De-risking Scale-up of a High Shear Wet Granulation Process Using Latent Variable Modeling and Near-Infrared Spectroscopy

In the development of wet granulated drug products, two primary sources of variance (disturbance) include the operational scale of the high shear wet granulation (HSWG) process and active pharmaceutical ingredient (API) lot-to-lot variability, particularly for formulations containing a high drug load. This paper presents a novel Process Analytical Technology strategy using latent variable modeling with near-infrared spectroscopy (NIRS) to reduce risk in scale-up operations of the HSWG process while simultaneously accounting for API lot-to-lot variability, even with limited manufacturing history. The process involves building a partial least square (PLS) model among the API material properties, the HSWG process parameters, and the NIRS end points of the HSWG process based on small-scale design of experiment batches. The PLS model is then used in an optimization framework to find suitable small-scale mechanical process parameters (impeller/chopper speed) that approximate a previous large-scale operation so as to keep the NIRS end point of large-scale operation constant. Prior to making additional large-scale batches with a new lot of API, NIRS end points of large-scale HSWG with the new API lot are predicted based on the PLS model developed from the small-scale operation. If the predicted NIRS end point for the HSWG using the new API lot is not within the target region, the risks associated with the scale-up operation can then be significantly reduced by modifying other HSWG process parameters such as the total amount of water added or total granulation time to achieve the target region. A case study is presented that demonstrates the effectiveness of this methodology during development and scale-up of a drug product manufactured using a HSWG process.