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A Prospect of Ranitidine Market Changes under the Expanding Influence of Genotoxic Impurities

April 22, 2020 By zhulikou431

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.

A Prospect of Ranitidine Market Changes under the Expanding Influence of Genotoxic Impurities

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, however, similar control documents can be queried on Henan Food and Drug Administration and Gansu Medical Products Administration websites to control the market tender and production to avoid risk expansion.

Part II: Analysis of the market layout of ranitidine products in China

According to the NMPA database and DXY Insight database, the ranitidine APIs registered in China are as follows:

Registration No.

Variety name

Enterprise name

Acceptance No.

Product source

Y20170002012

Ranitidine hydrochloride

Jiangsu Zhengji Pharmaceutical Co., Ltd.

CYHB1702947

Chinese-produced

Y20170002276

Ranitidine hydrochloride

Shanghai Huiren (Xiayi) Pharmaceutical Co., Ltd.; Shanghai Huiren (Xiayi) Pharmaceutical Co., Ltd.;

CYHT1500685

Chinese-produced

Y20180001451

Ranitidine hydrochloride

Saraca Laboratories Limited; Saraca Laboratories Limited; Beijing Lunarsun Pharmaceutical Co., Ltd.

Imported

Y20190001948

Ranitidine bismuth citrate

Zhuhai Free Trade Zone Livzon Synthetic Pharmaceutical Co., Ltd.

GYZ Zi H20153073

Chinese-produced

Y20190005110

Ranitidine bismuth citrate

Zhuhai Free Trade Zone Livzon Synthetic Pharmaceutical Co., Ltd.

GYZ Zi H19991148

Chinese-produced

Y20190003750

Ranitidine bismuth citrate

Changzhou Lanling Pharmaceutical Co., Ltd.

GYZ Zi H20020720

Chinese-produced

Y20190008200

Ranitidine hydrochloride

Jiangsu Baoshenglongcheng Pharmaceutical Co., Ltd.

GYZ Zi H20065262

Chinese-produced

Y20190007953

Ranitidine hydrochloride

CSPC Ouyi Pharmaceutical Co., Ltd.

GYZ Zi H13021369

Chinese-produced

Y20190007917

Ranitidine hydrochloride

Jiangsu Hi-stone Pharmaceutical Co., Ltd.

GYZ Zi H20056110

Chinese-produced

Y20190007896

Ranitidine hydrochloride

Chongqing Southwest Synthetic Pharmaceutical Co., Ltd.

GYZ Zi H50020569

Chinese-produced

Y20190007892

Ranitidine hydrochloride

Shanxi Yunpeng Pharmaceutical Co., Ltd.

GYZ Zi H34022329

Chinese-produced

Y20190008155

Ranitidine hydrochloride

Gooddoctor Pharmaceutical Group Co., Ltd.

GYZ Zi H21024396

Chinese-produced

Y20190008117

Ranitidine hydrochloride

Beijing Taiyang Pharmaceutical Industry Co., Ltd.

GYZ Zi H11021158

Chinese-produced

Y20190008028

Ranitidine hydrochloride

Suzhou Homesun Pharmaceutical Co., Ltd.

GYZ Zi H32022484

Chinese-produced

Y20190008001

Ranitidine hydrochloride

Green Peak Environmental Protection Tech

GYZ Zi H32022107

Chinese-produced

Y20190007991

Ranitidine hydrochloride

Sinopharm Shantou Jinshi Pharmaceutical Co., Ltd.

GYZ Zi H44021514

Chinese-produced

Y20190007980

Ranitidine hydrochloride

Donggang Hongda Pharmaceutical Co., Ltd.

GYZ Zi H21020626

Chinese-produced

Y20190008093

Ranitidine hydrochloride

Chongqing Qingyang Pharmaceutical Co., Ltd.

GYZ Zi H50020669

Chinese-produced

Y20190007748

Ranitidine hydrochloride

Hangzhou Minsheng Pharmaceutical Co., Ltd.

GYZ Zi H33021717

Chinese-produced

Y20190008758

Ranitidine hydrochloride

Shijiazhuang Haili Pharmaceutical Co., Ltd.

GYZ Zi H13022292

Chinese-produced

Y20180001798

Ranitidine hydrochloride

Shanghai Xiandai Hasen (Shangqiu) Pharmaceutical Co., Ltd.; Shanghai Xiandai Hasen (Shangqiu) Pharmaceutical Co., Ltd.

CYHT1600738

Chinese-produced

Y20180001790

Ranitidine hydrochloride

Hubei Merryclin Pharmaceuticals Co., Ltd.; Hubei Merryclin Pharmaceuticals Co., Ltd.

CYHT1600832

Chinese-produced

Y20190009617

Ranitidine hydrochloride

Jiangsu Zhengji Pharmaceutical Co., Ltd.

GYZ Zi H20054166

Chinese-produced

By the beginning of Apr. 2020, 23 ranitidine API enterprises have completed the API, excipient and pharmaceutical packaging material registration in the CDE database of the NMPA, most of which are Chinese enterprises, with only one imported API manufacturer.

According to the NMPA database and DXY Insight database, Chinese manufacturers of ranitidine formulations are as shown in the following table:

We can see from the above data that there have been many Chinese manufacturers of various ranitidine formulations, with a total of 577 approvals received. Enterprises that have passed the consistency evaluation so far include CSPC Ouyi Pharmaceutical Co., Ltd. and Shandong ReYoung Pharmaceutical Co., Ltd., as verified according to the databases.

Part III: Prediction of the compliance measures that Chinese drug regulators may take

Chinese drug regulators are not expected to follow immediately considering that ranitidine is a common clinical drug, although the U.S. FDA requires ranitidine manufacturers to take measures to gradually remove it from the market. According to my work experience, Chinese drug regulators are expected to take the following compliance actions:

※Conduct special inspections of similar products to improve the production and sales compliance levels.

※Organize experts to work out the impurity safety limits, require all ranitidine manufacturers to meet the safety limits in the transition period and prohibit products that do not conform to the limits from selling.

※In the meantime, require manufacturers to put forward changes ASAP, and permit the continued sales after the changes if the impacts of genotoxic impurities can be avoided through process changes.

Anyway, Chinese drug regulators will not always keep the laissez-faire attitude, as the EU and FDA continue to regulate ranitidine and similar products; consequently, the market changes are expected to bring pressure to all enterprises involved.

Note: This article does not constitute any value judgement or investment advice.

1-FDA《FDA Updates and Press Announcements on NDMA in Zantac (ranitidine)》

2-    FDA Updates and Press Announcements on NDMA in Zantac (ranitidine)

3-    EDQM website information

4-    NMPA website information

5-    Henan Food and Drug Administration website information

6-    Gansu Medical Products Administration website information

7-    DXY Insight database

 

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Editor's Note:

En-CPhI.CN is a vertical B2B online trade platform serving the pharmaceutical industry,

for any copyright disputes involved in the articles,

please email: Julia.Zhang@imsinoexpo.com to motify or remove the content.

 

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