A Tool for the Semiquantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process Conditions

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

“…For this reason pharmaceutical companies had to present extensive analytical data. To avoid unnecessary analytical testing, Teasdale et al 28 took the challenge to develop an approach that would allow the likelihood of potential carryover of a GTI to be assessed ahead of performing analyses. In line with the ICH M7 …”

“…29 option 4 control strategy, the scientific approach proposed by Teasdale 28 is based on physicochemical properties and process factors that influence the fate and purge of an impurity. In order to assess the carryover of potential GTIs into API, AstraZeneca developed a tool based on the assessment of key physicochemical properties of the agent of concern, relating them to the downstream processing conditions.…”

“…Multiplying the purge factors for individual stages yields an overall purge factor. Teasdale et al 28 provided a case study, presenting both the outcome of the predictive purge factor and the real measured values. Theoretical purge factors were calculated for three potentially genotoxic impurities in the synthesis of AZD9056 (Scheme 1).…”

“…Table 4. Summarized results of the case study for the synthesis of AZD9056 (based on Teasdale et al 28 ).…”

“…Additionally, one minor modification regarding the physical process parameter was proposed, i.e. a recrystallization step was included within the physical process parameter, while according to Teasdale et al 28 recrystallization would be described within the solubility parameter. The theoretical purge factors were then compared with measured values and with the results of depletion studies.…”