(442c) Determining the Dissolution Profile of Tablets from Continuous Pharmaceutical Manufacturing Process By Employing Non-Destructive Analytical Spectroscopic Methods

In 2004, the FDA released guidance for the industry introducing process analytical technology (PAT) and the concept of real-time release testing (RTRt). As defined by ICH Q8 [1], real-time release testing (RTRt) is the capability to assess and ensure the quality of a drug product during manufacturing, using process data that usually comprises appropriate combinations of measured material attributes and process controls.

The dissolution profile of tablets is a critical quality attribute (CQA) in pharmaceutical development and manufacturing, which needs to be properly monitored and controlled. To ensure effective RTRt and process control, any oral solid dosage application should tackle this concern, as tablet dissolution measurement through wet chemistry is time-consuming and unsuitable for RTRt.

This study aims to develop a model based on process analytical technology (PAT) measurements, process parameters, and the amount of controlled-release polymer to predict the dissolution profile of individual tablets produced in a direct compaction continuous line. The model uses partial least squares (PLS) regression and spectral preprocessing, and its performance is compared to traditional dissolution testing methods. A design of experiments (DoE) was explored to investigate the effect of blender speed, throughput, compression force, and release-controlling excipient and (active pharmaceutical ingredient) API concentrations on the dissolution profile of tablets.

The results were used to create a dissolution soft-sensor model capable of predicting tablet dissolution as a function of the measurable inputs. This model can subsequently be employed to determine, in real-time, whether tablets meet or fail to meet dissolution specifications and devise a diversion strategy for non-compliant products. This strategy can be used to implement real-time quality control of the final product.

References

[1] ICH, Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers (Nov. 11, 2010), www.ich.org.

[2] Pawar, P., Wang, Y., Keyvan, G., Callegari, G., Cuitino, A. and Muzzio, F., 2016. Enabling real-time release testing by NIR prediction of dissolution of tablets made by continuous direct compression (CDC). International journal of pharmaceutics, 512(1), pp.96-107.

[3] Andrés D. Román-Ospino, Ravendra Singh, Marianthi Ierapetritou, Rohit Ramachandran, Rafael Méndez, Carlos Ortega-Zuñiga, Fernando J. Muzzio, Rodolfo J. Romañach, Near-infrared spectroscopic calibration models for real-time monitoring of powder density, International Journal of Pharmaceutics, Volume 512, Issue 1,2016, Pages 61-74,