On the design of complex drug candidate syntheses in the pharmaceutical industry

| The overall goal of a process chemistry department within the pharmaceutical industry is to identify and develop a commercially viable approach to a drug candidate. However, the high chemical complexity of many modern pharmaceuticals presents a challenge to process scientists. Delivering disruptive, rather than incremental, change is critical to maximizing synthetic efficiency in complex settings. In this Review, we focus on the importance of synthetic strategy in delivering ‘disruptive innovation’ — innovation that delivers a step change in synthetic efficiency using new chemistry, displacing any prior synthetic route. We argue that achieving this goal requires visionary retrosynthetic strategy and is tightly linked to the discovery and development of new reactions and novel processes. Investing in high-risk innovation during the route design process can ultimately lead to safer, more robust and more efficient manufacturing processes capable of addressing the challenge of high molecular complexity. Routinely delivering such innovation in a time-bound environment requires organizational focus and can be enabled by the concepts of expansive ideation, strategy aggregation and strategy selection. REVIEWS NATURE REVIEWS | CHEMISTRY VOLUME 1 | ARTICLE NUMBER 0016 | 1 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Ideation Ensuring the robust and expansive evaluation of all key strategic bonds, developing a much fuller retrosynthetic analysis before entering the lab, and using the collective wisdom of multiple researchers to raise and address concerns. Strategy aggregation Taking the multiple synthetic proposals, or proposed disconnections, and collating them into clusters of aligned core disconnection strategies or reactivities, not focusing on any individual technology or precedent. Key experiments can rapidly be explored in the lab to assist in the triaging of strategies. Strategy selection Aligning the team on selecting a strategy, not an individual synthesis proposal. The selected strategy should have multiple related synthetic options (for example, shared reactivity patterns or common intermediates) such that high-risk disruptive approaches can be investigated, while data gained from the exploration can be applied to lower-risk proposals. Appropriate selection can also lead to a more effective staged approach to synthesis development, which is often crucial in aligning work to the risk of the drug progressing to market. synthetic purpose (FIG. 1a) between discovery and process groups is becoming more pronounced as target complexity increases. Simple modifications of the discovery synthesis, followed by optimization and scale-up, will often not support the commercial demands of a chemically complex marketed drug. Innovation in all aspects of development is becoming an imperative and requires creative route designs, the discovery and large-scale implementation of novel enabling reactions, and the embracing of state-of-the-art technologies or cutting-edge academic research. However, as a compound moves into clinical development, the comfort of the functioning route used in early development can inhibit innovation, because leveraging existing technology minimizes synthetic risk, especially as it relates to critical process-facing parameters (FIG. 1a). This makes change challenging in a time-bound environment; reinventing a route to a molecule can incur additional risk, cost and time in developing an alternative approach (in discovery, demonstration and data collection). Thus, any alternative chemistries explored need clear and obvious values if they are to change the technology used to prepare a new therapeutic. The discovery of unprecedented transformations or de novo applications of known methods, enabled by an innovative synthetic strategy, can offer the best approach to minimize risk while aiding speed to a process chemistry organization. The disparity between needing to develop a new synthesis and minimizing risk to the progression of the compound to the market is profound; the key to both is disruptive innovation. The term ‘disruptive innovation’ may seem inappropriate in this context, but it defines what modern process chemistry teams routinely need to accomplish in today’s pharmaceutical environment9. The concept of disruptive innovation was defined by Clayton M. Christensen as an innovation that creates a new market or value network, which replaces existing networks9. Although this was originally in the context of the global economy, we can apply the concept to chemistry or, more specifically, to the synthesis of molecules. Disruptive chemical innovation should deliver novelty that displaces prior approaches; that is, in the case of a synthesis, new reactions or strategies that result in a synthesis significantly (not incrementally) advanced from prior approaches. As mentioned above, the increasing complexity (both chemical and regulatory) of modern clinical candidates more frequently means that the original discovery or medicinal synthesis needs to be replaced, even from an early point of development. To manage the attrition risk present when developing a new medication, organizations will often develop transitional approaches, which can support the early phases of clinical studies. In developing a disruptive commercial synthesis, any route-scouting activities need to be disruptively different to justify the investment in additional development. However, in approaching this challenge we need to understand that the process of route invention is highly influenced by the bias of an individual chemist, caused by lack of precedent for a key transformation or the comfort of an incumbent synthesis. Such bias can hinder the ability or desire of an organization to take scientific risk in route scouting, resulting in incremental improvements being delivered. We will attempt to show through multiple case studies how a three-tiered approach of expansive ideation, strategy aggregation and strategy selection can manage these risks and maximize the probability of discovering disruptively innovative syntheses. One key consideration is that the designation of a route as disruptively innovative, especially in the beginning of the route-scouting endeavour (before a demonstration of viability), is entirely based on perceived potential. Nature Reviews | Chemistry Discovery Potential drug candidate Development Chemical space A B C