Pauli, Victoria Isabell, Krumme, Markus and Kleinebudde, Peter (2020) From powder to tablets: Investigation of Residence Time Distributions in a Continuous Manufacturing Process Line as Basis for Continuous Process Verification. European journal of pharmaceutics and biopharmaceutics, 153. pp. 200-210. ISSN 09396411

Abstract

In Continuous Manufacturing (CM), process units are directly connected to each other forming a continuous process line. In combination with suitable on-line process analytical technologies, CM enables the dynamic manipulation of process parameters in response to the current observed process conditions and hence, facilitates real-time process control. However, 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 process 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. 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 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 material hold-up in the line. And 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.

Item Type:	Article
Date Deposited:	14 Jul 2020 00:45
Last Modified:	14 Jul 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41649