Improving Inhaled Product Testing: Methods for Obtaining Better In vitro-In vivo Relationships - Pharmaceutical Technology

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Improving Inhaled Product Testing: Methods for Obtaining Better In vitro-In vivo Relationships
Even in an industry in which all product development is complicated by the intricacies of human biology, orally inhaled products (OIP) stand out as singularly demanding.


Pharmaceutical Technology
Volume 37, Issue 2

Applying representative breathing profiles

Because multistage-cascade impactors require a constant air-flow rate for successful operation, the issue of applying breathing profiles that better represent real- life demands a two-stage solution: decoupling the flow rate and volume through the device from the flow rate and volume through the impactor, and identifying the most suitable profile for testing.

The mixing inlet is an established option for decoupling flow rates. Designed to fit between the inlet of a range of cascade impactors and a USP induction port or AIT, it allows the cascade impactor to be operated under steady-state conditions, as a constant flow-rate aerosol sampler (in the way that it was designed), while at the same time permitting application of a reduced or variable flow rate through the inhaler. A gentle mixing action ensures effective, turbulence-free mixing of the make-up (i.e., sheath) and sample-laden air streams prior to introduction into the impactor, resulting in minimal internal losses (4, 13).

Assessment of the most appropriate breathing profile for testing is an ongoing and more complex question. For inhalers with an active delivery mechanism, such as pMDIs and some DPIs, there is experimental evidence to suggest relatively low sensitivity to test flow rate (13, 14). Nebulizer testing, on the other hand, in which dose aerolization relies on patient tidal breathing, has already undergone significant revision with the release of two, new, harmonized monographs: Ph.Eur. 2.9.44 and USP 1601 (15, 16). These came into force in January 2012 and August 2011, respectively, and include four different breathing profiles for assessing dose delivery for different patient groups: adult, child, infant, and neonate.

For the majority of DPIs, the motive force driving the device is supplied solely by the patient, and so they are widely referred to as passive DPIs. The breathing profile selected, therefore, impacts the dose dispersion process as well as inhalation of the resulting particles. Here, the application of more representative breathing profiles is generally acknowledged as being important, but there is considerable debate about what is actually required.

Focusing on DPIs


Figure 3: Standard dry-powder inhaler testing involves application of a square wave profile, the dimensions of which are derived from the established flow rate.
Pharmacopeial monographs for testing DPIs specify the application of a flow rate that results in a pressure drop of 4 kPa across the device, which is considered broadly representative of an adult patient's inhalation strength. DPIs vary considerably in terms of flow resistance so, in practice, test flow rates span a broad range of values, from around 30–40 L/min for a high resistance device up to the imposed limit of 100 L/min for those with much lower resistance. The defined flow rate is applied for the time taken to draw 4 L of air through the device if following pharmacopeial specifications or 2 L if following FDA guidance, in the form of a square wave profile (see Figure 3).

While this procedure is logical as part of a standardized, routine, quality-control test, some evidence has been presented to suggest that using a 4-kPa pressure drop gives a flow rate that is unrealistically high for certain patient groups with impaired lung function. Likewise, the total inspired volume has also been questioned. On this basis, suggestions have been made that lower flow-rate testing should be carried out, possibly with smaller total volumes, in the development of products for pediatric use, for example, or for the treatment of chronic obstructive pulmonary disease (COPD) or asthma (17).

On the other hand, as DPI technology spreads into the delivery of systemic therapies, contrary arguments have also been proposed (18). Research suggests that, in a group of adult users with no lung impairment, an 8-kPa pressure drop could be achieved, which suggests that test flow-rates should be much higher if the same inhalation maneuver is applied during use. This latter point is crucial. If, for systemic delivery, patients are instructed to inhale in a different way to optimize the deposition profile of the active, then testing needs to reflect this. Equally important, beyond these considerations of test flow rate, there is a broader issue of the shape of the applied breathing profile during testing.

During patient use, air is drawn through the DPI to fluidize and aerosolize the dose, thus forming a cloud of particles, of which a large proportion is fine enough to be drawn into the lung. The mechanisms involved in this aerosolization process are complex, but it can be postulated that the acceleration of air through the powder plug results in the application of shear forces, thus giving rise to dispersion and device emptying. If the device does not empty, or the force applied is insufficient to disperse the dose to a respirable size (typically taken to be less than 5 microns), then drug delivery efficiency is impaired (18).

This proposed mechanism has led to the suggestion that it is not only the flow rate applied during testing that is important but also the rate at which that flow rate ramps up from zero. In conventional, pharmacopeial testing, the air is effectively "on" or "off", with near instantaneous acceleration. In contrast, data for healthy adults indicates that it may take up to 0.5 seconds to achieve peak inspiratory flow, thus giving an appreciably slower acceleration rate (18).


Figure 4: A test setup for dry-powder inhaler testing incorporating the Alberta Idealized Throat, a mixing inlet, and a breathing simulator.
These debates have resulted in the application of electronic or artificial lungs and the introduction of new breathing simulators that enable detailed exploration of the impact of breathing profile on device performance during routine testing (2, 19). Capable of applying profiles typical of the intended patient populations and ramping up air flows in a variable but closely defined way, these systems allow researchers to determine how critical quality attributes may be affected by patient-to-patient variability in this area. This research is an ongoing but critical area in the development of DPI technology (see Figure 4).


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