Process Control of Drug Product Continuous Manufacturing Operations\u2014a Study in Operational Simplification and Continuous Improvement

Abstract

PurposeThe purpose of this manuscript is to demonstrate that implementation of gravimetric measurements provides the same assurance of product quality and process control as spectroscopic measurements (1) for control of drug content in a fixed-dose combination (FDC) tablet and (2) for identification of non-conforming material.MethodsA wet granulation continuous tableting line was used to make the FDC drug product batches. Comparative data was generated for ten batches using near-infrared (NIR) spectroscopy for core tablets, and gravimetric in-process control measurements (IPCs) applied to the ratio control of intra- and extra-granular blend (IG and EG). HPLC reference data were collected to further demonstrate uniformity at each stage of the production process, including IG, final blend, and core tablets. All possible sources of variation not directly detectable by the gravimetric measurements were considered and quantified.ResultsThe two IPC measurement techniques showed excellent agreement where both were within 2% of the target drug concentrations and within 2% of each other for the ten comparative batches. The NIR was more sensitive to material and process variations than the gravimetric IPCs; thus, it was more variable within and across batches. Gravimetric IPCs were demonstrated as an effective replacement for spectroscopic measurements for continuous tableting operations, capable of ensuring on target manufacturing and detection of non-conforming material.ConclusionsAs pharmaceutical companies continue to push toward operational simplicity and sustainable manufacturing processes, soft-sensor and gravimetric controls as alternatives to their spectroscopic counterparts will be applied more broadly for process monitoring and control.