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Best Tool for the Job

The growing global demand for inexpensive and effective therapies for asthma and other pulmonary diseases provides a stimulus to develop generic inhaled products. However, inhaled products are recognised as presenting a significant deformulation challenge. This is especially the case for dry powder inhalers (DPIs), which derive their performance from a network of interactions between the patient, the inhaler and the drug formulation itself.

Unique Challenge

Achieving regulatory approval for a new generic relies on developing a product with demonstrated bioequivalence to a reference labelled drug (RLD). Deformulation – the unpicking and rationalisation of those characteristics of the RLD that deliver its performance – provides the underlying understanding needed to reach this goal. Across the generic industry, the pressure to be ‘first to file’ is intense, since the prize is a six-month period of exclusivity. As a result, the workflows associated with generic development are becoming both refined and well-defined – particularly for tablets, which remain the focus of many generic manufacturers (1).

In a tablet, the active pharmaceutical ingredient (API) is delivered to the patient in a controlled state with critical material attributes (CMAs) – such as particle size – closely monitored during the manufacturing process. By contrast, in DPIs both the API and any excipient particles are in a dynamic, rather than static, state of dispersion, with dispersion occurring during product use. This defining difference substantially increases the complexity of DPI development (both generic and innovator) and helps to explain why, for instance, Advair – one of the most commercially successful DPIs – experienced very little generic competition even after it had been off-patent for some considerable time (2).

A basic knowledge of how DPIs work provides greater understanding of the practical implications of the resulting need to control dispersion. The majority of DPIs are passive, meaning that the only energy available to empty the device and disperse the dose is that which comes from the inhalation manoeuver of the patient. As the patient inhales, air is drawn through the device, aerosolising the powder dose to a respirable size and entraining it in the inhaled air flow.

For correct deposition in the lung, the API must be delivered at a particle size of around 1-5 microns, with a size of 2-3 microns being optimal for penetration to the deep lung. Particles in this respirable size range tend to be cohesive as a result of strong inter-particle forces, so the central challenge in developing a DPI is how to ensure a good dose dispersion with a relatively low energy input. As the FDA guidance for DPIs makes clear (3), the development of a successful product relies on the careful consideration of:
  • The configuration and design of the device
  • The packaging of the formulation (which can be bulk reservoir, blister or capsule)
  • The properties of the formulation
This is in addition to the inhalation characteristics of the target patient group.

Regulatory Framework

The FDA’s Guidance for Industry on the development of DPIs emphasises the importance of particle characterisation, highlighting the techniques that can be most helpful (3). The particle size or size distribution of the API is clearly identified as a critical quality attribute (CQA) – a parameter that defines clinical performance – because of its influence on where the drug deposits in the lung. Other CQAs include the morphology and crystal habit of the API, which can also directly influence in vivo behaviour.

The adoption of a Quality by Design (QbD) approach, which is now mandated for generic development, relies on understanding the way in which CMAs of the formulation interact with device parameters to control these CQAs. For DPIs, this creates a requirement to elucidate the dynamics of the dispersion process. A major focus in the selection and application of particle characterisation methods is therefore to identify those that can provide the necessary insight.

Both the European and US Pharmacopoeias specify the technique of cascade impaction for measuring the aerodynamic particle size distribution (APSD) of DPIs. This technique typically involves size fractionation of the delivered dose, on the basis of particle inertia, followed by analysis of the resulting fractions, typically by high-performance liquid chromatography (HPLC). This produces APSD data specifically for the API.

Technique Limitations

Cascade impaction data are highly valued for assessing the efficiency and consistency of drug delivery, but are more limited in terms of providing insight into the dynamics of dispersion. Here, laser diffraction – a technique that enables real-time tracking of the dispersion process – has an established history (4,5). By measuring the evolution of particle size during the course of an actuation, laser diffraction provides a detailed understanding of how the dispersion is proceeding. For example, it is possible to see whether the extent of dispersion increases linearly as a function of flow rate through the product, or whether there is a proportion of agglomerated material present that cannot be readily dispersed within the normal range of flow rates that might be applied by any given patient group (6). These data support the development of formulations that disperse in an efficient way under representative conditions.

The technique highlighted by the FDA’s guidance regarding morphological studies within DPI development is microscopy, an established technique that has some important limitations. It is labour-intensive, time-consuming and, importantly, does not usually distinguish between the different components of a formulation. In many DPI formulations, carrier particles are used to aid dispersion of the cohesive API. Being able to differentiate the various components of the formulation can therefore be important.

In a carrier-based formulation, the API attaches to larger carrier particles with a weaker bond than would be established between cohering API particles.

During actuation, the API is then stripped from the carrier with relative ease. For these formulations, understanding the mechanisms of dispersion is helped by having the ability to determine, for example, whether larger particles in the delivered dose are agglomerates of API, API and excipient, or excipient alone. Such information cannot be gathered with microscopy – which does not reliably differentiate excipient and API – but can be accessed easily using the relatively new technique of morphologically directed Raman spectroscopy (MDRS).

Alternative Approach

The MDRS method involves using morphological data to guide the efficient application of Raman spectroscopy, which in turn provides chemical identification. This approach enables the detection and characterisation of discrete chemical species within a formulation – a capability that is extremely valuable in the deformulation of DPIs.

Modern automated imaging systems measure tens of thousands of particles in a matter of minutes, to produce statistically robust particle size and shape distribution data with minimal manual input. Such systems offer an efficient alternative to conventional microscopy, and are used widely to measure particles in the size range 1μm to 1,000μm in many pharmaceutical products, including dry powders, liquids and creams. Using MDRS, the morphological data gathered by automated imaging are used to classify particles and identify those that can be usefully analysed by Raman spectroscopy. Spectra are then acquired for these particles to enable the chemical identification of discrete populations within a multi-component mixture.

In DPI development, the non-destructive nature of MDRS offers the potential to extend the informational productivity of testing by cascade impaction. Using HPLC to analyse the size-fractionated samples produced in cascade impaction necessitates dissolution, meaning that any information about the physical characteristics of particles within a specific size fraction is lost. In contrast, MDRS allows collected fractions to be reliably identified as either excipient or API, before being characterised individually with respect to size and shape to elucidate dispersion behaviour.

Recent research has established the potential value of this approach, and commercial accessories to streamline the use of MDRS in combination with the Next Generation Impactor (NGI) – one of the cascade impactors routinely used for inhaled product research – are expected to be available this year. These accessories capture fractions of the dose on a slide that is immediately transferrable to an automated imaging system, thus eliminating the need for any intermediate sample preparation/handling step. The following case study demonstrates the application of this strategy and, more generally, the potential value of MDRS.

Case Study

A commercially available DPI containing two APIs was actuated into an NGI (Copley Scientific, UK) to disperse and fractionate the dose. A collection disk was placed in the collection cup at stage three of the impactor to capture particles on a suitable surface for MDRS. This stage was selected because, at the test flow rate, it would be expected to capture particles that are likely, on the basis of size, to deposit in the lung. This fraction of the dose is therefore of particular interest from the point of view of assessing the likely efficiency of drug delivery. The collected dose was transferred to a Morphologi G3-ID (Malvern Instruments Ltd, UK) for analysis by MDRS.

Particle size and shape distribution data were measured for the sample, and the results were then used to select more than 1,500 particles for chemical identification. Raman spectra were gathered for each of the selected particles and compared with a reference library. Comparing the measured spectra with those of the pure APIs and of lactose – an excipient in the formulation – enabled secure chemical classification of all particles in the selected population of interest.

Figure 1 (see full PDF of article) shows an example spectrum for a specific particle, alongside reference spectra for the two active ingredients. Clear spectral features associated with both APIs are observed within the particle’s spectrum, suggesting that it contains both components. This particle can therefore be designated a multi-component agglomerate (MCA). In a similar way, MCAs containing one or both APIs and lactose can also be identified. A summary of the results for all the particles from the stage three sample are shown in Figure 2 (see full PDF of article).

This figure shows chemical identification data for the stage three sample. These data indicate that of the particles in this size fraction classified as of interest, only around 1% are API 1 alone. The majority are API 2, but there are appreciable numbers of discrete lactose particles and multi-component agglomerates. Example particle images are shown for each type of identified particle.

These data provide far more insight into how the formulation is dispersed than the averaged data gathered using cascade impaction followed by HPLC analysis. For example, they show whether or not both of the APIs detach from the lactose with equal ease, or are likely to co-locate in the lung, on the basis of their size. This information is extremely helpful for understanding how a DPI delivers clinical efficacy: a critical step in deformulation.

The Way Forward

Subtle and complex interactions – between the device, formulation and inhalation profile of the patient – define DPI performance and make these products a challenging target for generic developers. It is especially difficult to learn how to effectively control formulation dispersion during the actuation of a DPI to achieve clinical efficacy goals.

MDRS is a relatively new technique that enables the morphological characterisation and chemical identification of discrete ingredients within a multi-component blend. Efficient and non-destructive, it has the potential to extend the informational productivity of cascade impaction – an established method used to measure the APSD of DPIs – to elucidate dispersion behaviour. Using MDRS, it is possible to gather detailed information about the composition of a formulation and the dispersion characteristics of individual components within it. In combination with real-time aerosol measurement techniques like laser diffraction, such data provide the knowledge needed to successfully commercialise generic DPIs.

References
1. Accelerating the deformulation workflow for oral solid dosage forms. Visit: www.malvern.com/en/support/resource-center/whitepaper/wp141209deformulationworkflowosd.aspx
2. Visit: http://online.wsj.com/news/articles/SB10001424052748703628204575618332675513808
3. FDA, Guidance for Industry: Metered dose inhaler and drypowder inhaler drug products. Chemistry, manufacturing and control documentation. Visit: www.fda.gov/downloads/drugs/guidances/ucm070573.pdf
4. Begat P et al, The role of force control agents in high-dose dry powder inhaler formulations, Journal of Pharmaceutical Sciences 98(8): pp2,770-2,783, 2009
5. Kippax et al, Unlocking the secrets of the dry powder inhaler plume, Proc Drug Delivery to the Lungs 17, 2006
6. Behara SRB et al, Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and de-agglomeration behaviour under dynamic conditions, European Journal of Pharmaceutical Sciences 42(3): pp210-219, 2011


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Dr Paul Kippax is Product Group Manager at Malvern Instruments. A chemist and colloid scientist by background, he has long experience and in-depth understanding of particle characterisation techniques, and specific expertise in the application of laser diffraction and analytical imaging to pharmaceutical industry challenges.
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Dr Paul Kippax
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