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

Teasdale, Andrew; Fenner, Simon; Ray, Andrew; Ford, Agnes; Phillips, Andrew R.

doi:10.1021/op100071n

Cited by 51 publications

(91 citation statements)

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“…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 …”

Section: Theoretical Purge Factor Determination Approachmentioning

confidence: 99%

“…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.…”

Section: Physicochemicalmentioning

confidence: 99%

“…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).…”

Section: Physicochemicalmentioning

confidence: 99%

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

Section: Physicochemicalmentioning

confidence: 99%

“…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.…”

Section: Lapanja Et Almentioning

confidence: 99%

See 4 more Smart Citations

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

Lapanja¹,

Časar²,

Jurca³

et al. 2017

ACSi

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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.

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Section: Theoretical Purge Factor Determination Approachmentioning

confidence: 99%

Section: Physicochemicalmentioning

confidence: 99%

Section: Physicochemicalmentioning

confidence: 99%

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

Section: Physicochemicalmentioning

confidence: 99%

Section: Lapanja Et Almentioning

confidence: 99%