Martin D. Johnson

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance. May 20–21, 2014 Continuous Manufacturing Symposium

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are.This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chemistry toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment especially for workup to assist in straightforward deployment in the laboratory. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process analytical technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystallization. Involve all parts of the organization from discovery, research and development, and manufacturing in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chemistry, physical chemistry, and chemical engineering skills at the chemistry-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the critical economic drivers is critical to driving the transformation in manufacturing.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Continuous-flow technology is devised and implemented for manufacture of a drug candidate in clinical trials. Go with the flow in drug manufacturing Although many commodity chemicals are manufactured using continuous flow techniques, pharmaceuticals are still mostly produced in large single batches. Cole et al. report a protocol for the small-volume continuous preparation of multi-kilogram quantities of a cancer drug candidate, prexasertib monolactate monohydrate, under current good manufacturing practices. Advantages of the approach include safer handling of hazardous reagents and intermediates, as well as yield and selectivity improvements in both the reaction and purification stages. Concurrent analytical monitoring also facilitated rapid trouble-shooting during the manufacturing process. Science, this issue p. 1144 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.

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

A key pharmaceutical intermediate (1) for production of edivoxetine·HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solvent composition, stoichiometry, and operations temperature were optimized to produce 12 g h−1 crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h−1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000–6000 L batch reactors.

An automated repeating batch with catalyst recycle approach to nitro group hydrogenolysis

An automated repeating batch approach has been developed for the rapid screening and scale up of a nitroaromatic to aniline catalytic hydrogenolysis. Advantages of this approach include the ability to scale up in small equipment using readily available powdered catalysts, rapid reaction kinetics due to high catalyst to substrate ratio, lower overall catalyst use, high throughput from a small reactor, and the ability to refresh the catalyst without manual intervention.

Continuous Platform To Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds

ABSTRACT Introduction: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for this interest as well as many considerations and challenges that exist today concerning continuous manufacturing. Areas covered: Continuous processing is defined and many reasons for its adoption are described. The current state of continuous drug substance manufacturing within the pharmaceutical industry is summarized. Current key challenges to implementation of continuous manufacturing are highlighted, and an outlook provided regarding the prospects for continuous within the industry. Expert commentary: Continuous processing at Lilly has been a journey that started with the need for increased safety and capability. Over twelve years the original small, dedicated group has grown to more than 100 Lilly employees in discovery, development, quality, manufacturing, and regulatory designing in continuous drug substance processing. Recently we have focused on linked continuous unit operations for the purpose of all-at-once pharmaceutical manufacturing, but the technical and business drivers that existed in the very beginning for stand-alone continuous unit operations in hybrid processes have persisted, which merits investment in both approaches.

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

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.

Mechanistic investigation of a Ru-catalyzed direct asymmetric reductive amination reaction for a batch or continuous process scale-up: an industrial perspective

A comprehensive assessment of a Ru-catalyzed direct asymmetric reductive amination (DARA) reaction for producing an intermediate for an active pharmaceutical ingredient (API) was carried out. Experiments were conducted to investigate the impact of process parameters (such as reaction temperature, time, concentration, pressure, Ru-catalyst concentration, acid catalyst, and reagent stoichiometry) on chemo- and stereo-selectivity, and yield. An analysis of experimental data led to the development of a mechanistic mathematical model that was mathematically consistent with data from laboratory development and manufacturing campaigns. A combinatory approach outlined herein could be used to provide the optimum conditions for the DARA process. Furthermore, the feasible operating region was mapped out, which highlighted the complexity of the investigated chemistry and aided in developing the control strategy and regulatory submission package pertinent to this reaction. The efforts allowed the process to be successfully validated and scaled using a plug flow reactor (PFR) to manufacture 3200 kg of (S)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine under current Good Manufacturing Practice (cGMP).