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. 2019 Jun 9:125:216-231.
doi: 10.1016/j.compchemeng.2019.03.001.

A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing

Qinglin Su  1 , Sudarshan Ganesh  1 , Mariana Moreno  1 , Yasasvi Bommireddy  2 , Marcial Gonzalez  2   3 , Gintaras V Reklaitis  1 , Zoltan K Nagy  1
Affiliations

A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing

Qinglin Su et al. Comput Chem Eng. .

Abstract

The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD implementation. This advance has since been evolving into the concept of Quality-by-Control (QbC). In this study, the concept of QbC is discussed, including a definition of QbC, a review of the recent developments towards the QbC, and a perspective on the challenges of QbC implementation in continuous manufacturing. The QbC concept is demonstrated using a rotary tablet press, integrated into a pilot scale continuous direct compaction process. The results conclusively showed that active process control, based on product and process knowledge and advanced model-based techniques, including data reconciliation, model predictive control (MPC), and risk analysis, is indispensable to comprehensive QbC implementation, and ensures robustness and efficiency.

Keywords: Pharmaceutical continuous manufacturing; Process automation; Process control; Quality-by-Control; Quality-by-Design; Systems integration.

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Figures

Fig. 1.
Fig. 1.
The systematic progression in quality assurance via QbT, QbD, and QbC.
Fig. 2.
Fig. 2.
A systematic framework for fault-tolerant process control design & risk analysis.
Fig. 3.
Fig. 3.
A hierarchical implementation of control systems for a continuous direct compaction process.
Fig. 4.
Fig. 4.
Major steps in Natoli BLP-16 rotary tablet press.
Fig. 5.
Fig. 5.
Network setup in continuous tablet manufacturing pilot plant at Purdue University.
Fig. 6.
Fig. 6.
Tablet weight measurement real-time monitoring and control.
Fig. 7.
Fig. 7.
Data reconciliation with Level 0 control experiment with at-line Sotax AT4 sampling.
Fig. 8.
Fig. 8.
The hierarchical Level 1 PID (top) and Level 2 MPC (bottom) control for continuous tablet press at DeltaV DCS system.
Fig. 9.
Fig. 9.
Online integrated data reconciliation and process control of Level 1 and 2 for continuous tablet press.
Fig. 10.
Fig. 10.
Risk assessment for three level control designs (top: Level 0 control only; center: Level 1 control; bottom: Level 2 control).
Fig. 11.
Fig. 11.
Continuous improvement in QbC system in pharmaceutical continuous manufacturing.
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