Disadvantages of the traditional discontinuous batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent intensive, recovering solvent is necessary to achieve the goal of sustainable manufacturing. A simple vapor-liquid equilibrium (VLE) setup was designed and the reliability was assessed, from which the VLE data of a two-solvent system was obtained and, accordingly, the distillation columns were designed. The recovered solvent purities were > 99.9 wt% for the first solvent (Solvent 1) and > 99.8 wt% for the second solvent (Solvent 2), and the recovery yields were 94.9% and 98.3 %, respectively. From the E-factor analysis, there was approximately 30% less waste generated in the ICM process, compared to a corresponding batch process. After integrating the Solvent Recovery system, E-factors for both batch and ICM processes decreased significantly, from 1.63 to 0.29 and from 0.77 to 0.21, respectively.
Most drugs are still manufactured by time-intensive and cost-inefficient batch processes; however, the pharmaceutical industry is undergoing a transition to continuous processes to benefit from the reduced lead time, cost, and footprint and improved quality associated with this new methodology. Herein we report some key results of a fully automated end-to-end integrated continuous manufacturing (ICM) pilot plant, and describe the relevant E-factor analysis. The overall yields of the batch and ICM processes are 86.4%, and 88.0%, respectively. The solvent recovery yields for Solvents 1 and 2 are 95.8%, and 94.1% in batch, and are 98.3% and 94.9% in the ICM process. The E-factor value reduced significantly from 1.627 with batch to 0.770 with ICM (~ 53% reduction), and after integrating the Solvent Recovery unit operation it decreased from 0.292 for the batch process to 0.210 for ICM (~30% reduction). The application of a seamless, continuous ICM process could reduce waste generation and lower the E-factor, resulting in a positive outcome for our planet.
There is a tremendous opportunity to modernize the pharmaceutical manufacturing industry—relinquishing outdated machines that have been used for decades, and replacing them with state-of-the-art equipment that reflect contemporary advanced technologies. The implementation of continuous manufacturing, can positively impact our health care sector. Important benefits include the creation of manufacturing jobs in the United States, the establishment of capabilities and capacity to quickly produce drugs critical to U.S. citizens, the reduction of health care costs through efficient manufacturing, and access to better quality drugs through more sophisticated and reliable processes. The application of continuous manufacturing will enable the U.S. Government, in partnership with pharmaceutical companies, to address issues such as drug shortages, national emergencies, the Strategic National Stockpile, and the delivery of critical drugs to distant geographies. The article provides a detailed example of a critical aspect of continuous manufacturing: the ability to overcome technical challenges encountered by batch technologies.
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.