Intertek Pharmaceutical Services Commercial Director Chris Vernall on how the new FDA nasal bioequivalence guidances support an in vitro only bioequivalence pathway and continue wider industry focus on evolving analytical and in silico tools for generic OINDP testing
What is the main difference in in-vitro bioequivalence (IVBE) recommendations between the May 2023 nasal draft guidances and the previous draft guidances?
For the first time, the FDA has provided a true “in-vitro only” BE pathway that excludes not only endpoint studies, but also potentially in vivo pharmacokinetic (PK) work. Previously, the agency has required in-vivo PK and comparative clinical endpoint studies in addition to in vitro testing, which was both time-consuming and expensive.
This is a milestone that the FDA has been building towards and makes it possible for generic companies to have confidence in adopting an in-vitro only BE strategy – with the potential for huge cost and time savings. Following an IVBE only pathway could result in a 10-fold saving versus IVBE plus PK and an endpoint study.
The FDA indicated its willingness to accept nasal spray ANDA submissions without clinical endpoint studies if the in vitro data studies submitted were sufficient when it approved Apotex’s ANDA for a generic version of Nasonex mometasone furoate nasal spray in 2016. However, the agency had not provided sponsors with any guidance as to what it considered sufficient since that time.
From May 2023, these new guidance documents are more explicit about the IVBE tests required, and that, if an appropriate package of data is received, it may be possible to avoid both in-vivo PK and comparative clinical end-point studies (for the first time), as long as the generic formulation is Q1 and Q2 equivalent to the reference product.
What tests are recommended in the new guidances?
The new fluticasone propionate (FP), fluticasone furoate (FF) and mometasone furoate (MF) draft guidances still call for the standard IVBE tests for nasal spray products: single actuation content (SAC), droplet size distribution (DSD), drug in small particles / droplets, spray pattern, plume geometry and priming / re-priming.
In addition to those tests, these new guidances are the first that include recommendations for dissolution tests for nasal suspensions, and they include new recommendations for drug particle size distribution (PSD) in the in vitro only pathway. The 2019 guidances omitted any mention of dissolution testing (unless you inferred this from a statement about ‘orthogonal tests’).
