Quantitation of Genetox Impurities Using a Surrogate Standard Approach

Heather Wang, Regina Nardi, Yuri Bereznitski, Roy Helmy, David J. Waterhouse

Analytical Chemistry, Merck Research Laboratories, Merck Sharp & Dohme Corp., Rahway, USA..

DOI: 10.4236/jasmi.2013.33021                

Abstract

With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).

Keywords

Potential Genotoxic Impurity (PGI); Active Pharmaceutical Ingredient (API); Mass Spectrometry;Surrogate Standard; Analyte; Relative Response Factor (RRF)

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	T. McGovern and D. Jacobson-Kram, “Regulation of Genotoxic and Carcinogenic Impurities in Drug Substances and Products,” Trends in Analytical Chemistry, Vol. 25, No. 8, 2006, pp. 790-795. http://dx.doi.org/10.1016/j.trac.2006.06.004
[2]	V. Gangadhar, P. Saradhi and R. Rajavikram, “The Determination and Control of Genotoxic Impurities in APIs,” Pharmceutical Technology, Vol. 35, 2011 pp. s24-s30. http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=738391&pageID=3
[3]	L. Muller, R. J. Mauthe, C. M. Riley, M. M. Andino, D. D. Antonis, C. Beels, J. De George, A. G. M. De Knaep, D. Ellison, J. A. Fagerland, R. Frank, B. Fritschel, S. Galloway, E. Harpur, C. D. N. Humfrey, A. S. Jacks, N. Jagota, J. Mackinnon, G. Mohan, D. K. Ness, M. R. O’Donovan, M. D. Smith, G. Vudathala and L. Yotti, “A Rationale for Determining, Testing, and Controlling Specific Impurities in Pharmaceuticals That Posses Potential For Genotoxicity,” Regulatory Toxicology and Pharmacology, Vol. 44, No. 3, 2006, pp. 198-211. http://dx.doi.org/10.1016/j.yrtph.2005.12.001
[4]	“Guidance for Industry Q3A Impurities in New Drug Substances,” ICH, 2008. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127984.pdf
[5]	P. Kushwaha, “Genotoxic Impurities in Pharmaceuticals,” Pharmainfo.net, 2010. http://www.pharmainfo.net/reviews/genotoxic-impurities-pharmaceuticals
[6]	A. Teasdle, D. Elder, S.-J. Chang, S. Wang, R. Thompson, N. Benz and I. H. Snaches Flores, “Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate Control,” Organic Process Research & Development, Vol. 17, No. 2, 2013, pp. 221-230. http://dx.doi.org/10.1021/op300268u
[7]	M. Oss, A. Kruve, K. Herodes and I. Leito, “Electrospray Ionization Efficiency Scale of Organic Compounds,” Analytical Chemistry, Vol. 82, No. 7, 2010, pp. 2865-2872. http://dx.doi.org/10.1021/ac902856t
[8]	C. G. Enke, “A Predictive Model for Matrix and Analyte Effects in Electrospray Ionization of Singly-Charged Ionic Analytes,” Analytical Chemistry, Vol. 69, No. 23, 1997, pp. 4885-4893. http://dx.doi.org/10.1021/ac970095w
[9]	P. Kebarle, “A Brief Overview of the Present Status of the Mechanisms Involved in Electrospray Mass Spec-trometry,” Journal of Mass Spectrometry, Vol. 35, No. 7, 2000, pp. 804-817. http://dx.doi.org/10.1002/1096-9888(200007)35:7%3C804::AID-JMS22%3E3.0.CO;2-Q
[10]	M. Yamashita and J. B. Fenn, “Electrospray Ion Source. Another Variation on the Free-Jet Theme,” Journal of Physical Chemistry, Vol. 88, No. 20, 1984, pp. 4451-4459. http://dx.doi.org/10.1021/j150664a002
[11]	D. I. Carroll, I. Dzidic, R. N. Stillwell, K. D. Haegele and E. C. Horning, “Atmospheric Pressure Ionization Mass Spectrometry: Corona Discharge Ion Source for Use in Liquid Chromatograph-Mass Spectrometer-Computer Analytical System,” Analytical Chemistry, Vol. 47, No. 14, 1975, pp. 2369-2373. http://dx.doi.org/10.1021/ac60364a031
[12]	J. F. Anacleto, L. Ramaley, F. M. Benoit, R. K. Boyd and M. A. Quilliam, “Comparison of Liquid Chromatography/Mass Spectrometry Interfaces for the Analysis of Polycyclic Aromatic Compounds,” Analytical Chemistry, Vol. 67, No. 22, 1995, pp. 4145-4154. http://dx.doi.org/10.1021/ac00118a018