The US Food and Drug Administration (FDA) has come a long way when it comes to locally acting orally inhaled and nasal drug products (OINDPs) and in the next five years of generic drug user fees, the agency is looking at further progress on some unique challenges, according to a regulatory science report on OINDPs.
FDA’s Office of Generic Drugs (OGD) explained how the performance of OINDPs has been notoriously difficult to characterize because of a lack of understanding of the complex interactions between active and inactive ingredients, device design and characteristics, and stability across the life of these products.
“There were no clear in vitro to in vivo correlations and predictive methodologies to determine regional deposition and local availability of these products. To design OINDPs that meet BE [bioequivalence] standards, the generic industry needed tools that could direct product development toward bioequivalent products,” the agency said.
Between 2009 and 2012, OGD led a series of studies on OINDPs that laid the groundwork for future research.
And when the first generic drug user fees were instituted, OGD published 39 product-specific guidance documents on OINDPs that included a combination of in vivo and in vitro BE studies.
“Further research has since allowed FDA to clearly establish the weight-of-evidence approach for regulatory approval of generic OIDPs, and to articulate the justifications as to why each piece of the weight-of-evidence approach is critical in the process of determining BE,” FDA said.
As a result, FDA published the first product-specific guidance for a metered dose inhaler in April 2013 (Albuterol), and the first dry powder inhaler guidance in September 2013 (fluticasone propionate and salmeterol xinafoate). FDA has since developed and published 17 product-specific guidance documents for these complex products.
“FDA looks to use this body of work to streamline the review process by creating tools and methods to simplify the product data for ANDA review, or to better characterize product performance to meaningfully reflect lung deposition, and clinical effects, by establishing an in vitro to in vivo correlation,” the report said.
The report also lays out OGD’s overarching goals and areas for research over the next five years of GDUFA II.
The first goal will be to build on earlier research, FDA said, “to create clear pathways to establish BE, without the need for comparative clinical endpoint studies."
A second key development area “will be to gain a better understanding of in vitro assessments and their impact on BE, such as the use of dissolution and in silico CFD [computational fluid dynamic] modeling to predict product performance,” the report said.
Areas of focus for dry powder inhaler (DPI) products include exploring new tools to develop a deeper understanding about formulation-device interactions, which can influence possible batch-to-batch variability.
Other research will aim to determine the effect of excipients on dissolution and bioavailability for DPI products, as well as to identify new products, including novel formulations and new device considerations.
“For example, researchers have only a basic understanding of DPI products that utilize a carrier excipient other than lactose, so expanding tools to develop an understanding of these products will be important,” the report said. “Combining with the research models built under GDUFA, FDA can evaluate CFD and other advanced analytical tools to evaluate critical characteristics of devices newer to market, such as those for which spray velocity and spray duration may be the rate-limiting determinants in drug delivery to the site of action in the lung.”
For nasal aerosol and spray products, the report also said the next five years of research will provide alternatives to comparative clinical endpoint BE studies, and support a better understanding of in vitro, dissolution and modeling tools to be used for ANDA reviews.
FDA will also continue work on the development and validation of Morphologically Directed Raman Spectroscopy (MDRS), and other orthogonal methods, such as dissolution and rheological tests for the in vitro only BE assessment of nasal suspension products.