Key strategic considerations for pooling multiple drug substance batches in biopharmaceutical drug product...

The manufacture of a single biopharmaceutical drug product (DP) batch often requires drug substance (DS) from multiple DS batches. A DS pooling strategy provides operational flexibility, optimizes inventory utilization, and enables production of DP batches of varying sizes to meet fluctuating clinical and commercial demand. This article examines key considerations for designing and implementing an effective DS pooling strategy. These aspects are related to DS, DP, validation of DS pooling, pre- and post-pool DP stability assessment, regulatory considerations, approval and feedback, batch traceability, the timing of introducing a DS pooling strategy, age of DS batches at the time of pooling, pooling multiple containers from a single DS batch vs. multiple DS batches, number of DP batches from pooled and non-pooled DS, and post-validation (or post-approval) implementation of the DS pooling strategy. Only DS batches that have been successfully released (i.e., meet DS release specifications) should be used for pooling. During DP manufacture using pooled DS, it is important to ensure homogeneity of the pooled material through appropriate mixing techniques and in-process controls (IPCs) or in-process monitoring (IPM) at least until the DP manufacturing process is validated. Before implementing DS pooling for commercial manufacturing, the authors recommend validating this approach by manufacturing at least one process performance qualification (PPQ) DP batch using pooled DS. Manufacturers are expected to demonstrate that DS pooling does not adversely affect the DP stability trajectory. Although no regulatory guidelines explicitly address DS pooling or its implementation requirements, this review summarizes relevant regulatory principles and published regulatory feedback on some aspects of DS pooling for the benefit of manufacturers and readers. Overall, this article aims to support the design and implementation of a scientifically sound DS pooling strategy.