Module 3 - Strategic case studies in practice

Table 2.2.2.2-2 Critical Compound Combinations responsible for N -nitrosamine formation in sartans N- Nitrosamine NOX Source Amine Source Amine nitrosated by NOX Critical Compound Combination

O

O

N H DMA

N N

N DMF

NaNO 2

reagent/solvent

NDMA

N O

N N , N- DMA

N N , N -DMA

N

NaNO 2

reagent/solvent

NMPA

N TEA

N H

O NN

reagent/reagent

DEA

NDEA

NaNO 2

-

Cl

N

N TEA

reagent/catalyst

H

TEA HCl

O NN

N

N

NaNO 2

reagent/reagent

DIPNA

DIPEA

DIPEA

O NN

N

N

NaNO 2

reagent/reagent

EIPNA

DIPEA

DIPEA

O

O

H N

reagent/solvent

O

N

N O NMP

N

HO

OH

NaNO 2

NMBA

MBA

N Cl

O NN

HN

NaNO 2

reagent/catalyst

-

TBAB

DBA

NDBA

N

TBA

2.2.2.3. Root-causes identified in the pioglitazone case

In January 2019, NDMA was reported in some batches of pioglitazone HCl, in what was the first such report for a non-sartan medicinal product since June 2018. The manufacturer of the pioglitazone API concerned proposed that the preliminary root cause was the use of NaNO 2 and HBr in an early step of the process, followed by the use of DMF and HCl in a later step. This root cause requires either sodium nitrite or another form of nitrosating agent (NOx) to be carried over across several steps before DMF is introduced (e.g. as the nitrous acid salt of the pyridine moiety). Other root causes were also considered, including the use of solvents (e.g. DMF) contaminated with NDMA. However, it was not possible to investigate some of these other causes as no retained samples of raw materials were available. This case was also the first time a N- nitrosamine has been detected in an API when its formation does not occur in the final synthetic step, and where sources of nitrite would need to be carried over across multiple unit operations including aqueous work-ups and crystallizations. A joint EDQM/EU inspection

EMA/369136/2020

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