EFPIA workflows for quality risk management of nitrosamine risks in medicines (ver 2.0)

The updated workflow has been published in EFPIA HP(link). The API workflow includes detailed information compared to the ver1.0. And the IQ consortium set of three conditions to investigate the potential formation of a N-nitrosamine from a vulnerable is newly included. In line with EMA guidance and given the comprehensiveness of the three conditions, absence of formation of a N-nitrosamine from the corresponding amine using these three conditions leads to the conclusion that the drug substance and/or drug product is absent of risk from this N-nitrosamine.

Conditions 1:
Amine, AcOH (~ a third of overall reaction volume), NaNO2 solution in water (1.5 eq), overall reaction media concentration 0.1 M (add water if required to reach this concentration), 20-25⁰C temperature with a cap on to avoid NOx depletion. No co-solvents to be added - reaction could be a slurry.

Conditions 2:
Amine, dilute HCl* so that pH is between 3 and 4, NaNO2 solution in water (1.5 eq), overall reaction media concentration 0.1 M (add water if required to reach this concentration), 20-25⁰C temperature with a cap on to avoid NOx depletion. Monitor pH at each time points and adjust if necessary. No co-solvents to be added - reaction could be a slurry.

*if the API is a salt of a strong acid, use the API salt in water instead of dilute HCl and do not adjust the pH

Conditions 3:
Amine free base, organic solvent that solubilises the amine (e.g. acetonitrile, tetrahydrofuran, or other aprotic solvent), tert-butyl nitrite (1.5 eq), overall reaction media concentration 0.1 M, 20-25⁰C temperature with a cap on to avoid NOx depletion. Reaction could be performed with deuterated solvent in an NMR tube if desired. Note that this anhydrous method can lead to the formation of nitrosamines that are unstable under aqueous conditions. Such instability can be used as part of a rationale to justify the absence of N-nitrosamine risk in the drug substance and/or product.

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I highlighted the updates from ver1.0 in yellow or circled them in red, as far as I knew. Yellow highlight and red circle are used in the same manner. If you are interested in it, please check the details.

efpia-nitrosamines-quality-risk-management-workflows-sep-2022 highlight.pdf (781.6 KB)

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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.

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Dear @AndyTeasdale,

Thank you for the additional information. I understand we should focus on only actual nitrosamine impurities under the conditions.

And I want to ask you about the degradation of tertiary amides and sulfonamides of API. The likelihood for degradation of tertiary amides and sulfonamides to form the corresponding secondary amine in the API or DP should be assessed for potential of nitrosamine formation, according to the guidance note2 for EFPIA DP workflow. Tertiary amides and sulfonamides are considered stable in many cases. Is the “degradation” intended for the liquid type of medicine? I am worried many DP would be the risk of nitrosamine contamination if tertiary amides had serious concerns. I would appreciate it if you could share your thoughts.