Application of ICH Q9 Quality Risk Management Tools for Advanced Development of Hot Melt Coated Multiparticulate Systems.

This study aimed to apply quality risk management based on the The International Conference on Harmonisation guideline Q9 for the early development stage of hot melt coated multiparticulate systems for oral administration. N-acetylcysteine crystals were coated with a formulation composing tripalmitin and polysorbate 65. The critical quality attributes (CQAs) were initially prioritized using failure mode and effects analysis. The CQAs of the coated material were defined as particle size, taste-masking efficiency, and immediate release profile. The hot melt coated process was characterized via a flowchart, based on the identified potential critical process parameters (CPPs) and their impact on the CQAs. These CPPs were prioritized using a process failure mode, effects, and criticality analysis and their critical impact on the CQAs was experimentally confirmed using a statistical design of experiments. Spray rate, atomization air pressure, and air flow rate were identified as CPPs. Coating amount and content of polysorbate 65 in the coating formulation were identified as critical material attributes. A hazard and critical control points analysis was applied to define control strategies at the critical process points. A fault tree analysis evaluated causes for potential process failures. We successfully demonstrated that a standardized quality risk management approach optimizes the product development sustainability and supports the regulatory aspects.

Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer.

The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.

Use of mechanistic simulations as a quantitative risk-ranking tool within the quality by design framework.

The purpose of this study is to evaluate the use of computer simulations for generating quantitative knowledge as a basis for risk ranking and mechanistic process understanding, as required by ICH Q9 on quality risk management systems. In this specific publication, the main focus is the demonstration of a risk assessment workflow, including a computer simulation for the generation of mechanistic understanding of active tablet coating in a pan coater. Process parameter screening studies are statistically planned under consideration of impacts on a potentially critical quality attribute, i.e., coating mass uniformity. Based on computer simulation data the process failure mode and effects analysis of the risk factors is performed. This results in a quantitative criticality assessment of process parameters and the risk priority evaluation of failure modes. The factor for a quantitative reassessment of the criticality and risk priority is the coefficient of variation, which represents the coating mass uniformity. The major conclusion drawn from this work is a successful demonstration of the integration of computer simulation in the risk management workflow leading to an objective and quantitative risk assessment.

Monitoring mammalian cell cultivations for monoclonal antibody production using near-infrared spectroscopy.

Near-infrared (NIR) spectroscopy as a process monitoring and process supervision technique is reviewed in the context of biomanufacturing.An industrial pilot-plant mammalian cell cultivation process has been chosen to illustrate the use of on-line in-situ NIR monitoring by means of an immersion transflectance NIR probe.NIR calibration development must be performed carefully and should incorporate a number of steps to obtain a properly validated model which exhibits long-term robustness and is independent of process scale. A description of such good modelling practises is given. In general, NIR can be as accurate as the reference methods employed and at least as precise provided that sufficient spectral selectivity and sensitivity exists.NIR can also be used as a direct technique for very fast process monitoring and process supervision, thus enabling one to follow the trajectory of a process. This alternative to the indirect use of NIR through laborious calibration development with direct reference methods has been little explored. Since NIR is sensitive to both chemical and physical properties, the analysis of whole samples enables relevant process information to be captured and thus generates better process state estimates than by simply looking at defined process parameters one at a time.