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To date, the Offi ce of Generic Drugs (OGD) has posted seven product specifi c recommendations for microsphere products to provide guidance on bioequivalence study design. OGD is working to develop recommendations for other PLA/PLGA-based drug pro- ducts. Compared to the bioequivalence studies of conventional dosage forms, bioequivalence studies on microspheres are more complicated. Microspheres may have multi-phasic release profi les both in vitro and in vivo, which warrant a carefully designed bioequivalence study to capture signifi cant diff erences in product performance during each phase.

Currently, no PLA/PLGA-based generic drug products have been approved. This can be attributed to several factors. Adequate char- acterization of PLA/PLGA needs to be submitted in an ANDA, which may sometimes be challenging. Compendial methods of in vitro release testing of PLA/PLGA-based products are lacking. In addition, the clinical study (i.e., clinical endpoint or pharmacokinetic bioequivalence study) may be a challenge to perform. Recognizing these challenges associated with development of generic PLA/PLGA- based drug products, a regulatory science research program was established under the Generic Drug User Fee Amendments (GDUFA) and is being implemented by OGD to provide new tools for ANDA review and support generic product development.1

GDUFA Regulatory Science Program

Since the enactment of GDUFA in July 2012, OGD has awarded grants and contracts for multiple research projects involving PLA/PLGA- based drug products in various dosage forms, such as microspheres,

implants, and in situ gelling systems. Broadly, these projects can be categorized into four areas: (1) development of in vitro-in vivo correlations (IVIVC), (2) development of in vitro release testing (IVRT) methods, (3) characterization of PLA/PLGA, and (4) modeling and simulation of PLA/PLGA-based drug products (Table 2).

IVIVC of Risperidone Microspheres

It is challenging to develop a reproducible and discriminatory in vitro release method for microspheres, and it is even more challenging to develop an IVIVC for these products. A Level A IVIVC may allow an in vitro release method to be used as a surrogate for bioequivalence studies if any changes occur in formulation and/or manufacturing process post approval. Microspheres often have multiphasic in vitro release and in vivo PK profi les, which makes the deconvolution of in vivo data and correlation with in vitro data very challenging. In addition, the lack of compendial in vitro release testing methods also hinders development of an IVIVC for microspheres.

A study was conducted to explore the possibility of developing an IVIVC for risperidone microspheres that are equivalent in formulation composition but prepared with diff erent manufacturing processes.14 The physicochemical properties of the microspheres were sensitive to minor manufacturing changes, such as solvent systems. Two in vitro release methods (sample-and-separation and USP apparatus 4) were investigated. Compared with the sample-and-separate method, the USP apparatus 4 method showed better discriminatory power for diff erentiating release profi les of compositionally equivalent microspheres with manufacturing diff erences. Level A IVIVCs were

Table 2. Research projects involving PLA/PLGA-based drug products Research category Development of IVIVC Project title In vitro-in vivo correlations of parenteral microsphere drug products In vitro-in vivo correlations of parenteral microsphere drug products In vitro-in vivo correlations of ocular implants Development of IVRT methods Dissolution methods for parenteral sustained release implant drug products Development of hydrogel-based in vitro dissolution apparatus for microparticle formulations A biorelevant dissolution methods for particulate dosage forms in the periodontal pocket

Characterization of PLA/PLGA Infl uence of raw materials, manufacturing variables, and storage conditions on release performance of LAI (long-acting injectable) microsphere products

Modeling and simulation of PLA/ PLGA-based LAI drug products

Computational drug delivery: leveraging predictive models to develop bioequivalent generic LAI products Development of PBPK simulation for long-acting injectable microspheres

Data-fusion based platform development of population PKPD modeling and statistical analysis for bioequivalence assessment of long-acting injectable products

Pharmacometric modeling and simulation for evaluation of bioequivalence for leuprolide acetate injection Awardee University of Connecticut University of Michigan University of Colorado University of Connecticut Akina, Inc.

Magee-Womens Research Institute & Foundation

University of Michigan Qrono, Inc. Simulations Plus

University of Massachusetts Lowell

University of Utah Year started 2013 2013 2013 2014 2014 2015 2015 2015 2015 2015 2015

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