P331: Mapping bioequivalence (BE) recommendations in product-specific guidances (PSGs) for polymeric long-acting injectables (LAI)
Poster Presenter
Haoyi Cui
ORISE Fellow
FDA United States
Objectives
To outline bioequivalence (BE) study recommendations in current LAI product-specific guidances (PSGs) and briefly explore alternative BE approaches for LAI products development, incorporating insights from research and discussions with prospective generic drug applicants from a pre-ANDA perspective.
Method
A literature review and data mining using FDA databases were conducted to summarize the main design of the BE approaches in current PSGs for Poly (lactic-co-glycolic acid) (PLGA) -based LAI products.
Results
The FDA has approved over 20 NDAs for LAI products, which are based on PLGA as of February 2026. However, only six generic PLGA-based LAI products are currently approved by the FDA. This limited availability is largely due to challenges associated with complex formulation, excipients, and BE study designs for PLGA-based LAIs. The complexity of PLGA formulation presents significant challenges for generic product development. Small differences in raw material control and drug product manufacturing process may result in significant product performance deviations. Generally, in vivo pharmacokinetic (PK) studies are recommended for demonstrating BE of generic LAI products, where study designs include single-dose or multiple-dose studies conducted in parallel or crossover formats. Although most BE studies with PK endpoints are conducted in healthy subjects, many PSGs on LAI products are recommended to conduct these studies in patients due to safety concerns. Comparative clinical endpoint BE studies designed as a randomized, double-blind, parallel, in vivo study involving male and non-pregnant female patients have also been recommended for some LAI products. In addition, due to complexity in release profiles, in vitro drug release testing (IVRT) has also been included in the PSG to support either BE or quality.
To continue the efforts on promoting generic development and approval of complex LAI products, GDUFA-funded internal and external research has been conducted focusing on developing new methods for characterizing polymers and drug products as well as conducting IVRT.
Conclusion
The development of PSGs and ongoing internal and external research efforts play a crucial role in facilitating the development and approval of generic LAI products. The research efforts have been recognized and adopted by generic drug industry as evident through pre-ANDA inquiries and ANDA submissions. These efforts could address unmet clinical needs and improve the accessibility of these therapies. This study offers valuable insights into the PSG recommendations of LAI products, highlighting challenges and gaps in their generic drug development. These efforts not only inform and advance the development and revisions of PSGs for LAI generics but also support the assessment of ANDA submissions.
