Module 3 - Strategic case studies in practice

2. N- nitrosative de-alkylation of the reagents TEA, DIPEA and N , N- DMA (trialkyl amines), finally yielding NDEA, DIPNA, EIPNA and NMPA; hydrolytic dissociation of the catalyst TEA HCl (quaternary ammonium salt) to give the tertiary amine TEA, followed by N- nitrosative de- alkylation, finally yielding NDEA. Table 2.2.2.2-1 N- nitrosamine formation routes and classification of reaction types N- Nitrosamine Route of Formation Reaction type classification NDMA N N O NH NaNO 2 /HX O N heat/hydrolysis

Hydrolytic and/or thermal degradation of DMF to give DMA and subsequent N- nitrosation N- nitrosative de-alkylation of the tertiary amine DIPEA Hydrolysis of quaternary ammonium salt TEA HCl to give the tertiary amine TEA and subsequent N- nitrosative de-alkylation N- nitrosative de-alkylation of the tertiary amine DIPEA Hydrolytic and/or thermal degradation of NMP to give the secondary amine MBA and subsequent N- nitrosation N- nitrosative de-alkylation of the tertiary amine N , N- DMA Nitrosation of the secondary amine DBA and/or N- nitrosative de-alkylation of the tertiary amine TBA N- nitrosative de-alkylation of the tertiary amine DIPEA

O NN

NDEA

NaNO 2 /HX

N

O NN

H

+ Cl -

hydrolysis

NaNO 2 /HX

-

N

Cl

N

H 3 O

DIPNA

O NN

NaNO 2 /HX

N

EIPNA

O NN

NaNO 2 /HX

N

O

NMBA

O

heat/hydrolysis

NaNO 2 /HX

NH

O

N

HO

N O

HO

N

NMPA

NaNO 2 /HX

N

N N

O

NDBA

O NN

NaNO 2 /HX

HN

O NN

NaNO 2 /HX

N

It became evident, however, that the proposed root cause analysis focussed only on degradative mechanisms for amine generation and N- nitrosamine formation, not taking into account the potential presence of secondary and tertiary amine impurities in the applied solvents, reagents and catalysts. According to the final report of the Lessons Learnt Exercise, the ICH Q3C (R7) solvent DMF represents a source of DMA due to the production process and due to thermal and hydrolytic degradation. The ICH Q3C (R7) solvent NMP is a source of 4-methylaminobutyric acid due to the production process and due to hydrolytic degradation. Furthermore, monoalkylamines, dialkylamines, trialkylamines and quaternary alkyl ammonium salts are potential sources of secondary and tertiary amines due to their industrial production processes. In most cases, drug substance manufacturers propose test parameters and acceptance criteria for solvents, reagents and catalysts, usually based on suppliers’ specifications but frequently delineated simply from Ph. Eur. reagent specifications defined for use in different analytical procedures according to the Ph. Eur. general notices. Often, the impurity profiles of the raw materials remain undisclosed. A literature survey on the industrial production and on the quality specifications of solvents, reagents and

EMA/369136/2020

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