Science Concentrates PROCESS CHEMISTRY
Side reaction may have sparked sartan recalls
C R E D I T: S H UT T E RSTO CK
C&EN Global Enterp 2019.97:5-5. Downloaded from pubs.acs.org by WEBSTER UNIV on 03/02/19. For personal use only.
Impurities found in batches of the drugs were traced back to multiple manufacturers there may be one additional case of Over the past eight months, more than a cancer over the lifetimes of those people. dozen companies around the world have According to ZHP, NDMA formed during voluntarily recalled hundreds of batches its manufacturing process. ZHP and the of generic versions of the drug valsartan, other API manufacturers make their generand related products losartan and irbeic valsartan through methods that differ sartan, commonly prescribed to treat from how Novartis, which developed the high blood pressure and heart failure. drug, originally synthesized it. The most recent recall occurred earlier on his blog In the Pipeline. Information Philippe Andre, a pharmacist and audithis month. According to the Agency for posted on ZHP’s website in August 2018 tor at the China-based company QualandHealthcare Research and Quality, about also supports this explanation: “The imre, thinks the impurity was probably pro1.6 million people purchased valsartan in purity was generated in the side reaction duced in a key tetrazole-forming step in the US in 2016. between a trace-amount degradate of a The recalled products contained active the synthesis. Andre has inspected ZHP’s solvent and the reagent in the down-stream facilities for good manufacturing practice pharmaceutical ingredients (APIs) with step.” ZHP did not respond by press time (GMP) compliance for drug-product clitrace amounts of either N-nitrosodimeto C&EN’s requests for comment on the ents, but he does not test substances or thylamine (NDMA) or N-nitrosodiethylorigin of the impurity. review synthetic routes. His understandamine (NDEA), which are both probable According to the FDA, Hetero Labs uses ing of how ZHP makes the drug is based human carcinogens. Testing by compaa process similar to ZHP’s to manufacture on a 2014 Chinese patent assigned to ZHP nies and the US Food and Drug Adminisvalsartan, but the levels of NDMA detected for the improved method for forming the tration has revealed that the impurities in its products have been generally lower tetrazole ring of valsartan. For this key came from multiple API manufacturers, than those found in the ZHP products. In facilities that synthesize valsartan and re- step, ZHP uses sodium azide, which leads a statement to C&EN, the FDA did not lated sartan molecules and then sell them to higher yields compared with Novartis’s confirm the route to the impurity but noted original patented route, which uses tributo companies that make the final tablets that an investigation is ongoing. It added tyltin azide. that reach consumers. Information about that “the reuse of materials, how one of these API manuPossible route to NDMA impurity such as solvents, may cause facturers produces valsartan the presence of an impurity has led experts to think that Acidic H3C N H3C CH3 in processes which otherwise these impurities were made N conditions O NaNO2 + N do not appear to be at risk for through a side reaction of H CH3 forming these impurities.” The one step in the compound’s Sodium Dimethylamine FDA declined to explain which synthesis. nitrite NDMA materials may have been reused The four API manufacturers and which impurities may have formed as This reagent switch requires chemists that produced the impure sartans are Hetea result. to get rid of excess sodium azide by addro Labs, Mylan Laboratories, and AurobinThe synthetic origins of the NDEA do Pharma, all based in India, and Zhejiang ing sodium nitrite, which under acidic impurity are still unclear; Lowe suggestconditions can form nitrous acid. Andre Huahai Pharmaceutical (ZHP), in China. ed that it could have formed through says nitrous acid likely reacted with small ZHP was the first to disclose the presence a similar chemical route involving diamounts of dimethylamine to produce of the NDMA impurity after receiving a ethylformamide as a solvent instead of NDMA. Dimethylamine is a degradation complaint from a drug company customer dimethylformamide. product of the solvent used in the reaction, in June 2018 about an unidentified imThe FDA tells C&EN that the impurities dimethylformamide. purity in valsartan API that the customer were hard to detect using the analytical A Novartis spokesperson told C&EN received from ZHP. methods provided by the manufacturers that, according to company chemists’ FDA testing found that in some cases, because they weren’t designed to target the understanding of ZHP’s process and public the impurity concentrations in valsartan impurities. To help industry and regulatory information released by agencies like the exceeded the agency’s acceptable intake FDA, this sodium azide–based side reaction agencies keep track of the impurities, the levels for people. The FDA’s scientists FDA has published three gas chromatograis likely how NDMA formed. Pharmaceutiestimate that if 8,000 people took the phy/mass spectrometry methods to detect cal industry insider Derek Lowe suggested highest valsartan dose (320 mg) from NDMA and NDEA.—TIEN NGUYEN the same synthetic pathway in a Jan. 4 post the recalled batches daily for four years, FEBRUARY 25, 2019 | CEN.ACS.ORG | C&EN
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