Module 3 - Strategic case studies in practice

nitrosata ble compounds to ≤100 µg/kg in toys made with elastomers, which can potentially be taken into the mouth. The German Bundesinstitut für Risikobewertung (BfR) calculated a yearly exposure of 50 or 68 ng (depending on the assessment strategy) assuming the maximum release limit of 0.05 mg/kg rubber is met, and the inflating time equates to 5 hours per year. In Cosmetics, the level of N- Nitrosamines should not exceed 50 µg/kg with specific recommendation for NDELA (SCCS 2011 and 2012). Veterinary medicinal products (VMPs) The Guideline on assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products (EMA/CVMP/SWP/377245/2016) refers to mutagens of extremely high carcinogenic potency (cohort of concern), i.e., aflatoxin-like-, N -nitroso-, and alkyl-azoxy structures as follows: Intakes even below the TTC are theoretically associated with a potential for a significant carcinogenic risk and a case-by-case approach using e.g., carcinogenicity data from closely related structures, if available, should be developed to justify acceptable intakes for authorised VMPs. Principally, these substances should not occur as an impurity of an API or a VMP, due to their extremely high carcinogenic potency. 2.2.2.1. Introduction on root-causes for the presence and formation of N -nitrosamines in chemical API synthesis Initially in July 2018 a Referral Procedure (EMEA/H/A-31/1471) under Article 31 of Directive 2001/83/EC for sartans with tetrazole ring containing products (further referred to as “ Sartans Referral Procedure”) was triggered to assess the impact of N- nitrosamine impurities on the benefit-risk balance of valsartan medicinal products. It became evident that the detected levels of NDMA, and subsequently, other detected N -nitrosamines including NDEA, diisopropyl- N -nitrosamine (DIPNA), ethylisopropyl- N -nitrosamine (EIPNA) and 4-(methyl)(nitroso)amino)butanoic acid (NMBA) exceeded limits based on ICH M7(R1) principles for substances of the “cohort of concern” defined in this guideline and calculated considering a lifetime daily exposure, referenced there as “acceptable intake”(AI), further stated as “ICH M7(R1) limit” in this report. The procedure was extended in September 2018 to cover all EU authorised Angiotensin-II-receptor antagonists/blockers, possessing a tetrazole ring: i.e. candesartan, irbesartan, losartan, olmesartan and valsartan (further referred to as “sartans”), as synthesis steps of tetrazole rings common to those sartans led to nitrosamine formation. On 31 January 2019, EMA’s CHMP concluded its Article 31 review setting temporary limits on the API applicable within a transition period of two years and defining stricter long-term requirements based on technical limits. Of note, at the time of the opinion of the sartans referral, only API root causes had been identified. Subsequent to the Sartans Art. 31 referral, one API manufacturer informed the EU authorities and European Directorate for the Quality of Medicines (EDQM) that it had discovered NDMA in some batches of its pioglitazone API. The NDMA levels in the concerned pioglitazone batches were below the interim limits set for sartans (based on ICH M7(R1) ) but the presence nonetheless of an N- nitrosamine in a non-sartan API was a significant finding. As a precaution, the EDQM reviewed immediately all Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) applications for this substance and in April 2019, EMA and National Competent Authorities (NCAs) requested that MAHs for pioglitazone who were using certain reagents in their manufacturing processes check their processes, to rule out the presence of N- nitrosamines. 2.2.2. Presence and formation of N -nitrosamines in human medicinal products

EMA/369136/2020

Page 9/90