Drugs

CDER Easing Bioequivalence for Inhaled Drugs

A new CDER regulatory science report details the agency’s efforts to ease bioequivalence (BE) requirements for locally-acting orally inhaled and nasal drug products (OINDPs). The report emphasizes the challenges to demonstrate BE for proposed generic OINDPs since the traditional PK [pharmacokinetic] approach used for systemically acting drugs is not directly applicable to these products, which deliver drugs to the site of action in the lung and nose, respectively.

Under the reauthorized generic drug user fee program, one goal for orally inhaled drug products is to “create clear pathways to establish BE, without the need for comparative clinical endpoint studies,” the report says. “For example, assessing the sensitivity of the conventional in vitro BE tests to detecting potential in vivo product performance differences between qualitatively and quantitatively (Q1/Q2) the same test and reference inhalation solution products. As well as explore the possibility of in vitro only BE, or BE based on PK and in vitro BE, once a correlation can be clearly identified for lung dissolution. Another project will be to classify suspension inhalation aerosol products based on the complexity of the formulation, and then explore the possibility of an in vitro only BE option for products with a few excipients.”

Another key development area will be to have a better understanding of in vitro assessments and their impact on BE, such as the use of dissolution and in silico computational fluid dynamic (CFD) modeling to predict product performance, according to the report. The goal is to develop a model for in vitro BE, which can be standardized across the class of products. “This could include predictive in vitro testing, such as realistic mouth-throat models, and dissolution testing, and/or predictive in silico models, such as an in vitro only BE method utilizing CFD.”

For locally acting nasal products, the report says CDER aims to 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 for nasal aerosol and spray products. “FDA will apply these tools to new formulations and complex nasal products in development, hopefully to replace the comparative clinical endpoint BE study requirement for ANDAs,” it says. “FDA will 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.”

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