After Valsartan Recalls, Regulators Grapple with Nitrosamine Contamination in APIs

Recalls of valsartan, the API found in Novartis’ blood-pressure treatment, Diovan, and its generic descendants, have underscored vulnerabilities in the way that the pharmaceutical industry assesses and manages global supply-chain risks. The recalls were initiated in the United Stated and European Union in July 2018, after N-nitrosodimethylamine (NDMA), was found in API used to manufacture generic angiotensin receptor blockers (ARBs). The nitrosamine, classified as a probable carcinogen, was found in active ingredient manufactured by Zhejiang Huahai Pharmaceutical Company, an API supplier in China, and a number of generic products using it were removed from pharmacy shelves (1). 

FDA released analytical methods for detecting the contaminant in August 2018 (2). Later, regulators in Germany found low levels of another nitrosamine, N-nitrosodiethylamine (NDEA), in one batch of losartan manufactured in India by Hetero Labs. Zhejian Huahai had also detected NDEA in some lots of its valsartan API, and alerted FDA; subsequent testing by FDA confirmed its presence in several lots of valsartan API and in three lots of valsartan sold by Torrent Pharmaceuticals (3), that used that API. 

As a precaution, to ensure that synthesis process changes or other factors have not resulted in systemic contamination of sartan drugs now on the market, the European Medicines Agency (EMA) will now expand its review of nitrosamine impurities to include four other widely-prescribed active ingredients: 

candesartan, irbesartan, losartan, and olmesartan.

As the agency explained in a press release announcing the effort on Sept. 21, 2018 all these compounds share a tetrazole ring structure (4). Different synthesis routes could lead to the formation of nitrosamine impurities during manufacturing.

Also on Sept. 21, 2018, the General European Official Medicines Control Laboratories Network (GEON) published three methods for detecting the impurities. These analytical tests were developed in Ireland, France, and Germany by the Public Analyst’s Laboratory in Galway (PALG); the French OMCL in Montpellier and the German OMCL at the Chemisches und Veterinär-Untersuchungsamt (CVUA) (5):

• PALG’s method, based on headspace-gas chromatography and mass spectroscopy (GC-MS) (single quad), can be used to determine the presence of NDMA in APIs and sartan tablets

• The French method, based on high-performance liquid chromatography and ultraviolet (HPLC-UV) analysis, can be used to test both API and finished drug product

• CVUA’s method uses atmospheric pressure chemical ionization-ultra-high-performance liquid chromatography and mass spectroscopy (APCI-UHPLC-MS/MS) to both detect and quantify NDMA in drug products.

FDA and EMA have emphasized that patients who continue to take medications that may contain these impurities face very low risks of developing serious health problems. In August 2018, FDA scientists said that it would take 8000 patients taking the maximum daily dose of the drug (320 mg) each day for four years, to result in one additional case of cancer (6). Regulatory agency officials have asked that patients remain on these medications until their physicians prescribe alternatives. 

However, regulators must now grapple with the question of how members of a class of potent probable carcinogens wound up in the pharmaceutical supply chain in the first place.  NDMA, widely used in cancer research, was the poison of choice in two sensational murders in the U.S. and Germany (7) in 1978, while growing evidence of its impact and that of other nitrosamines helped drive public area smoking bans and intensive process changes in the food industry.  

Dangers of nitrosamines

According to the World Health Organization, nitrosamines are not used industrially in the US or Canada, but may still be released as byproducts from municipal wastewater treatment facilities and some industrial manufacturing facilities (8). 

Since research in the 1950s first revealed their carcinogenic effects on animals (9), regulators have worked to reduce potential exposure, and efforts have helped lead to tobacco regulation (10) and regional smoking bans at offices, restaurants, and other indoor public areas in many parts of the world. Food processors have studied their generation during heat- (11) and acid-catalyzed manufacturing, and come up with alternative methods to reduce or prevent their release.

It is believed that the NDMA contamination could have resulted from changes that Zhejiang Huahai made to its manufacturing process in 2012, using a method that was patented in 2014 (12) to reduce waste and improve product yield.  

Depending on which press report one reads, the presence of contaminant was either discovered by the manufacturer during process optimization, or by Novartis’ generic drugs subsidiary Sandoz, during routine raw material testing (13). 

The company had submitted documentation of the process change to regulators, and no objections were found. “FDA and the European EDQM approved the changed process, but may have missed the potential formation of some genotoxic impurities,” says Philippe Andre, a cGMP auditor with Qualandre, based in Zhejiang, China, who inspected the Zhejiang Huahai facility.

These issues would not have come up in a customer review of changes to the manufacturing process, either. So if the resulting problems reflect a failure of change management, it occurred at a fundamental level.

Media reports of past warning letters and quality issues at Zhejiang Huahai’s facilities (14) may have obscured the fact that the manufacturer had followed all the legal requirements, and submitted all required documentation.  

 “The inspections revealed some problems, none of them critical and all unrelated to the presence of NDMA in valsartan,” says Andre. 

Zhejiang Huahai had no quality control or cGMP failures in this case. In fact, Andre says, the firm’s quality management was much better than average. “The contaminant was present and toxic at levels below the reporting limit for impurities specified in the pharmacopeia,” he says.

Andre sees a need for manufacturers and regulators to pay more attention to potential risks in the manufacturing process. “In this case, the focus was on control of the related substances of synthesis and other impurities above the reporting threshold (0.05% in the case of valsartan), rather than on the safety of the chemical synthesis processes. Preventing such failure would require a more attentive assessment of the production processes,” he says.

As Andre explains, in order to synthesize the tetrazole cycle in the valsartan molecule, Zhejiang Huahai’s improved process replaced tributyltin azide with the more toxic compound, sodium azide.  As a result, the yield of tetrazole formation was much better. However, sodium nitrite was used to destroy the excess sodium azide remaining after the synthesis step. Sodium nitrite is a well-known decontaminating agent of sodium azide in acidic conditions, Andre says. 

Under acidic conditions, sodium nitrite forms nitrous acid, which could react with the residue of dimethylamine in dimethylformamide-the solvent that is used in the tetrazole-forming reaction-to generate NDMA, says Andre.

Closer scrutiny of synthesis needed 

Facility inspections cannot, and are not meant to, assess the synthesis process, says Andre; regulators must do that based on information provided by manufacturers. The risk of NDMA contamination could have been predicted during that assessment, he says.

He suggests that the current situation may stem from focusing on the wrong priorities (i.e., controlling the related substances of synthesis) as required by the pharmacopeia, Andre says. 

“The possible formation of nitrosamines from nitrites and secondary amines in acidic conditions was already well-known to the food industry,” says Andre. “The use of sodium nitrite should have been a red flag prompting a check of possible presence of secondary amines, but it was not,” he says.

In this case, the API manufacturer and customers apparently followed the rules and standards set by regulatory agencies and pharmacopeias, says Anders Fuglsang, founder of Fuglsang Pharma. “So we arrive at the million-dollar question: Are regulatory agencies and pharmacopeias doing a good enough job, if a sponsor can comply with regulations and yet send a product on the market which contains carcinogens,” he asks. “We can’t test for everything, but I’m not entirely happy with that statement as a patient or consumer,” he says.

Fuglsang hopes that there will be an independent analysis of the root cause of the nitrosamine contamination, performed by independent experts outside of regulatory agencies or pharmacopeias. In the end, he says, “we can only find what we are looking for.” But the sartan API contamination case suggests a need to focus more closely on assessing potential risks during process synthesis review. “All sorts of chemicals or residual impurities may never show up in the standardized testing mandated by pharmacopeias,” says Fuglsang.  

Preventing situations like this from occurring in the future will be complex, Fuglsang notes, given the different players involved-from the pharmacopeias, which set standards for the APIs and excipients, to the regulatory agencies, whose guidelines refer to the pharmacopeias and standards for development, to finished drug manufacturers who buy API and excipients from subcontractors, to subcontractors who make the API, and the national testing labs, which test products to ensure that they meet standards.

In the end, it will be crucial to get all these different stakeholders together to discuss issues and to see the bigger picture. At this point, Fuglsang says, “that may be wishful thinking.”

References 

1. FDA Press Release, “FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity,” fda.gov,  July 17, 2018.
2. FDA Press Release, “FDA Announces Preliminary GC/MS Headspace Method…” August 2018.
3. J. Christensen, "FDA Finds Additional Impurity in Heart Drug," cnn.com, September 15, 2018, https://www.cnn.com/2018/09/13/health/valsartan-recall-additional-impurity-fda/index.html
4. EMA Press Release, “Valsartan: Review of Impurities Extended to Other Sartan Medicines,” ema.europa.eu, September 21, 2018.
5. EDQM Press Release, “OMCLs Release Three Methods for Determination of NDMA in Sartans,”edqm.eu, September 21, 2018.
6.  J. Christensen, “FDA Expands Recall of Blood Pressure Drug", cnn.com, August 10, 2018.
7. C. Purdy, “A Common Blood Pressure Medicine is Being Recalled Because it Was Mixed With NDMA,” qz.com, July 18, 2018.
8. R.G. Liteplo et al., “Concise International Chemical Assessment Document 38: NDMA,” World Health Organization,Geneva, 2002.
9. P. Magee and J. Barnes, “Production of Malignant Primary Hepatic Tumors in the Rat by Feeding NDMA,” British Journal of Cancer, 10(1) pp114-122 (1956).
10. A. Tricker et al., “NItroso Comounds in Cigarette Tobacco and Their Occurrence in Mainstream Tobacco Smoke,” Carcinogenesis 12(2); 257-261 (1991).
11.M. Jagerstad, “Genotoxicity of Heat Processed Foods, Mutation Research 574(1-2), 156-172 (August 2005).
12. Patents Issued to Zhejian Huahai Pharma Co., Ltd, justia.com, www.patents.justia.com/assignee/zhejiang-huahai-pharmaceutical-co-ltd
13. A. Harney, B. Hirschler, “Toxin at the Heart of Drug Recall Shows Holes in Medical Safety Net,” Reuters.com, August 22, 2018,
14. F. Southey, “US FDA Flagged GMP Concerns at Valsartin Manufacturing Plants in Two 483s,” in-pharmatechnologist.com, August 22, 2018.