Development of Near Infrared Spectroscopy-based Process Monitoring Methodology for Pharmaceutical Continuous Manufacturing Using an Offline Calibration Approach.

A near-infrared (NIR) calibration was developed using an efficient offline approach to enable a quantitative partial least-squares (PLS) chemometric model to measure and monitor the concentration of active pharmaceutical ingredients (API) in powder blends in the feed frame (FF) of a tablet press. The approach leveraged an offline "feed frame table," which was designed to mimic the full process from a NIR measurement perspective, thereby facilitating a more robust model by allowing more sources of variability to be included in the calibration by minimizing the consumption of API and other raw materials. The design of experiment (DOE) for the calibration was established by an initial risk assessment and included anticipated variability from factors related to formulation, process, environment, and instrumentation. A test set collected on the feed frame table was used to refine the PLS model. Additional fully independent test sets collected from the continuous drug product manufacturing process not only demonstrated the accuracy and precision of the model but also illustrated its robustness to material variability and process variability including mass flow rate and feed frame paddle speed. Further, it demonstrated that a calibration can be generated on the offline feed frame table and then successfully implemented on the full process equipment in a robust manner. Additional benefits of using the feed frame table include streamline model monitoring and maintenance activities in a manufacturing setting. The real-time monitoring enabled by this offline calibration approach can be useful as a key component of the control strategy for continuous manufacturing processes for drug products, including detecting special cause variations such as transient disturbances and enabling product collection/rejection based upon predetermined concentration limits, and may play an important role in enabling real-time release testing (RTRt) for manufactured pharmaceutical products.

A systematic approach to development of liquid chromatographic impurity methods for pharmaceutical analysis.

A strategy for developing chromatographic methods designed to determine impurities and degradation products in active pharmaceutical ingredients and drug products is presented. Selectivity is achieved by evaluating a chromatographic space comprised of 12 stationary/mobile phase combinations. Stationary phases predicted to be orthogonal based on their hydrophobic subtraction model parameters used. The particle sizes, column dimensions, and gradient times chosen provide high peak capacities and allow operation at backpressures that can be achieved with standard instrumentation. The mobile phases utilized are compatible with MS detection and cover a wide range of pH, solvent strength, and solvent selectivity. Analyte detection is accomplished using a combination of diode array and mass spectroscopic detectors which allow mixtures of project compounds to be injected and selectively detected. Automation of data acquisition and processing is accomplished using AutoChrom software from ACD\Labs. The strategy is illustrated with detailed data from two case studies and summary data from nineteen pharmaceutical projects.

A simple and efficient approach to reversed-phase HPLC method screening.

The development and utility of an efficient HPLC method screening strategy using only four columns for the separation of pharmaceutical compounds and related impurities is presented. The strategy established a two-column approach to enable rapid early method development, along with a four-column approach for commercial method development of the analytical methods utilized to verify the quality of drug substance or drug product. Mobile phases consisted of acetonitrile or methanol with aqueous trifluoroacetic acid for low pH screening, and ammonium hydroxide for high pH screening. Examples are provided to demonstrate the practicality and orthogonality of the method screening process. A unique system suitability check, using commercially available compounds, was incorporated as a tool for troubleshooting and for ensuring adequate system performance prior to screening. Initial testing of the strategy revealed that the columns chosen were successful in leading to assay and impurity methods for 40 pharmaceutical compounds.