Skip to main content

Modern Approaches to Estimating the Content of Genotoxic Impurities in Drugs (a Review)

This review considered international approaches to assessment of the content of genotoxic impurities (residual solvents and various inorganic and organic impurities) in drugs. Foreign and domestic regulations defining requirements for the classification, control, and toxicological risk assessment of potential genotoxic impurities in drug substances and drugs were compared. The use of highly sensitive and specific analytical methods for detecting genotoxic impurities in drugs was justified. The need to improve the domestic regulatory framework on the control of elemental genotoxic impurities (heavy metals) and to prepare guidelines on the assessment of potentially genotoxic organic impurities in drugs was demonstrated.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. T. McGovern and D. Jacobson-Kram, Trends Anal. Chem., 25(8), 790 – 795 (2006).

    Article  CAS  Google Scholar 

  2. K. L. Dearfield, M. C. Cimino, N. E. McCarroll, et al., Mutat. Res., Genet. Toxicol. Environ. Mutagen., 521, 121 – 135 (2002).

    Article  CAS  Google Scholar 

  3. R. Wear and C. Sharma, Int. J. Toxicol. Pharmacol. Res., 5(1), 33 – 41 (2013).

    Google Scholar 

  4. A. D. Durnev and A. S. Lapitskaya, Ekol. Genet., X(3), 41 – 52 (2012).

  5. Russian Federation State Pharmacopoeia, XIIth Ed., Moscow (2007).

  6. European Pharmacopoeia, 7th Ed., Suppl. 8.2; URL:

  7. United States Pharmacopeia, 38th Ed.; URL:

  8. E. L. Kovaleva, Standardization of Drug Substances and Drugs in Tablet Dosage Form [in Russian], Grif i K, Moscow (2012), p. 66.

  9. Guideline for Elemental Impurities Q3D ICH Harmonised Guideline; URL: Q3D_Step_4.pdf

  10. R. W. Kashyap, B. Mitali, S. S. Rao, et al., Pharm. Technol., 36(3), 58 – 72 (2012).

    Google Scholar 

  11. Impurities in New Drug Substances Q3A(R2) ICH Harmonized Tripartite Guideline; URL: Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2_Guideline.pdf

  12. Impurities in New Drug Products Q3B(R2) ICH Harmonised Tripartite Guideline; URL: Site/ICH_Products/Guidelines/Quality/Q3B_R2/ Step4/Q3B_R2_Guideline.pdf

  13. Guideline on the Limits of Genotoxic Impurities (EMEA/CHMP/QWP/251344/2006); URL: http://www.ema. library/Scientific_guideline/2009/09/WC500002903.pdf

  14. Impurities: Guideline for Residual Solvents, Q3C(R5) ICHHarmonised Tripartite Guideline; URL: Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf

  15. R. Kroes, A. G. Renwick, M. Cheeseman, et al., Food Chem. Toxicol., 42(1), 65 – 83 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. L. Muller, R. J. Mauthe, C. M. Riley, et al., Regul. Toxicol. Pharmacol., 44(3), 198 – 211 (2006).

    Article  PubMed  Google Scholar 

  17. Press Release. European Medicines Agency, EMEA/ 275367/200; URL: GB/document_library/Press_release/2009/11/WC500014204.pdf

  18. D. Polyakova, online, 699(28) (2009); URL:

  19. 2.html#.VUyfm2zk_7U

  20. Draft Guidance for Industry, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (CPMP/QWP/159/96 Cor.); URL: regulatoryinformation/guidances/ucm079235.pdf []

  21. A. V. B. Reddy, J. Jaafar, K. Umar, et al., J. Sep. Sci., 38(5), 764 – 779 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, M7 ICH Harmonised Tripartite Guideline; URL: Products/Guidelines/Multidisciplinary/M7/M7_Step 4.pdf (accession date: Aug. 25, 2014).

  23. S. V. Moiseev, V. I. Krylov, T. V. Masterkova, et al., Vedomosti NTsESMP, No. 1, 15 – 19 (2014).

  24. A. A. Illarionov, L. N. Grushevskaya, L. M. Gaevaya, et al. Khim.-farm. Zh., 48(6), 48 – 53 (2014); Pharm. Chem. J., 48(6), 408 – 413 (2014).

  25. D. Paul and K. Paul, World J. Pharm. Pharm. Sci., 4(2), 1124 – 1153 (2015).

    CAS  Google Scholar 

  26. Pharmeuropa, 26.2, 7 – 9 (2014).

  27. Pharmeuropa, 26.3, 206 – 207 (2014).



Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to O. A. Matveeva.

Additional information

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 49, No. 11, pp. 41 – 48, November, 2015.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Matveeva, O.A., Kovaleva, E.L. Modern Approaches to Estimating the Content of Genotoxic Impurities in Drugs (a Review). Pharm Chem J 49, 765–770 (2016).

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI:


  • genotoxic impurities
  • drugs
  • threshold of toxicological concern (TTC)