Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs

Currently, most drugs are still manufactured by batch processes, whereby raw materials are charged into a unit operation (e.g., reactor, filter), processed, and discharged all together as a single load. There are many starts and stops, interposed with labor intensive steps that increase the possibility of product defects and human-based errors. Currently, pharmaceutical manufacturing operates at 2–3 sigma (∼6.7–30.9% defects; sigma is the number of standard deviations between the process mean and the nearest specification limit), suggesting a significant deviation from other industries that have achieved six sigma (∼0.0003% defects). By eliminating the breaks between steps, which are inherent of batch processing, and reducing the opportunities for human error, continuous manufacturing enables more reliable and faster production. The entire manufacturing process can be fully automated and able to run uninterrupted, reducing lead times and manufacturing costs, ultimately improving better patient access. The pharmaceutical industry is gradually transitioning from batch to continuous manufacturing.

There are six continuously manufactured drug products that have been approved in the US (i.e., Orkambi, Symdeko and Trikafta by Vertex, Prezista by Johnson & Johnson, Verzenio by Eli Lilly, Daurismo by Pfizer), four in EU (i.e., Orkambi and Symkevi by Vertex, Prezista by Johnson & Johnson, Verzenios by Eli Lilly), and two in Japan (i.e., Tramacet by Johnson & Johnson, Verzenio by Eli Lilly) and more are under development. Despite all these advances in continuous manufacturing there are still no example of products approved via end to end integrated continuous manufacturing (ICM). ICM of pharmaceuticals has many advantages, including improved quality, reduced lead time and cost, and decreased environmental impact. As reported by CONTINUUS Pharmaceuticals in 2019, an ICM process for a specific pharmaceutical product can reduce costs by 35–40%, the number of unit operations by 80–85%, solvent usage by >55%, waste reduction by ∼30%, footprint by ∼90%, and energy usage by 50–60%, when compared with the corresponding batch process. Therefore, ICM implementation can lead to a more sustainable and environmental-friendly pharmaceutical industry. To estimate how “green” a process is, several metrics are conventionally used: process mass intensity (PMI), E(environmental)-factor, atom economy, and carbon efficiency, among which PMI and E-factor are currently the most used. PMI is defined as the total mass of material in a process (or process step) used to produce a specified mass of a particular product. By comparison, PMI = E-factor + 1.

The Green Chemistry Institute Pharmaceutical Roundtable recommended the use of PMI because it focuses on process efficiency and provides the opportunity for a holistic implementation of green chemistry ideologies, and not just that of waste. Reaction7, and crystallization26–35 are usually two necessary steps in the continuous manufacturing process of pharmaceuticals. They can occur simultaneously when the reaction rate is high and the solubility of the synthetic intermediate or active pharmaceutical ingredient (API) in the solvent is low – this is known as reactive crystallization. A high level of supersaturation is often encountered in reactive crystallization processes, usually resulting in high nucleation rates and small crystal sizes. The formation of small-sized crystals in pharmaceutical manufacturing processes is essential in improving drug properties, such as dissolution rate and bioavailability. Often, additional downstream operations (e.g., milling) to reduce the crystal size are required. However, crystals that are too small may also be undesirable, as they can disrupt downstream operations (e.g., filtration, filling operation). Therefore, it is important to monitor and control the crystal size distribution in a reactive crystallization process. Common process variables that influence the crystal size distribution include stirring rate, temperature, and reactant concentration/supersaturation.

Batch-manufactured pharmaceuticals are analyzed by offline laboratory instruments (e.g., HPLC) to verify their quality attributes. However, since continuous manufacturing eliminates the starts and stops of batch manufacturing, an in-line/on-line continuous process monitoring and control, based on the utilization of process analytical technology (PAT), is better suited to this mode of manufacturing. PATs can provide real time data on critical material attributes (CMAs) and activate feed-forward and feedback control actions. This strategy of continuously monitoring the process/process material and employing instantaneous corrective steps through fully automated control loops results in a more robust manufacturing system, and subsequently, better final drug product quality. Common PATs used in the pharmaceutical manufacturing process include ReactIR, focused beam reflectance measurement (FBRM), Raman spectroscopy, near-infrared spectroscopy (n-IR), particle size analysis, UV-vis spectroscopy, and at-line ultra-performance liquid chromatography (UPLC). In the present study, the continuous reactive crystallization of an API in a PFR-CSTR cascade system with in-line PATs was developed and investigated. The performance of the reactor cascade was estimated by RTD measurements. Several continuous reactive crystallization experiments were performed to investigate the crystal morphology, crystal size distribution, reaction and crystallization yields, and supersaturation level. Inline ReactIR and FBRM were applied to monitor the reactant concentration and the crystal chord length distribution, respectively.