Development of Real-Time and Accelerated Dissolution Methods for a Long-Acting Levonorgestrel Intrauterine System

SUMMARY/ABSTRACT
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.

Grant Number: 5U01FD005443-10
NIH Institute/Center: FDA
Principal Investigator: DIANE BURGESS