It was not so long ago when Valsartan manufacturers started dreading the need for immediate risk assessment of the presence of nitrosamines in their medicinal products. In the summer of 2018, not only the weather got hot. The topic of N-itrosodimethylamine (NDMA) being detected in a Valsartan API batch manufactured in China heated up as well (Quality Concern Rises Over Valsartan Crisis). As previous investigations carried out by major regulatory agencies (EMA and FDA) determined that NDMA may cause cancer, large batches of drug products began being recalled.
Let’s go back a few steps. Certain drug manufacturing processes pose a risk for the formation of genotoxic impurities (GTIs), such as nitrosamines. N-nitrosodimethylamine (NDMA), like many structurally similar nitrosamines, is potentially carcinogenic even at low exposure levels. Consequently, nitrosamines are closely monitored by drug regulators.
In 2018, nitrosamine impurities, including NDMA, were discovered in Valsartan, an Angiotensin II receptor blocker (ARB) medication used to treat high blood pressure and heart failure. This led to a global recall of Valsartan and several other ARB drugs. Some ARB drug products contained as much as 17 µg NDMA in a single tablet; the FDA estimated that this would result in one additional case of cancer for every 8,000 patients taking the drug at the highest dose. European regulatory agencies estimated the cancer risk at 1 in 3,390.
As a response to the findings of unacceptable levels of nitrosamines methods have been shared by regulatory agencies and supporting laboratories to quantify these specific nitrosamines in Valsartan products.
On September 13, 2019, the FDA announced that preliminary tests also found low levels of NDMA in Ranitidine (original brand name Zantac®), a heartburn medication used by millions of patients daily. Pharmaceutical companies Novartis and Apotex announced that they were recalling all of their generic Ranitidine products sold in the US and other territories.
The EMA has published Information on nitrosamines for marketing authorisation holders (MAHs) and Questions and answers in addition to the notice. It is the responsibility of the MAH to ensure their medicinal products are of acceptable quality and safety. Nitrosamines are not expected to be formed in the majority of the APIs, however, these impurities can form during production under certain conditions, or when some specific solvents, reagents or raw materials are used. All authorised human medicinal products containing chemically synthesized APIs are to be reviewed, and risk evaluation should be conducted at the latest within six months of the publication of the EMA document, and confirmatory testing of all products with risk of the presence of nitrosamines identified should conclude within the next three years.
Thermo Fisher Scientific can support your impurity analysis needs with compliance-ready chromatography and mass spectrometry instrumentation capable of quality testing of pharmaceutical impurities in cGMP environments.
How to best analyse nitrosamines in Ranitidine and Valsartan by LC-MS
The FDA is maintaining up-to-date official testing methodology for manufacturers and regulatory agencies. A recent publication details the FDA method validated to ICH Q2(R1) for detection and quantitation of NDMA in Ranitidine. As Ranitidine products can thermally degrade to form NDMA, established GC-MS based methods for NDMA are not suitable.
A liquid chromatography and high-resolution accurate mass (HRAM) mass spectrometry (LC-MS) method was developed by US FDA using the Thermo Scientific™ Q Exactive™ LC-MS/MS system. For instrument control and data processing, the Thermo Scientific™ Chromeleon™ Chromatography Data System (CDS) may be used to address all the regulatory and GMP requirements asked to be fulfilled by pharma industries.
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The FDA also shared a method validated following ICH Q2(R1) for the determination of six nitrosamine impurities (NDMA, NDEA, NEIPA, NDIPA, NDBA, & NMBA) in ARB drug products including Valsartan.
GC-MS methods for nitrosamines cannot directly detect N-nitroso-N-methyl-4-aminobutyric acid (NMBA) and other nitrosamines detected in some ARB drugs. Thus, a single HRAM LC-MS method was developed by the US FDA capable of quantifying all of the six above nitrosamine impurities simultaneously. The US FDA method utilizes the exceptional acquisition speed, sensitivity, and resolving power of the Thermo Scientific™ Q Exactive™ HF-X LC-MS/MS system for the determination of these trace level genotoxic impurities.
EDQM – European Pharmacopoeia https://www.edqm.eu/en/ad-hoc-projects-omcl-network