2025 AIChE Annual Meeting

(41b) Development and Implementation of a Continuous Manufacturing Process for a Complex Modified Release Formulation

Authors

Ricardo Sousa - Presenter, R&D Drug Product Development
Bereket Yohannes, Rutgers, the State University of New Jersey
Rodrigo Osawa, Hovione Farmaciencia S.A.
Susana Ramos, Hovione Farmaciencia S.A.
Joao Saccas, Hovione
João Henriques, Hovione FarmaCiência SA
Huolong Liu, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Wenli Li, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Syed Shahriyar, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Weixian Shi, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Ashish Soman, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Irfan Mohammed, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
Justin Burt, Alexion, AstraZeneca Rare Disease, New Haven, CT, USA
This presentation will discuss detailed results and challenges encountered during the entire CDC development activity, highlighting the valuable learnings in implementation of a continuous manufacturing process for a complex modified release formulation Continuous direct compression (CDC) has emerged as a promising approach for pharmaceutical manufacturing, offering improved process efficiency and control. Building upon initial laboratory development, this study presents the scale-up and implementation of a high drug loading, modified release formulation in a CDC-10® line. The main objectives were to develop a control strategy for content uniformity of API and polymers, along with robust process parameters for loss in weight feeders, linear blenders, and the rotary tablet press.

Hold-up mass in the blenders was measured at different rotational speeds to establish the optimal setup. The residence time distribution (RTD) for each unit operation was developed using step changes in the feeders and spike studies. RTD parameters were calibrated based on near-infrared (NIR) predictions for blend and content uniformity. For these modified release tablets, NIR models were developed for both the active ingredient and the release-rate controlling polymer.

NIR-based prediction models were initially developed offline in a lab setup mimicking the tablet press' feed frame. Over 1000 NIR spectra with variables such as lots of excipient and API , water content, and blending process parameters, were collected for NIR model development to quantify blend uniformity A DRLS probe (Sentronic), which is the same as the one used in lab, was installed in the CDC-10® line feed frame for real-time blend uniformity monitoring. Additionally, a Bruker multi-purpose analyzer (MPA-II®) was used to develop an NIR tablet content uniformity model. During initial CDC process development stages, tablet samples were collected at high frequency for HPLC testing to further confirm NIR models predictions.

RTD models were represented by two continuously stirred tanks (CSTR) and a plug flow reactor. Model parameters were calibrated using the NIR models predictions with minimal error values. NIR and RTD predictions for content uniformity were confirmed by HPLC test results.

A one-hour technical batch was run to demonstrate process and formulation robustness and evaluate the accuracy of the NIR and RTD models. The manufactured tablets were within specification for content uniformity, defect-free, and exhibited a dissolution profile matching that of lab-developed prototypes.

In conclusion, an acceptable CDC process was developped for the modified release tablet despite the numerous challenges encoutered. The control strategy, while it still needs further tuning, can deliver acceptable process and product performance, signifying the importance of comprehensive benchmarking of formulation, process, and PAT tools.