Control of Genotoxic and Elemental Impurities

NDMA/NDME: Regulatory Perspective & Lesson Learned

Case Study: What’s gone wrong in Valsartan?

Valsartan is an angiotensin II receptor blocker (ARB) that treats high blood pressure and heart failure.


In July 2018, EMA & FDA cited a major issue related to genotoxic impurity, NDMA (N-nitrosodi-methylamine), and subsequently NDEA (N-nitrosodiethylamine)

An API used to manufacture generic angiotens in receptor blockers (ARBs) was supplied by two Chinese companies, Zhejiang Huahai and Zhejiang Tianyu. It was later discovered in API manufactured by Indian manufacturer Hetero Labs.

Both NDMA and NDEA are considered genotoxic compounds as they contain a nitroso group, which is a gene mutating group.

Most ARBs have a chemical structure that includes a ‘Tetrazole’ group. These impurities also have potential to roll over to other ‘Zoles’ such as Omeprazole.

Regulatory perspective of post approval changes

As per EDQM guideline (revised 2014) for revisions to an approved certificate of suitability (CEP,) major change is seen as changes in manufacturing process/addition of an alternative manufacturing process for a starting material, intermediate or final substance likely to change the qualitative and/or quantitative impurity profile. (e.g., new reagents, solvents, materials are introduced in the synthesis).

The alternation of solvent was a major change, however the manufacturer missed reporting the generation of the new impurity (NDMA/NDEA).

EDQM subsequently (September 2018, with implementation date of January 2019) changed the above revision guideline to include evaluation for genotoxic impurities as well.

Apart from valid CEPs, a few India companies withdrew their filings while four were suspended by EDQM.

USFDA guideline ‘The guidance Changes to an Approved NDA or ANDA’ is clear to alert manufacturers to evaluate and assess the new impurities that may form during the changes.

New draft guidance Post-approval Changes to Drug Substances Section VIII.B (Changes in Route of Synthesis of One or More Steps) clearly states explicitly about impact assessment as per ICH M7 for genotoxic impurities.

Nitroso impurities are very well studied and documented in food industry and drinking water specifications worldwide. However, their origin and impact were not studied or extrapolated in pharmaceutical substance manufacturing processes.

Lesson Learned

To avoid cases similar to this in the future, the pharmaceutical industry may have to consider adopting a collaborative approach during the research, development, and manufacture of drug substances to absorb the knowledge available in other domains.

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