A Generic Industry Approach To Demonstrate Efficient Purification of Potential Mutagenic Impurities in the Synthesis of Drug Substances

Lapanja, Nevenka Kragelj; Zupančič, Borut; Časar, Renata Toplak; Orkić, Damir; Uštar, Matjaž; Satler, Astrid; Jurca, Sabina; Doljak, Bojan

doi:10.1021/acs.oprd.5b00061

Cited by 11 publications

(20 citation statements)

References 12 publications

(27 reference statements)

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“…The ICH M7 guideliScheme 4: Synthesis of vortioxetine hydrochloride (adapted from Lapanja et al 29 ). Table 6.…”

Section: Resultsmentioning

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%

“…by McLaughlin et al 33 and by Lapanja et al 29 McLaughlin et al 33 applied purge factor assessment tool to six MIs in the synthesis of a development compound MK-8876 (Scheme 3). Theoretical purge factors were compared with the analytically determined purge factors.…”

Section: Lapanja Et Almentioning

confidence: 99%

“…Lapanja et al 29 also used the same approach for assessing the presence of four potential MIs in the vortioxetine synthetic process (Scheme 4). Additionally, one minor modification regarding the physical process parameter was proposed, i.e.…”

Section: Lapanja Et Almentioning

confidence: 99%

“…Summarized results of the case study for the synthesis of vortioxetine (based on Lapanja et al 29 ).…”

Section: Funding Sourcesmentioning

confidence: 99%

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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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“…The ICH M7 guideliScheme 4: Synthesis of vortioxetine hydrochloride (adapted from Lapanja et al 29 ). Table 6.…”

Section: Resultsmentioning

confidence: 99%

Section: Physicochemicalmentioning

confidence: 99%