IVIVC of parenteral PLGA microspheres

There have been only a dozen parenteral extended release formulations that are designed to deliver drugs from a week up to 6 months since the first introduction of Lupron Depot® made of poly(lactic-coglycolic acid) (PLGA) microspheres in 1989. All parenteral extended release formulations are made of PLGA in the form of microspheres, solid implants, and in situ forming implants. Over the past few decades, the development of in vitro–in vivo correlation (IVIVC) for parenteral products has increasingly gainedmore significance. A Level A IVIVC can open thepossibility for an in vitro releasemethod to beused as a surrogate for bioequivalence studies. This can minimize the need for human studies and reduce the regulation burden. Accordingly, establishing IVIVCs for parenteral products is expected to propel the development of both generic and innovator products. In the case of PLGA microspheres, due to their complex characteristics (e.g., long-term (weeks to months) release and multi-phasic release profiles), deconvolution of in vivo data and correlation with in vitro release data has been very challenging. In addition, the lack of compendial in vitro release testingmethods has delayed the development of IVIVCs for PLGA microspheres and other extended release parenterals. The IVIVC study by Professor Burgess and her team in this issue is important as it presents the possibility that IVIVCs for parenteral polymeric microspheres can be established [1]. The study by Professor Burgess and her team shows that Level A IVIVCs can be established for parenteral PLGA microspheres. The Burgess group elected to work with compositionally equivalent risperidone-loaded PLGA microspheres prepared with different manufacturing processes. The physicochemical properties (e.g., porosity and particle size) of the risperidone-loaded PLGA microspheres were sensitive to minor manufacturing changes, such as different solvent systems and microsphere collection procedures, which subsequently resulted in changes in their in vitro and in vivo performance. The two most commonly used in vitro release methods for parenteral PLGA microspheres (e.g., sample-and-separate and USP apparatus 4) were investigated in this IVIVC study. Compared with the sample and separatemethod, the USP apparatus 4methodwas superior in its ability to discriminate between the compositionally equivalent risperidone microspheres with manufacturing differences. The ability to distinguish drug release properties from microspheres made by different manufacturing processes is critical in evaluating different formulations that consist of the same drug and polymer. The developed IVIVCs can be very useful to guide formulation and/or process development