ICH Guideline M7 on DNA-reactive impurities: salient points

April 16th, 2013 Leave a reply »

ICH Guideline M7 on DNA-reactive compounds was issued on 6 February 2013 [1]. This Draft Consensus Guideline, formulated with input from representatives from pharma, may change after regulatory bodies receive comments.

“Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk”

INTRODUCTION. The ICH has set limits down to as low as micrograms / day for impurities in APIs that might react with DNA. Both controlling and assaying for impurities at such low levels can require large amounts of resources.

RELATED TERMS. Mutagens alter the genetic code, while genotoxins are defined as compounds that react with DNA and cause cancer. Carcinogens cause cancer by damaging genetic material directly or indirectly [2,3]. Clastogens are compounds that cause a change in the appearance of chromosomes, due to the breakage, addition or deletion of genetic material [4]. Teratogens produce abnormalities in developing fetuses, and are not necessarily mutagens [2]. Altered genetic code may be repaired enzymatically [5], or lead to mutations in offspring, or to programmed death of the cell (apoptosis) [4]. Strictly speaking, genotoxic impurities (GTIs) have been demonstrated to be genotoxic, while potentially genotoxic impurities (PGIs) may be genotoxic [6].

SALIENT POINTS OF ICH M7. Although it is not specifically stated, ultimately the final guidance should replace the 2008 draft Guidance, “Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches” [7]. In the current Guideline five categories of impurities with potential carcinogenic and mutagenic activity were proposed, with corresponding actions. Applicants need to propose limits for GTIs, based on data from toxicology studies. Two complementary in silico analyses are recommended to predict mutagenicity of PGIs. Permissible levels of PGIs are higher in many categories than in the staged TTC levels provided in the earlier Guidance; limits again depend on the number of days over which the compound will be administered to humans.

The M7 Draft Consensus Guideline is consistent with earlier guidance in many ways. For instance, a QbD approach may be accepted if an applicant understands processing parameters and chemical fate of impurities. Following the processing over the lifecycle of the drug is also stressed: knowledge from manufacturing can be used to control operations. The M7 guideline does not override ICH S9, which mentions that higher limits may be set for impurities in drugs to treat advanced stages of cancer [8].

For strategies on identifying and controlling genotoxic impurities, see the excellent volume by Teasdale [9] and other discussions [6].

1. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_2.pdf
2. Frank, P.; Ottoboni, M. A. The Dose Makes the Poison; Wiley; 3d ed.; 2011; pp. 90, 145, 158.
3. For instance, aflatoxin B1 is enzymatically activated and the resulting epoxide reacts with DNA: Baertschi, S. W.; Raney, K. D.; Stone, M. P.; Harris, T. M. J. Am. Chem. Soc. 1988, 110, 7929.
4. Juo, P.-S. Concise Dictionary of Biomedicine and Molecular Biology; 2nd ed.; CRC Press; 2002, pp. 283 & 105.
5. For instance, photodimers of thymine can be repaired by photolyase: Kao, Y.-T.; Saxena, C.; Wang, L.; Sancar, A.; Zhong, D. PNAS 2005, 102(45), 16128.
6. Anderson, N. G. Practical Process Research & Development – A Guide for Organic Chemists; 2nd edition; Academic Press: San Diego; 2012; pp. 379 – 386.
7. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079235.pdf
8. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM085389.pdf
9. Genotoxic Impurities: Strategies for Identification and Control; Teasdale, A., Ed.; Wiley Interscience; 2010.

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