Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies To Demonstrate Control

Abstract

The control of genotoxic impurities (GTIs) is a crucial activity that is performed for any new chemical entity intended for clinical use. A key element of this is the quality risk assessment. This article seeks to examine the primary components of such a strategy, focusing specifically on the effective use of in silico assessment tools to augment this process, in particular the calculation of theoretical purge factors based on the physicochemical properties of a specific GTI and its interrelationship to the process.

A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors

“…Application of the method offered herein provides a complementary basis upon which to assign a reactivity purge factor in the semiquantitative risk assessment developed by Teasdale. 2,3,4 The increased understanding of the interrelationship between the reaction rates and purge of impurities offered by this study may serve as a basis for further extension of this method.…”

“…Application of the overall purge factor to a given impurity provides insight into the risk that an impurity poses to product quality. The method described by Teasdale 2,3,4 has been utilized to assess risk of impurity carry-over to drug substance by Elder 5 and to support designation of Active Pharmaceutical Ingredient (API) Starting Materials by Faul. 6 The assignment of a purge factor for a mutagenic impurity over a unit operation requires an understanding of the degree of consumption or removal of the impurity.…”

“…This information can guide selection of one of the three standardized 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 reactivity purge factors (1, 10, or 100) that are integral to the semiquantitative risk assessment developed by Teasdale. 2,3,4 Results:…”

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

“…In 2013 Teasdale et al 30 published further and more detailed information about the determination of theoretical purge factors, alongside various case studies. Instructions are given on how to assign values for different physicochemical parameters, how to calculate the factors and how to evaluate the results.…”

Quantitation of Genetox Impurities Using a Surrogate Standard Approach

“…Once the synthetic process for the API preparation is finalized, an assessment is undertaken to evaluate the potential for genotoxic intermediates or reagents to persist, the potential for genotoxic impurities to form as by-products during the process, and the appropriate control limits for any alerting structures identified [6]. For PGI's that are reaction intermediates, reaction by-products, and for which standards are readily available, conventional analytical detection and quantitation methods typically allow for a relatively straightforward analysis.…”