Nitrosamine impurities were previously detected in batches of medicines containing the Angiotensin-II-receptor antagonist valstartan, leading to worldwide recalls of batches. Since the initial findings, nitrosamine impurities have been detected in some batches of other medicines including the diabetic treatment pioglitazone and heartburn medication ranitidine. The EMA has since announced that an EU-wide review of ranitidine has been initiated. In addition, CHMP have been requested to provide guidance for avoiding the presence of nitrosamine impurities in human medicines containing chemically synthesised active substances.
The Article 31 referral into the sartans class of medicines concluded that the nitrosoamine impurities are formed during synthesis of the tetrazole ring system, a common structural moiety in all sartans. As a consequence, several CEPs issued to manufacturers of valsartan were suspended, pending corrective actions such as development of new or modified steps in their manufacturing process and demonstrating that analytical methods are capable of detecting the trace amounts of nitrosamines detected in samples.
The acid catalysed reaction of nitrous acid with secondary amines can result in the formation of nitrosamines. It seems that in the case of sartans, some synthetic routes used sodium nitrite to quench an excess of the azide reagent used in formation of the tetrazole ring system, a structural feature common to all molecules in this class. When DMF is used as a solvent, trace amounts of dimethylamine can be present as an impurity and this can react with nitrous acid, formed from sodium nitrite, to form N-nitrosodimethylamine (NDMA).
The principle difficulty is that even if the quality of DMF is rigorously controlled by API manufacturers, at elevated temperatures or other reaction conditions decomposition of DMF with loss of the formyl group leads to formation of dimethylamine in-situ. Sensitive analytical techniques such as Headspace Gas Chromatography would be required to detect the low levels of NDMA present.
Computational and experimental studies have explored the mechanisms by which NDMA can be formed from Ranitidine during chloramination treatment of drinking water. The root cause for formation of NDMA in ranitidine medicines is perhaps more likely to be a result of the drug substance manufacturing process, although this has not yet been disclosed and publicly available synthetic routes do not use reagents common to the sartans.
The incidents are a reminder of the complexities of supply chains, particularly for generic products in which multiple API sources and finished product manufacturing sites may be registered for one or more Marketing Authorisations, as evidenced by the wide range of affected Marketing Authorisation Holders in the UK. The storing of reference samples according to EU GMP Annex 19 has also doubtless been useful in determining the extent of the problem historically and identifying potential root causes.
EUDRAC has offices located in Germany, UK and France. We can offer multidisciplinary expertise that links Regulatory CMC assessments of manufacturing processes with the context of relevant Non-Clinical guidelines and requirements, such as those described in ICH M7. Please get in touch if you would like to find out more information.