Wednesday, February 23, 2011

Process Wednesday: a little process history

From Anderson et al.'s recent review* in Organic Process Research and Development, a brief mention of the beginnings of process chemistry:
...Later, validation was required for processes to prepare APIs and intermediates, by recording compliance of batch operating parameters within specified limits and by subjecting the batch outputs to various pass/fail analyses by Quality Control departments operating independently of their manufacturing counterparts.

Before the 1970s most pharmaceutical companies paid relatively little attention to efficient process development. Scaleups from the laboratory were often based on lore, with experiences sometimes communicated only verbally. Through reactions on a larger scale, often kilograms, the different mass transfer and heat transfer rates exposed limits underlying seemingly straightforward operations.
Wow, really? Some of this is easily imaginable, especially the first part. So far as I understand, the old-school assembly line model is at work here: you make a bunch of widgets, test them all and throw out the bad ones. It's not surprising to imagine that manufacturing chemistry worked the same way and that data on what's working (and what's not) was probably not being passed back to the plant. (I wonder, were Deming and his friends ever involved in process/manufacturing chemistry?)

The second portion of the quote is harder to imagine today -- imagine not requiring some sort of written procedure or protocol for scaleup! The thought of allowing verbal lore to guide quite detailed and expensive scale-ups is amusing in hindsight. I'll bet there were a lot of messy cleanups to be had back then.

*Anderson, N.G.; Burdick, D.C.; Reeve, M.M. "Current Practices of Process Validation for Drug Substances and Intermediates." Org. Process. Res. Dev. 2011, 15, 162-172.

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