In the past decades, in vitro-in vivo correlation (IVIVC) has been successfully used to allow biowaivers for extended release oral products. Therefore eliminating the need for bioequivalence studies for minor manufacturing changes and generic drug product applications. Until now, biowaivers have not been granted for complex parenteral dosage forms (e.g. microspheres). Microspheres are considered high risk products as they are designed to release drug over long periods of time and they have complex formulations and processing methodologies. Minor manufacturing changes have the potential to affect microsphere physicochemical characteristics, which in turn may affect their in vivo performance. In vitro release testing is an important tool for quality control purposes as well as to predict microsphere in vivo performance. Although there is no compendial in vitro release method available for microspheres, FDA has recommended using USP apparatus 4 and, if applicable, USP apparatus 2 (Paddle) or any other appropriate method for microspheres. A USP apparatus 4 method has been successfully developed by our group for in vitro release testing of microspheres containing a range of different small molecules as well as protein therapeutics. The discriminatory ability of this method has been demonstrated using different dexamethasone microsphere formulations. In addition, method validation (robustness, ruggedness, and reproducibility) has been performed using the commercial Risperdal(R) Consta(R) product. IVIVCs and in vitro-in vivo relationships (IVIVRs) have been reported for microsphere products. However, these studies did not involve formulations that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences. Building on our previously standardized in vitro release method for Risperdal(R) Consta(R), it is proposed to develop IVIVCs for Q1/Q2 equivalent formulations with different manufacturing processes. Two model drugs (risperidone and naltrexone) have been chosen since they are in commercially available microsphere products that will shortly come off patent. Accordingly, generic formulations of these products are expected to enter into the regulatory process. Developing IVIVC for two model compounds will allow a fundamental understanding of the physicochemical properties of the microsphere/drug system and its relationship with in vitro and in vivo performance. This research will facilitate the establishment of appropriate in vitro release methods, and will help advance the regulatory review and approval processes for both innovator and generic microspheres. Moreover, the approaches taken to establish IVIVCs may be modified for other microsphere products. The developed IVIVCs for Q1/Q2 equivalent formulations prepared using different manufacturing processes will pave the way for the future use of IVIVCs to allow biowaivers. These studies will help reduce the need for human studies and provide the public with safe and effective generic microsphere products at reduced cost in a timely fashion.

Public Health Relevance

This proposal seeks to develop appropriate in vitro performance testing methods for microspheres that will allow the correlation of the in vitro and in vivo release data. This will provide a fundamental understanding of these products and their performance and hence facilitate the development of generic microsphere 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 products to the public with minimal delay.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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University of Connecticut
Schools of Pharmacy
United States
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