A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity

Müller, Lutz; Mauthe, Robert J.; Riley, Christopher M.; Andino, Marta M.; Antonis, David De; Beels, Chris; DeGeorge, Joseph J.; Knaep, Alfons G. M. De; Ellison, Dean; Fagerland, Jane A.; Frank, Rebecca D.; Fritschel, Betsy; Galloway, Sheila M.; Harpur, Ernest S.; Humfrey, Charles; Jacks, Alexander S.; Jagota, Nirdosh; Mackinnon, John D.; Mohan, Ganapathy; Ness, Daniel; O’Donovan, Michael R.; Smith, Mark D.; Vudathala, Gopi; Yotti, Larry P.

doi:10.1016/j.yrtph.2005.12.001

Cited by 412 publications

(204 citation statements)

References 35 publications

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“…1, an intermediate of the fluconazole was prepared from 1-(2,4-difluorophenyl)-2-[1,2,4]triazol-1-yl-ethanone (precursor of intermediate, in the scheme it is represented as compound 3). As per the study of Muller et al [9], this intermediate belongs to group 2 of genotoxic impurities and may cause the unwanted genotoxicity and carcinogenicity. According to the study of micronucleus assay by Fucic et al [10], fluconazole was caused genome damage in young animals and in new-born pups.…”

Section: Introductionmentioning

confidence: 85%

Method Development and Validation Study for Quantitative Determination of Genotoxic Impurity and Its Precursor in Fluconazole Sample by Liquid Chromatography–tandem Mass Spectrometry

Devanna

Reddy

2016

Int J Pharm Pharm Sci

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Objective: The objective of this work is method development and validation study for quantitative determination of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole, a genotoxic impurity and its precursor in a fluconazole drug sample by liquid chromatography-tandem mass spectrometry.Methods: LC-MS/MS analysis of these impurities was performed on Hypersil BDS C18 (100 mm x 4.0 mm, 3 µm) column. 5 mmol ammonium acetate and acetonitrile in the ratio of 65:35 (v/v) was used as the mobile phase with a flow rate of 0.4 ml/min. The developed method was accomplished with a short run time of 10 min. Triple quadrupole mass detector coupled with positive electrospray ionization was used for the quantification of genotoxic impurities in multiple reaction monitoring (MRM). Results:The method was validated as per International Conference on Harmonization (ICH) guidelines. The method was linear in the range of 0.30 µg/g to 11.37 µg/g for impurity A and 0.30 µg/g to 11.34 µg/g for impurity B with a correlation coefficient of 0.999. The accuracy of the method was in the range of 98.25 % to 100.53 % for both impurities. Conclusion:A specific, selective, highly sensitive and more accurate analytical method using LC-MS/MS coupled with positive electrospray ionization has been developed for the quantification of genotoxic impurity (1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole) and its precursor (1-(2,4-difluorophenyl)-2-[1,2,4]triazol-1-yl-ethanone) at 0.3 µg/g with respect to the 5.0 mg/ml of fluconazole.

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Section: Introductionmentioning

confidence: 85%

Method Development and Validation Study for Quantitative Determination of Genotoxic Impurity and Its Precursor in Fluconazole Sample by Liquid Chromatography–tandem Mass Spectrometry

Devanna

Reddy

2016

Int J Pharm Pharm Sci

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“…It has also been clarified and confirmed that durational adjustments to the TTC limit are acceptable for investigational studies. The proposal of a staged TTC was first described by the Pharmaceutical Research and Manufacturers of America (PhRMA) cross-industry workgroup led by Mueller et al 21 However, the SWP incorporated a dose rate correction factor of 2 to account for deviations from the linear extrapolation model which gives slightly different values than those from the original PhRMA proposal. The acceptable limits for daily intake of GTI according to the SWP are 5, 10, 20 and 60 μg/day for duration of exposure of 6-12 months, 3-6 months, 1-3 months, and less than 1 month, respectively.…”

Section: Ema Guideline On the Limits Of Genotoxic Impuritiesmentioning

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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“…As stated by the ICH safety guidelines (S2A and S2B), "for compounds giving negative results, the completion of 3-test battery, perform and evaluate in accordance with current recommendations, will usually provide a sufficient level of safety to demonstrate the absence of genotoxic activity." Thus, any compound that produces a positive result in one or more assays in the standard battery has historically been regarded as genotoxic, which may require further testing for risk assessment (Müller et al, 2006). …”

Section: Ich Guidelinesmentioning

confidence: 99%

“…Drug substances and their relative compounds such as impurities constitute an important group of genotoxic compounds. Thus, these compounds pose an additive concern to clinical subjects and patients (Müller et al, 2006). Considering the importance of this problem, the challenge for regulatory agencies is to form guidelines and standards for the identification and control of genotoxic compounds and their impurities especially in pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceuticals

Jouyban¹,

Parsa²

2012

Toxicity and Drug Testing

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A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity

Cited by 412 publications

References 35 publications

Method Development and Validation Study for Quantitative Determination of Genotoxic Impurity and Its Precursor in Fluconazole Sample by Liquid Chromatography–tandem Mass Spectrometry

Method Development and Validation Study for Quantitative Determination of Genotoxic Impurity and Its Precursor in Fluconazole Sample by Liquid Chromatography–tandem Mass Spectrometry

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

Genotoxic Impurities in Pharmaceuticals

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