Mo Jiang

Mathematical modeling and optimal design of multi-stage slug-flow crystallization

Abstract Inspired from experimental progress in continuous crystallizer designs based on air/liquid slug flow that generate crystals of target sizes at high production rates and low capital costs (e.g., Eder et al., 2010; 2011; Jiang et al., 2014; 2015; and citations therein), a mathematical model and procedure are derived for the design of slug-flow crystallizers with spatially varying temperature profiles. The method of moments is applied to a population balance model for the crystals, to track the spatial variation of characteristics of the crystal size distribution along the crystallizer length. Design variables for the cooling slug-flow crystallizer such as tubing lengths and types and numbers of heat exchangers are analyzed and optimized for product crystal quality (e.g., minimized secondary nucleation and impurity incorporation) and experimental equipment costs, while ensuring high yield. This study provides guidance to engineers in the design of slug-flow crystallizers including their associated heat exchanger systems.

Opportunities and challenges of real-time release testing in biopharmaceutical manufacturing

Real‐time release testing (RTRT) is defined as “the ability to evaluate and ensure the quality of in‐process and/or final drug product based on process data, which typically includes a valid combination of measured material attributes and process controls” (ICH Q8[R2]). This article discusses sensors (process analytical technology, PAT) and control strategies that enable RTRT for the spectrum of critical quality attributes (CQAs) in biopharmaceutical manufacturing. Case studies from the small‐molecule and biologic pharmaceutical industry are described to demonstrate how RTRT can be facilitated by integrated manufacturing and multivariable control strategies to ensure the quality of products. RTRT can enable increased assurance of product safety, efficacy, and quality—with improved productivity including faster release and potentially decreased costs—all of which improve the value to patients. To implement a complete RTRT solution, biologic drug manufacturers need to consider the special attributes of their industry, particularly sterility and the measurement of viral and microbial contamination. Continued advances in on‐line and in‐line sensor technologies are key for the biopharmaceutical manufacturing industry to achieve the potential of RTRT.

Challenges and opportunities in biopharmaceutical manufacturing control

Abstract This article provides a perspective on control and operations for biopharmaceutical manufacturing. Challenges and opportunities are described for (1) microscale technologies for high-speed continuous processing, (2) plug-and-play modular unit operations with integrated monitoring and control systems, (3) dynamic modeling of unit operations and entire biopharmaceutical manufacturing plants to support process development and plant-wide control, and (4) model-based control technologies for optimizing startup, changeover, and shutdown. A challenge is the ability to simultaneously address the uncertainties, nonlinearities, time delays, non-minimum phase behavior, constraints, spatial distributions, and mixed continuous-discrete operations that arise in biopharmaceutical operations. The design of adaptive and hybrid control strategies is discussed. Process data analytics and grey-box modeling methods are needed to deal with the heterogeneity and tensorial dimensionality of biopharmaceutical data. Novel bioseparations as discussed as a potential cost-effective unit operation, with a discussion of challenges for the widespread application of crystallization to therapeutic proteins.