Quantification of Structurally Alert Mutagenic Impurities in Meropenem Trihydrate Drug Substance by Liquid Chromatography with High Resolution Mass Spectrometer (LC-HRMS)
Potential mutagenic impurities in Active Pharmaceutical Ingredient, Meropenem Trihydrate were assessed and a novel analytical method for their quantification was developed and validated. This Liquid Chromatographic method using High Resolution Mass Spectrometer (LC-HRMS) technique is proved to be suitable for simultaneous quantification of all ten identified impurities with required specificity, sensitivity, resolution, precision, accuracy, and other method characteristics as per ICH Guidelines. The acceptable limit of less than 2.9 μg/g was considered for evaluations, based on drug substance dosage and duration of treatment. The method stands most sensitive with a Limit of Detection of 0.35 μg/g, considering the challenge full acceptance criteria as per current regulatory standards.
References
[1]
Baldwin, C.M., Lyseng-Williamson, K.A. and Keam, S.J. (2008) Meropenem: A Review of Its Use in the Treatment of Serious Bacterial Infections. Adis Drug Evaluation. Drugs, 68, 803-838. https://doi.org/10.2165/00003495-200868060-00006
[2]
Fish, D.N. and Singletary, T.J. (1997) Meropenem, a New Carbapenem Antibiotic. Pharmacotherapy, 17, 644-669. https://doi.org/10.1002/j.1875-9114.1997.tb03742.x
[3]
(1996) MERREM® IV (Meropenem for Injection), for Intravenous Use Initial U.S. Approval. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050706s037lbl.pdf
[4]
Cioju, O., Jensen, T., Pressle, T., KroglzJohansenl, H., Koch, C. and Hpiby, N. (1996) Meropenem in Cystic Fibrosis Patients Infected with Resistant Pseudomonas aeruginosa or Burkholderia cepacia and with Hypersensitivity to β-Lactam Antibiotics. Clinical Microbiology and Infection, 2, 91-98. https://doi.org/10.1111/j.1469-0691.1996.tb00212.x
[5]
Prival, M.J. and Zeiger, E. (1998) Chemicals Mutagenic in Salmonella typhimurium Strain TA1535 but Not in TA100. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 412, 251-260. https://doi.org/10.1016/S1383-5718(97)00196-4
[6]
Müller, L., Mauthe, R.J., Riley, C.M., Andino, M.M., De Antonis, D., Beels, C., De George, J., De Knaep, A.G.M., Ellison, D., Fagerland, J.A., Frank, R., Fritschel, B., Galloway, S., Harpur, E., Humfrey, C.D.N., Jacks, A.S.J., Jagota, N., Mackinnon, J., Mohan, G., Ness, D.K., O’Donovan, M.R., Smith, M.D., Vudathala, G. and Yotti, L. (2006) A Rationale for Determining, Testing, and Controlling Specific Impurities in Pharmaceuticals That Possess Potential for Genotoxicity. Regulatory Toxicology and Pharmacology, 44, 198-211. https://doi.org/10.1016/j.yrtph.2005.12.001
[7]
(2014) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf
[8]
Expert Knowledge Base, Derek (6.0.1)-Nexus (2.2.1); Statistical Based Software, Sarah (3.0.0) by Lhasa Limited. https://www.lhasalimited.org/blog/trusting-expert-derived-knowledge-an-overview-of-alert-creation-in-derek-nexus/
[9]
Lee, K., Yoo, W. and Jeong, J.H. (2022) Analytical Method Development for 19 Alkyl Halides as Potential Genotoxic Impurities by Analytical Quality by Design. Molecules, 27, 4437. https://doi.org/10.3390/molecules27144437
[10]
Raja, K.D., Ramana, V.S.V., Babu, K.R., Babu, B.K., Kumar, V.J., Kumar, K.S.R.P. and Sharma, H.K. (2020) Development and Validation of GC-MS Method for the Trace Level Determination of Structurally Alert Alkyl Halide Impurities in Cilastatin Sodium Drug Substance. IJPSR, 11, 5017-5026.
[11]
(2005) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Q2 (R1), Validation of Analytical Procedures: Text and Methodology. https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf
