The key point here and one that aligns to the EMA Q&A document is that if it is impossible to synthesise the N-Nitrosamine then it is assumed that it cannot be formed in vivo. A good example is within the Nitroso-Derivatives of Dihydropyridine Calcium Channel Blockers (CCBs)
Industry members, including contract manufacturing organizations (CMO) which specialize in custom synthesis of reference standards, have attempted to synthesize several nitroso-dihydropyridine CCBs. One example is the attempt to synthesize the putative N-nitroso-nifedipine under neutral conditions (alkyl nitrite) and classical acidic conditions (NaNO2/acid). The results from these experiments led to no formation of N-nitroso-nifedipine, and when using the classical conditions, aromatization of the dihydropyridine ring occurred, as expected. No nitrosation was reported to occur on the aromatic ring that was formed. Earlier literature reports support these experimental observations and revealed that treatment of dihydropyridine derivatives with NaNO2 using acidic conditions, results exclusively in aromatization of the dihydropyridine ring.