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

Abstract

Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.

Consolidating and Managing Data for Drug Development within a Pharmaceutical Laboratory: Comparing the Mapping and Reporting Tools from Software Applications

“…The cumulative carryover is calculated using the carryover values for individual steps calculated above: where carryover stage x → y denotes the carryover between two stages x and y where the impurity resides. For cases where the input value falls below a limit, the designation ND (not detected) is used. − …”

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities

“…The toxicity of drugs is not only related to the toxicity of active pharmaceutical ingredients (APIs) but also to impurities in drugs (Rayavarapu et al, 2015; Gunther et al, 2017). The drug regulatory agencies of various countries and international organizations require the identification and control of impurities in drugs—especially the control of genetic toxicity impurities (Pikul et al, 2016; Kragelj Lapanja et al, 2017). However, there are few reports on the toxicity of CAZ impurities.…”