Chemical process research and development in the 21st century: challenges, strategies, and solutions from a pharmaceutical industry perspective.

In process research and development (PR&D), the generation and manipulation of small-molecule drugs ranges from bench-scale (laboratory) chemistry to pilot plant manufacture to commercial production. A broad range of disciplines, including process chemistry (organic synthesis), analytical chemistry, process engineering (mass and heat transfer, unit operations), process safety (chemical risk assessment), regulatory compliance, and plant operation, must be effectively applied. In the critical handover between medicinal chemistry and PR&D, compound production is typically scaled up from a few hundred grams to several kilograms. Can the methodologies applied to the former also satisfy the technical, safety, and scalability aspects that come into play in the latter? Occasionally, the transition might occur smoothly, but more often the situation is the opposite: much work and resources must be invested to design a process that is feasible for manufacturing on pilot scale and, eventually, for commercial production. Authentic examples provide enlightening illustrations of dos and don'ts for developing syntheses designed for round-flask operation into production-scale processes. Factors that are easily underestimated or even neglected in the laboratory, such as method robustness, chemical hazards, safety concerns, environmental impact, availability of starting materials and building blocks in bulk quantities, intellectual property (IP) issues, and the final cost of the product, will come into play and need to be addressed appropriately. The decision on which route will be the best for further development is a crucial event and should come into focus early on the R&D timeline. In addition to scientific and technical concerns, the parameter of speed has come to the forefront in the pharmaceutical arena. Although historically the drug industry has tolerated a total time investment of far more than 10 years from idea to market, the current worldwide paradigm requires a reduction to under 10 years for the specific segment covering preclinical development through launch. This change puts enormous pressure on the entire organization, and the implication for PR&D is that the time allowed for conducting route design and scale-up has shrunk accordingly. Furthermore, molecular complexity has become extremely challenging in many instances, and demand steadily grows for process understanding and knowledge generation about low-level byproduct, which often must be controlled even at trace concentrations to meet regulatory specifications (especially in the case of potentially genotoxic impurities). In this Account, we paint a broad picture of the technical challenges the PR&D community is grappling with today, focusing on what measures have been taken over the years to create more efficiency and effectiveness.