A Curious Case of Drug Substance Bulk Properties Affecting the Tablet Dissolution Profile for a Fixed Dose Combination Drug Product

To support the launch of the authorized generic of Harvoni, a fixed dose combination of ledipasvir (LDV) and sofosbuvir (SOF), two batches of generic drug product (DP) were manufactured by a process identical to that for Harvoni, but analytical testing resulted in one batch failing stage III LDV dissolution, while the second passed stage II LDV dissolution on the low end of acceptance. All other analytical results for both DP batches passed. To investigate this, several small-scale DP batches were manufactured internally using the same API lots as those in the generic DP tablets, and dissolution testing showed that the low mean percent dissolved for LDV was repeatable. While the batch of LDV in the generic DP had previously been successfully used to manufacture Harvoni, the batches of SOF had not. This suggested that the SOF drug substance (DS) may be related to the slower release of LDV. Therefore, the bulk properties (particle size, surface area, and flowability) of the SOF used in the generic DP were compared with historic SOF batches that had been previously formulated successfully. The resulting data showed that the SOF used in the generic DP had a significantly smaller particle size, larger surface area, and more cohesive flow than historic batches, suggesting that the cohesiveness of the SOF inhibited the dissolution of LDV in the combination product. As a result, an alternative SOF batch having bulk properties similar to historic lots was selected to support the manufacture of a validation batch that passed stage I dissolution, and the generic of Harvoni was eventually launched successfully.