The assessment and control of genotoxic impurities (GTI) in pharmaceutical products has received considerable attention in recent years. Molecular functional groups that render starting materials and synthetic intermediates useful as reactive building blocks for small molecules may also be responsible for their genotoxicity. As a potential safety concern, it is important to understand the various issues related to GTIs and how they can be addressed for clinical and commercial phases of development. Justification that these impurities are controlled to safe levels must be obtained during development. This article will briefly discuss the multiple sources of anticipated impurities in a drug substance (also known as active pharmaceutical ingredient or API) synthetic route and how they are identified as GTIs in early chemical process development. A risk-based approach consistent with regulatory expectations is described for establishing control of GTIs. The approach includes process design considerations, impurity rejection information, and appropriate application of specifications. Analytical considerations for determination of GTIs at low levels are also discussed.

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Zn(BH4)2 (Yoon et al., 1976) was used to reduce monohydro-CD (5) and dihydro-CD (6). Analysis of the products by GLC demonstrated only monohydro-CDOH (7) (RT = 8.3 min) or dihydro-CDOH (8) (RT = 5.7 min) and no other dechlorinated derivatives. The stereochemistry of monohydro-CDOH ( 7) is unknown. The Cl mass spectra for these reduction products were characterized by the ion clusters; ( + H)+, [( + H) -HOH]+, and (M -Cl)+. These ions were found at m/e 455, 437, and 419 for monohydro-CDOH and m/e 421, 403, and 385 for dihydro-CDOH. The El mass spectra demonstrated major fragments at m/e 149, 184 (base peak), and 218 for monohydro-CDOH and m/e 149 and 184 (base peak) for dihydro-CDOH. These data suggest that reduction of monohydro-and dihydro-CD with Zn(BH4)2 forms pure standards of monohydro-and dihydro-CDOH while avoiding further dehalogenation (Scheme II). The dechlorinated derivatives of CD appear more sensitive to the alkalinity of the reducing agent than CD itself. Consequently, the structure of the reactant in addition to the base strength of the reducing agent must be considered in the preparation of CDOH and its analogues.

2009, 13, 285-291.]Dear Editor:We would like to acknowledge David Snodin's Letter to the Editor in which he comments on our recent Org. Process Res. DeV. (OPRD) paper ("Approaches to assessment, testing decisions, and analytical determination of genotoxic impurities in drug substances"). Three specific topics relating to the need for specification limits, risk assessment and need for routine testing were discussed in the letter, and we find his comments to be consistent with our paper.As stated in the paper, avoidance of genotoxic impurities (GTIs) as reagents, starting materials, synthetic intermediates and byproducts in chemical processing is an initial consideration