The US healthcare system is facing unprecedented challenges with unaffordable drug prices and shortages of critical small-molecule drugs. More than 60% of these shortages are due to quality issues, most of which stem from the ‘step-by-step, batch’ manufacturing process that pervades the industry. As a paradigm-shifting approach, we report here a fully automated, end-to-end, integrated continuous manufacturing (ICM) process for a small-molecule generic medication with built-in quality assurance. The entire ICM process has a 30.7 m2 modular footprint and a total residence time of < 24 h, with a throughput up to 4,800 tablets/h, or 40.3 × 106 tablets/year. The commercialization of this innovative ICM process will lead to a more efficient and sustainable manufacturing sector, and could significantly improve the affordability and accessibility of pharmaceuticals on a global scale.
We make the case for why continuous pharmaceutical manufacturing is essential, what the barriers are, and how to overcome them. To overcome them, government action is needed in terms of tax incentives or regulatory incentives that affect time.
Forms I-III and dihydrate carbamazepine (CBZ) were prepared and confirmed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Influences of supersaturation (σ), stirring, anti-solvent (H2O), and polymer type on the resultant polymorph are discussed. For a CBZ ethanol solution at 5 ºC, more than 10 h was required to form crystals when σ was 0.5, while less than 2s was required when σ was increased to 9.0. Very fine needle-shaped Form II crystals were obtained when σ ≥ 7.5. Higher stirring rates facilitated the formation of Form III CBZ. Continuous heterogeneous crystallization of Form III on Polyvinyl alcohol (PVA, MW 89,000-98,000) was achieved in a one-stage mixed suspension mixed product removal (MSMPR) crystallizer at 15 ºC and 300 rpm. At 5 ºC and 40 rpm, only Form II crystals were obtained. However, Form II CBZ gradually transformed to Form III within 2 residence times, and the transition process was irreversible.
An automated multi-stage continuous reaction system with in-line PATs for a high viscosity reactive crystallization process was developed in the present study. Data acquisition hardware and Labview software were used as the local control system. A “forward-backward” burst pumping strategy was developed to smoothly transfer the highly viscous hot slurry from one vessel to the next. In addition, a comparative analysis between a plug flow reactor (PFR) and continuous stirred-tank reactors (CSTRs) in series revealed that to achieve the same conversion, the latter would require more volume than the former, but less than a single CSTR. For a second-order reaction, the value of the Damköhler number necessary to achieve conversion of 90.0% in a single CSTR is 90. It is reasonable to approximate a PFR using CSTRs in series to obtain a high yield with a smaller reaction volume (compared with a single CSTR). As the probes could not be positioned in the hot slurry due to fouling issues, in-line focused beam reflectance measurement and React IR were used to monitor the crystal size and reactant concentration in the vessel containing the cold slurry. E-factors of batch and continuous processes were also compared and the continuous reaction could obtain a lower E-factor because less waste was generated.
An automated continuous clarification bypass system was developed to remove the suspended particulate matter (SPM) in the prereaction material. Compared to commercially available duty/standby filters, the proposed clarification bypass system is able to self-clean and does not require detachment of the filter and manual cleaning. In a stainless steel (SS) filter, the effects of flow direction, ultrasonication, and viscosity were investigated. The data showed that the filtration performance could not meet the requirement of high clarification efficiency because of the high switch frequency. The deposition of crystals on the SS filter medium, and not the SPM, was the primary cause of the pressure build-up. Experiments with PTFE filter elements with comparable pore size and surface area to the stainless-steel filter were performed, and improved filtration performance was observed. At the beginning of the SPM filtration process with the PTFE filter elements, three filtration mechanisms occurred. As the filtration cake formed on the filter element surface, straining gradually dominated the filtration process, while the effects of impingement and entanglement became negligible.
Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academia, industry, and regulatory agencies, are the optimal solution for ensuring a solid future for this promising manufacturing technology.