Unlike the earlier EMA guideline, which simply stated that factors such as limited life expectancy and seriousness of disease can be used as the basis for establishing alternative limits, ICH M7 explicitly states that this guideline does not apply to drug substances and drug products intended for advanced cancer indications as defined in the scope of ICH S9.
Another interesting aspect of this is the question as to whether the oncology therapy area is a “special case” or whether the same logic applies to other treatments of life‐threatening conditions. To date experience has been that extrapolation to other life‐limiting conditions has been difficult in terms of regulatory acceptance.
1.1.10 Conclusions
Despite the substantive progress made in the evolution of the European guidelines [9], it was clear as described above significant challenges remained in terms of interpretation and also alignment with other key guidelines. It is for this reason MIs were adopted as an ICH topic, and it is this process and outcomes that are described in Chapter 2.
References
1 1 ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk European Directorate for the Quality of Medicines and Healthcare. EMA/CHMP/ICH/83812/2013.
2 2 ICH Q3A: Impurities in New drug substances (R2), October 2006.
3 3 European Directorate for the Quality of Medicines and Healthcare (2000). Enquiry: alkyl mesilate (methane sulfonate) impurities in Mesilate salts. PharmEuropa 12: 27.
4 4 Committee for Proprietary Medicinal Products, Position paper on the limits of Genotoxic Impurities, London 18th December 2002, CPMP/SWP/5199/02/draft 2.
5 5 Committee for Medicinal Products for Human Use (CHMP), Guidelines on the Limits of Genotoxic Impurities, London 23rd June 2004. CPMP/SWP/5199/02.
6 6 ICH Q3C Residual Solvents (R6), October 2016.
7 7 Snodin, D.J. and McCrossen, S. (2013). Mutagenic impurities in pharmaceuticals: a critique of the derivation of the cancer TTC (threshold of toxicological concern) and recommendations for structural‐class‐based limits. Regul Toxicol Pharmacol 67: 299–316.
8 8 Muller, L., Mauthe, R.J., Riley, C.M. et al. (2006). Regulatory Toxicology and Pharmacology 44: 198–211.
9 9 Committee for Medicinal Products for Human Use (CHMP), Guidelines on the Limits of Genotoxic Impurities, London 26th June 2006. CPMP/SWP/5199/02.
10 10 CHMP SAFETY WORKING PARTY (SWP), Question & Answers on the CHMP Guideline on the Limits of Genotoxic Impurities. London, 17 December 2009. EMEA/CHMP/QWP/251344/2006Q&A.
11 11 Elder, D.P. and Teasdale, A. (2015). Is avoidance of genotoxic intermediates/impurities tenable for complex, multistep syntheses? Organic Process Research and Development. 19: 1437–1144.
12 12 Bercu, J.P., Hoffman, W.P., Lee, C.y., and Ness, D.K. (2008). Reg Toxicology and Pharmacology 51 (3): 270–277.
13 13 CHMP Scientific article 5(3) Opinion on the potential risks of carcinogens, mutagens and substances toxic to reproduction when these substances are used as excipients of medicinal products for human use. London, 18 October 2007. EMEA/CHMP/SWP/146166/2007.
14 14 GRAS List: http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASListings/default.htmExcipients
15 15 Teasdale, A., Elder, D.P., and Snodin, D. (2010). Analytical approaches for the detection of epoxides and hydroperoxides in active pharmaceutical ingredients, drug products and herbals. Journal of Pharmaceutical and Biomedical Analysis 51: 1015–1023.
16 16 EDQM (2008). Potentially genotoxic impurities and European pharmacopoeia monographs on substances for human use. PharmEuropa 20 (3): 426–427.
17 17 Guidance for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches Draft, Center for Drug Evaluation and Research (CDER) December 2008.
18 18 Concept Paper on the Development of a Guideline on the Assessment of Genotoxic Constituents in Herbal Substances/Preparations, Committee for Medicinal Products (CHMP), European Medicines Agency, London, 25 October 2006. (EMEA/HPPC/413271/2006).
19 19 ICH Topic S9 Non‐clinical Evaluation for Anticancer Pharmaceuticals, Step 3, EMEA/CHMP/ICH/646107/2008.
20 20 ICH S9 guideline on nonclinical evaluation for anticancer pharmaceuticals ‐ questions and answers. EMA/CHMP/ICH/453684/2016
Notes
1 1 Now CHMP.
2 2 It is important to recognize that the risk factors in terms of probability of an MI being present at levels of concern are specific to the MI in question, its physicochemical properties, and process conditions.
2
ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
2.1 Introduction
ICH M7 [1] was first introduced in June 2014, undergoing a first revision in July 2017. The guidance itself is a multidisciplinary guideline reflecting the fact that mutagenic impurities are both a quality and safety topic. It focuses on the control of mutagenic impurities and was introduced to address differences that existed between regional guidelines pertaining to genotoxic (mutagenic) guidelines, the principle regional guidelines being the European Medicines Agency (EMA) guideline [2], supplemented by its associated Question and Answer (Q&A) document [3] and the draft Federal Drug Administration (FDA) guideline [4]. No formal guidance was ever published by Pharmaceutical and Medical Devices Agency (PMDA), Japan. A comprehensive overview of the chronological development of the EMA and FDA draft guidelines is described in Chapter 1. These guidelines were introduced to address a perceived gap in existing impurity guidelines ICH Q3A [5] and Q3B [6] relating to management of DNA reactive mutagenic impurities that may arise during the synthesis of the active form and through degradation of either/both the drug substance (DS)/drug product (DP). Although broadly similar within their concept, there were nevertheless sufficient enough differences between the EMA and FDA guidelines to render a global approach challenging.
Clear within the ICH M7 concept paper [7] was a desire to harmonize these guidelines and to specifically address areas of uncertainty. Critical areas identified within the concept paper included:
1 Use