Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances

Pierson, Duane A.; Olsen, Bernard A.; Robbins, David; DeVries, Keith M.; Varie, David L.

doi:10.1021/op8002129

Cited by 88 publications

(60 citation statements)

References 22 publications

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“…This is because these impurities are typically the most difficult to purge and as a consequence may need to be added to the final API specification (i.e., option 1 in the ICH M7 guidance 4 ). Four stages back from the API was chosen to reflect commentary by Pierson et al, 16 who indicated that a reactive intermediate can typically be purged effectively if it is introduced four or more stages prior to the final API isolation stage (i.e., option 3 in the ICH M7 guidance 4 ). This is obviously a coarse measure, as it takes no account of the prevailing downstream chemistry or the total number of synthetic stages in the process (and indeed, some of the syntheses reported here have ≤4 stages in total).…”

Section: ■ Discussionmentioning

confidence: 99%

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Elder

Teasdale

2015

Org. Process Res. Dev.

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A survey of over 300 synthetic publications published in Organic Process Research & Development over a 10-year period (2001−2010) provides a top-level overview of current synthetic strategies. It reaffirms the widely held view within the pharmaceutical industry that the synthesis of complex, multistage pharmaceuticals is untenable without the use of reactive, potentially mutagenic intermediates and that calls for "avoidance" reflect a lack of awareness of the challenges inherent in modern synthetic chemistry. On the basis of this survey, we can conclude that the average number of steps required to synthesize each active pharmaceutical ingredient (API) was 6 (5.9) and that the average number of reactive intermediates per synthetic route was 4 (4.1). It was also noted that there are four major classes of reactive intermediate that are commonly utilised in the later stages of API syntheses, (i.e., the last four stages): alkyl halides, acid chlorides, aromatic amines, and Michael acceptors. There was minimal usage of highly potent compounds from the "cohort of concern", which suggests that any additional focus on "cohort of concern" would be misplaced. Most of the cited publications gave several different alternative synthetic routes. In all cases there was no evidence to suggest that any of these alternative routes could produce the final API (of typical complexity) without the need to use reactive intermediates at some stage of the synthesis. In addition, the number of reactive intermediates remained broadly similar irrespective of which route was selected, strongly challenging the notion that avoidance was ever a viable option. This again underpins the argument that control, not avoidance or ALARP, is the most appropriate strategy in the overwhelming majority of cases.

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Section: ■ Discussionmentioning

confidence: 99%

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Elder

Teasdale

2015

Org. Process Res. Dev.

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“…have the ability to remove GTIs along with other process impurities. Purging of impurities was previously addressed by Pierson et al 27 The risk of GTI carry over was defined considering the number of synthetic steps between the point of GTI appearance and final production step. If the GTI appears more than four steps before the final step, chemical rationale could be used to assess the need of GTI removal.…”

Section: Key Pointsmentioning

confidence: 99%

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 genotoxic impurity testing point can vary and needs to be determined with scientific basis and supporting data . The testing strategy for PGIs analysis is shown in Fig.…”

Section: Genotoxic Impurities Assessment and Controlmentioning

confidence: 99%

Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review

Reddy

Jaafar

Umar

et al. 2015

J of Separation Science

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Potential genotoxic impurities in pharmaceuticals at trace levels are of increasing concern to both pharmaceutical industries and regulatory agencies due to their possibility for human carcinogenesis. Molecular functional groups that render starting materials and synthetic intermediates as reactive building blocks for small molecules may also be responsible for their genotoxicity. Determination of these genotoxic impurities at trace levels requires highly sensitive and selective analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical research and development. Experimental guidance for the analytical determination of some important classes of genotoxic impurities is still unavailable in the literature. Therefore, the present review explores the structural alerts of commonly encountered potential genotoxic impurities, draft guidance of various regulatory authorities in order to control the level of impurities in drug substances and to assess their toxicity. This review also describes the analytical considerations for the determination of potential genotoxic impurities at trace levels and finally few case studies are also discussed for the determination of some important classes of potential genotoxic impurities. It is the authors' intention to provide a complete strategy that helps analytical scientists for the analysis of such potential genotoxic impurities in pharmaceuticals.

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Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances

Cited by 88 publications

References 22 publications

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

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

Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review

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