Reducing the Need for Clinical Bioequivalence Endpoint Studies

Paul Kippax Ph.D. Director Product Management: Morphology Malvern Instruments

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

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

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.

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.

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).

MDRS: Establishing a Place in the Analytical Toolkit for Pharmaceuticals

Case Study: Exploring the Role of MDRS in the Approval of a Generic Form of Nasonex

Nasonex is a nasal spray treatment for the alleviation and prevention of seasonal and year-round allergies that can also be used for the treatment of nasal polyps. The active ingredient is mometasone furoate, a steroid which acts to reduce inflammation. The product is a popular generic target with successful submissions both in Europe and the U.S.

Comments from the Committee for Medicinal Products for Human Use (CHMP) provide interesting insight into the approval of a European submission, which was supported by particle-size data specifically for the API in the suspension, differentiated from the excipient present. This submission was for the use of two different nasal spray devices, with one single formulation, with only one of the devices subjected to in vivo studies. The CHMP commented that it “considered particle-size distribution to be an adequate indicator of dissolubility, which is, in turn, an indicator of comparable safety and efficacy,”² concluding that particle-size data could therefore be used to confirm the equivalence of the two devices. The analytical technique applied to gather the API-specific particle-size data was Raman based.

The first FDA approval of a generic mometasone furoate from Apotex came earlier in 2017, just in time for the main allergy season in the US. It took eight years to review to the point of approval. This submission was noteworthy for its complexity—MDRS was used extensively and was specifically highlighted as being valuable in providing data to support the claim of bioequivalence.

The majority of generics use an identical API, but the Apotex submission was based on an anhydrous form of mometasone furoate, in place of the monohydrate used in the reference product. This was a complicating factor in the review process, necessitating demonstration that the API remained in its anhydrous form for the shelf life of the product. The review was also lengthened as a result of a FDA rejection of the results from the clinical endpoint BE study. This was because the formulations used for the study contained API manufactured at a site that was not intended for manufacture of the commercial product, and characterization of the two API batches revealed differences in the particle-size distribution between the two. This difference also necessitated repeating all six in vitro tests specified for the product. Finally, PK-endpoint BE studies were particularly challenging because of the requirement for an analytical technique with sufficient sensitivity to detect very low levels of API in the blood, used for an assessment of comparative systemic exposure.

Apotex used MDRS, (Morphologi G3-ID, Malvern Instruments) to simultaneously analyze the size, shape, and chemical identification of individual particles within their nasal spray suspensions. The resulting data enabled the company to confirm both the form of the drug and its particle size to significantly add to the weight of evidence presented to demonstrate BE. The FDA accepted these data in lieu of the rejected clinical endpoint study, echoing the conclusions of the CHMP that particle-size data for the API is a sound basis on which to compare clinical efficacy and safety. This acceptance sets a precedent in terms of submitting in vitro data in place of a clinical study and highlights an opportunity to change the established FDA weight-of-evidence approach to the approval of locally acting generic nasal sprays. Clinical studies are both expensive and time-consuming, so such a change could be important and valuable.

Conclusion

The ability of MDRS to differentiate an API from other ingredients within a formulation, and provide morphological data specifically for it, is driving its uptake across the pharmaceutical industry. The application of MDRS to size API particles in locally acting nasal spray formulations is proving particularly valuable. Comparative testing of a reference and test product makes it possible to confirm that the particle size of the delivered API is equivalent, supporting a claim of comparable dissolution characteristics, and consequently, equivalent clinical efficacy and safety. The acceptance by the FDA of such in vitro data in lieu of a clinical trial underlines the potential value of MDRS and its ability to accelerate generic development in a cost-efficient manner.

Paul Kippax, Ph.D., is leader, advanced materials group, at Malvern Panalytical.

References

1 ^‘“FDA embraced emerging technology for bioequivalence evaluation of locally acting nasal sprays.” FDA/CDER SBIA Chronicles. Available to view at: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM502012.pdf.   

2 “Characterizing nasal spray suspensions for regulatory and scientific purposes.” Brainshark, available for download at: www.malvern.com/en/support/events-and-training/webinars/W160517NasalSpraySuspensions.html.

3 FDA Draft Guidance for Mometasone Furoate Monohydrate. Sept. 2015. Available for download at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM461141.pdf.

4 Paul Kippax of Malvern Instruments answers questions about MDRS. Interview on oindnpews, available to view at: www.oindpnews.com/2017/02/paul-kippax-of-malvern-instruments-answers-questions-about-mdrs/4.

5 “Forensic analysis of an artificial sweetener commonly employed in hoax powder attacks using morphologically direct Raman spectroscopy.” Application note, available for download at: www.malvern.com/en/support/resource-center/application-notes/AN150130ForensicPowderRaman.html.

6 “Accelerating the deformulation workflow for oral solid dosage forms.” White paper available for download at: www.malvern.com/en/support/resource-center/Whitepapers/WP141209DeformulationWorkflowOSD.html.

7 D. Huck-Jones et al., “Introducing morphologically directed Raman spectroscopy—a powerful tool for the detection of counterfeit drugs,” Manufacturing Chemist, Oct 2016.

8 J. Gamble et al., “Monitoring process-induced attrition of drug substance particles within formulated blends,” Int. J. Pharm. 470 (1–2), 77–87 (Aug. 15, 2014).

9 “Novel analytical technologies for product deformulation—Part 2.” Recorded webinar, available to view at: www.malvern.com/en/support/events-and-training/webinars/W140819ProductDeformulation-2.html.