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established and validated for the prepared microspheres based on the in vitro release data obtained using USP apparatus 4. These results indicated that the developed USP apparatus 4 method was capable of discriminating risperidone microspheres that are Q1/Q2 equivalent but with manufacturing differences and predicting their in vivo performance in the investigated rabbit model. It is noted that the developed IVIVCs for risperidone microspheres are based on animal data and may not be fully extrapolated to humans.


A Reproducible Accelerated In Vitro Release Testing Method For Microspheres


A study was also conducted to develop a discriminatory and reproducible accelerated in vitro release method for risperidone microspheres that are Q1/Q2 equivalent, but with different inner structures resulting from differences in manufacturing16


. Since real


time release testing of microspheres requires extended periods of time, it is beneficial to develop a reproducible accelerated release method, which can correlate with real time release, to provide fast quality assessment and facilitate product development. Two in vitro release methods (sample-and-separation and flow through) were investigated. The results indicated that both methods were able to differentiate risperidone microspheres with different porosities under real time (37°C) and accelerated (45°C) conditions. However, it is worth noting that only the USP apparatus 4 method under the accelerated condition showed good reproducibility for formulations that are highly porous. Therefore, the accelerated release method using USP apparatus 4 may be suitable as a fast quality control for PLGA microspheres (even with porous structures).


20 | | May/June 2016


A Protocol For Assay Of PLGA In Clinical Products


Determination of Q1 sameness of PLGA between the test and reference products can be challenging as the composition of the PLGAs used in clinical products are not readily available and very limited studies have been conducted focusing on establishing experimental methods for determining critical characteristics of PLGA. A study was conducted to develop and validate an analytical protocol to determine some key characteristics of PLGA used in commercial microspheres, such as molecular weight, monomer ratio (L:G), and polymer end-group[16]. Trelstar® (3.75 mg strength) and Risperdal® Consta® were chosen as model products. The calculated L:G ratios of the PLGA in Trelstar® and Risperdal® were found to be 52:48 and 78:22, respectively. It was also found that the PLGA from both Trelstar® and Risperdal® possessed ester end-caps. Additional studies are currently ongoing to identify critical characteristics of PLGA for assessment of Q1 sameness.


Conclusions


These research studies have furthered the understanding of in vitro and in vivo performance of PLA/PLGA-based drug products and how in vitro studies and modeling tools could be used in generic drug development and review. OGD plans to conduct additional research studies for PLA/PLGA-based drug products as understanding of these products evolves. The outcomes from these studies may be used for developing new approaches to demonstrate bioequivalence for these products in the future.


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