The complexities of DPI testing

With the use of dry powder inhalers (DPIs) on the increase Mark Copley, of Copley Scientific, looks at effective product testing, which is both critical to successful device and formulation development and essential for routine QC

With the use of dry powder inhalers (DPIs) on the increase Mark Copley, of Copley Scientific, looks at effective product testing, which is both critical to successful device and formulation development and essential for routine QC

The increasing use of dry powder inhalers (DPIs) reflects growing recognition of the intrinsic benefits of the technology. Dry systems are advantageous in terms of sterility and stability, and play to existing industry strengths in the areas of powder formulation and processing. DPIs are breath actuated, synchronising drug delivery with inhalation, and eliminate the need for a propellant.

Interest has increased following the progressive phasing out of chlorofluorocarbons (CFCs) by the Montreal Protocol. CFCs were historically used as propellants in many metered dose inhalers (MDIs), and therefore DPIs offer an attractive alternative to complex MDI reformulation using hydrofluoroalkanes (HFAs).

Furthermore, dry powders open up a range of opportunities to deliver novel drug compounds for systemic circulation, in addition to traditional topical applications, i.e. asthma and COPD.

The underlying operating mechanisms of DPIs are, however, complex, so the development of a new formulation or device is not necessarily straightforward.

Performance characterisation principally involves delivered dose uniformity testing and aerodynamic particle size measurement. Together these methods determine the consistency of device operation and the proportion of the delivered dose that, because of its size, is likely to deposit in the deep lung. This information is critical for the development of better, more efficient products and for QC.

The majority of DPIs are classified as "passive" devices, which means operation relies solely on the patient's inspiration. Less common are active products that boost the efficiency of delivery through the use of an additional source of energy: a miniature air pump or an electronic vibrator or impeller.

Passive devices can be further classified as either device-metered or pre-metered. The former contains a reservoir of formulation from which the required dose is extracted during actuation, while in the latter doses are pre-measured during manufacture and stored in blisters, capsules or other cavities. For both types of passive device the drug delivery mechanism is the same.

As the user inhales, air is drawn through the DPI, fluidising/aerosolising the formulation. The powder forms a cloud that is drawn into the respiratory system, particles depositing in vivo as the patient holds their breath. Successful delivery relies on effective emptying of the device, and dispersion of the powder to a particle size small enough to deposit in the lungs. Failure to meet these goals each and every time the product is used compromises efficacy.

For deposition in the lungs, the target particle size is typically 1 to 5µm. Particles larger than this generally impact in the oropharynx and are swallowed, while smaller particles may be exhaled. Powders in this size range tend to be cohesive and flow poorly, so formulators often use a larger carrier particle for the active ingredient (API), to ease both handling of the product and its manufacture. Actuation must therefore supply sufficient energy to either disperse a relatively cohesive powder, or strip API from a carrier. This requires careful formulation and device development.

The performance of DPIs is characterised by delivery dose uniformity testing and aerodynamic particle size measurement, which quantify the consistency of delivery and likely deposition behaviour respectively. The energy the patient imparts during actuation, and the success of drug delivery, largely rely on the strength and duration of inhalation. Accurate assessment of product performance therefore depends on testing under conditions representative of those that will apply during use.

For in vitro testing the strength and duration of the patient's inspiration are replicated by the flow rate used and test time. The pharmacopoeias specify testing with a pressure drop of 4kPa across the device and a total air volume of 4 litres (2 litres in the case of FDA guidelines), this being broadly indicative of the pressure drop and total inspiration volume during forced inhalation.

These figures are considered representative of the critical parameters of a typical adult inhalation profile and as such are used to generate standardised profiles that are compatible with in vitro testing methods. Geriatric and paediatric patients with significantly weaker inspiration may, however, struggle to achieve the design performance of the device. It is therefore not uncommon to widen the scope of the test parameters to cover a broader target patient population, including typical use and unintentional misuse conditions.1

Since each DPI device has a unique pressure drop/flow rate relationship, based on the flow resistance of the device (see Figure 2) it is always necessary to determine a suitable air flow rate before testing. The cascade impactors used for aerodynamic particle sizing are constant flow rate devices, so it is necessary to modify the variable (bell-shaped) inhalation profile typically generated by the patient, into a square-wave form, with the same inspiration volume. This provides a constant flow rate that is maintained throughout the test.

During testing, air is drawn through the DPI using a vacuum pump, with a control valve throttling flow to the required rate (see Figure 3). Determining the test flow rate involves adjusting the control valve to give a pressure drop across the DPI of 4kPa and then replacing the device with a flow meter for flow rate determination. With low resistance DPIs this method can give very high flows so the pharmacopoeias specify an upper limit of 100 litres/min. Test duration is calculated from the determined flow rate and the specified total air volume. For example, if flow rate is set at 40 litres/min, test time will be 6 seconds to give an air volume of 4 litres (see Figure 4). These conditions are applied for both delivered dose uniformity testing and aerodynamic particle size measurement.

For accurate DPI characterisation, flow rate must also be stable, as otherwise product performance will vary. This is especially true for cascade impactor testing, which measures aerodynamic particle size, since the performance of the impactor itself is also air flow rate dependent. Ensuring critical flow across the flow control valve stabilises flow through the system (Figure 2) by eliminating the impact of fluctuations downstream of the valve: variability in pump performance, for example.

This critical flow condition is reached if the pressure downstream of the valve is less than half of the upstream pressure i.e. P3/P2 â"°Â¤ 0.5. Instruments such as the Critical Flow Controller TPK 2000 from Copley Scientific simplify set-up in accordance with these pharmacopoeia recommendations, measuring and recording all the parameters required for testing and controlling flow conditions.

Dose uniformity testing is designed to verify the consistency of delivery, from batch to batch and during each firing of the device. The DPI is actuated, under the defined test conditions, into standard apparatus (Figure 4) that captures the delivered dose, which is then analysed by High Pressure Liquid Chromatography (HPLC) to determine drug content. The regulators and pharmacopoeias define criteria for acceptability, specifying the number of dosage units that must be assayed, and limits for the results. For multi-dose systems, uniformity over the entire contents is assessed which means testing at the beginning, middle and end of product life; the first three, middle four and final three shots, for example.

Particle size measurement broadly indicates where in the respiratory system the drug will be deposited, but primarily exists to ensure the consistency of aerosol generation. Both the regulators and pharmacopoeias recommend the technique of cascade impaction because it measures aerodynamic particle size and allows direct recovery and quantification of the API. However a cascade impactor should not be thought of as a lung model, since deposition mechanisms in the lung are extremely complex, including not only impaction, but also diffusion and sedimentation, among others.3

Cascade impactors are precision-engineered instruments that separate a sample on the basis of particle inertia, which is a function of velocity and aerodynamic particle size. Particulate-laden air is drawn through a series of stages, each of which is machined with a specified number of nozzles of closely defined diameter; nozzle diameter decreases with increasing stage number. As the volumetric air flow through the instrument is constant, velocity increases from stage to stage. Particles with sufficient inertia impact on a collection surface beneath the nozzles while smaller particles are retained in the air stream and carried to the next stage. The result is a series of size fractions, typically 10µm or below in size. HPLC analysis of each fraction quantifies the amount of API present.

The pharmacopoeias recommend several commercially available impactors for the routine testing of DPIs, including the Next Generation Impactor (NGI) and Andersen Cascade Impactor (ACI), which are used globally for the majority of inhaler product analysis. The Multi-Stage Liquid Impinger (MSLI), still widely used in Europe, and the Marple Miller Impactor may also be employed in the US.

A pre-separator is normally added to the impactor inlet when testing DPIs to remove large boluses of powder such as lactose (carrier) and particles greater than around 10µm in diameter, prior to entry into the impactor. A right-angled induction port (or throat) is used to introduce the aerosol to the pre-separator; the inlet of which interfaces directly with the inhaler under test through the use of a mouthpiece adapter.

For all cascade impactors flow rate is critical since it affects the size of particles collected at each stage: the stage cut-off diameter. The setting and control of flow rate is discussed above, and in more detail in reference 4, but there remains the issue of how to determine impactor performance at the flow rate established for testing. For the NGI, accurate calibration data is available for operation at 15, 30, 60 and 100 litres/min and inter-polation between these points produces robust results. The ACI was originally designed to operate at 28.3 litres/min but additional stages are available for higher flows (60 and 90 litres/min). Calibration data exists for these modified versions and performance can be estimated for flow rates across the entire range; however, the calculated cut-off diameters are less accurate away from the calibration points.

Cascade impaction is a complex analytical technique and precise measurement depends on many factors.5 For DPI testing the following issues are especially relevant:

Particle re-entrainment: Dry particles are particularly prone to bouncing off the collection surface, in which case they become re-entrained in the air stream, ultimately collecting on the subsequent stage and being incorrectly sized.

Coating of the collection surface with greasy material such as glycerol or silicone, for example, minimises this effect.

Electrostatics: The build up of electrical charge can affect particle behaviour within the impactor so grounding it is a sensible precaution. The use of ionisers can neutralise electrostatic charge accumulation in the testing environment.

Environmental conditions: Monitoring environmental conditions - temperature and humidity - is important and control may be necessary with some formulations, such as hygroscopic materials.

Analysis of the results requires the recovery of sample from all internal surfaces using organic solvents, although in many cases, where inter-stage losses are low, it is necessary to recover drug only from the collection surfaces themselves. The regulators and pharmacopoeias specify acceptable ranges for impactor mass balance and describe the key parameters that characterise drug delivery. These include:

Fine Particle Dose (FPD) - typically the amount of material <5µm in size (or captured on the impactor stage with a cut-off diameter closest to this value and all smaller fractions)

Fine Particle Fraction (FPF) - FPD expressed as a percentage of the delivered dose

Mass Median Aerodynamic Diameter (MMAD)

Geometric Standard Deviation (GSD)

Full characterisation of the formulation may also be required by the regulators, but the use of stage groupings and abbreviated stacks may be permissible where justified.

DPIs have a valuable role to play in the delivery of inhaled drugs but are relatively complex in their mode of operation and are technically challenging to develop. With these systems, drug delivery is strongly dependent on the inhalation profile of the patient and this is reflected in product testing methods.

Performance is principally characterised through delivered dose uniformity testing and aerodynamic particle size measurement, which determine the consistency of delivery and give a broad indication of in vivo deposition behaviour. Effective testing protocols that recognise the unique features of DPIs deliver accurate and precise data that can be used to improve understanding, develop new and better systems, and verify the quality of manufactured products. mc

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