(T0930-06-35) Automated Adaptive Perfusion: A Novel In Vitro Drug Release Testing System for Complex Drug Products

Purpose: Drug release testing is critical for evaluating the product quality of drugs. An ideal in vitro drug release test (IVRT) should be discriminatory enough to detect the effect of changes in the manufacturing process and or variations in product quality on drug release. However, it may be challenging from an analytical perspective to test the drug release of complex drug products containing particulates. Often, a semi-permeable membrane such as dialysis membrane is needed to retain the particles while allowing the released drug to diffuse across the membrane. Yet, the process of diffusion highly depends on the drug concentration gradient and may become rate-limiting step if the rate of drug release from particles approaches or becomes faster than the rate of diffusion across the membrane. Recently, a novel IVRT method using adaptive perfusion (AP) has been successfully developed which overcome the limitation of measuring drug release through diffusion¹. The objective of the current work is to develop a fully automated IVRT method based on AP method.

Methods: The new IVRT method based on AP employs the principle of tangential flow filtration (TFF) and uses size-based separation of particulates. It can simultaneously measure the amount of drug released and the amount of drug remaining in particulates. In this study, a system control program was developed using LabVIEW to achieve the automation of the AP method. The automated system was validated by testing several difluprednate emulsion formulations with different globule size distribution (GSD) which were manufactured via different processes. The result generated with the new method was compared with the results obtained with previous AP method.

Results: The drug release profile obtained using the new automated AP method was found to have similar results (e.g., releasing rate and releasing extent) compared with results from the previous AP method. The customized LabVIEW control system (National Instruments, TX, U.S.) maintained constant retentate volume with high precision and accuracy through a feedback control algorithm. The automation function also led to less experimental time (8% less) and significantly simplified steps (72% less) compared with the previous manual AP method.

Conclusion: The automated AP system simplified the operational procedures, reduced the personnel burden and offers more reliable control mechanism compared to the previously reported AP method. Notably, the new automated AP improves the operation of AP, which paves the way for routine use of the AP method for IVRT studies of complex formulations. The automated AP method
may be used to support bioequivalence and product quality assessment of generic drugs and facilitate new drug product development by giving a deeper insight into drug release of complex formulations.

References: 1. Patel D, Zhang Y, Dong Y, Qu H, Kozak D, Ashraf M, Xu X. Adaptive perfusion: An in vitro release test (IVRT) for complex drug products. Journal of Controlled Release. 2021 May 10;333:65-75.

Acknowledgements: This work was supported in part by the U.S. FDA Critical Path funding. DZ and YZ were support in part by a fellowship from the Oak Ridge Institute of Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. FDA.

Disclaimer: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1. (a) User interface of the automated AP system. (b) Setup of the automated AP system.