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

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ABSTRACT:

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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION—THE FUTURE FOR CONTINUOUS DRUG SUBSTANCE MANUFACTURE

Successful innovation in manufacturing and the adoption of continuous manufacturing (CM) has an important role to play in the industry’s future. The vision for CM in the pharmaceutical industry is to exploit continuous processes to convert raw materials into safe, effective, and high-quality medicinal products. This vision is driven by the potential to improve control over quality, reduce costs, enhance process safety, and significantly reduce the timelines currently involved across the

REACTIONS: THE WIDER ADOPTION OF CONTINUOUS FLOW STRATEGIES IN PHARMA

Continuous flow synthesis has matured as a scientific area translating from a principle domain of chemical engineering to a technological tool now routinely used by many chemical synthesis laboratories and increasingly in process development and scale-up.1., 2., 3., 4., 5. Conducting synthetic reactions in flow can be used to access a variety of benefits that may include: (1) reduced hazard/increased safety from smaller reactor volume, relative ease of containment, reduction/removal of

WORKUP AND ISOLATION

Benefits of continuous reaction can often be realized even if the workup and isolation is batch. However, with the drive to develop reactions in continuous flow as part of an integrated end-to-end manufacturing strategy, it is also important to consider the optimal way to purify and isolate the products. Workup steps are often the dominant equipment and time costs of drug substance manufacturing processes and for flow processing to bring the expected benefits to the industry, the whole process

QUALITY ASSURANCE AND CONTROL

Although systematic approaches for assuring quality are commonly applied in the chemical, petrochemical, and oil refining (CPOR) industries, pharmaceutical products require a much higher degree of quality control. Although it is perfectly acceptable in processes involving only fluids to mix off-spec and above-spec quality to achieve a mixture that satisfies product quality specifications, most pharmaceutical products are in solid form and mixing off-spec (e.g., tablets) with on-spec solid

SAFETY

Continuous processing offers safety advantages compared to batch, including smaller reactor volumes and thus smaller potential events, higher heat transfer surface area per unit volume (A/V) for highly exothermic reactions or reactions running at temperatures close to thermal onset of decomposition, lower inventories and on demand production of hazardous reagents, ability to eliminate headspace and run 100% liquid filled, and higher containment for highly toxic compounds. Accumulation of large

PEOPLE, SKILLS, AND CULTURE

Establishing continuous processing in the Pharma industry is not simply to solve technical, engineering or scientific problems, far from it. Although we can realistically see a way to characterize processes and equipment, to design syntheses and reactors, or to build process trains that couple multiple unit operations, there will remain significant other challenges preventing the widespread adoption and establishment of CM of API. The skills and capabilities required to design, develop,

CONCLUSIONS

It is clear that the implementation of continuous processes for drug substance manufacture offers potentially significant advantages for the supply of medicines. Alongside the increasing number of examples where continuous processes have demonstrated clear benefits (e.g., hazardous chemistries), there are also areas where further developments will increase the opportunities for Pharma/fine chemicals to deliver safety, quality, and cost benefits for the right products with the right processes

ACKNOWLEDGMENTS

We would like to thank our “consultants” who made valuable comments to improve this paper: Dr Philip Dell’Orco, Glaxosmithkline US; Dr Ian Houson, CMAC, Strathclyde University, UK; Jim Cashman, Eli Lilly S.A. Irish Branch, Kinsale, Ireland; Prof Zoltan Nagy, CMAC, Loughborough University, UK/Purdue University US; Prof Tim Jamison, MIT, US and Prof Brian Glennon, UCD, Ireland. In addition, all of those who made helpful comments online and at the symposium.

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