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July 24, 2017

Reducing the Need for Clinical Bioequivalence Endpoint Studies

Raman Spectroscopy and MDRS Enable Determination of the Size and Shape of Specific Components Within a Multicomponent Blend

Reducing the Need for Clinical Bioequivalence Endpoint Studies

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  • Reviewing the recent approval of an abbreviated new drug application (ANDA) for a locally acting mometasone furoate nasal spray, the FDA highlighted the pivotal role played by an emerging analytical technology – morphologically-directed Raman spectroscopy (MDRS).1 By combining automated imaging with Raman spectroscopy, MDRS enables determination of the size and shape of specific components within a multicomponent blend. For the purposes of the ANDA, this capability was used to compare the size of the active pharmaceutical ingredient (API) in the reference and generic nasal sprays and confirm its close similarity. The resulting data were accepted in lieu of a clinical bioequivalence (BE) endpoint study, setting a precedent for future ANDAs that could help reduce the cost and complexity of tests associated with a submission and accelerate new products to market.

    In this article, the authors look at the challenge of demonstrating BE in a locally acting product alongside the added complexities of nasal spray development. The authors explain how the technique of MDRS works, the unique insight it can provide, and how these data are being used in the pharmaceutical industry, focusing on the particular example of the demonstration of BE cited previously. As this recent ANDA approval demonstrates, MDRS is a powerful analytical tool for the industry, allowing the ability to successfully access information to advance product formulation and development.

  • The Challenges of Locally Acting Nasal Sprays

    By definition, locally acting drug products do not deliver efficacy systemically through the attainment of a therapeutically active concentration in the bloodstream. Rather, they deliver localized action; the relief of hayfever symptoms via the use of a nasal spray is a prime example. This means that traditional pharmacokinetic (PK) approaches to the demonstration of BE, based on assessing the similarity of drug dissolution and absorption from in vivo measurements of drug concentration, are not necessarily appropriate. Locally acting drugs may never attain a measurable systemic concentration. This raises the critical question of how best to demonstrate that drug behavior at the target site is comparable.

    Demonstrating BE in a locally acting nasal spray poses additional challenges that are unique to the delivery method. The size of droplets delivered to the nose is the result of multiple interactions between the formulation and the device, and may also be affected by the technique/actuation force applied by the patient during product use. Furthermore, in a suspension nasal spray, the size of delivered droplets does not define the delivered size of the API, which may or may not be changed by the atomization process. As a result, the demonstration of BE in a locally acting nasal spray, particularly a suspension product, is far more complex than for products such as topical creams, where the dose is more closely controlled.

  • Exploring the Regulatory Requirements

    Click Image To Enlarge +
    Figure 1. A broad classification of the evidence required by both the FDA and EMA when assessing a claim of bioequivalence for a locally acting nasal spray. AUC=area under curve.

    The practical implications of this complexity are evident from general and specific guidance provided by the regulators. Although the FDA and EMA differ in terms of the approach taken to assessing a claim of BE for a locally acting nasal spray, the evidence required in both instances is similar and can be broadly classified, as shown in Figure 1.2

    A primary requirement is to demonstrate that the device and formulation are closely similar. For the device, this might include the matching of metered volume and actuator/pump design, while the formulation would typically be shown to be quantitatively and qualitatively the same – incorporating the same API, preferably in the same hydrated and polymorphic form (Q1/Q2 equivalence). Additionally, the physicochemical properties of the formulation, such as viscosity/rheology, may also need to be considered (Q3 equivalence), since these can influence the interactions between device and formulation, and hence drug delivery performance.

    A battery of in vitro tests is applied to confirm that the chosen device and formulation are acting together to achieve expected drug-delivery performance. Product-specific guidance for mometasone furoate monohydrate,3 for example, references the measurement of:

    • Single actuation content across the lifetime of the product
    • Droplet size distribution by laser diffraction
    • Drug content in small particles/droplets by cascade impaction
    • Spray pattern
    • Plume geometry

    PK studies are used to confirm the comparability of systemic exposure but, as highlighted above, are not, in combination with current in vitro methods, able to describe the fate of the drug within the nose with sufficient resolution. The final set of data provided is, therefore, typically a clinical endpoint study to demonstrate equivalent efficacy. However, such studies can be costly and time-consuming, difficult to implement (not least because of the need to recruit suitable patients), and somewhat unreliable. Going forward, identifying analytical strategies that can potentially help to eliminate the clinical trial/pharmacodynamics study requirement is an important goal for the cost-efficient and timely development of generic nasal sprays.

  • Introducing MDRS

    The technique of MDRS combines the capabilities of automated imaging and Raman spectroscopy. Automated imaging delivers statistically relevant size and shape data from captured images of individual particles. Tens of thousands of particles can be measured in a matter of minutes to generate number-based particle size and shape distributions. These data can provide the ability to determine the state of dispersion of particles within a formulation, and can also enable the differentiation of morphologically dissimilar components within a blend. However, they provide no chemical identification.

    Within MDRS, the generation of component-specific particle size and shape distributions is enabled through the use of Raman spectroscopy, an established technique that offers high chemical specificity for a wide range of pharmaceutically relevant molecules. The first stage within the MDRS measurement workflow is to capture images of the particles within a blend using automated imaging. The particles are then classified on the basis of their morphology. Raman spectroscopy is then applied to identify particles where this morphological classification alone is unable to provide component differentiation. Individual spectra are gathered for each particle of interest and compared with those in an in-house library, or external database, to securely identify the compound. This approach limits the more time-intensive Raman element of the analysis, cutting overall investigation times to a minimum. An alternative strategy is to randomly select a relatively large number of particles for Raman analysis to identify a specific component of interest within the blend, so that its morphology can be assessed. This may be more time-consuming, but can be productive when little is known about the morphology of the compound of interest.

    With either strategy, the net result is the same: MDRS delivers component-specific particle size and shape for each ingredient within a blend. With pharmaceutical applications, the component of interest is almost always the API, and MDRS is used to detect the amount of API present in a blend and its morphology.

    Comparing MDRS with some alternative techniques that could be considered for such analyses helps to highlight its benefits for certain applications. 4 For example, traditional Raman spectroscopy could be used to determine the overall amount of API in a blend, but MDRS, by focusing the Raman analysis on specific particles, enhances the speed of analysis. 5 The use of automated imaging to generate particle size and shape data within the MDRS workflow also provides improved resolution to changes in the state of dispersion of the formulation compared to the basic imaging capabilities of many Raman microscopes. On the other hand, microscopy is an established technique for comparing the morphology of alternative samples. The drawbacks here are that microscopy does not offer any chemical specificity, and is less practical; it is more time-consuming and is subject to operator bias.

    As a result of these advantages, the unique capabilities of MDRS are finding growing application across the industry (see call out box).

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