Preliminary Evaluation of Stability Data for Dolutegravir-Containing Triple Active Formulations Intended for PEPFAR. Degradation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide as the Limiting Factor.

FDA reviews applications that are filed under the PEPFAR program to ensure that these products are manufactured to FDA's stringent requirements. Dolutegravir is a comparatively recent molecular entity that represents an advance over previous products. The stability behaviors of tablets that contain dolutegravir, lamivudine, and tenofovir disoproxil fumarate and tablets that contain dolutegravir, emtricitabine and tenofovir alafenamide were surveyed and it was found that tenofovir-related degradants increase the most and are the parameters most likely to result in product failure. A desiccant is advantageous and this desiccant should remain in the bottle after it has been opened. In-use studies simulate consumer use. Bottles are stored at 30 °C/75% RH and opened for about 1 min a day. Water content increased significantly and the rate of degradation was faster than the degradation rate observed during long-term storage. The data predict that most formulations containing TDF will stay within specification over 4 years of long-term storage followed by dispensing one tablet per day. With the current data it appears that some TAF-containing formulations may fail under similar conditions. However, the data are limited and preliminary and it is possible that the situation may improve as more stability data are acquired.