America's top pharmacies, including CVS, Walgreens and Walmart, pulled one of their top-selling drugs from the shelves last autumn. The drug, heartburn medication Zantac, was also banned in the UK, France and Canada, while authorities in Bangladesh refused to allow shipments into the country. Existing stocks in the UK were put in quarantine.
The ban followed a discovery by investigators at the US Food and Drug Administration (FDA) that Zantac's active ingredient, ranitidine, had been contaminated with NDMA (N-nitrosodimethylamine), a known cancer-causing agent.
A CVS statement said the store was removing the drug "out of an abundance of caution due to a recent product alert from the FDA that ranitidine products may contain a low level of NDMA, which is a probable human carcinogen."
Not the first time
It wasn't the first time this had happened. In 2018, FDA agents blocked supplies of the blood pressure drug Losartan (valsartan) after a spot check revealed it had also been contaminated with NDMA.
Health agencies downplayed the risks to patients. Janet Woodcock, a director at the FDA, pointed out that all of us are exposed to some levels of NDMA every day. "Throw a couple of lamb chops on the barbecue, and you'd find NDMA after a good grilling. You have to put this in perspective," she said.1
Safe daily exposure is set at around 1 microgram, or one millionth of a gram. But some of the valsartan pills contained 17 micrograms—equivalent to eating 48 pounds (21 kg) of bacon in one sitting.
Although no one can be sure, contaminated pills could be causing thousands of new cancer cases every year. European health agencies have estimated that one out of every 3,390 people taking the contaminated drugs could develop cancer. There are 49 million prescriptions written for Losartan every year in the US alone, and 15 million for Zantac—plus countless millions of over-the-counter uses. It's unknown how many doses have been contaminated, or for how long.
The discovery opened a can of worms. The three drug companies responsible for supplying valsartan had all used a manufacturer in China, Zhejiang Huahai Pharmaceutical. After the initial ban, the FDA ordered another 51 recalls involving two related heart drugs supplied by 10 pharmaceutical companies.
FDA officials estimate that millions of people with high blood pressure (hypertension) in at least 30 countries could be unwittingly consuming high NDMA levels from contaminated drugs.
More to come
The real fear is that this is just the tip of the iceberg. The contamination of Zantac and Losartan was discovered after a random spot check, and the FDA admits it has limited resources and is checking less than 1 percent of drugs being shipped to the US.
The two discoveries were lucky breaks. "Valsartan is just the one we caught. Who knows how many more are out there?" said David Gortler, a former FDA medical officer.
The two drugs are generics, meaning they have aged out of patent protection, and any drug company has the right to supply them. Up to 90 percent of all prescriptions are written for a generic drug—which means there are no product safety checks on the vast majority of drugs being prescribed in the West.
Generics don't command the same price tag as patented drugs, and so suppliers look to cut manufacturing costs by using processing plants overseas, primarily in India and China. The plants source their raw materials locally, and there are no quality controls for impurities.
Contamination is also happening in the manufacturing processes. FDA inspectors who visited Huahai's factory in 2017 discovered the machinery was rusty, and tests that threw up safety worries were never followed up.
NDMA isn't the only contaminant being discovered in pharmaceuticals, nor is the problem restricted to unsupervised plants in Asia. Black mold (melanized fungi) contamination is becoming "increasingly common" in pharmaceuticals, and patients have died from the infection, say researchers at Bio Products Laboratory in the UK.2
Between 1990 and 1999, 5 percent of FDA product recalls were the result of fungal contamination, but this rose to 21 percent between 2000 and 2012. Most of the contamination is happening in processing plants that are not properly following controls for creating a sterile environment.3
Pharmaceuticals, including the BCG vaccine that protects against TB (tuberculosis), were contaminated at Sanofi Pasteur's manufacturing plant in Toronto, Canada, following a flood that damaged the building.
FDA inspections turned up 483 areas of mold, and the regulator issued a warning letter in 2012. Sanofi eventually decided to halt production, repair the building and recall four lots of the BCG, which resulted in a global shortage of the vaccine and significant financial losses for the company.
Perhaps the most infamous case of mold contamination, which also happened in 2012, caused 753 cases of fungal meningitis and 64 deaths. "Greenish-black foreign matter" was discovered in consignments of steroid injections, which were traced back to the processing plant, New England Compounding Corporation.
Its president and supervising pharmacist were indicted on racketeering charges and 25 counts of second degree murder for knowingly distributing contaminated products.4
Of all pharmaceuticals, vaccines have the highest risk of being contaminated. Five vaccines—including the MMR (measles, mumps, rubella) and varicella (chickenpox)—include weakened, live viruses, and these can be contaminated by microorganisms.
Since the contamination of the polio vaccine with simian virus 40 from the kidneys of macaque monkeys—which infected supplies for eight years up to 1963 (see box, right)—production processes have improved, although the risk of new contamination hasn't been completely removed.5
Scientists from the National Council of Research in Italy tested 44 batches of the most common vaccines—the MMR, HPV (human papillomavirus), flu vaccines and DTP (diphtheria, tetanus, pertussis)—and discovered that all of them had some contaminants. Several contained up to 20 foreign particles.
They used very sensitive equipment—more precise than that used by the production plants in their own quality control checks, which explains why the contamination wasn't being picked up. The scientists said they were "baffled" by the level of contamination but assumed it must be happening somewhere in the manufacturing cycle.
More worryingly, the scientists fear the contaminants aren't breaking down in the body. Instead, they are carried around in the bloodstream and could settle in tissues and organs, possibly causing inflammation.
Adverse reactions to vaccines that aren't listed on product information sheets—like fever, epilepsy, speech loss, muscle pains, walking problems and hypersensitivity, which have been suffered by people after a vaccination—could perhaps be caused by undetected contamination.6
See you in court
Drug contamination has finally become a hot topic. The American Medical Association is carrying out an urgent review, and independent testing could be on the cards. The US Congress is also looking at ways to make drugs safer and has requested the Government Accountability Office to conduct a review of the FDA's supervision of manufacturing plants overseas.
The courts are also getting involved. Around 140 lawsuits have been filed against Huahai and the US-based drug companies so far, and another 500 are being evaluated. The cases involve people who took valsartan between 2015 and 2018 and developed cancer.
Despite these moves, the FDA continues to play down the risks. It has decided not to notify patients who have taken contaminated drugs before a recall. As the FDA's Janet Woodcock said: "It's not like if you took valsartan you have to be checked for cancer."
The 500 potential litigants would disagree, and there may well be many more waiting in the wings.
Tens of millions of American children were given at least one dose of a polio vaccine that had been contaminated with a monkey virus between 1955 and 1963, when the contamination was discovered. By 1961, it was estimated that up to 90 percent of Americans younger than 20 years old had been given the shot.
The virus—simian virus 40, from the macaque monkey—was known to cause cancer in rodents, and it was feared it might do the same in people. A German study carried out 27 years after the vaccine was withdrawn couldn't find any link, and yet people with rare types of cancer had simian virus 40 in their tumors.
Alerted to these cases, researchers from the US National Institutes of Health tracked the incidence of the rare cancers—ependymomas, a cancer of the nervous system, osteosarcomas, or bone cancer, and mesotheliomas, cancers of the lungs and chest—among people born between 1947 and 1952, between 1956 and 1962 and, finally, between 1964 and 1969.
Although these people were very likely to have had the contaminated polio vaccine, the researchers said there wasn't a spike in the number of cases of these rare cancers. Although two of the cancers are still rare, cases of mesotheliomas have increased, but among older people who wouldn't have had the vaccine.1
None for me
NDMA (N-nitrosodimethylamine)—or nitrosamine—isn't a chemical you'd willingly take. Health agencies have estimated it's safe for humans to consume no more than 1 microgram—one millionth of a gram—each day, and we can easily do that if we eat some meat from the barbecue, for instance. But the levels of NDMA discovered in supplies of drugs have been as high as 17 times that.
It's a carcinogen, or cancer-causing agent, and a dose of less than one milligram can mutate mouse cells and make them cancerous. Anyone who takes 2 grams will be dead within days—as was demonstrated by a vindictive man in Oklahoma who poisoned the family of an ex-girlfriend by adding a vial of NDMA to a pitcher of lemonade.
It used to be added to rocket fuel and is still found in tobacco smoke, and it is also used to cure meat.