In July 2018, the U.S. Food and Drug Administration (FDA) warned of the presence of unacceptable amounts of N-nitrosodimethylamine (NDMA) -- a potential human carcinogenic compound -- in some batches of Valsartan, a type of blood pressure drug called an angiotensin II receptor blocker (ARB), prescribed to treat high blood pressure and heart failure. The FDA announced a recall of several drug products containing this active principle ingredient (API). Since that time, additional genotoxic impurities came up in sartan’s API and a number of medications in this class of drugs have been voluntary recalled by more than 40 major manufacturers – the majority of them from India and China.
Valsartan The FDA estimated that about three million Americans take valsartan to control blood pressure or protect their hearts, and the recent recall affects more than half of the United States’ supply of the drug.
The valsartan drug was first introduced under the brand name Diovan, approved by the U.S. FDA in 1996. After patent expiration in 2012, generic manufacturers began producing and distributing the drug, with China and India dominating the U.S. ARB generics market today.
A modification in the manufacturing process by using dimethylformamide (DMF) as a solvent to increase yields and reduce costs seems to be responsible for a side reaction (in specific conditions) producing nitrosamine compounds. However the contamination may also result from the reuse of materials, such as solvents. In fact, several manufacturing violations, including impurity control, change control and cross contamination have been outlined after FDA investigation.
Quality concern is even more urgent when it comes to generic drugs because they represent the majority of the consumed medicines and as such are more likely to create a significant impact on public health.
Gas chromatography combined with mass spectrometry provides an efficient analytical approach for routinely testing nitrosamine impurities in drug ingredients and final products. NDMA and NDEA (N-nitrosodiethylamine) were the initial impurities found in different ARB classes of drugs, however, the list of nitrosamine impurities being monitored is growing steadily.
Very recently the European Commission revised the monographs of five sartans API to include manufacturers’ obligations to revise manufacturing processes and develop appropriate control strategies to assure NDMA and NDEA are not introduced into the final product. To allow manufacturers to make the necessary changes to their process, a transition period of two years has been agreed by competent authorities and strict temporary limits on levels of these impurities are introduced in the test section of the monographs. After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of nitrosamines.
Therefore, manufacturers will have to test every production batch for those nitrosamine impurities.
The FDA is maintaining up-to-date official testing methodology for manufacturers and regulatory agencies. The latest methods, published few months ago, involve a combined Headspace-GC-MS/MS method and a combined direct injection GC-MS/MS method to detect and quantify simultaneously up to five nitrosamines impurities in ARB API and finished drug products.
Thermo Fisher Scientific is actively supporting laboratories by providing robust and highly sensitive analytical solutions for routine testing of sartan products, as shown in the recent Application Note AN21922. Thermo Scientific™ TSQ 9000™ Triple Quadrupole GC-MS/MS combined with the new Thermo Scientific™ TriPlus™ 500 GC Headspace Autosampler or alternatively used with direct liquid injection, exceeds the sensitivity level required by the official methods and are today the solution of choice in some important pharma laboratories in India for ensuring the safety of their products. A dedicated configuration for maximum performance can be provided which combines headspace and the liquid injection capability on the same GC and offers sensitivity, flexibility and the required productivity for QC testing laboratories. The unique NeverVent™ technology introduced with the TSQ 9000 is particularly valuable for maximizing instrument uptime during maintenance and assuring the required sample throughput. For instrument control and data processing, the Thermo Scientific™ Chromeleon™ Chromatography Data System (CDS) is addressing all the regulatory and GMP requirements asked by pharma industries.
FDA scientists have developed novel and sophisticated testing methods specifically designed to detect additional emerging nitrosamine impurities, including N-Nitroso-N-methyl-4-aminobutyric acid (NMBA), responsible for the recent recall of 87 lots of losartan potassium tablets. A dedicated LC-HRMS method released by FDA indicates the use of the Thermo Scientific™ Q Exactive™ hybrid quadrupole-orbitrap mass spectrometer or Q Exactive™ HF-X hybrid quadrupole-orbitrap mass spectrometer is capable of delivering high sensitivity detection by monitoring the accurate m/z values of the protonated or deprotonated impurity ions or their fragments.
Upcoming (at the time of writing) the third Annual Elemental and Genotoxic Impurities Workshop is taking place in Hyderabad, India. The workshop aims to get a better understanding of the causes of contamination, how to improve early detection and ultimately achieve better control of impurities within acceptable limits. Leading global experts are gathering to focus on updates and developments in impurity-related challenges and breakthroughs, aiming to address what went wrong and how to avoid it in the future.