The U.S. FDA released the FDA Updates and Press Announcements on NDMA in Zantac (ranitidine) on April Fools’ Day to explain the change characteristics of the genotoxic impurities in ranitidine products and request all ranitidine manufacturers to remove such products from the market. This important document on pharmaceutical product safety was released on April Fools’ Day (Apr. 1, 2020), however, it is not deemed as a joke but an important regulatory signal by the pharmaceutical industry of each country.
The change characteristics of the genotoxic impurities in ranitidine products mentioned by the FDA in the said document are as follows:
※NDMA levels increase in ranitidine even under normal storage conditions;
※NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers.
※The older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA.
The above information shows that the genotoxic impurities in ranitidine products do not exist stably but continue to increase with the circulation time and external conditions, which will produce unacceptable risks to patients, therefore, the eventual removal from the market is one of the official measures.
As a common clinical drug, ranitidine is mainly used to treat peptic ulcer, reflux esophagitis, Zollinger-Ellison syndrome and upper gastrointestinal hemorrhage and relieve the stomachache, heartburn and acid reflux as a result of hyperchlorhydria. If ranitidine is to be substituted, it may greatly affect many patients.
Genotoxic impurities have been concerned about by the Chinese pharmaceutical industry and patients, not since ranitidine but since the valsartan event of Huahai Pharmaceutical in middle 2018. Next, I’d like to sort out the related Chinese regulation changes and the possible trend of market changes according to the information I have.
Part I: Compliance actions taken in China specific to genotoxic impurities
In middle 2018, Zhejiang Huahai discovered and voluntarily reported to the European and U.S. drug regulators about the situation of the genotoxic impurities in valsartan API manufactured by it. This event pushed forward the genotoxic impurity risk involved in ICH M7 and was highly valued by the European and U.S. drug regulators. In 2018 Q4, the U.S. FDA and EU EMA successively inspected Zhejiang Huahai and issued warning letters. Furthermore, the EU EDQM also released analytical methods specific to the genotoxic impurities NMDA and NDEA and the control limits in the transition period. Zhejiang Huahai eventually passed the reinspection of the EU and was lifted the warning in 2019 Q4 after continuous efforts, meaning that its goods could continue to be exported to the EU market. Zhejiang Huahai completed the supplementary application in China in Mar. 2020 and the sales of its valsartan API and formulation could be resumed in the Chinese market.
The following table lists the compliance actions taken by the Chinese drug regulators:
Name | Compliance action |
Chinese Pharmacopoeia Commission | Revise the valsartan quality standard and add the process assessment requirements. |
Chinese Pharmacopoeia Commission | Add the Guideline for the Control of Genotoxic Impurities to the 2020 edition of Chinese Pharmacopoeia. |
Center for Drug Evaluation, NMPA | Release the Technical Guidelines for the Research of Genotoxic Impurities of Drugs. |
National Medical Products Administration (NMPA) | News Spokesperson of the NMPA on the Situation of Valsartan API of Huahai Pharmaceutical |
After the occurrence of this ranitidine genotoxic impurity event, there has been no similar control document that can be queried on the NMPA website so far,...
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