CommentaryAchieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20–21, 2014 Continuous Manufacturing Symposium
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.
REFERENCES (10)
The integration of flow reactors into synthetic organic chemistry
J Chem Technol Biotechnol
(2013)- et al.
Deciding whether to go with the flow: Evaluating the merits of flow reactors for synthesis
Angew Chem Int Ed
(2011) - et al.
Novel process windows for enabling, accelerating, and uplifting flow chemistry
ChemSusChem
(2013) - et al.
Continuous flow multi-step organic synthesis
Chem Sci
(2010) - et al.
Green and sustainable chemical synthesis using flow microreactors
ChemSusChem
(2011)