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Agnes Shanley is senior editor of Pharmaceutical Technology.
Experts blame the recalls, not on cGMP failures, but on inadequate risk assessment of processes that can generate toxic impurities.
It is not unusual to hear of cGMP and quality failings in API and finished drug manufacturing, especially as more functions are outsourced. Between October 2016 and September 2017, out of 3343 citations for quality systems failures, roughly 11% were likely due to problems with supplier quality management, according to Phil Johnson, senior principal for quality and compliance services at IQVIA (1).
But the root causes for some quality failures can be extremely difficult to sort out. This is becoming particularly evident in the valsartan recalls, which began in July 2018 after traces of the toxic nitrosamine, N-nitrosodimethylamine (NDMA), were found in the APIs used to manufacture generic sartans, the angiotensin inhibitor blockers (ARBs) prescribed to some patients to treat high blood pressure.
By August 27, 2018, valsartan from 16 different suppliers had been yanked from pharmacy shelves (2). NDMA, classified as a “probable human carcinogen,” was found in API made by Zhejiang Huahai, a manufacturer in China. But subsequently, traces of another nitrosamine contaminant, nitrosodiethylamine (NDEA), were discovered in a batch of another ARB, losartan, made in India by Hetero Labs, and in lots of API made by Zhejiang Huahai and of generic valsartan distributed by Torrent Pharmaceuticals.
NDMA’s toxic effects in animals have been known since the 1950s (3), and it was the poison of choice in two murders in 1978 (4). Over the past few decades, growing evidence of nitrosamines’ potential impact on human health has helped drive public area smoking bans and intensive process changes in the food industry (5,6). While investigations into the root cause of the contamination continue, this article touches on some questions that the case has brought up so far. Of particular concern is the way that the industry assesses process synthesis risks, especially for small-molecule APIs whose processes may generate trace levels of genotoxic impurities. Most of these compounds are manufactured overseas, but compendial testing requirements may not be enough to clue manufacturers into the need to monitor and test for trace levels of genotoxic contaminants. As offshoring and outsourcing trends continue, the recall suggests that developing solutions will be crucial.
It is believed that NDMA contamination resulted from changes that Zhejiang Huahai made to its manufacturing process in 2011 and 2012, using a method that was patented in 2014 to reduce waste and improve product yield. Zhejiang Huahai had submitted documentation for the process change to regulators, and no objections were found. “The FDA and the European Directorate for the Quality of Medicines and Healthcare (EDQM) approved the changed process, but may have missed the potential for formation of genotoxic impurities,” says Philippe André, a cGMP auditor with Qualandre, based in Zhejiang, China, who inspected the Zhejiang Huahai facility.
What began as a single case has snowballed into a major risk-assessment puzzle. The European Medicines Agency (EMA) is considering not only valsartan and losartan, but candesartan, irbesartan, and olmesartan in its efforts to find root cause (7). Both FDA and the General European Official Medicines Control Laboratories Network (GEON) published methods
for testing for the impurities in August and September (8,9). FDA and EMA also found cGMP deficiencies at the company’s facility. FDA placed the company’s products under Import Alert on September 28 (10), when EMA also revoked its right to sell the product in Europe (11). In an FDA 483 published on September 21, based on inspections in July and August (12), FDA found fault with the company’s change-control system and its “failure to evaluate all potential risks from the 2011 manufacturing process change.” The company had hired an outside lab to conduct a small-scale research project assessment without pilot-scale testing or a formal risk assessment, the inspectors wrote. In addition, the 483 found that the company did not have a quality agreement in place with that outside lab. Inspectors also found fault with Zhejiang Huahai’s inconsistent classification of risks in different process change documents. Where the initial change request classified the process change as critical, DMF amendments sent in 2013 classified the changes as minor, inspectors wrote. Among other problems, FDA inspectors also singled out inadequate validation, cleaning procedures, analytical methods, sampling and testing, and equipment maintenance: However, observers see some of
these observations as focusing more on procedural details rather than fundamental risk assessment problems. Many of the problems noted during FDA’s site inspection may not have led to the presence of nitrosamines in valsartan, says André.
“If Zhejiang Huahai did not identify the need to develop a control strategy to reduce the new risks introduced with the optimized process, neither did regulators when they approved the process change,” he says, “and the manufacturer’s failure in this regard was just part of an industry-wide failure led by the regulators.”
In response to the valsartan recall, André’s company is now conducting audits that zero in on the potential for any process to generate genotoxic impurities. So far, audits have found three problematic synthetic drug substances, says André. One of them is levocarnitine, synthesized from a probable carcinogen, epichlorohydrin. Depending on how it is synthesized, the compound may not only contain epichlorohydrin, but also traces of cyanide.
The yield of synthesis is not great, André says, so it is difficult to predict whether a residue of unreacted epichlorohydrin might be carried over in the final product. Nevertheless, he asks, “Which impurities does the US Pharmacopoeia require testing for? Chlorides, sulfates, sodium and potassium, none of which is toxic at such levels.” He wonders how many manufacturers of this compound are even aware of the potential risk.
Even the Chinese manufacturing process for acetaminophen (a.k.a. paracetamol) is a point of concern, says André, since one of the early intermediates is the probable carcinogen, 1-chloro-4-nitrobenzene. “We have audited most of the major Chinese manufacturing plants of acetaminophen, and found no evaluation of and no testing for 1-chloro-4-nitrobenzene at any of them,” he says. André sees a need for manufacturers and regulators to pay much closer attention to potential risks in the manufacturing process. “In the valsartan 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.
Zhejiang Huahai’s improved process replaced tributyltin azide with the more toxic compound, sodium azide, says André. As a result, the yield of tetrazole formation was much better. However, sodium nitrite was used to destroy the excess sodium azide that remained after the synthesis step. Sodium nitrite is often used as a decontaminating agent of sodium azide in acidic conditions, André says. However, under these conditions, it 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 André.
“The possible formation of nitrosamines from nitrites and secondary amines in acidic conditions was already well-known to the food industry,” says André. “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.
“So we arrive at the million-dollar question: Are regulatory agencies and pharmacopeias doing a good enough job, if a sponsor can comply with [most] regulations and yet send a product on the market which contains carcinogens,” asks Anders Fuglsang, founder of Fuglsang Pharma. “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.
Preventing situations like this from occurring in the future will be complex, says Fuglsang, and require getting all the different players involved to see the bigger picture, from pharmacopeias and regulators, to finished drug manufacturers, API manufacturers, and national testing labs. “At this point,” he says, “that may be wishful thinking.”
André sees the root cause study as an opportunity for the industry to look more deeply into the way it approaches risk assessment. This will be especially important for API syntheses that may result in residual levels of potentially genotoxic impurities. “I hope we will all draw the right lessons from this [recall] debacle,” says André. “Despite its mistakes and deficiencies, Zhejiang Huahai basically did what the regulators expected from them at the time. Stoning the company would be a distraction from the critical deficiency in the regulatory supervision of drug substances,” he says.
1. P. Johnson, “Quality In, Quality Out:Regulatory Drivers of Supplier Quality Management in the Pharm and Biopharma Industries,” Xtalks Webcast (September 18, 2018).
2. FDA, “Valsartan Products Under Recall,” fda.gov, August 28, 2018.
3. P. Magee and J. Barnes, “British Journal of Cancer , 10 (1) 114-122 (1956),
4. C. Purdy, “A Common Blood Pressure Medicine is Being Recalled Because it Was Mixed With NDMA".
5. A. Tricker et al, Carcinogenesis 12(2); 257-261 (1991).
6. M. Jagerstad, Mutation Research 574(1-2), 156-172 (August 2005)
7. EMA, “Valsartan: Review of Impurities Extended to Other Sartan Medicines,” Press Release, September 21, 2018.
8. FDA, “FDA Announces Preliminary GC/MS Headspace Method for Determining NDMA in valsartan” Press Release, August, 2018.
9. EDQM, “OMCLs Release Three Methods for Determination of NDMA in Sartans,” Press Release, September 21, 2018.
10. FDA Press Release, “FDA Places Zhejiang-Huahai on Import Alert,” fda.gov , September 28, 2018.
11. EMA, Press Release, “EU Inspection Finds Zhejiang Huahai Site Non-Compliant,” ema.europa.eu , September 28, 2018.
12. FDA, Form 483, fda.gov
Vol. 42, No. 10
When referring to this article, please cite it as A. Shanley, “Sartan Recalls Beg the Question: Is Compendial Impurity Testing Enough?” Pharmaceutical Technology 42 (10) 2018.