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Report

December 3

Ranitidine and How Was it Possible that Potentially Harmful Product Made It to Market?

Unraveling the timeline that led to over 7 pharma companies recalling their products off the market.

 

What Happened?

Several pharma companies have voluntarily recalled their Ranitidine products due to concerns of possible contamination from a probable carcinogen, N-nitrosodimethylamine (NDMA).  This falls on the back of the discovery of NDMA in Valsartan last year. Click here to read more. Ranitidine is also known as the brand name Zantac which is manufactured by Sanofi.

 

How did it start?

A citizen petition was sent to the FDA on September 9th, 2019 by Valisure, a Connecticut-based online pharmacy.  Their facility is unique because they are not part of the pharmaceutical manufacturing system, and they do not perform release testing, stability testing or any related services for pharmaceutical manufacturers. They have elected to maintain voluntary registration status with the FDA, and Valisure tests all batches of medication that they sell.  It was during this testing that extremely high levels of NDMA were found in every lot tested, across multiple manufacturers. They described that the Ranitidine molecule contains both a nitrite and dimethylamine group which are well known to combine to form NDMA.  Therefore, their conclusions following testing was that Ranitidine is inherently unstable.
 
In addition to their findings, Valisure have requested that the FDA promulgate regulations requiring robust independent chemical batch-level testing and verification of medicines.  At present, the US does not require independent batch level testing prior to release on market, whereas, this is current practice within the EU for medicines manufactured outside of the EU.
 
Following receipt of this petition, on September 13th, the FDA released a statement to industry that they have been informed that some Ranitidine medicines, including product commonly known as Zantac, contain the impurity NDMA at low levels. The levels of NDMA that the FDA found in Ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods. 
 
The FDA conducted their own testing to confirm if they see the same test results as reported by Valisure. During their investigation, they highlighted that the method used by Valisure required temperatures of 130°C. The FDA suggested an alternative method that would be more suitable for analysing Ranitidine that does not require such high temperatures.  The heating process as required by the method triggers NDMA formation, resulting in false positive test results.  The FDA shared their method online and requested that manufacturers conduct their own testing to confirm the levels and presence of NDMA in products released to the market. The acceptable daily intake limit for NDMA, as set by the FDA, is at 0.096 micrograms or 0.32ppm for Ranitidine.
 
Following shortly after the FDA’s announcement, pharma companies began voluntarily recalling their Ranitidine products off the market. The timeline of events is given in Table 1 below.
 
Table 1: Investigation of NDMA in Ranitidine Timeline
Date Activity
September 9th 

Valisure sent a petition to the FDA informing them of their discovery of extremely high levels of N-Nitrosodimethylamine NDMA, a probable human carcinogen, in every lot tested, across multiple manufacturers and dosage forms of Ranitidine.

September 13th

The FDA released a statement communicating to industry that they have been informed that some Ranitidine medicines, including product commonly known as Zantac, contain impurity NDMA at low levels.  The levels the FDA is finding in Ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.

September 24th

The FDA announces the first voluntary recall of prescription Ranitidine capsules due to NDMA impurity found in the recalled medicine.

September 26th

The FDA announce another voluntary recall of OTC Ranitidine tablets manufactured by Apotex Corp and labelled by Walgreens, Walmart and Rite-Aid.  Low levels of the impurity NDMA were found.  The FDA has informed health care professionals to not provide recalled products to patients.  In addition, the FDA reiterates the progress of their investigation, and shares a test method for which regulators and industry should use to examine the levels of NDMA in Ranitidine.  Note - This method does not require high temperatures.

October 2nd

The FDA state that the method used by the third-party lab is not suitable for testing Ranitidine because heating the sample generates NDMA.  An alternative LC-HRMS test was suggested and used by the FDA who conducted their own analysis on a selection of products.  The FDA share this method here.

October 8th

The MHRA released a drug alert for GSK who recalled unexpired stock of Zantac prescription only medicines from pharmacies in the UK.

October 23rd

The FDA posted a second method for which manufacturers and regulators can use to detect and quantify NDMA in Ranitidine.  This LC-MS/MS method uses more widely available technology than the LC-HRMS method posted originally. Link to the method is available here.

In addition, an Indian Generics company voluntarily recalls all prescription and OTC Ranitidine tablets and capsules manufactured by themselves. Their OTC medicines may also be labelled by retailers such as Walgreens, Walmart, CVS, Target and Kroger.  Sanofi also voluntarily recalls OTC Ranitidine.

October 25th

The MHRA released a drug alert for a UK Pharma Manufacturer who recalled unexpired stock from pharmacies due to possible contamination with an impurity.

October 28th

An additional 3 pharma companies voluntarily recalled Ranitidine of which the FDA have issued an alert to health care professionals and patients. 

November 1st

FDA conducts laboratory analysis of Ranitidine and nizatidine products.  Conclusion: FDA has determined that the levels of NDMA in Ranitidine and nizatidine are similar to the levels you would expect to be exposed to if you at common foods like grilled or smoked meats.

November 8th

The FDA alerts patients and health care professionals of another voluntary recall by Aurobindo Pharma USA.  This includes OTC, prescription and Ranitidine syrup because these products were found to have contained unacceptable levels of NDMA.

The FDA has advised companies to recall Ranitidine products if testing shows levels of NDMA above the acceptable daily intake of 96 nanograms per day or 0.32 ppm.

The FDA also reiterates that the NDMA levels found by themselves are similar to the levels a consumer would expect to be exposed to when eating common foods like grilled and smoked meats.

November 12th

Two additional voluntary recalls of Ranitidine were announced by the FDA.  

November 19th

The MHRA released a drug alert for another two UK Pharma Companies who recalled all unexpired stock of Ranitidine Oral Solution and Ranitidine Tablets.

November 21st

The MHRA released a drug alert for another four UK Pharma Companies who have recalled stock from pharmacies and retail stores due to possible contamination with an impurity.

November 22nd

Two repackagers voluntary recalls of Ranitidine were announced by the FDA because they main contain unacceptable levels of NDMA.  

 

So, How Did Ranitidine Get Contaminated?

The FDA are still investigating.
 
A few things that the FDA have noted:
  • Not all Ranitidine medicines marketed are being recalled.
  • Some companies may have conducted additional testing to quantify the levels of NDMA, and where the levels are above acceptable daily intake, they issue a recall; however, some companies may choose to issue a recall without conducting testing and based only on the potential for NDMA to be present in the drug.
  • The FDA has tested numerous Ranitidine products on the market and have found levels of NDMA that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.
  • The FDA have also conducted tests that simulate what happens to Ranitidine after it has been exposed to acid in the stomach with a normal diet. The results of these tests indicate that NDMA is not formed through this process.
  • Ranitidine and Nizatidine were both found to contain NDMA. The FDA has tested alternative drugs to Ranitidine and Nizatidine and have found the following alternatives to contain no NDMA.  In addition, the manufacturing processes of these medicines indicate that they should not contain NDMA:
    • Pepcid (Famotidine)
    • Tagamet (Cimetidine)
    • Nexium (Esomeprazole)
    • Prevacid (Lansoprazole)
    • Prilosec (Omeprazole)
  • Consumers and patients can consider using the above alternative OTC products approved for their condition.
 
This stresses the importance of developing fit for purpose methods and validating these methods for specific products.  Although the notifying laboratory used a method that was not fit for purpose, the FDA has acted to inform the industry. Both the regulators and industry have conducted or are currently conducting their own investigations into the presence of NDMA in Ranitidine. 

 

What Happens Now?

The FDA is still working with manufacturers to investigate the true source of NDMA and to understand the root cause of low levels of NDMA present in the drugs. In addition, below is a list of areas where the FDA are continuing their investigation:
 
  • The Impact of Other Older Drugs - The FDA have been asked if testing methods have changed since these products were first approved, and considering this situation, should the safety of other older drugs be investigated. The FDA have an ongoing assessment and surveillance to ensure similar impurities can be kept out of the drug supply.
  • Postmarket Surveillance – The FDA maintain a robust practice of postmarket surveillance and risk evaluation programs to identify adverse events that did not appear during the product development process. Evaluations occur on more than 2 million adverse event reports submitted every year, and the FDA use this information to recommend actions to improve product safety and protect the public.
  • Request for Information – The FDA are working with manufacturers and global regulators to provide clear and actionable information.
 
To keep updated with the continuing investigation, visit the FDA’s website here.
 
Monitoring product performance through routine quality control batch release testing is an important part of the manufacturing process and supply of medicines to market.  We have created a Best Practices Guide which details the best statistical tools for QC data analysis.  Click here or on the button below to download your free copy today.
 
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About the Author

Theresa Webster is the Marketing Director at Broughton Laboratories. After studying at the University of North Carolina at Charlotte receiving a BSc in Biology and a BA in Chemistry, Theresa began her career here at Broughton Laboratories, as a Commercial Projects Manager. She developed business start-ups from idea to fully operational divisions, in particular, the stability storage facility and software services. Theresa led the software services division to become a stand-alone business in 2012 as Broughton Software providing the industry's leading LIMS solution for Quality Control Laboratories. She has rejoined the team at Broughton Laboratories in 2018 with a focus to ensure the customer's evolving needs are continually met by our services.