The Increased Scale-Up Risk with Catalyzed Reactions

The probability of failure is increased for catalyzed reactions of which, for example, enantioselective reactions are a prominent contemporary class. The special additional risk is that catalytic system may be more easily shut down by small, even trace, impurities that are difficult to measure much less control. Put another way, a catalyzed reaction is susceptible to poisoning and this can lead to slowing or complete interruption in conversion with no easily identifiable c ause. Catalyzed reactions are inherently less rugged than the uncatalyzed because the catalytic substance, by definition, is used in lower than stoichiometric quantity and so would be disproportionately affected by a particular quantity of a catalyst poison. Impurities in the inputs to a catalyzed process can also accelerate reaction. When, as after a switch to a different source of an input, they are not added performance may deteriorate or fail completely. Neil G. Anderson wrote in Practical Process Research & Development, First Edition, pg. 194: “the importance of trace beneficial impurities may become evident only by failure of the reaction when using different lots of starting materials, reagents, or solvents.” Thus the recommendation to perform laboratory experiments with the same materials to be used in the plant goes double for catalyzed reactions and this includes chemicals used to wash and prep the reactor.

A catalyzed reaction can more easily be shut down without leaving forensic evidence. If it is a catastrophic failure it can poison our minds as much as our reactions. We may start to harbor conspiracy delusions. “Have we been harmed by some disgruntled or mentally disoriented employee? Have some operators made an error and covered it up? Are we now engaged in a long, expensive, and ultimately fruitless failure investigation?” It may seem far fetched, but I was embroiled in such a situation once. Human minds, in the absence of a clear causal connection for a phenomena, are programmed to find signs suggesting hypotheses even in random data.

When a procedure that has been running successfully at large scale  suddenly fails and if laboratory experiments with the identical raw materials run immediately afterwards succeed, these ideas come to mind and make the resulting further inquiry even more difficult to bear.

A suggestion that may be just too inconvenient and divisive to implement should at least be contemplated. When a clear most probable cause cannot be detected after a failure the next run performed at that scale, to be fair, should use a completely different group of operators or  should be run with special laboratory oversight. If the team is al completely different a second failure will at least rule out malevolent intervention by a team member. What must be avoided is  the situation where a second failure would throw what is likely unwarranted suspicion upon employees who would have participated in both failing runs.