Intranasal drug products have continued to attract attention in recent years on the back of growing understanding around the benefits of delivery systems targeting the nose.
However, for generics companies seeking to pursue this opportunity via an abbreviated new drug application (ANDA), the pathway to demonstrating bioequivalence with a reference listed drug (RLD) is beset with challenges. In particular, the requirement to satisfy the US Food & Drug Administration’s requirement for a “weight-of-evidence” approach can demand the inclusion of a comparative clinical endpoint study to provide in vivo evidence of pharmacokinetic equivalence in the rate and extent of absorption at the local site of action.
To avoid this, regulators have paved the way for applicants to pursue alternative in vitro methods in recognition of advances in the capabilities of analytical techniques. Specifically, the use of validated approaches employing morphologically-directed Raman spectroscopy (MDRS) have been accepted, where scientifically justifiable, by the FDA’s Office of Generic Drugs as a method for eliciting supporting data on API particle characteristics in lieu of a comparative clinical endpoint BE study for a nasal suspension drug product, with the precedent for this approach set as far back as 2016.[1]
MDRS is an integrated analytical technique that not only measures the size and shape of particles with a microscope but also provides chemical identification by Raman spectroscopy. These benefits are key when considering formulated drug products in suspension, where the API co-exists with other undissolved excipients. These excipients can have a broad particle-size distribution (PSD), and any overlap with the API can add significant complexity to the task of isolating and determining API particle size. This issue can be overcome, however, through the physico-chemical nature of the MDRS analysis.
It is known that the particle size of the API has a direct bearing on dissolution of the drug, which in nasal delivery occurs in the epithelial mucous fluid layer. As such, comparisons between measurements of dissolution kinetics for a test and reference product are also valuable for providing an orthogonal approach to verifying similarities and/or differences in particle size and validating the MDRS-based method for assessing API particle size.
As a pioneer in alternative bioequivalence for oral and nasally inhaled drug products (OINDPs), and with a strong history of working closely alongside the FDA to progress in vitro and in silico methods in this area, Nanopharm set out to evaluate the MDRS methodology for characterizing nasal suspension drug products. The studies, which received partial funding via FDA research programmes, used a combination of techniques to investigate both drug substance particle size in nasal suspensions as well as dissolution rate, analysing equivalence between test and reference products.[2]
Analysis was conducted on four batches of mometasone furoate monohydrate (MFM) API formulated into nasal suspension formulations with qualitative and quantitative equivalence to the RLD, Nasonex®. The batches underwent in vitro BE tests, including droplet size distribution, spray pattern and plume geometry, dissolution analysis, and high-performance liquid chromatography. MDRS was used to track particle size distribution of the API both prior to and following incorporation into a complex nasal product.
The study results revealed that MDRS was successful in isolating the API population to allow for drug-specific particle sizing and characterisation within the formulated nasal suspension. This, in turn, facilitated comparative analysis between the test and reference products. However, given the identified limitations of MDRS regarding minimum particle size detection, the study also underlined the necessity of dissolution as an orthogonal technique for tracking the influence of the “invisible” sub-micron APIs in a complex nasal suspension.
These findings are highly significant for generics companies facing the onerous requirement to undertake comparative clinical endpoint studies in an effort to arrive at a similar evidence base. Combined, the use of MDRS and dissolution analysis were shown to uncover robust data on critical material and process attributes that illuminate aspects of drug quality and demonstrate bioequivalence between test and reference drug products.
Crucially, these conclusions are aligned with the direction of travel being taken by the US FDA, where momentum is gathering behind in vitro and in silico methods of analysis in the area of bioequivalence. Since accepting the use of MDRS-driven data into the submission for the first generic mometasone furoate nasal spray, the agency has incorporated its use into a variety of product-specific guidance (PSG) documents for generic drug development, with particular reference to nasally delivered drug products.
It is important to acknowledge that challenges still remain in relation to in vitro approaches when it comes to securing the accurate, robust evidence base necessary for product approval. However, encouraged by a clear invitation from regulators to replace costly and time-consuming comparative clinical endpoint studies, and supported by the expert analytical services of partners such as Nanopharm, generics manufacturers today are in a favourable position to exploit these accelerated pathways in pursuit of new opportunities in the expanding nasal spray market.
[1] https://www.fda.gov/media/97705/download
[2] https://pubmed.ncbi.nlm.nih.gov/34008082/
