Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 2: Step 2 Synthesis

Continuous manufacturing, also known as continuous processing, is defined by the continuous charging of materials into the system and the continuous discharge of the product throughout the entire process duration. While most industries like food, petrochemicals, and automotive have long embraced automated and continuous manufacturing, the pharmaceutical sector has traditionally favored a batch process. Currently operating at approximately 2−3 sigma quality (equivalent to 6.7−30.9% defects or failed/rejected products), the pharmaceutical industry requires significant improvement to achieve the 6 sigma quality (approximately 0.0003% defects). This is one of the reasons that the pharmaceutical manufacturing sector is transitioning from batch to continuous operations.

The advantages of continuous manufacturing mainly include: (1) flexibility; (2) leaning out the supply chain; (3) agility and reduced scale-up efforts; (4) real-time quality assurance; (5) societal benefits; (6) improved engineering systems; (7) reduced footprint and investment costs; and (8) decentralized and individualized manufacturing. MIT introduced a groundbreaking end-to-end Integrated Continuous Manufacturing (ICM) line in 2011, showcasing aliskiren hemifumarate as the model drug. The process started from a chemical intermediate and underwent the necessary reactions, separations, crystallization, drying, and formulation within a seamless and tightly controlled process.

The total throughput of the plant was 45 g/h (equivalent to 2.7 × 10⁶ tablets per year). Building on this success, CONTINUUS Pharmaceuticals unveiled an end-to-end ICM pilot plant in 2019, reporting a throughput of 4800 tablets per hour (equivalent to 40.3 × 10⁶ tablets per year) and a total residence time of less than 30 h. Meanwhile, there have been a few examples of continuously manufactured drug products that have gained approval in Japan (e.g., Tramacet by Johnson & Johnson, Verzenio by Eli Lilly), the EU (e.g., Orkambi and Symkevi by Vertex, Prezista by Johnson & Johnson, Verzenios by Eli Lilly), and the US (e.g., Orkambi, Symdeko, and Trikafta by Vertex, Prezista by Johnson & Johnson, Verzenio by Eli Lilly, Daurismo by Pfizer), with additional drugs currently in development. The real-time monitoring of continuous manufacturing processes through process analytical technology (PAT) is critical for quality assurance.

The Food and Drug Administration (FDA) defines PAT as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality”. Focused beam reflectance measurement (FBRM) and React IR are two common PATs used in the API manufacturing process. FBRM is usually used to monitor, predict, and control the crystal size distribution (CSD) during crystallization or reactive crystallization processes. Leyssens et al. used FBRM to investigate the crystallization of needle-shaped CDP323−2 particles and developed a crystallization process to deliver products meeting the required quality attributes. Glennon et al. investigated the feasibility of in situ monitoring of polymorphic transition through FBRM, and the results showed that FBRM was able to detect the transition of the δ-polymorph of D-mannitol to the thermodynamically stable β-form through changes in crystal population and morphology. ReactIR is an in situ mid-infrared-based system and is designed to study reaction progress and provide specific reaction information about the initiation, conversion, intermediates, and end points. O’Brien et al. studied the high-yielding asymmetric deprotonation trapping of N-Boc piperidine using s-BuLi and a (+)-sparteine surrogate, and ReactIR allowed the direct observation of a prelithiation complex.

Every year, influenza viruses significantly affect worldwide health, leading to 3−5 million severe cases of illness and approximately 1 million deaths. The economic impact is estimated to be approximately $90 billion in the United States alone. Despite the availability of influenza vaccines, antiviral drugs play a crucial role in prophylaxis and treatment. Baloxavir marboxil (S-033188, trade name Xofluza) is a drug developed and marketed by Shinogi and Roche to treat seasonal influenza A and influenza B. Baloxavir marboxil is unique in its ability to block viral replication by specifically targeting the endonuclease function encoded by the polymerase acidic protein (PA) subunit with the viral polymerase complex. A practical benefit of baloxavir marboxil is its requirement for just a single oral dose, potentially enhancing patient compliance.

In this Part 2 of a two-part series, we summarize all the unit operations in the Step 2 synthesis (from S-033447 to S-033188, see Scheme 1) of baloxavir marboxil. The process includes reaction to S-033188, crystallization and purification of S-033188, continuous rotary filtration of S-033188, and continuous wet milling and drying of S-033188 (Figure S1 for the block diagram). All of these unit operations were run continuously, but separately. The next step will be their seamless integration.

Read Part 1 here