A Highly Toxic (Carcinogenic) Impurity in a Drug Substance required a specification as low as 0.000007%

During the synthesis of the drug PGE-6134091, a highly potent a-2 adrenergic Receptor Agonist, a batch of drug substance failed the Ames test.  It was subsequently found that phenazene impurities in the ppm range were responsible, and after discussions with FDA, a limit of 70 ppb (0.000007%) was set for these impurities.  (J Randall, presented at OPRD, New Orleans, March 2003).

The carcinogenic phenazine impurities arise during the early stages and could be deliberately synthesised by the method shown below.

If a transfer hydrogenation was used, however, low levels of phenazines were produced.