Mark Copley is Sales Director at Copley Scientific.

Mark Copley

Pressurized metered dose inhalers (pMDIs) are an inexpensive, frontline technology for the treatment of asthma and other pulmonary diseases. Some patients, however, find it difficult to achieve the coordination needed to successfully use a pMDI. Along with novel breath-actuated pMDIs, add-on devices, such as spacers and/or valved holding chambers (VHCs), eliminate the requirement to coordinate device actuation with inhalation and make conventional pMDI technology more effective for a broader spectrum of patients. Globally, the incidence of asthma and chronic obstructive pulmonary disease (COPD) continues to rise, and the use of add-on devices is increasing proportionately. This increasing use is reflected in a new, draft, United States Pharmacopeia (USP)chapter, issued January 2014, which specifies new test methods for pMDIs with add-on devices (1).

Add-on devices and the impact on drug delivery

	What is an add-on device and why is it used?

 The ‘go to’ technology for treating asthma and COPD, pMDIs are small, inexpensive, convenient to use and suitable for the delivery of a wide range of drugs. When actuated, these products use a propellant to aerosolize a fixed volume of liquid formulation to a respirable size. To ensure that the aerosolized particles are successfully drawn into the lung, the patient must inhale slowly and deeply upon actuation of the device. However, some patients lack the required coordination to synchronize these two events. This limitation curtails the successful use of pMDIs by certain patient groups, such as pediatrics, geriatrics, and even some adults. Breath-actuated pMDIs are one solution but add-on devices are more routinely used to address this issue because they can be retrofitted to a range of pMDIs that are already on the market.

	A spacer is an open-ended piece of tubing or plastic cylinder that is connected to the mouthpiece of the pMDI. A VHC is similar but incorporates a one-way valve close to the patient interface. With a VHC, the pMDI can, therefore, be actuated into an enclosed dead space. The valve only opens to release the aerosol once the patient starts to inhale. An important advantage of a VHC is that uncoordinated use of the pMDI/add-on device does not result in the exhalation maneuver emptying the holding chamber of the therapeutic aerosol back through the pMDI actuator, which can be an issue with a simple spacer design.

	Both types of add-on device interface with the pMDI at one end, typically via a rubber connection, thereby creating a seal, and have either a mouthpiece or a face mask at the other end to enable easy use by the patient. Either add-on device results in the patient inhaling the drug from a reservoir of aerosolized particles, not dissimilar to a nebulizer, rather than directly from the pMDI. In this way, the add-on devices eliminate the need to precisely coordinate inhalation and actuation, broadening the accessibility of pMDI technology to a wider range of patient groups.

	How does the use of an add-on device affect the way in which drug is delivered to the patient?

 When a patient uses a pMDI without an add-on device, the drug particles are inhaled almost instantaneously as the formulation is aerosolized. Providing that the patient’s technique is correct, the size of particles inhaled will, therefore, be relatively well defined. Delivered particle size is a function of the device design (actuator and canister) and the properties of the formulation, which includes the propellant.

	In contrast, when an add-on device is used, the patient inhales drug from a reservoir of aerosolized particles. The additional dead volume provided by the add-on device not only provides an opportunity for aerosol expansion, but also particle impaction, settling, and/or electrostatic deposition, within the add-on device (2, 3). This means that the particle size distribution of the aerosol cloud made available to the patient may change considerably ahead of inhalation. Certain sized particles may be preferentially retained in the spacer and the size distribution of particles received by the patient may now differ from that delivered by the pMDI. Variability in the drug-delivery process is also introduced by the fact that the device actuation may be completely co-ordinated with the inhalation maneuver, or completely uncoordinated, depending on the technique adopted by the individual user.

	What tests are recommended in the proposed USP chapter and how do they differ from the standard tests used for pMDIs?

The general pharmacopeia tests for the assessment of pMDI performance and for quality control (QC) center on the measurement of two parameters--delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD). In DDU testing, the pMDI is actuated into a dose uniformity sampling apparatus (DUSA) that captures the emitted formulation on a filter. Subsequent analysis of the captured dose, usually by high-performance liquid chromatrography (HPLC), reveals how much active ingredient is present.

	APSD measurements are made using a multistage cascade impactor (4). This instrument size fractionates an emitted dose on the basis of particle inertia, which is a direct function of aerodynamic particle size. Chemical analysis of the collected, sized samples enables the determination of an APSD specifically for the active ingredient.

	Because the particle size delivered by a pMDI is generally unaffected by the patient’s inhalation profile, the test conditions applied for these analyses have been set on the basis of convenience. The first cascade impactors used in orally inhaled product analysis were developed for air sampling and originally designed and calibrated to operate at 1 SCFM (standard cubic foot per minute). This value directly translates to the 28.3 L/min used for APSD measurement today for pMDIs. The same figure has, therefore, been adopted for DDU testing.

	The tests set out in the new, draft chapter for testing pMDIs with add-on devices (1) are based on experience gained in Canada over the past 10 years following the publication of a standard for testing by Health Canada (5). The methods reflect that, as with a nebulizer, the amount of drug received by the patient with this type of set-up will be influenced by the inhalation profile of the user. The tests in the new chapter, therefore, call for the application of specific breathing profiles during DDU testing to reflect the physiology of the intended user (see 

	In DDU testing for pMDIs with add-on devices, the combined product is actuated into a filter housing, thereby collecting the dose in much the same way as a DUSA is used for standard pMDI testing. However, a patient relevant breathing profile is applied during testing, rather than a constant 28.3 L/min air flow rate. Furthermore, tests are carried out to measure the efficiency of the valve, in the case of VHCs, by comparing the dose received when use is coordinated and uncoordinated with device actuation.

	Performance is optimal and directly comparable with a pMDI without an add-on device, if the patient inhales as the device is actuated. This is termed ‘coordinated use.’ In contrast, the worst-case scenario, in terms of performance, is if actuation coincides with exhalation, (i.e., ‘uncoordinated use’). Using a suitable breathing simulator, testing can be carried out under both of these conditions to provide a ratio of drug delivered and hence the efficiency of the valve. For spacers (without valve), testing for co-ordinated use is all that is required. When testing spacers/VHCs with facemasks, these are generally removed, and testing is performed using the integral mouthpiece.

	Cascade impactors operate at a constant flow rate so breathing simulators are not applied during APSD measurement. Rather, testing is carried out at a constant flow rate broadly representative of the patient population within the constraints of calibrated commercial impactor performance. The next generation impactor (NGI), which has a calibrated flow rate range of 15 to 100 L/min, is a popular choice for this aspect of testing although other cascade impactors can be used. The particle size range of interest for inhalation to the lung is usually taken as sub-five micron, and this is reflected in the tests that recommend comparison of the sub-five-micron dose (i.e., the emitted fine particle mass) with and without an add-on device.

	As with DDU testing, the method specified for APSD measurement has been modified to assess the potential impact of coordinated and uncoordinated use. Testing is carried out with impactor sampling and actuation coordinated and, in the case of VHCs, also with impactor sampling starting after a two-second time delay. This delay provides time for the particle size distribution to evolve inside the VHC and directly quantifies the impact of uncoordinated use in terms of the dose that is likely to deposit in the lung. Testing after five and 10 seconds provides further insight into the residence behavior of the aerosol within the add-on device and is also recommended (5).

	Is new equipment needed to test in accordance with the revised USP chapter?

For a laboratory working solely on pMDI technology, it may be that new equipment will be required given that the new draft chapter calls for the application of breathing profiles during testing. However, breathing simulator technology has advanced considerably in the last decade, and cost-effective, compact models are increasingly a standard piece of inhaled product testing equipment.

	The Copley Scientific BRS breathing simulator range, for example, includes a number of models specifically tailored to the testing of different orally inhaled products. These systems enable the user to:

		Apply different wave patterns (e.g., square, sinusoidal, triangular, or user defined)

		Alter tidal volume (i.e., the volume of each inhalation and/or exhalation)

		Separately vary the duration of inhalation and exhalation, if required (inspiratory/expiratory ratio)

		Introduce a delay after inhalation and/or exhalation

		Control the number of breathing cycles during each test

		Commence the breathing cycle at the beginning of the inhalation or exhalation maneuver.

	The availability of such flexible systems is supporting the application of breathing simulators beyond the scope of the pharmacopoeial test methods to more generally explore the performance of inhaled products in line with quality by design (QbD) (6). At the same time, these units also make it straightforward to test under the conditions specified for pMDIs with add-on devices through the provision of specially developed adapters and filter holders.

	To meet the requirement for a time delay between actuation of the device and the start of APSD measurement, a timer-controlled, fast-acting, two-way solenoid valve provides a simple, cost-effective solution. Products, such as the breath-actuated controller BAC 2000 (Copley Scientific), provide near instantaneous starting and stopping of the air flow during testing and have both delay and inhaled time functions (7). Such products streamline testing in line with the new draft chapter, easing the task of gathering the information required to ensure the safety and efficacy of using pMDIs with add-on devices.

	1. USP In-Process Revision <1602>, “Spacers and Valved Holding Chambers used with Inhalation Aerosols,” Pharmacopeial Forum 40 (1) (January 2014).

	2. J.P. Mitchell et al., Respiratory Care 52 (3) 283-300 (2007).

	3. J. Anhøj et al., Br J Clin Pharmacol. 47 (3) 333-336 (1999).

Understanding cascade impaction and its importance for inhaler testing

	5. CSA Group Standard, CAN/CSA-Z264.1-02 (R2011) “Spacers and Holding Chambers for Use with Metered-Dose Inhalers,” (Canadian Standard Association, 2011).

Using breathing simulators to enhance inhaled product testing

	7. F. Chambers et al., “Evaluation of the Copley TPK-S as a Device for Control of Delay Times and Inspiration Volumes Applied to pMDI/Spacer Testing,” poster presented at APS Inhalation (London, UK, February 2003). PT


	Mark Copley is sales director at Copley Scientific, Colwick Quays Business Park,Private Road No. 2, Colwick, Nottingham,NG 4 2JY, United Kingdom.

Articles

The role of add-on devices and how they affect drug delivery with a pressurized metered dose inhaler.

Exploring Newly Introduced Methods for Testing MDIs with Add-On Devices

	The technique of cascade impaction is used to measure the aerodynamic particle size distribution (APSD) of all orally inhaled products (OIPs). The resulting data are broadly indicative of likely deposition behavior in the respiratory tract and support development of a target drug-delivery efficiency. Cascade impaction is widely acknowledged as being unable to completely replicate the complex aerodynamics and deposition behaviors taking place in the throat and lungs. The lungs operate under high humidity conditions, and within them volumetric flow rate decelerates with each bifurcation, establishing complex velocity profiles across the lung structure. The resulting mechanisms of particle deposition, which include sedimentation and diffusion as well as impaction, are difficult to comprehensively simulate. Improving the relationship between 

 behavior, however, is becoming increasingly important for a number of reasons, including the successful implementation of quality by design (QbD), the need to reduce the costs of OIP development, and the desire to achieve 

	Steps to modify cascade impaction to secure better 

 relationships (IVIVRs) range from the use of new testing equipment, such as the Alberta Idealized Throat (AIT) and state-of-the-art breathing simulators, to the adoption of more efficient information-gathering techniques, including Abbreviated Impactor Measurement (AIM).

	Multistage impactors consist of a series of stages each made up of a nozzle plate, with a specific nozzle arrangement, and a collection surface. Sample-laden air is drawn into the impactor, at a constant volumetric flow rate, and passes sequentially through the stages. Because nozzle size and total nozzle area decrease with stage number, the particles are progressively accelerated. At each stage, particles with sufficient inertia break free of the prevailing air flow and impact on the collection surface, thus producing a series of mass fractions that can be analyzed to determine how the active is distributed with respect to size.

 shows a typical pharmacopeial cascade impactor setup for dry-powder inhaler (DPI) testing that includes a number of essential ancillaries. The device is interfaced to the cascade impactor using an appropriate mouthpiece adapter and an induction port. Flow rate through the cascade impactor is controlled by the critical flow controller/flow meter, and a vacuum pump draws air through the whole system.

	It is possible to draw a loose connection between the different elements of this setup and the real-life scenario that it aims to reflect. The induction port represents the mouth and throat, and the cascade impactor sizes those particles most likely to deposit in the lungs. The flow controller/flow meter ensures application of a stable and suitably representative flow rate during testing.

	Assessing the established setup against the information requirements for knowledge-led product development highlights some of its limitations. The standard

 United States Pharmacopeia (USP)/European Pharmacopoeia (Ph.Eur) 

 General Chapter <601> "Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers" and Ph. Eur. Section 2.9.18 "Preparations for Inhalation", for example, is well-suited to precision manufacture and delivers reliable, consistent performance, but it is now widely recognized as having a tendency to significantly underpredict the amount of emitted dose captured by the upper respiratory tract for some products, relative to clinical data (1). Thus, irrespective of deposition behavior within the lung, the USP induction port tends to overestimate the extent of whole-lung deposition.

	Of equal importance is the fact that this setup requires the application of a constant flow rate through both the device and the cascade impactor, whereas in clinical use, inhaled products are subject to a range of user breathing profiles. The constant flow rate required by cascade impactors results in a square wave form, rather than the infinitely variable, broadly bell-shaped patterns of real patients. Furthermore, impactors ideally require multiple volume changes to guarantee reliable and complete sizing of the aerosol. This requirement invariably results in a test volume that is greater than the inhalation volume of at least part of the intended patient population.

	Finally, there is the overarching concern of productivity. Cascade impaction has long been recognized as a time-consuming, manually intensive task, which becomes even more limiting as demands for more valuable and discriminating data grow. Alleviating the burden of analysis is, therefore, important for continued advancement, especially in R&D environments in which budgets are being increasingly cut.

	Better representation of throat deposition

	The goal of more closely simulating deposition in the mouth and throat focuses attention on alternatives to the standard 

 induction port. One such is a human throat cast (2–5). These alternatives offer the advantage of accurately reflecting the physiology of a throat. Experimental work, however, has shown significant differences in deposition behavior between different throat casts (1). Although these differences are to be expected given the variability in human anatomy, they complicate results interpretation within the context of standardization and routine analysis. Furthermore, reproducible, precision manufacturing of such casts is complex, which makes them difficult to mensurate and qualify. Because casts are also not easy to handle or to interface with the impactor, they are less than ideal from a practical standpoint.

	These limitations have stimulated interest in developing solutions that fall between a throat cast and the standard induction port (6). These solutions include the Alberta Idealized Throat (AIT). Developed by researchers at the Aerosol Research Laboratory of Alberta (University of Alberta, Canada), the AIT has a standardized and highly reproducible but human-like internal geometry that lends itself to precision manufacture. Its performance is independent of flow rate and, with both pressurized metered-dose inhalers (pMDI) and DPIs, it has been shown to collect more of the emitted dose than the USP induction port (1, 7, 8). Indeed, the ability of the AIT to more closely replicate 

deposition behaviour in the throat compared with the USP induction port has been directly confirmed in a number of studies, some of which include marketed OIPs (9–11). AIT geometries are also available in child and infant forms, which widens their appeal for 

	Experimental study: Assessing AIT performance

The APSD of a pMDI (active ingredient salbutamol) was measured in a collaborative project with Melbourn Scientific (UK) using an impactor (Next Generation Impactor, Copley Scientific) with both the USP induction port and an AIT (7). Testing was carried out at a flow rate of 30 L/min, according to pharmacopeial guidance for MDIs, with six replicate measurements conducted in each case. All collection stages of the NGI and the AIT were coated with silicone oil applied in n-hexane solution (1% w/v), which is a standard practice that reduces particle bounce (i.e., the re-entrainment of particles impacting at high velocities). The USP induction port was left uncoated as is done for routine testing.

shows averaged collection data for each component of the test equipment including a combined mass recorded for the throat and inhaler mouthpiece. Values for fine-particle dose (FPD), fine-particle fraction (FPF), geometric standard-deviation (GSD), and mass median aerodynamic diameter (MMAD) were determined from these data. Calculations were based on total emitted mass/actuation and the assumption of a 5-micron upper limit for FPD and FPF.

	Deposition data for the throat/mouthpiece shows that the AIT captures more of the dose, thus reducing the mass of drug entering the cascade impactor. This result is attributed to differences in the geometry of the two interfaces, rather than any coating effect (7).

 shows averaged cumulative APSDs based on the amount of material exiting the mouthpiece/throat. Here, use of the AIT shifts the APSD to finer sizes across the entire size range, thus suggesting that not all particle sizes are equally retained relative to the standard induction port. In a parallel experiment with a DPI, the same effect was observed (7). These are early results and further research is required. The results, however, underline the fact that better representation of mouth/throat deposition may influence assessments of regional deposition in the lung, which is a function of particle size, as well as estimates of whole lung deposition. From an 

 perspective, use of the AIT ensures that only the portion of the aerosol that would actually deposit in the lung is sized by the cascade impactor, therefore providing more relevant data.

	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.

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 

	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).

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 

	In recent years, the search for improved productivity in inhaler product testing has fueled interest in AIM (20). A key focus is quality control (QC) testing, but the approach also holds promise for R&D. AIM involves separation of a sample into far fewer fractions than a multistage cascade impactor, thereby delivering some important benefits:

		Less complicated analysis, which results in reduced likelihood of error

In R&D, the proposal is that requirements for better productivity may be met by applying the human respiratory tract (HRT) version of the AIM concept, which focuses attention on those parts of the APSD that are crucial for the assessment of drug-delivery performance (see 

). Published studies highlight industrial interest in this approach (21–23). The potential that AIM offers for reducing human error and enhancing data integrity may also support the development of better IVIVRs that are based on more secure results.

	AIM-HRT consists of two impaction stages, a filter, and a spacer to modify aerodynamic performance. It separates the dose into a coarse particle mass (>5 microns), a fine particle mass (<5 microns), and an extra-fine particle mass (<1 micron). These fractions would typically be associated with mouth/throat deposition, lung deposition, and, potentially, loss via exhalation, respectively. The technology, however, enables the cut-off diameter of the stages to be varied, as necessary, to produce results that more closely correlate with measured 

 data, if available. Some studies indicate that this can be achieved by using a cut-off diameter closer to 3 microns rather than 5 microns (24). In the future, AIM may, therefore, enable the acceleration of design of experiments and screening trials although there is considerable debate about its uptake.

	The conventional test cascade-impactor setup used to measure the APSD of all OIPs was originally developed with QC testing in mind. It fulfills this function well because it allows a highly discriminating and reproducible measure of product quality. The conventional setup has drawbacks, however, for researchers trying to access a more detailed understanding of inhalation technology and obtain better IVIVRs that will further development. One concern is better representation of deposition behavior in the mouth and throat, and another is the application of more representative breathing profiles during testing, in which they may have an impact on dose emission and the resulting aerosol APSD generated. The issue of analytical productivity remains pressing in an environment of ever deeper cost-cutting.

	Instrument suppliers are responding positively to these requirements by introducing new products such as the mixing inlet, sophisticated breathing simulators, new interfaces such as the AIT, and AIM equipment that streamlines testing. These new products potentially allow for significant advances in the area of inhaled-product testing within the R&D environment. In the future, such innovations offer the opportunity to shape 

 testing into a far more effective tool for the rapid advancement of inhaler technology for the widest possible range of drug therapies.

	1. Y. Zhang, K. Gilbertson, and W.H. Finlay, 

 Dry Powder Inhaler Device Equivalence Screening Study Using the Hydraulic Lung," poster presentation at Drug Delivery to the Lungs (DDL) 22 (Edinburgh, Scotland, 2011).

	3. B. Olsson, et al., Proceedings of Respiratory Drug Delivery 2008 Conference (Phoenix, AZ, 2008), Vol 1, pp. 197-205.

	4. B. Olsson, E. Berg, and M. Svensson, Proceedings of Respiratory Drug Delivery 2010 Conference (Orlando, FL, 2010), pp. 225–234.

	5. M. Svensson and E. Berg, Proceedings of Respiratory Drug Delivery 2008 Conference (Phoenix, AZ, 2008), pp. 391-394.

	6. Y. Zhang, T. L. Chia, and W. Finlay, 

	7. M. Copley, J. Mitchell, and D. Solomon, 

	8. A. Watkins, T. Gerrish, and N. Childerhouse, Proceedings of Respiratory Drug Delivery 2012 Conference (Phoenix, AZ, 2012), pp. 877-882.

	9. B. Grgic, W.H. Finlay, and A.F.Heenan, 

J. Aerosol Med. and Pulmonary Drug Deliv.

	12. W. Finlay, Proceedings of Respiratory Drug Delivery 2012 Conference (Phoenix, AZ, 2012), pp. 325-336.

	13. N.C. Miller, M.J. Maniaci, S. Dwivedi, and G.W. Ward, Proceedings of Respiratory Drug Delivery Conference (Orlando, FL, 2000), pp. 191-196.

, 7.3 (Supplement) Chapter 2.9.44, "Preparations for Nebulisation: Characterisation" (EDQM, Strasbourg, France, 2012), 3803-3805.

First Supplement, General Chapter <1601>, "Products for Nebulization–Characterization Tests" (US Pharmacopeial Convention, Rockville, MD, 2011), pp. 4729-4732.

	17. D.K. Nadarassan, K.H.Assi, and H. Chrystyn, 

	20. M. Copley, J. Mitchell, E. McAulay and D. Russell-Graham, 

	22. G.Keegan and D.A.Lewis, Proceedings of Respiratory Drug Delivery 2012 Conference (Phoenix, AZ, 2012), pp. 465-468.

	23. G.Keegan and D.A.Lewis, Proceedings of Respiratory Drug Delivery 2012 Conference (Phoenix, AZ, 2012), pp. 469-472.

is sales director at Copley Scientific, Colwick Quays Business Park, Private Road No. 2, Colwick, Nottingham, NG4 2JY, UK, Tel: +44 0 115 961 6229, 

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.