Strategies for the identification, control and determination of genotoxic impurities in drug substances: A pharmaceutical industry perspective

Journal of Pharmaceutical and Biomedical Analysis

Volumn 55, Issue 4, 2011, Pages 662-667

  Raman, N V V S S ^a   Prasad, A V S S ^a   Ratnakar Reddy, K ^a  

^a Hetero Drugs Limited   (India)

Author keywords

Control; Drug substances; Genotoxic impurities; Identification; Pharmaceutical industry

Indexed keywords

CARCINOGEN; MUTAGENIC AGENT;

ANALYTIC METHOD; DIAGNOSTIC TEST ACCURACY STUDY; DRUG IMPURITY; DRUG INDUSTRY; FLUORESCENCE; GAS CHROMATOGRAPHY; GENOTOXICITY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; PRIORITY JOURNAL; REVIEW; SENSITIVITY ANALYSIS; TOXICITY TESTING;

CHEMISTRY TECHNIQUES, ANALYTICAL; CHEMISTRY, PHARMACEUTICAL; DRUG CONTAMINATION; DRUG INDUSTRY; EUROPE; MUTAGENS; PHARMACEUTICAL PREPARATIONS; QUALITY CONTROL; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 79955468501     PISSN: 07317085     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jpba.2010.11.039     Document Type: Review

References (52)

1. International Conference on Harmonisation Guideline on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use, S2(R1) 2008.
2. Govern T.Mc., Kram D.J. Regulation of genotoxic and carcinogenic impurities in drug substances and products. Trends Anal. Chem. 2006, 25:790-795.
3. International Conference on Harmonisation Guideline on Impurities in New Drug Substances, Q3A(R2) 2006.
4. International Conference on Harmonisation Guideline on Impurities in New Drug Products, Q3B(R2) 2006.
5. International Conference on Harmonisation Guideline for Residual Solvents, Q3C(R4) 2009.
6. European Medicines Agency Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents 2008, Doc. Ref. EMEA/CHMP/SWP/4446/2000, European Medicines Agency.
7. Ramakrishna K., Raman N.V.V.S.S., Narayana Rao K.M.V., Prasad A.V.S.S., Subhaschander Reddy K. Development and validation of GC-MS method for the determination of methyl methanesulfonate and ethyl methanesulfonate in imatinib mesylate. J. Pharm. Biomed. Anal. 2008, 46:780-783.
8. Raman N.V.V.S.S., Ratnakar Reddy K., Prasad A.V.S.S., Ramakrishna K. Development and validation of RP-HPLC method for the determination of genotoxic alkyl benzenesulfonates in amlodipine besylate. J. Pharm. Biomed. Anal. 2008, 48:227-230.
9. Raman N.V.V.S.S., Ratnakar Reddy K., Prasad A.V.S.S., Ramakrishna K. Validated chromatographic methods for the determination of process related toxic impurities in pantoprazole sodium. Chromatographia 2008, 68:481-484.
10. Raman N.V.V.S.S., Ratnakar Reddy K., Prasad A.V.S.S., Ramakrishna K. Development and validation of GC-MS method for the determination of methyl and ethyl camphorsulfonates in esomeprazole magnesium. Chromatographia 2008, 68:675-678.
11. European Medicines Agency Guideline on the Limits of Genotoxic Impurities 2007, CPMP/SWP/5199/02, EMEA/CHMP/QWP/251344/2006, European Medicines Agency.
12. Kroes R., Renwick A.G., Cheeseman M., Kleiner J., Mangelsdorf I., Piersma A., Schilter B., Schlatter J., Scothorst F., Vos J.G., Wurtzen G. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem. Toxicol. 2004, 42:65-83.
13. European Medicines Agency Question and answers on the CHMP. Guideline on the Limits of Genotoxic Impurities, Doc. Ref. EMA/CHMP/SWP/431994/2007 2009, European Medicines Agency.
14. Muller L., Mauthe R.J., Riley C.M., Andino M.M., Antonis D.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., Jagota N., Mackinnon J., Mohan G., Ness D.K., Donovan M.R.O., Smith M.D., Vudathala G., Yotti L. A rationale for determining, testing and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul. Toxicol. Pharmacol. 2006, 44:198-211.
15. Center for Drug Evaluation and Research, Food and Drug Administration Guidance (Draft) for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches 2008, Center for Drug Evaluation and Research, Food and Drug Administration.
16. Pharmeuropa 2008, 20:426-427.
17. Callis C.M., Bercu J.P., DeVries K.M., Dow L.K., Robbins D.K., Varie D.L. Risk assessment of genotoxic impurities in marketed compounds administered over a short-term duration: applications to oncology products and implications for impurity control limits. Org. Process Res. Dev. 2010, 14:986-992.
18. International Conference on Harmonisation Guideline on Nonclinical Evaluation for Anticancer Pharmaceuticals, S9 2009.
19. Humfrey C.D.N. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicol. Sci. 2007, 100:24-28.
20. Bercu J.P., Morton S.M., Deahl J.T., Gombar V.K., Callis C.M., van Lier R.B.L. In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances. Regul. Toxicol. Pharmacol. 2010, 57:300-306.
21. Ashby J., Tennant R. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat. Res. 1988, 204:17-115.
22. Ashby J., Tennant R.W. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. 1991, 257:229-308.
23. Fetterman B.A., Kim B.S., Margolin B.H., Schildcrout J.S., Smith M.G., Wagner S.M., Zeiger E. Predicting rodent carcinogenicity from mutagenic potency measured in the Ames Salmonelly assay. Environ. Mol. Mutagen. 1997, 29:312-322.
24. Dobo K.L., Greene N., Cyr M.O., Caron S., Ku W.W. The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. Regul. Toxicol. Pharmacol. 2006, 44:282.
25. Snodin D.J. Genotoxic impurities: From structural alerts to qualification. Org. Process Res. Dev. 2010, 14:960-976.
26. http://www.mdl.com/products/predictive/qsar/index.jsp.
27. http://www.multicase.com/products/prod01.htm.
28. Deductive Estimation of Risk from Existing Knowledge, marketed by LHASA Ltd., Leeds, UK, https://www.lhasalimited.org/index.php/derek.
29. Pierson D.A., Olsen B.A., Robbins D.K., DeVries K.M., Varie D.L. Approaches to assessment, testing decisions, and analytical determination of genotoxic impurities in drug substances. Org. Process Res. Dev. 2009, 13:285-291.
30. Elder D.P., Lipczynskib A.M., Teasdalec A. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). J. Pharm. Biomed. Anal. 2008, 48:497-507.
31. Elder D.P., Teasdale A., Lipczynski A.M. Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs). J. Pharm. Biomed. Anal. 2008, 46:1-8.
32. Elder D.P., Delaney E.D., Teasdale A., Eyley S., Reif V.D., Jacq K., Facchine K.L., Oestrich R.S., Sandra P., David F. The utility of sulfonate salts in drug development. J. Pharm. Sci. 2010, 99:2948.
33. Taylor G.E., Gosling M., Pearce A. Low level determination of p-toluenesulfonate and benzenesulfonate esters in drug substance by high performance liquid chromatography/mass spectrometry. J. Chromatogr. A 2006, 1119:231-237.
34. Elder D.P., Snodinb D., Teasdalec A. Analytical approaches for the detection of epoxides and hydroperoxides in active pharmaceutical ingredients, drug products and herbals. J. Pharm. Biomed. Anal. 2010, 51:1015-1023.
35. Robinson D.I. Control of genotoxic impurities in active pharmaceutical ingredients: a review and perspective. Org. Process Res. Dev. 2010, 14:946-959.
36. Raillard S.P., Bercu J., Baertschi S.W., Riley C.M. Prediction of drug degradation pathways leading to structural alerts for potential genotoxic impurities. Org. Process Res. Dev. 2010, 14:1015-1020.
37. Patterson D.E., Powers J.D., LeBlanc M., Sharkey T., Boehler E., Irdam E., Osterhout M.H. Development of a practical large-scale synthesis of denagliptin tosylate. Org. Process Res. Dev. 2009, 13:900-906.
38. Cimarosti Z., Bravo F., Stonestreet P., Tinazzi F., Vecchi O., Camurri G. Application of quality by design principles to support development of a control strategy for the control of genotoxic impurities in the manufacturing process of a drug substance. Org. Process Res. Dev. 2010, 14:993-998.
39. Sun M., Bai L., Terfloth G.J., Liu D.Q., Kord A.S. Matrix deactivation: a general approach to improve stability of unstable and reactive pharmaceutical genotoxic impurities for trace analysis. J. Pharm. Biomed. Anal. 2010, 52:30-36.
40. International Conference on Harmonisation Guideline on Validation of Analytical Procedures, Q2(R1) 2005.
41. Sun M., Liu D.Q., Kord A.S. A systematic method development strategy for determination of pharmaceutical genotoxic impurities. Org. Process Res. Dev. 2010, 14:977-985.
42. Liu D.Q., Sun M., Kord A.S. Recent advances in trace analysis of pharmaceutical genotoxic impurities. J. Pharm. Biomed. Anal. 2010, 51:999-1014.
43. Liu D.Q., Chen T.K., McGuire M.A., Kord A.S. Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process. J. Pharm. Biomed. Anal. 2009, 50:144-150.
44. Bai L., Sun M., An J., Liu D.Q., Chen T.K., Kord A.S. Enhancing the detection sensitivity of trace analysis of pharmaceutical genotoxic impurities by chemical derivatization and coordination ion spray-mass spectrometry. J. Chromatogr. A 2010, 1217:302-306.
45. Li W. Trace analysis of residual methyl methanesulfonate, ethyl methane sulfonate and isopropyl methanesulfonate in pharmaceuticals by capillary gas chromatography with flame ionization detection. J. Chromatogr. A 2004, 1046:297-301.
46. David F., Jacq K., Sandra P., Baker A., Klee M.S. Analysis of potential genotoxic impurities in pharmaceuticals by two-dimensional gas chromatography with Deans switching and independent column temperature control using a low-thermal-mass oven module. Anal. Biochem. 2010, 396:1291-1300.
47. Alzaga R., Ryan R.W., Worth K.T., Lipczynski A.M., Szucs R., Sandra P. A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization headspace gas chromatography-mass spectrometry. J. Pharm. Biomed. Anal. 2007, 45:472-479.
48. Raman N.V.V.S.S., Ratnakar Reddy K., Prasad A.V.S.S., Ramakrishna K. Development and validation of LC methods with visible detection using pre-column derivatization and mass detection for the assay of voglibose. Talanta 2009, 77:1869-1872.
49. Prasanna S.J., Sharmaa H.K., Mukkanti K., Sivakumaran M., Kumar K.S.R.P., Kumar V.J. Validation of a sensitive ion chromatography method for determination of mono ethyl sulfate in Indinavir sulfate drug substance. J. Pharm. Biomed. Anal. 2009, 50:1065-1069.
50. Maddula S.R., Kharkar M., Manudhane K., Kale S., Bhori A., Lali A., Dubey P.K., Sarma K.R.J., Bhattacharya A., Bandichhor R. Preparative chromatography technique in the removal of isostructural genotoxic impurity in rizatriptan: use of physicochemical descriptors of solute and adsorbent. Org. Process Res. Dev. 2009, 13:683-689.
51. Yogeshwar Reddy M., Kista Reddy C., Ramesh V., Raju G., Kishore K., Saravanan G., Suryanarayana M., Debashish D. A sensitive and selective GC-MS method for analysis of process related genotoxic impurities in atenolol. Chromatographia 2010, 71:733-736.
52. Snyder R.D., Green J.W. A review of the genotoxicity of marketed pharmaceuticals. Mutat. Res. 2001, 488:151-169.