There are four levonorgestrel-releasing intrauterine systems (LNG-IUSs) approved by the U.S. FDA. However, to date, there are no approved generic LNG-IUSs. Development of LNG-IUSs is challenging: 1) long acting (up to 5 years); 2) locally acting; and 3) drug-device combination products. Under our U.S. FDA grant (RFA-FD-15-006), we have successfully developed and optimized a processing method for qualitatively and quantitatively (Q1/Q2) equivalent LNG-IUSs using Mirena as the reference product. Physicochemical characterization methods, and a reliable real-time release testing method with discriminatory capability, have been developed. This allowed determination of the impact of drug particle size, physical structure (dimensions and configuration of the device) as well as the source of the outer membrane on in vitro drug release. We have also established accelerated testing methods using hydro-organic media. With these methods in hand, the next logical step to enable development of generic equivalents of the LNG- IUSs is to understand the design space of LNG-IUSs based on the quality target product profiles (QTPPs). Accordingly, it is now necessary to systematically investigate the impact of critical process parameters (CPPs), formulation variations, and the device physical structure (dimensions and configuration) on the release profiles. This will require the development of non-Q1/Q2 equivalent LNG-IUSs, since Q1/Q2 equivalent formulations are limited in terms of the composition and concentration of the excipients. Over the past two decades, our laboratory has made considerable contributions to the formulation development and in vitro release testing (both real- time and accelerated) of many different long-acting complex parenteral drug products. In collaboration with the FDA, we have developed appropriate in vitro approaches to enable bioequivalence recommendations for these complex parenteral drug products, through evaluation of the impact of raw material attributes, as well as processing and formulation parameters on their performance. Building on this knowledge, it is now proposed to develop a manufacturing method for LNG-IUSs suitable for adaption to commercial manufacturing that will allow identification of the CPPs and evaluation of their impact on the critical quality attributes (CQAs). The influence of processing parameters, formulation variations and device physical structure on the release rate of LNG-IUSs will be quantitatively determined. In addition, a robust accelerated release testing method will be developed to reduce the time for in vitro performance testing. Liletta (a similar product to Mirena) will be investigated as a second commercial comparator. This research will facilitate the establishment of bioequivalence recommendations for generic LNG-IUSs.
This proposal seeks to investigate qualitatively and quantitatively inequivalent (non-Q1/Q2 equivalent) levonorgestrel (LNG) intrauterine system (IUS) formulations to understand the impact of critical pharmaceutical processing, formulation variations and physical structure of the device on the in vitro drug release characteristics. This research aims to facilitate the development of bioequivalence recommendations for generic IUS products through an in vitro only approach and hence simplify the development of such generic products. As a consequence of the proposed research, the regulatory burden will be reduced and clinical studies will be minimized without sacrificing product quality and safety while delivering cost-effective generic intrauterine system products to the public with minimal delay.
