Pioglitazone is a diabetes drug (thiazolidinedione-type, also called “glitazones”), a prescription drug indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The EMA investigation also led to the detection of N-nitrosodimethylamine (NDMA) levels in some Pioglitazone products.
Nitrosamines are classified as probable human carcinogens (i.e. substances that could cause cancer). They are present in foods and water, and most people are exposed to them daily in small amounts. However, their presence in medicines is largely avoidable and the relatively low risk they pose to patients does not make them acceptable. Nitrosamines were first detected in sartan medicines in June 2018. Authorities in the EU took swift action: affected batches were recalled from pharmacies; patients and healthcare professionals were given appropriate advice on alternative treatments, and medicines across the EU were subjected to additional tests to guarantee they did not pose unacceptable risks to patients.
In January 2019, NDMA was reported in some batches of Pioglitazone and it was the first such report for a non-sartan since June 2018. The amount of NDMA present in the affected batches would lead to exposure below the 96 ng/day agreed interim limit from the Article 31 review of sartans. The manufacturer of the Pioglitazone API concerned proposed that the preliminary root cause was the use of NaNO2 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 NaNO2 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 potential root causes were also considered, including the use of solvents (e.g., DMF) contaminated with NDMA. However, this has not yet been further investigated. This case was also the first time an N-nitrosamine was detected in an API where its formation does not occur in the final synthetic step and where sources of nitrite would need to be carried over across several synthetic steps consisting of multiple unit operations, including aqueous work-ups and crystallisations, before coming into contact with a secondary amine.
Following an inspection, the manufacturing routes of all sources of Pioglitazone in the EU were assessed for the risk of N-nitrosamine formation. Only one of these routes uses sodium nitrite as well as sources of secondary amines. The other manufacturing routes were all deemed not to pose a risk of N-nitrosamine formation. MAHs using pioglitazone from those manufacturers using sodium nitrite in their processes were subsequently contacted and requested to provide risk assessments for potential N-nitrosamine formation and batch analysis data on batches of their APIs. No other contaminated sources of Pioglitazone have been identified as yet.
To summarize, the use of NaNO2 and DMF in different but subsequent synthetic steps represents the most likely source of NDMA formation (Figure 1). In this case, NDMA formation is considered principally avoidable by replacing DMF as the nitrosatable solvent or by selecting an alternative route for the manufacture of Pioglitazone HCl. The option to choose between different manufacturing processes demonstrates the need for thorough justification of the entire route during manufacturing process development.
Figure1. Critical compound combinations responsible for N-nitrosamine formation in Pioglitazone HCl
|N-nitrosamine||NOx source||Amine source||Amine nitrosated by NOx||Critical compound combinations|
EMA continues to work to ensure manufacturers are taking appropriate measures to avoid or keep impurities below acceptable limits. As part of strengthened monitoring of manufacturing, EMA and national authorities are also requesting as a precaution that companies using certain reagents to manufacture the diabetes medicine and test their products and check their processes to rule out the presence of nitrosamine impurities, in particular nitrosodimethylamine (NDMA).
For detailed information visit, https://www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf