Defining the ‘Dose’ for Dry Powder Inhalers: The Challenge of Correlating In-Vitro Dose Delivery Results with Clinical Efficacy

The lung is an established route for the delivery of drugs to patients with a wide range of inhaled products being available to treat respiratory conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. From a pharmaceutical performance perspective, the fundamental requirement of any inhalation drug delivery system is that it can generate and deliver an efficacious respirable mass of the therapeutic agent to its site of action in the respiratory tract. Various device delivery technologies such as nebulizers, pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) have been developed to achieve this. Recent decades have seen a steady increase in the use of DPIs, with a substantial number of originator and, more recently, generic products, being successfully commercialized in the EU, US and the rest of the world. There are three important criteria which must be satisfied for the approval of inhaled products such as DPIs: safety, clinical efficacy and appropriate chemistry, manufacturing, and controls (CMC) (the latter also referred to as Quality). These products are developed with reference and consideration of applicable regulatory guidelines and pharmacopoeial standards.

The DPI is a relatively low dose solid dosage form and has proven to be a highly versatile and successful drug delivery platform. Commercial DPI products are available as drug only or drug-excipient formulations in capsule, reservoir or blister based packaged presentations. Whilst the DPI can now be considered to be a well-established drug delivery system, it is somewhat unique compared to other solid dosage forms in that the successful delivery of the drug to the patient is dependent on the aerodynamic particle size distribution (APSD) of the active pharmaceutical ingredient (API) emitted from the inhaler. Even though it is vital during development to control the physico-chemical characteristics of the API(s) and any excipients, it is this APSD, and its often complex relationships to other parameters in the DPI, that must be understood, and, most importantly, controlled. There is one other unique aspect where the DPI is different to other standard solid dosage forms, namely that the success of the actual drug delivery to the lung is, in part, influenced by patient factors including handling, use and inhalation technique. This makes the understanding of the in-vitro pharmaceutical performance characteristics of DPIs, and their relationships to clinical/patient outcomes, a vital part of DPI development.

The in-vitro pharmaceutical performance of DPIs is evaluated and controlled using established specialized analytical testing methods. However, as medical science advances, it is always valuable to reexamine these methods and their limitations, the data they generate, and what such data means with respect to the clinical dose and dose definition in terms of the claimed product labelled dose. This article considers how the dose of DPI products is described and measured, with reference to manufacturers’ product labeling and health authority guidance, and it reviews and explores the implications of these definitions as technology and clinical understanding matures.

Understanding the Complexity of DPIs

Comparing the concept of DPI ‘dose’ with reference to standard solid dosage forms – tablets and capsules – helps to give an indication of the complexities associated with DPI pharmaceutical performance dose definitions.

For standard tablets and capsules, the terms ‘dose’, ‘strength’, and ‘label claim’ are generally used interchangeably and tend to simply be the compositional mass of the API present in the tablet or capsule. However, the concept of the pharmaceutical product ‘label claim’ or ‘strength’ may be different for patients and health care professionals alike, with patients considering the ‘label claim’ as what is written on the product/packaging, and with those with knowledge of the art additionally considering what is stated in the product information documentation/leaflet. Indeed, the FDA website simply states that ‘the strength of a drug product tells how much of the active ingredient is present in each dosage’. This ‘strength’ numerical value may be associated with the moiety, salt or solvated salt form of the API, depending on the product, and any country or region-specific API naming conventions, but is relatively easily understood by both patients and healthcare professionals. For a solid dosage form such as an immediate release tablet, the dose is typically the amount of API physically delivered/administered (by ingestion) to the patient.

The delivery of an API to the target organ/site of action is complex, and the labelled ‘dose’ or dosage ‘strength’ value could incorrectly be interpreted to be the total amount of API systemically available, although the time for absorption and subsequent pharmacological action may not be ‘immediate’, for example, in controlled or sustained release drug delivery systems. The specified tests for solid dosage forms, such as tablets and capsules, therefore include assays for the determination of the amount of API present, and methods for quantifying the rate of disintegration and dissolution of the product, which confirm quality and characterize the delivery profile of the API as a function of time. These data can be compared against the requirements for therapeutic efficacy, as elucidated by clinical trials, to determine the final marketed dose/strength of the product.

The situation with DPIs is markedly different. Firstly, even though work is on-going,1 there is, to date, no compendial test or standard to ‘measure’ or indicate the ‘dissolution rate’ of an API in the lung. Secondly, the loaded or metered dose of an API is not the same as the amount of the API which is drawn by the patient from the device during use, and hence available to the targeted region of the lung. DPIs typically rely solely on the energy provided by the inhalation maneuver of the patient for drug delivery, with most DPIs having no active (or breath-assisted) delivery mechanism. As the patient inhales, air is drawn through the pre-metered or device-metered dose of powder formulation resulting in the fluidization and inspiratory air entrainment of the API and subsequent emission from the inhaler mouthpiece; and this is often referred to as the ‘delivered dose’. Typically, DPIs have delivered doses which are at least 80% of the metered dose, for example, from the publically available EU product information, 88% for the blister-based mono therapy product Incruse®Elipta®, 88% for the capsule-based mono therapy product Seebri®Breezhaler® and 94% for the inhaler device reservoir product Bretaris®Genuair®. However, even though this delivered mass of API is now ‘aerosolized’ and ‘available’ to the patient, travelling into the body with the inspired breath, only a fraction of the dose is in an appropriate respirable particle size for delivery to the target region of the lung. Additionally, where inhalation is weak or ‘shallow’, or when the inspiration technique applied is not as described in the product information leaflet, then there may be situations where the device may not be able deliver the amount of API which is claimed in the product information documentation. For example, the publically available US prescribing information for the capsule-based monotherapy Spiriva®Handihaler® provides instructions for the procedure to be followed if the correct breathing was not achieved. This suggests that a greater scrutiny of the relationships between loaded dose, delivered dose and the dose reaching the lung is required.

The dispersion and penetration of the API to the lungs requires particles of an appropriate respirable size, with an upper aerodynamic particle size limit typically being accepted as less than five microns. The aerosolization process in DPIs is driven by the inhalation maneuver of the patient and must therefore not only enable the emission of the API from the device/blister/capsule and the device, but also disperse the emitted mass to an APSD of less than five microns, since particles larger than this will tend to impact on the oropharynx and be swallowed. DPIs are capable of dispersing any emitted (delivered) dose; however, no current commercial DPI product achieves full dispersion of the emitted dose to particles less than five microns in size under representative conditions. Consequently, even though the DPI can be considered to be a well understood pharmaceutical dosage form, there are still both development challenges, and opportunities, especially as technology advances.2 The extent of dispersion is dependent on the performance of the device, the properties of the formulation, flow rate, device resistance and the patient’s inhalation maneuver, with some products exhibiting greater dependence on such parameters than others. For example, the flow rate can affect the performance of devices with different resistances.3 Such factors introduce a further disconnect between the loaded dose, the delivered dose and the actual dose delivered to the target region of the lung.

There is one further complexity – namely, the fate of particles that actually reach the lung. The penetration of particles to different areas of the lung is, in part, a function of their aerosolized aerodynamic particle size. So, for example, if the aim is to reach the deep lung then a particle size of approximately two to three microns, or even less, may be appropriate.4-6 This is important, since while it is generally accepted that sub-five micron particle size doses are required for delivery to the lung, not all of the sub-five micron particles may be equally, or proportionally, clinically effective. This is especially true when considering the availability of the API for dissolution within the far from optimal dissolution environment of the lung. Additionally, dissolution and solubilization of the API may, as for standard solid dosage forms, be changed by the presence of excipients which may alter the molecular mobility of the API, affect cellular uptake and therefore may also be a factor in determining efficacy, and the speed of onset of therapeutic action.

Such factors, coupled with the fact that the terms ‘dose’, ‘strength’ or ‘label claim’ are provided for commercialized DPIs by manufacturers and health authorities, means that any relationships between the analytically determined delivered (but not necessarily respirable) dose of DPIs and clinical efficacy are not as readily elucidated as would be for standard solid dosage forms. It is also clear that the simplistic definitions of ‘strength’, as defined by the FDA and delivered dose, defined by the EMA guideline on the pharmaceutical quality of inhalation and nasal products as ‘the quantity of drug substance that is available to the user, ex device on a per dose basis’,7 may describe a quality attribute, however they do not, and arguably cannot, satisfactorily describe the actual efficacious dose of DPIs. This creates some potential ambiguity for product development, regulators, health care professionals and clinicians alike and raises the question of how best to describe and label DPI performance so as to promote their effective use within clinical settings and patient groups. This situation is exacerbated when considering the practicalities, and limitations, of the in-vitro methodologies which are used to characterize the pharmaceutical performance of DPIs.

Current in-vitro Pharmaceutical Performance Test Methods for DPIs

The in-vitro pharmaceutical performance of DPIs is determined by measuring the aerosolization characteristics of the API using two established pharmacopoeial testing methods to determine i) the delivered dose and ii) the APSD. These quantify the total single mass of drug delivered from the mouthpiece of the device – the delivered dose – and the mass of emitted respirable drug. Even though the delivered dose is now often reported in public product information documentation, there is little publically available information about the clinically more relevant APSD, for example, the fine particle dose (FPD) which is also sometime referred to as the in-vitro respirable dose. This raises potential questions concerning the limitations, or even the relevance, of using the delivered dose as a representation of clinical dose of DPIs, especially when more valuable information is available from the APSD. Additionally, the APSD of DPIs involves the determination of the total mass emitted from the inhaler and is, in essence, an indirect measurement of ‘delivered’ dose.

The accuracy, precision and variability of any pharmaceutical method, together with any required limits, is important to consider, and understand, when attempting to relate the dose of any drug product with any clinical and patient outcomes. This is particularly true for the somewhat unique methodologies used to determine the delivered dose and APSD of DPIs, described in the European Pharmacopoeia (Ph.Eur.),8,9 and in the US Pharmacopoeia (USP).10 In both compendia, the flow rate applied during testing is prescribed as that which corresponds to a 4kPa pressure drop across the inhaler device, a numerical figure representative of a fixed inspiratory strength of inhalation of a typical adult user which in itself may not be appropriate for all patients as this is dependent on specific factors (e.g. age, gender, disease and severity). The duration of testing is set to reflect the total volume of an adult breath – either 2L or 4L depending on the specific pharmacopoeia or health authority guidance. Furthermore, the delivered dose is generally an average of perhaps up to 30 determinations, with % relative individual and average requirements based on up to +/-35% of the average result for Ph. Eur., or +/-25% of the label claim, for the FDA draft guidance.11 This suggests that the in-vitro determined delivered dose of DPIs can consist of analytically variable data sets, and different regional requirements, with obvious implications when trying to develop relationships between delivered dose and clinical outcomes. It is interesting to note that limits for the uniformity of delivered dose are currently only presented in the Ph. Eur. and FDA draft guidance, with the USP removing such limits in 2014.

To measure delivered dose, the inhaler is actuated into a sampling apparatus containing a filter using a vacuum system drawing air through the inhaler at the predefined flow rate. A chemical assay of the delivered dose sample captured in the sampling apparatus is then performed, typically using high pressure/performance liquid chromatography. The APSD is measured using the technique of multistage cascade impaction, which involves size fractionation of the dose based on the principle of particle inertia. An assay of each size fraction generates an APSD specifically for the API, and from this, values are generated for metrics such as the FPD and any size fractions (stage groupings). The FDA draft guidance states that the ‘optimal APSD for most aerosols has generally been recognized as 1-5 μm’ but there is, perhaps surprisingly, no regulatory guidance regarding the relationship of the delivered dose to the APSD except for the so-called ‘mass balance’ requirements for the emitted dose from the APSD testing where the Ph. Eur.9 states a requirement of +/- 25% of the average determined delivered dose and in the USP,10 the requirement is +/- 15% of the target delivered label claim.

An additional key point to note about these pharmaceutical performance in-vitro tests is that even though the methodologies are well understood, they are essentially static and standardized, and take very little account of the impact of the patient’s inhalation maneuver and technique and/or variability in patient physiology, even though these factors are known to impact the active drug delivery mechanisms of DPIs, and hence their clinical efficacy.12 The EMA guideline does specify that delivered dose uniformity is assessed as a function of patient flow rate, to at least attempt to make some assessment of the impact of the patient, albeit, in-vitro. This potentially limits the applicability of in-vitro data when DPIs are used in clinical settings, for example in dose ranging studies. However, these established in-vitro methodologies have successfully supported the marketing authorization applications of a plethora of DPI products.

The Labeling of Commercial DPI Products

When it comes to the relationship between the measured in-vitro pharmaceutical performance descriptors and label claims, current practice can be confusing, and can appear perhaps conflicting both within, and between, regions, especially when the classical understanding of the ‘dose’ and ‘strength’ of solid dosage forms is considered. For EU products, for example, the label claim is typically presently defined as the delivered dose, as measured by the uniformity of delivered dose method described above. One important aspect of the use of the reported value (label claim) of the delivered dose is that the value is the expected mean drug content for a large number of delivered doses collected from many units under defined experimental conditions.10 Additionally, the delivered dose is developed based on the average of sets of typically 10, or if second level testing is required, 30 values, which are generated to determine the uniformity of delivered dose. Moreover, there are FDA draft guidance and EMA guideline limits that the delivered dose of any batch tested must be +/-15% of the label claim delivered dose of the drug product. If the limits for the uniformity of delivered dose and the mass balance requirements in USP <601>, where the emitted dose generated from APSD testing must be within 85-115% of the target label claim are considered, it would appear that DPI products may meet such pharmaceutical performance requirements but the data used to determine the delivered dose of a product may be inherently variable, albeit in specification. Such accepted ‘variability’ of the results used to determine the delivered dose clearly suggests that any relationships between delivered dose and the more clinically relevant FPD may be susceptible to an inherent variability. Also, to add to any confusion, there are subtle differences in how the pharmacopoeias and guidance/guidelines currently name the delivered dose uniformity test, for example, the European authorities use different descriptions; ‘uniformity of delivered dose’ (Ph. Eur.), ‘delivered dose uniformity’ (EMA guideline), with the US FDA draft guidance preferring ‘dose content uniformity’.

While the tests for uniformity of delivered dose and APSD may be well established, such important product descriptors may not always be used in any product labeling. In the EU, the label claim of DPIs is generally the delivered dose, for example 55 μg for Incruse®Elipta®, 44 μg for Seebri®Breezhaler® and 322 μg for Bretaris®Genuair®, and such information is usually on the product and/or product packaging handled (and therefore perceived) by the patient, and health care professional.

While the EU has generally moved to the inclusion of the delivered dose as a label claim/inclusion on product packaging, in the US it is not necessarily the delivered dose that is used for the label claim – it can also be the metered dose. Labeling can be further confused by the fact that it can be based on either API salt, API solvated salt form, or API moiety. The potential confusion raised by these practices is clearly demonstrated in the example of the commercial DPI combination product, Anoro® Ellipta® (EU) and Anoro™ Ellipta™ (US), which contains formulations of two APIs, namely umeclidinium bromide and vilanterol trifenatate, each contained in a single blister on a dual blister strip. From the publically available product information documentation, the loaded (pre-dispensed) dose of each API is the same in both the EU and US versions of the product. However, the US product uses the metered dose, expressed in terms of API moiety, as the packaging/product label claim (62.5/25 μg for each API, respectively), whereas in the EU, the delivered dose of the API moiety is used for the packaging/product label claim (55/22 μg for each API, respectively). This EU product, to the layman, could be perceived as a ‘lower’ strength/value, but, more importantly, raises the question of how such descriptions of ‘dose’ and ‘strength’ and ‘label claim’ are related to the efficacious FPD.

Furthermore, in certain instances the actual name of the API can be different between the regions due to naming conventions, for example, the monotherapy DPI products Seebri®Breezhaler®(EU) and Seebri®Neohaler®(US) contain the same single API, albeit at different approved doses. However, not only are the loaded dose and delivered dose defined differently (API moiety in the EU and the API salt in the US), but, due to nomenclature and convention differences, the API salt is named as ‘glycopyrronium bromide’ in the EU, and ‘glycopyrrolate’ in the US. While such differences in describing label claim have no clinical relevance, they would require some consideration during any evaluations or product development activities, and do again raise some questions concerning the lack of harmonization for the global labeling of DPIs.

Moving Forward – The Role of the Delivered Dose and Fine Particle Dose

As previously stated, the two main pharmaceutical performance tests are the uniformity of delivered dose and APSD, with only the former being referenced in any product label claim/packaging label. While the delivered dose may be a useful metric, the preceding discussion suggests that the link between in-vitro pharmaceutical performance testing, ‘label claim’ and clinical efficacy may be tenuous at best since the ‘label claim’ does not quantify, or at least indicate, the amount of API that reaches, or is capable of reaching, the lung, or indeed, any specific region of the lung. This is especially true when considering the smaller particles of the APSD, e.g. below two microns, which can be defined here as the extra-fine particle dose (eFPD). For example, for pMDIs scintigraphy studies have suggested that extra-fine particles may be homogenously distributed throughout the airways regardless of disease state.13 However, it is clear that all parts of the delivered dose and FPD may require monitoring; for example, the EMA guideline states that control of the particle size above five μm may be necessary, with the FDA draft guidance stating that a complete profile of the dose should be determined.

Indeed, the importance of the APSD for product performance is beginning to be recognized, with the USP starting to publish DPI drug product monographs which contain specific requirements and limits for delivered dose, and APSDs. But what about the actual APSD measurements/results themselves? Even though FPD does not currently appear as information on the label claim of a marketed product, it can be argued that this parameter is perhaps a more appropriate ‘dose’ or ‘strength’ descriptor, especially for health care professionals, with at least some, albeit limited, closer relevance to therapeutic effect.

Moreover, such APSD measurements are performed during the development of DPIs and form part of the CMC information in marketing authorization dossiers. Furthermore, the importance of APSD determinations for demonstrating in-vitro equivalence between two DPIs is reflected in EU guidelines and US guidance for the development of generic orally inhaled products.14,15 However, even though the use of APSD may sound an attractive proposition, the use of cascade impactor measurements can significantly deviate from in-vivo patient use perspectives which presents correlation challenges.16 Even so, a growing understanding of the sub-five micron dose may provide scope to improve data generation, interpretation and usage, more specifically with respect to the characterization of the potential clinical ‘value’ associated to the sub-five and sub-two micron particles.

The traditional, and accepted, view of inhaled drug delivery is that it is particles in the range of 1-5 microns that are optimally aerodynamically sized for deposition in the pulmonary region, with larger particles depositing in the throat and trachea and those smaller than one micron leaving the body in the exhaled breath. While this simplistic view has proven valuable to describe pulmonary delivery, there is some recent evidence which suggests that this general description may, in part, be too broad a generalization, and that in fact, finer particles, namely those in the extra-fine and even sub-micron size range, may have a more significant clinical relevance. Indeed, it has now been suggested that not all of the sub-micron sized particles are lost through exhalation, with those particles that are not exhaled being potentially capable of being delivered to the lung.13 Current research4,6,17 is beginning to suggest that extra-fine particles may: Achieve improved pulmonary deposition than coarser analogues and penetrate more effectively into the peripheral lung; result in lower oropharyngeal deposition, less local side effects and less systemic absorption from any oral/buccal dose; not be readily exhaled; enable lower dosing regimens; result in a more uniform localized therapeutic response; offer more consistent, less inhalation profile dependent drug delivery; and offer the possibility of faster transport across the lung interface.

The impact of such sub-micron particles for patient outcomes has yet to be fully elucidated and their fate in the lung is the subject of ongoing studies. Any evidence for the increase in clinical relevance of the extra-fine region of the FPD may begin to challenge whether terms such as FPD and fine particle fraction (FPF) (the dose or fraction respectively that lies below five microns in size) are sufficient to formally describe, or indeed, label, the pharmaceutical performance and dose of DPIs. Moreover, this would also add to the argument that only having the delivered dose as part the label claim to describe the aerosolized ‘dose’ characteristics is not sufficient. Even though these metrics provide information about the amount of API that may be available to be deposited in the lung, they do not describe or differentiate the APSD.

In order to exemplify this, the pharmaceutical performance of two hypothetical DPI products is presented in Table 1 and Figure 1. The Next Generation Impactor (NGI) data was generated using CITDAS V3.10 software (Copley Scientific, UK). It can be seen from Table 1 that both products have identical loaded doses, and delivered doses (uniformity of delivered dose test) but different delivered doses, as determined during the APSD analysis. In terms of label claim and, importantly, what would be presented on the product and packaging, both products in the EU would have the ‘dose’ of 88 micrograms. To the casual observer, such as a patient, based on the presentation of the products, it would be incorrectly concluded that the products were equivalent in terms of ‘dose’ or ‘strength’.

Table 1. In-vitro NGI aerosolization performance of two hypothetical DPI products. Generated using CITDAS V.3.10 software at 60 L/min.
 Figure 1. In-vitro NGI aerosolization performance of two hypothetical DPI products. Generated using CITDAS V.3.10 software at 60 L/min.

However, it is evident from both Table 1 and Figure 1, that even though the label claims defined as loaded dose, delivered dose and the FPD are similar, the APSD delivered dose and eFPD characteristics can be very different, which would not be reflected in the product/packaging label according to the evident current commercial product labeling practices and, most importantly, may not be a guarantee of equivalent patient outcomes. Additionally, the converse would be true if the eFPD characteristics were identical, the delivered doses, and hence label/packaging claims, may be different. Moreover, there could be a situation where the APSD profiles of two products are different, but they may have similar pharmacokinetic and pharmacodynamic profiles.

The data in Table 1 and Figure 1 are illustrative and provide examples of the types of pharmaceutical performance data of DPIs that would be expected to be included in any marketing authorization application dossier submitted to health authorities. However, these data also serve to highlight the disparity between the labeling of DPI products and their packaging and the actual clinically relevant ‘dose’ and ‘strength’. Additionally, the data also suggest that, in view of the relatively small masses, there is a relatively limited resolution, and therefore differentiation, in the extra-fine particle size region of the APSD when using cascade impactors such as the NGI. While such apparent differences in APSD may be quantifiable and controllable, especially in any clinical setting, it may be necessary to further extend the capabilities available to quantify and characterize particles in any APSD, including the sub-two micron range, the so-called eFPD. This is particularly true since advances in medical respiratory technology are beginning to enable a deeper understanding of the behavior of inhaled particles in the lung.

Conclusion

The inherent complexities of DPIs and the challenges of formally defining the clinically representative ‘dose’ or ‘strength’ of a DPI product can make the understanding of the pharmaceutical performance of DPI products difficult. This is further complicated by some differences in the product labeling practices within, and between regions such as the EU and US. Such factors can make it difficult to securely link clinical efficacy with label dose claim and/or the in-vitro delivered dose and FPD. This is especially true when considering the numerical value of the delivered dose as a representation of the ‘dose’ of a DPI, and the in-vitro methodology, and limits, used to generate such data.

However, the understanding of the link between (aerodynamic) particle size and clinical efficacy is advancing with the advent of invitro analytical and medical imaging technologies. For example, techniques such as those based on three dimensional lung imaging are allowing a greater level of scrutiny of the dispersion of APIs in the body.18 And studies are on-going investigating the in-vitro predictive dissolution of APIs.1 Most especially, recent research suggests that extra-fine particles may play a more important role in pulmonary drug delivery than was originally thought.5 In order to further elucidate the nature of the in-vitro pharmaceutical performance, and clinical outcomes, large scale in-vivo studies are required. This is particularly true in order to clinically determine the path of extra-fine and submicron drug particles through the pulmonary region, and their clinical effect, and to validate the in-vitro and computational strategies used to develop DPI technologies.

In some ways, it is now beginning to appear that the standard invitro testing methodologies may not be entirely appropriate for the full characterization of DPIs both in-vitro, and for correlation with the clinical dose. Indeed, APSD equipment can be modified in order to better correlate in-vitro/in-vivo data, for example, by using anatomically derived throat models, such as the Alberta idealized throat, and mixing inlets.19 However, it seems evident that there is potential for improvement in the way we characterize the in-vitro dose of DPIs. In tandem with medical technology advances, particle size analysis methodologies are advancing, for example, techniques using patient breath simulation profiles and single particle aerosol mass spectrometry (SPAMS) are being developed for the characterization, and greater scrutiny, of DPIs.20 Such concerted technological advances may allow an improved understanding and measurement of those characteristics of a DPI dose that are most important, and will support our efforts to bring more precise definitions for the performance, dose and label claim of DPIs and advance the technologies available to deliver enhanced therapeutic outcomes. Furthermore, a move towards changing the dose labeling of DPIs closer to the clinical dose could additionally assist physicians in prescribing decisions and practices.

References

  1. Shur J. The development of predictive dissolution methods for orally inhaled drug products. Available at http://ipacrs.org/assets/uploads/outputs/02_UoB_JS_FInal_HOv2.pdf
  2. Hoppentocht M, Haggendoorn P, Frijlink HW, de Boer AH. Technical and practical challenges of dry powder inhalers and formulations. Advanced Drug Delivery Reviews. 2014;75:18-31
  3. Buttini F, Brambilla G, Copelli D, et al. Effect of flow rate on in vitro aerodynamic performance of NEXThaler® in comparison with Diskus® and Turbohaler® dry powder inhalers. J Aerosol Med Pulm Drug Delivery. 2016;29:167-178.
  4. Lewis DA. Expert opinion: reviewing current thinking on the in-vitro/in-vivo behavior of particles in the extra-fine region. ondrugdelivery. 2015;Issue 62;4-9. Available at http://www.ondrugdelivery.com/publications/62/Issue_62_Hi_Res.pdf
  5. Usmani OS. Small-airway disease in asthma: pharmacological considerations. Curr Opin Pulm Med. 2015: 21:55-67.
  6. Lavorini F, Pedersen S, Usmani OS. Dilemmas, confusion, and misconceptions related to small airways directed therapy. CHEST. 2016 (in press). Available online 11th August 2016.
  7. European medicine agency committee for medicinal products for human use (CHMP) guideline on the pharmaceutical quality of inhalation and nasal products. EMEA/CHMP/QWP/49313/2005 Corr. 2006. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003568.pdf
  8. European Pharmacopoeia 9, 2017. Preparations for inhalation 0671.
  9. European Pharmacopoeia 9, 2017. Preparations for inhalation: aerodynamic assessment of fine particles 2.9.18.
  10. United States Pharmacopoeia 39. 2017. Inhalation and nasal drug products: aerosols, sprays, and powders – performance quality tests <601>.
  11. FDA Center for drug evaluation and research (CDER) guidance for industry. Metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products. Chemistry, manufacturing, and controls documentation, (draft), 1998. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070573.pdf
  12. Demoly P, Hagedoorn P, de Boer A, Frijlink H. The clinical relevance of dry powder inhaler performance for drug delivery. Resp Med. 2014;108:1195-1203.
  13. De Backer W, Devolder A, Poli G, et al. Lung deposition of BDP/Formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med Pulm Drug Deliv. 2010;23:137-148.
  14. European medicine agency committee for medicinal products for human use (CHMP) guideline on the requirement for clinical documentation for orally inhaled products. 2009. CPMP/EWP/4151/00 Rev. 1. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003504.pdf
  15. FDA Draft guidance on fluticasone propionate; salmeterol xinofoate. 2013. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm367643.pdf
  16. Singh D, Nichols SC. Understanding the key differences between inhaled in vivo drug delivery and in vitro characterization of inhalation aerosols. Proceedings Respiratory Drug Delivery to the Lungs. 2015:289-292.
  17. Jabbal S, Poli G, Lipworth B. Does size really matter- relationship of particle size to lung deposition and exhaled fraction. J Allergy and Clin Immunol. 2017 (in press). Available online 10th January 2017.
  18. Conway J, Fleming J, Bennett M, Havelock T. The co-imaging of gamma camera measurements of aerosol deposition and respiratory analtomy. J Aerosol Med Pulm Drug Deliv. 2013;26:123-130.
  19. Copley Scientific. Quality solutions for inhaler testing. 2015. Available at http://www.copleyscientific.com/files/ww/brochures/Inhaler%20Testing%20Brochure%202015_Rev4_Low%20Res.pdf
  20. Morrical BD, Balaxi M, Fergenson D. The on-line analysis of aerosol-delivered pharmaceuticals via single particle mass spectrometry. Int J Pharm. 2015;489:11-17.

Author Biographies

David Lewis is Head of Laboratory at Chiesi’s research centre in Chippenham, UK. He holds a B.Sc. in Physics (1989) and M.Sc. and Ph.D. in Aerosol Science (1990 & 1994), from Essex University. David established the UK Research Centre in Chippenham, which opened in July 2009.

Stephen Edge is an Analytical Expert at Novartis Pharma AG in Basel, Switzerland. He holds a Ph.D. in Polymer Science (1990) from The University of Wales. His pharmaceutical career began working with John Staniforth at the University of Bath. He joined Novartis in 2006 where he has supported the development of dry powder inhaler products and has authored over 100 research articles and has been a member of various industry consortia working groups.

Dilraj Singh is a Regulatory CMC manager with Novartis Pharma AG, Basel, Switzerland. Dilraj graduated with a PhD in Pharmaceutics from the University of Bradford School of Pharmacy, England, and completed a post-doctoral research fellowship in inhalation technology at Virginia Commonwealth University, USA. Dilraj has 20 years’ experience within the pharmaceutical industry encompassing product development and regulatory affairs. Dilraj has several publications, patents and conference contributions, and Novartis representative on European Pharmaceutical Aerosol Group.

Tim Rouse joined Chiesi in 2011 and is currently undertaking a part-time PhD at the University of Bath. Tim has worked for a number of prominent companies involved with inhaled drug delivery since entering the field in 2004. During this time, he has been involved in solid state characterisation, analytical and formulation design projects. Tim is a co-inventor of 2 Chiesi patents relating to particle engineering.

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