This shows the peak flowrate achieved when inhaling through nine different resistances, plotted against the peak inspiratory mouth pressure. Each DPI will have a pressure-flow curve that depends upon its airflow resistance, and the intersections with the pressure-flow curves of a particular patient group is indicative of the likely operating points in practice. For example, healthy children (under nine and a half years old) will, on average, achieve a pressure drop of approximately 6 kPa across the high-resistance HandiHaler, producing a flowrate of almost 40 L/min.

As you can see from Figure 1, two of the 30, 60 and 90 L/min legacy test flowrates fall short of even healthy paediatric data, and only the 90 L/min test flowrate falls into the expected region between children and adults. For the HandiHaler, these test flowrates have even less relevance, with children and adults achieving pressure drops between 6 and 8.5 kPa. Whilst a flowrate of 30 L/min through the HandiHaler has a reasonable pressure drop of ~4 kPa, 60 and 90 L/min have pressure drops of 16 and 36 kPa respectively — very unlikely to be achieved by a human in practice!

A better method

If the goal of in vitro studies is to gauge how a product is likely to perform in vivo, a first step might be to characterise the inspiratory flow profiles of the target patient group. Constructing the mean pressure-flow curve, together with ±2 standard deviations, will produce three reference curves that include at least 95% of the sample population (assuming a normally distributed dataset). Superimposing the pressure-flow curve of the DPI then determines the three test flowrates. In Figure 2 opposite (a hypothetical example), the three test pressure drops would be 5, 6.5 and 7.5 kPa, corresponding to flowrates of ~95, 110 and 120 L/min through the DPI.

Of course this would just be a first step. A second step might be to evaluate ramp-up rates as a function of pressure drop, for example, and interpolate these data to predict likely operating ramp-up rates depending upon device resistance. A third step would be to look at the range of inhaled volumes for the target patient group. With these three key parameters — Peak Inspiratory Flowrate (PIFR), peak ramp-up rate, and inhaled volume — it’s possible to create three reference inspiratory flow profiles based on typical patient use, representing ‘normal’, ‘weak’ and ‘strong’ inhalations.

Whilst the primary purpose of collecting in vitro data for marketed products is to ensure that they meet specification and offer acceptable consistency in performance, perhaps the flowrates used in testing don’t matter as product data is only used for comparative purposes. However, such a mismatch between the flowrates achieved in actual use and the qualifying test flowrates simply means that any variations observed in the laboratory are very unlikely to reflect real use. So then we have to return to the original question — why do we test inhalers at all? It’s not just about proving but also about ensuring that we’re designing optimised inhalers. If we continue to adhere to these historic practices, are we missing out on an opportunity to innovate?

Regulators need to take a fresh look at inhaler testing methods. Swinging plus or minus 50% around the sixties was a sensible starting point — recent research indicates that we can now do something much more meaningful.

This article was taken from issue 8 of Insight magazine. Get your free copy of the latest issue here.

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References
1. FDA, Bioequivalence for Orally Inhaled and Nasal Drug Products, Table 14.2, p373
2. Bell, J. H., Hartley, P. S., Cox, J. S. G., Dry powder aerosols I: A new powder inhalation device, Journal of Pharmaceutical Sciences 60 (10), 1559 (1971)
3. Marple, V. A., History of impactors — the first 110 years, Aerosol Science and Technology 38.3, 247- 292 (2004)
4. Harris, D. S., Scott, N., Willoughby, A., How does airflow resistance affect inspiratory characteristics as a child grows into an adult?, DDL21 Conference Proceedings, 79-87 (December 2010)