Over the past few decades, parenteral sustained release products (such as microspheres and implants) have emerged as an advanced alternative to traditional drug products. Currently there are more than twenty innovator microsphere and implant products on the market and several of these are either off patent or about to come off patent. Consequently, generic equivalents of these products are in various stages of development. It is crucial to ensure the quality and safety of these sustained release parenterals. In vitro release testing is important for quality control purposes as well as to predict in vivo performance and is recommended as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. However, due to the lack of compendial in vitro release methods available for parenteral sustained release drug products, many different procedures and non-standard apparatus are used (e.g. sample-and- separate, dialysis membrane, and flow-through methods). This makes inter-laboratory comparisons difficult and complicates the regulatory review process. However, in recent years, considerable progress has been made towards the development and acceptance of standardized in vitro release methods for parenteral microspheres. Until now, few studies have reported the development of in vitro release testing methods for parenteral implants. In particular, no in vitro release testing methods using USP standard apparatus has been reported for in situ forming implants. Over the past 16 years our laboratory has made considerable progress in the development and validation of in vitro release methods for complex parenteral products (i.e. microspheres, liposomes and implants). A robust USP apparatus 4 method for microspheres has been developed with demonstrated capability of distinguishing formulation differences and predicting in vivo performance. In addition, an accelerated USP apparatus 4 method has been developed as a rapid quality control method with discriminatory ability for implant formulations. Following these studies, it is proposed to conduct a systematic evaluation of current in vitro release methods for pre-formed and in situ forming parenteral implants that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences. The most appropriate, robust release method(s) capable of detecting manufacturing differences and predicting in vivo performance will be identified and/or developed. Dexamethasone and leuprolide acetate (drugs that are in commercial implant products) have been chosen as model drugs for pre-formed and in situ forming implants, respectively. A comprehensive understanding of current in vitro release methods, and of the effect of manufacturing differences on critical physicochemical properties and in vitro performance of both pre-formed and in situ forming implants will be obtained. This research will facilitate the development of bioequivalence recommendations for generic implant products, which will in turn help provide the public with safe and effective generic products at reduced cost and in a timely fashion.

Public Health Relevance

This proposal seeks to systematically evaluate current in vitro dissolution testing methods for parenteral sustained release implant products and to identify and/or develop the most appropriate, robust dissolution testing method(s) with the capability of detecting manufacturing differences and predicting in vivo performance. This will facilitate the development of bioequivalence recommendations for generic parenteral sustained release implant drug products and hence facilitate the development of generic implant products. Consequently, the regulatory burden will be reduced and human studies will be minimized without sacrificing product quality and safety.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Connecticut
Schools of Pharmacy
United States
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