Design of experiments as a tool for LC–MS/MS method development for the trace analysis of the potentially genotoxic 4-dimethylaminopyridine impurity in glucocorticoids

Székely, György; Henriques, Bruno; Gil, Marco; Ramos, Antonio J.; Álvarez, Carlos Márquez

doi:10.1016/j.jpba.2012.07.006

Cited by 51 publications

(25 citation statements)

References 19 publications

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“…Some representative examples are for MMS (methylmethane sulfonic acid) and EMS (ethylmethane sulfonic acid) in Lopinavir and Ritonavir 59 , TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl) in filibuvir 60 and 4-dimethylaminopyridine in glucocorticoids 61 .…”

Section: Analytical Collaborationsmentioning

confidence: 99%

Mutagenic Impurities: Precompetitive/Competitive Collaborative and Data Sharing Initiatives

Elder

White

Harvey

et al. 2015

Org. Process Res. Dev.

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Pre-competitive and competitive collaborations have flourished during the development of the ICH M7 guidelines (mutagenic impurities). The majority of these interactions are 'honest broker' type arrangements, where an autonomous, independent third party is tasked with coordinating the activities of the consortium. Sometimes, more than one 'honest broker' can be involved in the activity. Lhasa has been at the centre of many of these collaborative initiatives; i.e., Derek Nexus Pharmaceutical Intermediates, Excipients, Zeneth, Mirabilis. The Product Quality Research Institute (PQRI) coordinated activities allowing a mechanistic understanding of the reaction mechanism for the formation of sulfonate esters, which after the Viracept withdrawal had been at the forefront of regulatory thinking. Other 'not for profit' organisations that have played a role in the advancement of the greater understanding of mutagenic impurities include the various trade organizations, i.e. the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industry Associations (EFPIA).The other collaborative interactivity is the JDI (Just Do It). This is primarily focussed on analytical collaborative efforts, where individuals have collaborated on areas of mutual interest. To a lesser extent this has also been seen in the area of pharmaceutical intermediates, where individual companies have collaboratively pooled data on areas of common interest, e.g. acyl/sulfonyl halide false positives. The majority of the most significant JDI collaborations involve sharing feedback on the use and applicability of a second structure activity relationship system (SAR), analytical methodologies and analytical strategies.One of the key outcomes of these collaborations are peer reviewed scientific publications whereby other interested parties (including regulators) can be made aware of the findings from the consortia. Going forward, the area of mutagenic impurities enshrined under ICH M7, will continue to be a fruitful area for precompetitive collaborations of all types building on the success of the previous initiatives described.

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Section: Analytical Collaborationsmentioning

confidence: 99%

Mutagenic Impurities: Precompetitive/Competitive Collaborative and Data Sharing Initiatives

Elder

White

Harvey

et al. 2015

Org. Process Res. Dev.

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“…DoE has been used in optimizing other steps of the typical metabolomics workflow, including sample preparation and data processing (A et al 2005; Eliasson et al 2012; Zheng et al 2013). LC-MS methods have also been improved in this manner, however the response of interest has typically been targeted to one metabolite or a single class of compounds (Zhou et al 2009; Székely et al 2012; Kostić et al 2013; Riter et al 2005). …”

Section: Introductionmentioning

confidence: 99%

Comprehensive optimization of LC–MS metabolomics methods using design of experiments (COLMeD)

Rhoades

Weljie

2016

Metabolomics

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Introduction Both reverse-phase and HILIC chemistries are deployed for liquid-chromatography mass spectrometry (LC-MS) metabolomics analyses, however HILIC methods lag behind reverse-phase methods in reproducibility and versatility. Comprehensive metabolomics analysis is additionally complicated by the physiochemical diversity of metabolites and array of tunable analytical parameters. Objective Our aim was to rationally and efficiently design complementary HILIC-based polar metabolomics methods on multiple instruments using Design of Experiments (DoE). Methods We iteratively tuned LC and MS conditions on ion-switching triple quadrupole (QqQ) and quadrupole-time-of-flight (qTOF) mass spectrometers through multiple rounds of a workflow we term COLMeD (Comprehensive optimization of LC-MS metabolomics methods using design of experiments). Multivariate statistical analysis guided our decision process in the method optimizations. Results LC-MS/MS tuning for the QqQ method on serum metabolites yielded a median response increase of 161.5% (p<0.0001) over initial conditions with a 13.3% increase in metabolite coverage. The COLMeD output was benchmarked against two widely used polar metabolomics methods, demonstrating total ion current increases of 105.8% and 57.3%, with median metabolite response increases of 106.1% and 10.3% (p<0.0001 and p<0.05 respectively). For our optimized qTOF method, 22 solvent systems were compared on a standard mix of physiochemically diverse metabolites, followed by COLMeD optimization, yielding a median 29.8% response increase (p<0.0001) over initial conditions. Conclusions The COLMeD process elucidated response tradeoffs, facilitating improved chromatography and MS response without compromising separation of isobars. COLMeD is efficient, requiring no more than 20 injections in a given DoE round, and flexible, capable of class-specific optimization as demonstrated through acylcarnitine optimization within the QqQ method.

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“…Katerina et al [59] and Szekely et al [45] extensively worked on the analysis of potential genotoxic impurities in meropenem and glucocorticoids, respectively. Use of LC-MS/MS in the study helped in identifying genotoxic impurities in trace levels, reducing the cost per Agilent Zorbax C18 Column 50 mm×3 mm ID, 3.5 µm dp [43] Poroshell 120SB C18 Column 150 mm×4.6 mm ID, 2.7 µm dp [44] Zorbax Eclipse Plus C18 Column 100 mm×4.6 mm ID, 3.5 µm dp [47] Varian Polaris C18 A Column 150 mm×2 mm ID, 5 µm dp [48] Poroshell 120EC C-18 Column 100 mm×4.6 mm ID, 2.7 µm dp [5] Zorbax SB C18 column 150 mm×4.6 mm ID, 5 µm dp [49] Eclipse Plus C18 RRHD Column 100 mm×2.1 mm ID, 1.8 µm dp [50] Poroshell HPH C18 Column 50 mm×2.1 mm ID, 2.7 µm dp [51] Zorbax SB-CN Column 200 mm×4.6 mm ID, 5 µm dp [52] Zorbax RX C8 Column 250 mm×4.6 mm ID, 5 µm dp…”

Section: Role Of Lc-ms In the Profiling Of Genotoxic Impuritiesmentioning

confidence: 99%

“…Gemini C18 Column 50 mm×2 mm ID, 3 µm dp [45] Gemini C18 Column 150 mm×3 mm ID, 3 µm dp [62,63] Gemini NX C18 Column 250 mm×4.6 mm ID, 5 µm dp [64-68] Luna C18 Column 250 mm×4.6 mm ID, 10 µm dp [69] Luna C18 Column 150 mm×3 mm ID, 5 µm dp [70] Gemini C18 Column 150 mm×4.6 mm ID, 3 µm dp [71] Shiseido CAPCELL PAK C18 Column 150 mm×2 mm ID, 5 µm dp [44,72] …”

Section: Gl Sciencesmentioning

confidence: 99%

Application of Liquid Chromatography Coupled With Mass Spectrometry in the Impurity Profiling of Drug Substances and Products

Akshatha

Gurupadayya

2018

Asian J Pharm Clin Res

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As the drug safety and efficacy is hampered in the presence of an impurity, the international regulatory agencies laid down stringent limits for the control of impurities in the active pharmaceutical ingredient and pharmaceutical formulations. The conventional approaches lack the characterization of impurities in trace levels, due to sensitivity issues, hyphenated techniques are preferred. Among the modern hyphenated techniques, liquid chromatography-mass spectrometry (LC-MS) has high sensitivity and can analyze large number of organic compounds in a short period of time. In the present study, the impurity profiling of various drug substances and products using LC-MS about past 6 years were retrospect for its importance, instrumentations, and applications.

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Design of experiments as a tool for LC–MS/MS method development for the trace analysis of the potentially genotoxic 4-dimethylaminopyridine impurity in glucocorticoids

Cited by 51 publications

References 19 publications

Mutagenic Impurities: Precompetitive/Competitive Collaborative and Data Sharing Initiatives

Mutagenic Impurities: Precompetitive/Competitive Collaborative and Data Sharing Initiatives

Comprehensive optimization of LC–MS metabolomics methods using design of experiments (COLMeD)

Application of Liquid Chromatography Coupled With Mass Spectrometry in the Impurity Profiling of Drug Substances and Products

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