During the past few decades, long-acting drug products (such as intrauterine devices/systems and subdermal implants) have successfully delivered contraceptive steroids in a controlled manner over periods of years. Among these drug products, the levonorgestrel intrauterine system (IUS) is considered a highly effective and reversible contraception option and is preferred by women of all ages. Currently, there are three long-acting levonorgestrel IUSs on the U.S. market and several of these are about to come off patent. Consequently, generic equivalents of these products are expected to enter into the regulatory review and approval process in the near future. Therefore, it is crucial that appropriate in vitro performance testing methods are available to ensure product quality and safety and streamline the regulatory review process. In vitro release testing is an important tool that not only ensures product quality and consistent performance, but also assists in the product development and regulatory review processes. In vitro release testing has been recommended as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. However, at present, there is a lack of compendial or FDA recommended in vitro release methods available for the long-acting levonorgestrel IUSs and the information available in the literature is extremely limited. This has been a major obstacle to product development and regulatory review. Over the past 17 years, our laboratory has made considerable contributions to the development and validation of in vitro release methods (both real- time and accelerated) for long-acting complex parenteral drug products (such as microspheres, and implants). For example, an accelerated USP apparatus 4 method has been developed as a rapid quality control method with discriminatory ability for implant formulations. Most recently, in collaboration with the FDA, our laboratory has been developing appropriate in vitro release methods capable of detecting manufacturing differences and predicting in vivo performance for complex parenteral drug products (such as microspheres, in situ forming implants, as well as ophthalmic ointments). Building on the knowledge gained in these studies, it is now proposed to develop appropriate, robust in vitro release methods (both real-time and accelerated) that can discriminate levonorgestrel IUSs (that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences) and can predict their in vivo performance. An effort will be made to develop accelerated release method(s) using compendial dissolution apparatus. Mirena has been chosen as the Reference List Drug (RLD) since it will be the first IUS to come off patent. A comprehensive understanding of the effect of manufacturing differences on critical physicochemical and mechanical properties of levonorgestrel IUSs and their in vitro and in vivo performance will be obtained. This research will facilitate the establishment of bioequivalence recommendations for generic levonorgestrel IUSs, which in turn will help provide the public with safe and effective generic products at reduced cost and in a timely fashion.
This proposal seeks to develop robust real-time and accelerated in vitro dissolution methods that are capable of discriminating manufacturing differences and predicting in vivo performance for a long-acting levonorgestrel intrauterine system. This will facilitate the development of bioequivalence recommendations for generic long- acting levonorgestrel intrauterine systems and hence facilitate the development of such generic products. As a consequence of the proposed research, the regulatory burden will be reduced and human studies will be minimized without sacrificing product quality and safety while delivering cost-effective generic long-acting levonorgestrel intrauterine products to the public with minimal delay.