A scientist at a China-based company that makes crucial ingredients for generic drugs warned a year before the start of a global recall that some blood-pressure pills could become tainted with potentially cancer-causing chemicals, according to court documents.
Zhejiang Huahai Pharmaceutical Co. makes active ingredients for generic drugs including valsartan, which is taken by millions of people to treat hypertension. In July 2018, valsartan made with Huahai’s products was recalled for containing N-Nitrosodimethylamine, or NDMA, a chemical that can increase the risk of cancer after prolonged exposure at the levels detected in the drugs.
People who are prescribed blood-pressure treatments often take them routinely for years. Generic valsartan, which is part of a class of drugs known as angiotensin II receptor blockers, has been sold in the U.S. for a decade. Since the first batches were recalled, there has been a global effort — and legal wrangling — aimed at figuring out how NDMA got into the drug, and whether pills should have been removed from pharmacies sooner.
When Novartis AG detected NDMA in valsartan ingredients it bought from Huahai during routine testing in June 2018, the potential for the drug to become contaminated during manufacturing wasn’t well-known. The Swiss drugmaker developed the brand-name version of valsartan, marketed as Diovan, and its Sandoz unit sells a generic.
While the discovery surprised Novartis and regulators, an internal Huahai email shows that some of its officials were told of the possibility as early as July 2017. The message was made public last month in multidistrict litigation in the U.S. District Court in New Jersey.
The email from scientist Jinsheng Lin, who worked in a special quality unit at Huahai, was written as the company was trying to alter its approach to production of another heart drug called irbesartan, a chemical cousin of valsartan. A proposed new way to make irbesartan, he wrote, was unlikely to work because of a potential contamination issue.
The process created an impurity that “is similar to the N-nitrosodimethylamine that occurs in valsartan when quenched with sodium nitrite, and its structure is very toxic,” Lin wrote.
Plaintiffs’ lawyers in the U.S. have seized on the message, which was addressed to Lin’s supervisor and other company managers, as evidence that Huahai could have acted earlier to protect consumers.
“This is somebody, in 2017, clearly stating the root cause for the NDMA in the valsartan and recognizing that it is in the valsartan,” plaintiffs’ attorney Adam Slater, of the law firm Mazie Slater Katz Freeman, said in a hearing in September, according to a transcript unsealed April 18. “What is the explanation from counsel for why Dr. Lin, almost a year before the disclosure to the rest of the world, knew that there was NDMA and knew exactly how it was being caused?”
Since the recall, similar problems have surfaced in more medications. Digestive drug Zantac was pulled from the market in 2020 for containing NDMA. Some versions of the widely used generic diabetes drug metformin were recalled. Pfizer Inc. and Sandoz found nitrosamines — the chemical family that includes NDMA — in muscle relaxers, smoking-cessation drugs and other blood-pressure pills.
Allison Brown, a Skadden, Arps, Slate, Meagher & Flom lawyer representing Huahai in the U.S., said the company couldn’t have known based solely on the email that a carcinogen would be formed in its production of valsartan.
“This email involves complex scientific issues that will be addressed by scientific experts in the valsartan litigation,” Brown said in a statement. “This email was written in Chinese and highlights the difficulties associated with translating from the original language and culture.”
Lin didn’t respond to a request for comment sent to a personal email account. Huahai didn’t respond to a request for comment.
Evidence battle
Hundreds of people in the U.S. sued Huahai and other drugmakers in 2019, alleging they got cancer after taking valsartan. The claims were consolidated to streamline pretrial proceedings.
Lawyers have been haggling over evidence and testimony, a debate complicated by security laws in China. In one instance, the court ordered that Huahai official Baohua Chen be deposed, but defense lawyers say China’s government wouldn’t let him leave the country. As a result, the plaintiffs have sought a default judgment against Huahai; a ruling on the motion is pending.
Huahai wanted to keep the full text of Lin’s email confidential, but a retired judge overseeing pretrial disputes, Thomas Vanaskie, ruled against the company in January. The plaintiffs posted the email on the docket in March.
“This literally is a smoking-gun document,” Slater, the plaintiffs’ lawyer, said at a June 2021 proceeding.
Seven Huahai managers who were addressees on Lin’s email had been asked to produce documents related to the recall, but it was only included in records from Min Li, Lin’s boss, according to Slater. At the hearing in September, Slater said that Huahai never meant to reveal the email, but it slipped through because Li transferred files to a new laptop in June 2018, causing the message to be re-dated to a time period after Novartis informed Huahai of the contamination.
Jessica Priselac, an attorney at the law firm Duane Morris who represented Huahai until April, said in September that Huahai didn’t try to hide the email. The company doesn’t have a centralized server, so emails don’t get saved unless they’re saved on personal computers, she said. Priselac didn’t respond to an email seeking comment.
Vanaskie said the circumstances surrounding the discovery of the email were “troubling” but declined to force Huahai to do a new document search, saying there wasn’t any direct evidence that anyone at the company deliberately destroyed evidence. He said that he would require Huahai to produce documents about the project Lin was working on to improve irbesartan production.
Chemical reaction
Global regulators have determined that NDMA was caused by chemical reactions that occur as valsartan is manufactured. In February 2019, the European Medicines Agency said in a 41-page report that the compound sodium nitrite and a solvent called dimethylformamide, or DMF, react with each other to form NDMA in the drug. The conclusion was largely based on analyses conducted at the request of the EMA by pharmaceutical companies that sold the recalled valsartan.
At the time of the first recall in 2018, the FDA said there was no way companies could have known to test products for NDMA. An agency inspector raised concerns in 2017 about Huahai’s quality testing after a visit to its factory in Linhai, but regulators took no immediate action. The FDA banned Huahai from sending product from the factory to the U.S. in 2018; it lifted the ban last year.
"Because it was not anticipated that NDMA would occur at unacceptable levels in the manufacturing of the valsartan API, manufacturers at that time would not have been expected to test for it as an impurity, said Audra Harrison, an FDA spokeswoman.
Since the valsartan recall, the industry now knows what processes may lead to nitrosamine contamination and has better analytical technology to detect the compounds, Harrison said.
Quenching, a part of the drugmaking process that was the focus of Lin’s email, is used to eliminate excess amounts of a chemical that may be toxic but that creates essential reactions in manufacturing. In valsartan, sodium azide helps form a critical “tetrazole ring” of four nitrogen atoms and one carbon atom, but it must be removed from finished pills. Sodium nitrite is one option for quenching sodium azide.
At the end of his message, Lin pointed to a 2013 valsartan patent from another Chinese company that discusses using an alternative to sodium nitrite in quenching. The patent doesn’t mention NDMA, but Lin wrote that it recommends the substitution because sodium nitrite produces the dangerous impurities.“This indicates that other companies have paid attention to the quality problem very early on,” Lin wrote. “So leaders please pay attention to this issue.”
