Why The US FDA Requested Ranitidine Withdrawal; How Other Withdrawals Could Follow
Executive Summary
Agency worried what might happen beyond expiry or room temperature to generate carcinogenic impurities in ranitidine; will guide assessment of nitrosamine risks in other drugs.
Concerns about nitrosamine impurities led the US Food and Drug Administration on 1 April to request immediate withdrawal of all prescription and over-the-counter ranitidine drugs, commonly known as Zantac, from the US market, and to ask pharmaceutical companies to check for similar risks in their other drug products.
The agency plans to provide guidance soon on how it expects manufacturers to assess the risk of nitrosamine formation in all their drug products. EU regulators imposed a similar requirement last year but have deferred the deadline for risk evaluations due to the COVID-19 pandemic. (Also see "More Time For EU Nitrosamine Evaluations Due To COVID-19" - Pink Sheet, 27 Mar, 2020.)
The FDA’s ranitidine withdrawal request applies to all batches even if, as expected, they met all specifications before they were marketed and stability testing programs showed they remained within specification after they were marketed.
The agency decided to make the request after finding that unacceptable levels of the nitrosamine N-Nitrosodimethylamine, (NDMA), a probable human carcinogen, can form during storage above room temperature or beyond expiry, as can occur after purchase by consumers.
“This presence of NDMA in ranitidine that occurs over time may be a fixable problem, and we’re open to companies demonstrating that reformulated, their product will have you in a way that is stable.”
“Clearly, we can’t have products on the market that if they’re stored under conditions consumers might store them under, that they would become unacceptable, explained Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research.
Valisure Had Called For Market Removal
The FDA’s decision comes six months after Valisure LLC, a New Haven, CT, pharmacy and analytical laboratory, filed a citizen petition with the agency urging removal of ranitidine from the market. Valisure found several milligrams of the impurity in ranitidine tablets it tested, well above the FDA’s 96 nanograms per day threshold of concern. (Also see "FDA And EMA Evaluate Claims As Nitrosamine Worries Turn To Zantac" - Pink Sheet, 15 Sep, 2019.)
Valisure CEO David Light told the Pink Sheet he applauds the FDA’s action to request withdrawal of ranitidine from the market, although he said he’s “a bit frustrated it’s taken this long.”
He noted that Canada and dozens of other countries removed it from their markets shortly after the FDA said in September 2019 that it was evaluating the potential risk of NDMA in ranitidine.
FDA Tested Valisure’s Findings
The FDA followed up on the concerns Valisure raised in its citizen petition by doing its own studies.
When FDA laboratories tested ranitidine from a dozen manufacturers, they found levels generally below the threshold of concern. (Also see "US FDA Finds Zantac Poses Little Risk, But Concerns Linger" - Pink Sheet, 3 Nov, 2019.)
The FDA also launched its own months-long stability tests on various manufacturers’ ranitidine products to ascertain the storage risks. It was these tests that led to the market withdrawal request even though most of the products fared well.
“We didn’t observe unacceptable levels of NDMA in many of the samples that we tested,” said Woodcock. “However, since we didn’t know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured.”
The agency also is investigating whether, as Valisure contends, ranitidine use leads to formation of NDMA in the human body. Woodcock said that FDA toxicologists “are quite skeptical of that,” but the agency set up a human trial to answer the question and will share those results when it has them.
Valisure also is working on a clinical study of that question, along with researchers at Memorial Sloan Kettering Cancer Center in New York.
Market Reentry Remains A Possibility
The door is open for ranitidine manufacturers to get their products back on the market, however.
Woodcock told reporters “this presence of NDMA in ranitidine that occurs over time may be a fixable problem, and we’re open to companies demonstrating that reformulated, their product will have you in a way that is stable.”
Depending on the cause of the impurity formation, it is possible that changes to drug packaging, product formulation or transportation conditions could reduce NDMA formation, she suggested.
CMC Review Implications
Asked about the chemistry, manufacturing and review implications of the FDA’s decision to request ranitidine market withdrawal based on excessive temperature or length of storage, the agency told the Pink Sheet that it “will assess any supplement or application for ranitidine that demonstrates control and appropriate limitation of NDMA over the proposed labeled shelf-life and storage conditions.”
The agency went on to lay out its expectation for any ranitidine stability program “to test for the formation of NDMA through labeled shelf life and at a temperature higher than controlled room temperature to ensure any labeled expiration date will result in product that does not contain excessive NDMA.”
Additionally, the FDA said such a stability program should “evaluate in-use conditions (i.e., simulate reasonably expected consumer use such as opening a bottle daily) and evaluate whether NDMA forms at temperature and humidity conditions higher than controlled room temperature.”
As for how to evaluate any other impurities that might arise, the agency called attention to the stability testing provision in the good manufacturing practice regulations for finished pharmaceuticals at 21 US Code Section 211.166 as well as to the International Council on Harmonization’s Q1A(R2) guideline on stability testing of new drug substances and products.
Assessing Nitrosamine Risks Among Other Drugs
Woodcock said the forthcoming guidance on steps manufacturers should take to detect impurities like nitrosamines in any of their drug products will call for routine testing as well as a chemical risk assessment “to look at what is the probability of generating them.”
She notes that after working on nitrosamine risks of angiotensin II receptor blockers like valsartan that came to light in 2018, (Also see "The Reaction To Valsartan Impurities: More Scrutiny, More Testing And Tighter Limits" - Pink Sheet, 11 Feb, 2019.) the agency “developed a sophisticated and large-scale model of which drugs might be at risk for developing the impurities during manufacturing.”
The FDA also is working with regulatory partners around the world and industry to advance these efforts “because there’s a large number of drugs and we need to cover them all as quickly as possible.”
Singapore recently sparked scrutiny of one such drug after recalling three metformin products due to discovery of a nitrosamine impurity. (Also see "Global Scare Over Nitrosamine Impurities Extends To Diabetes Medication" - Pink Sheet, 6 Dec, 2019.)