The Food and Drug Administration (FDA) regulates pharmaceutical drug products to ensure a continuous supply of high-quality drugs in the USA. Continuous processing has a great deal of potential to address issues of agility, flexibility, cost, and robustness in the development of pharmaceutical manufacturing processes. Over the past decade, there have been significant advancements in science and engineering to support the implementation of continuous pharmaceutical manufacturing. These investments along with the adoption of the quality-by-design (QbD) paradigm for pharmaceutical development and the advancement of process analytical technology (PAT) for designing, analyzing, and controlling manufacturing have progressed the scientific and regulatory readiness for continuous manufacturing. The FDA supports the implementation of continuous manufacturing using science-and risk-based approaches.

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built an automated two-stage mixed suspension mixed product removal (MSMPR) crystallization platform for a model compound (carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes the integration of PAT tools (online Raman microscopy and focused beam reflectance microscopy, FBRM) for real-time monitoring. A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).

Modular assembly line: a promising approach to reduce drug shortages, assure quality, and improve affordability.

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The pharmaceutical industry faces multiple challenges (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities) because of its current batch-wise approach to manufacturing. Recent regulatory support for continuous manufacturing and advances in continuous process technologies have caused an increase in interest from some drug manufacturers to modernize their production processes. However, many of these companies have focused on hybrid processes, where only certain steps are continuous, while others remain batch. Herein, the quality by design (QbD)-based design strategy and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant that produces both small-molecule active pharmaceutical ingredient (API) and oral solid dosages (OSDs) are discussed. Additionally, important quality and economic matters pertaining to scale-up and commercialization are addressed. ICM has significant benefits, including better quality control, increased supply chain flexibility, a lower capital investment (in the example provided, a ∼ 90% reduction), and lower operating costs (in the example provided, a 33.6% reduction for API and 29.4% reduction for tablets).

The continuous reactive crystallization of an active pharmaceutical ingredient (API) in a plug flow reactor (PFR)-continuous stirred tank reactor (CSTR) cascade system with in-line PATs was developed and investigated. Residence...

Encrustation is a risk factor that can cause product and process failure in continuous crystallization processes. Mitigation, prevention, and control of encrustation have been extensively researched. Various risk mitigation strategies proposed in the literature, such as coating of crystallizer walls, use of additives to control encrustation kinetics, and periodic steady-state operation show promising results in delaying or preventing encrustation. Because of the increased interest in the use of continuous crystallization in industrial applications, it is important to understand this risk factor further. This review presents recent developments on dynamic models, mechanisms, and risk factors for encrustation in continuous crystallization processes. Various design and control strategies to mitigate the encrustation risk are also summarized. Appropriate control strategies should be implemented during continuous crystallization to avoid the impact of encrustation on drug substance quality.

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