Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Process alternatives for continuous crystallization, i.e., cascades of mixed suspension, mixed product removal crystallizers (MSMPRCs) and plug flow crystallizers (PFCs), as well as batch crystallizers are discussed and modeled using population balance equations. The attainable region approach that has previously been used in the design of chemical reactor networks and separation systems is applied to the above-mentioned alternatives for crystallization processes in order to identify attainable regions in a diagram of mean product particle size vs. total process residence time. It is demonstrated that the boundaries of these attainable regions can be found numerically by solving appropriate optimization problems and that the region enclosed by these boundaries is fully accessible. Knowing the attainable region of particle sizes, it is possible to generate feasible process alternatives that allow specific particle sizes to be obtained in a given process configuration. The attainable regions presented in this article are useful to determine whether a desired mean particle size can be achieved in a specific crystallizer type. The concept of the attainable region is illustrated on three case studies: the cooling crystallization of paracetamol grown from ethanol, the anti-solvent crystallization of L-asparagine monohydrate from water using isopropanol as the anti-solvent and the combined cooling/anti-solvent crystallization of aspirin from ethanol using water as the anti-solvent.

in Wiley Online Library (wileyonlinelibrary.com) Providing enantiomerically pure products is of key importance in the fine chemicals, food, and pharmaceutical industries. A continuous preferential crystallization process is presented that allows the separation of conglomerate forming enantiomers in a stable, robust, and flexible way. This is achieved by coupling two continuous crystallizers by exchanging their clear liquid phases. Each crystallizer is connected to a suspension mill responsible for in situ seed generation through particle breakage. The dynamic and steady-state behavior of this process is extensively analyzed for racemic feed streams through process simulations, and parameter regions, which yield pure enantiomers in both crystallizers, are identified. For enriched feed streams, it is further shown when this novel flow sheet is capable of outperforming an ideal batch process in terms of solvent consumption per unit mass of desired enantiopure product produced.

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

The electrohydrodynamic stability of a liquid bridge was studied in steady and oscillatory axial electric fields with a novel apparatus aboard a space shuttle. To avoid interphase transport, which complicates matters in terrestrial, matched-density systems, the experiments focused on a liquid column surrounded by a dielectric gas. The micro-gravity acceleration level aboard the spacecraft kept the Bond number small; so interface deformation by buoyancy was negligible. To provide microgravity results for comparison with terrestrial data, the behaviour of a castor oil bridge in a silicone oil matrix liquid was studied first. The results from these experiments are in excellent agreement with earlier work with isopycnic systems as regards transitions from a perfect cylinder to the amphora shape and the separation of an amphora into drops. In addition, the location of the amphora bulge was found to be correlated with the field direction, contrary to the leaky dielectric model but consistent with earlier results from terrestrial experiments. Next, the behaviour of a bridge surrounded by a dielectric gas, sulphur hexa fluoride (SF6), was investigated. In liquid–gas experiments, electrohydrodynamic ejection of liquids from ‘Taylor cones’ was used to deploy fluid and form bridges by remote control. Experiments with castor oil bridges in SF6 identified the conditions for two transitions: cylinder–amphora, and pinch-off. In addition, new behaviour was uncovered with liquid–gas interfaces. Contrary to expectations based on perfect dielectric behaviour, castor oil bridges in SF6 could not be stabilized in AC fields. On the other hand, a low-conductivity silicone oil bridge, which could not be stabilized by a DC field, was stable in an AC field.

A liquid bridge is a column of liquid, pinned at each end. Here we analyse the stability of a bridge pinned between planar electrodes held at different potentials and surrounded by a non-conducting, dielectric gas. In the absence of electric fields, surface tension destabilizes bridges with aspect ratios (length/diameter) greater than π. Here we describe how electrical forces counteract surface tension, using a linearized model. When the liquid is treated as an Ohmic conductor, the specific conductivity level is irrelevant and only the dielectric properties of the bridge and the surrounding gas are involved. Fourier series and a biharmonic, biorthogonal set of Papkovich–Fadle functions are used to formulate an eigenvalue problem. Numerical solutions disclose that the most unstable axisymmetric deformation is antisymmetric with respect to the bridge’s midplane. It is shown that whilst a bridge whose length exceeds its circumference may be unstable, a sufficiently strong axial field provides stability if the dielectric constant of the bridge exceeds that of the surrounding fluid. Conversely, a field destabilizes a bridge whose dielectric constant is lower than that of its surroundings, even when its aspect ratio is less than π. Bridge behaviour is sensitive to the presence of conduction along the surface and much higher fields are required for stability when surface transport is present. The theoretical results are compared with experimental work (Burcham & Saville 2000) that demonstrated how a field stabilizes an otherwise unstable configuration. According to the experiments, the bridge undergoes two asymmetric transitions (cylinder-to-amphora and pinch-off) as the field is reduced. Agreement between theory and experiment for the field strength at the pinch-off transition is excellent, but less so for the change from cylinder to amphora. Using surface conductivity as an adjustable parameter brings theory and experiment into agreement.

The design, development, and implementation of a pilot-scale continuous Schotten−Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystallization processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a production rate of 3 kg/day in a 72 h continuous run. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersaturated conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a standard walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low volume pharmaceuticals.

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