From powder to tablets: Investigation of residence time distributions in a continuous manufacturing process train as basis for continuous process verification.

The essence of Continuous Manufacturing (CM) resides in the fact that continuous process units are directly connected to each other forming a continuous process train. The thorough understanding of material flow in this train based on suitable sensors, including on-line process analytical technologies and other sensors, is key in understanding the time-domain behavior of the system and the process. This real-time monitoring correlated with the time domain material flow behavior could be used to close control-loops. In practical terms, the implementation of such a control strategy is only feasible, if the overlying control system knows precisely what material is when and where at all times. Consequently, thorough knowledge of the residence time distribution (RTD) of the material throughout the whole manufacturing network needs to be established early on in development. Once RTD is well understood, its constant observation could also be used for continuous process verification purposes hinging on the argument that the flow pattern of the material is unchanged. As continuous processes that run over extended periods of time are susceptible to unforeseen incidents like equipment wear-out or clogging, drifts or shifts in RTD could indicate such issues early on. The presented work aims to demonstrate this proposed concept for an integrated wet-granulation CM process. To achieve this aim, three steps were completed: First, thorough RTD knowledge was generated, by inducing endogenous step-tests in active pharmaceutical ingredient (API) content in the range of ±30% at varying process conditions, and analyzing the material RTDs via NIRS analysis at four different locations in the line. Second, it was demonstrated that also low-level step tests of ±5% and even ±3% are sufficient for accurate RTD determination. This validated the possibility of continuous RTD assessment during (pre-)validation trials or even commercial manufacturing, as the drug product would comply with required quality characteristics (content uniformity, assay). In the third step, it was then demonstrated that recurring low-level step testing during routine manufacturing could be used as a way to determine the current system health, as observed changes in RTD indicated blockages and accidental material hold-up in the line. While deliberate changes in API content during commercial production might seem counter intuitive, they would actually aid in ensuring the production of quality product in a better way, than running at constant process settings over an extended period of time without the constant assessment of system health.