Module 3 - Strategic case studies in practice

Thus, nitromethane and its potential oxidative degradation to nitrosating agents cannot be excluded currently as a contributing factor in this case. Some ranitidine HCl batches were found to be contaminated significantly with NDMA. For more information, please refer to the ranitidine referral under Article 31 of Directive 2001/83/EC.

2.2.2.2. Confirmed root-causes identified in the sartans referral

Further to the sartans Article 31 review and based on the reviews of responses from API manufacturers and assessments of CEP dossiers by EDQM in relation to N- nitrosamine impurities, 11 sartan CEPs out of a total of 125 were suspended, including 7 valsartan CEPs, 2 irbesartan CEPs and 2 losartan potassium CEPS, triggering recalls of the concerned medicinal products by the responsible NCAs. However, it has to be noted that the vast majority of sartan CEPs (i.e. > 90 %) were not affected, indicating high probability of process-specific route causes. Olmesartan and candesartan CEPs were considered valid by EDQM both throughout the Referral Procedure and until now, enabling the corresponding medicinal products to remain available as alternative medicines. In general, 5-substituted-1H-tetrazoles (further referred to as “tetrazoles”), known to exist in equilibrium of the 1H and 2H-tautomeric forms [Wittenberger, S. J., (1994)], can be synthesized by various procedures [Benson F.R., (1947); Herr R.J., (2002)] including by the reaction of organic nitriles with inorganic and organometallic azide reagents via a concerted 1,3 dipolar cycloaddition reaction or closely related ionic mechanisms. To avoid the use of toxic and explosive hydrazoic acid (HN 3 ), alternative reagents or reagent / catalyst combinations such as sodium azide (NaN 3 ), tributyltin azide (Bu 3 SnN 3 ), triethylammonium chloride (TEA HCl)/ sodium azide, tributyltin chloride (Bu 3 SnCl) / sodium azide or zinc bromide (ZnBr 2 ) / sodium azide etc. are frequently preferred for synthesizing tetrazoles [Herr R.J. (2002), Himo, F et al. (2003)]. Regarding active substance dossiers, most processes for tetrazole synthesis were developed by manufacturers of starting materials, intermediates and active substances on the basis of genotoxic azide reagents. In order to speed up reactions and to shift the equilibrium of the cyclization reaction towards the product, it is required to add catalysts (phase transfer, Lewis acids), to apply reagents in excess and/or to perform the reactions at high temperatures in suitable solvents with higher boiling points [e.g. N , N- dimethylformamide (DMF), dimethylsulfoxide (DMSO) and N- methylpyrrolidone (NMP)] over several hours [Herr, R.J., (2002)].

Figure 2.2.2.2-1 Basic structural features and standards synthesis of tetrazoles [Wittenberger, S. J., (1994); Herr, R.J., (2002)]

EMA/369136/2020

Page 12/90