Following is the announcement of Zhejiang Huahai Pharmaceutical Co., Ltd. on the discovery of trace genotoxic impurities in unknown impurities of valsartan APIs
In July 7, 2018, July 9, 2018, July 13, 2018, July 16, 2018, July 20, 2018 and July 24, 2018, the company published the public notice of the Zhejiang Hua Hai pharmaceutical industry Limited by Share Ltd on the discovery of extremely trace gene toxic impurities in the unknown impurities in valsartan raw materials (No. 2018-059), Zhejiang Hua Hai. Progress bulletin on the discovery of toxic impurities in extremely trace genes in the unknown impurities in valsartan APIs (2018-061, 2018-064, 2018-065, 2018-068) and the discovery of extremely trace gene toxicity in the unknown impurities in valsartan raw materials by the Limited by Share Ltd of Zhejiang Hua Hai pharmaceutical industry Clarification Bulletin of impurities (No. 2018-069).
The companys public interest in the Valsartan incident has been further explained as follows:
1. Why should we recall the preparation of valsartan raw material and the drug produced from this raw material?
In June 15, 2018, in the process of optimizing the production process of valsartan, one of the unknown impurities was found to be nitroso - two methylamine (NDMA). The impurity is the trace impurity produced by the current registered process in the normal production of valsartan API. The production process of the company has passed through the relevant countries.
It is approved by the Department of pharmacy and is in conformity with the regulations and standards. According to the relevant scientific literature based on animal experiments, the impurity contains genotoxicity, but there is limited evidence of carcinogenicity in humans. Considering the risk prevention, the company decided to recall valsartan APIs listed at home and abroad, and jointly decided to recall valsartan APIs with relevant domestic customers.
A valsartan product manufactured in the companys valsartan stock.
Two. What is the risk of taking the preparation containing this impurity? What measures should be taken?
The content of the impurity in valsartan preparation is very small. The list of carcinogens published by the international organization for cancer research (IARC) of the WHO (WHO), which was published in October 27, 2017, classified NDMA as a 2A carcinogen, and the 2 A is a substance that has a corresponding data support in animal experiments, but with limited evidence of human carcinogenicity.
2/4 and NDMA belong to 81 kinds of 2A substances, including acrylamide, beverages with temperatures higher than 65 degrees and red meat, which are ubiquitous in fried foods. In addition, disrupted shift work is also a type 2A carcinogenic risk behavior.
Although NDMA is found to increase the incidence of cancer in very high dose animal studies, there is no sufficient data to support the carcinogenic effect of the impurity on human body. People taking medicine with valsartan must not stop taking drugs without authorization. The risk of hypertension is more direct and serious. Whether or not to stop medicine or change medicine must be guided by the doctor, and the patient can contact the doctor to replace any other valsartan drugs that do not involve the recall or choose alternative medication.
Three, why China and the us recall notice later than Europe?
Before the company discovered the impurity autonomously, the regulatory authorities of various countries did not set an acceptable control limit standard for the impurity. After the incident, the company took the initiative to communicate with relevant customers and regulators, because the assessment and supervision requirements of the drug regulatory agencies of various countries were different, and the announcement time was also slightly different.
Based on the consideration of risk prevention, the company announced at noon on July 13, 2018 that the products of valsartan raw materials and valsartan raw materials produced at home and abroad were issued at noon on the domestic market.
Beijing time on July 14, 2018, issued a recall of our company listed in the United States valsartan product announcement.
Four. Is the company reporting to the pharmaceutical supervisory and administrative department in time?
On July 6, the company reported to the domestic drug regulatory authorities the detection of trace N-nitrodimethylamine (NDMA) impurities in the export of valsartan raw materials.
What pharmaceutical manufacturers are involved in this recall? How do you inquire about the products to be recalled?
There are 6 pharmaceutical companies involved in the use of valsartan raw materials in China. The Valsartan preparation products produced by the Hunan Qianjin Xiangjiang pharmaceutical Limited by Share Ltd have not been out of the factory. The other 5 enterprises listed products are beyond the limit of NDMA, respectively, Chongqing Kang Carl Pharmaceutical Co., Ltd., Jiangsu Wan Gao pharmaceutical Limited by Share Ltd , Shandong Yi Jian Pharmaceutical Co., Ltd., Hainan Huanglong pharmaceutical Limited by Share Ltd, Harbin Sanlian pharmaceutical Limited by Share Ltd. As of July 23, 2018, the company has completed the recall of all the APIs in China.
The website of the 5 pharmaceutical production enterprises has disclosed relevant recall information, including the telephone number that the enterprise is responsible for recalling. In order to facilitate the publics timely mastery of the recall range of valsartan drugs being used, 5 production enterprises have worked with information technology companies. At 22 July 26, 2018, the scavenging query function was on-line, and the real-time query was realized through the traceability code of 3/4 Taobao, Tmall, Alipay, Ali health and other mobile phones. The situation can be understood by inquiring the enterprise website.
Six. Why is impurity NDMA found in raw material of valsartan?
Based on the companys current survey, NDMA is an unexpected trace of process impurities produced during the production process of the current registered process. The reason is that in the specific process, the trace impurities produced by solvent degradation and the side reaction produced by the latter reagent. The current process has been approved by the relevant national drug regulatory authorities. NDMA (N- nitroso two methylamine) molecular formula C2H6N2O, molecular weight 74.08, yellow liquid, soluble in water, ethanol, ether, dichloromethane, and two methylamine and nitrite in the acid condition reaction and formation. The substance exists widely in the environment.
7. Why should the process of valsartan be changed? Does the change process conform to the rules?
The original technology of the company has such problems as low conversion rate, large amount of three wastes, and fluctuation of isomer impurity level. After changing the production process of valsartan, the conversion rate is increased by about 30%, the production of three wastes is reduced by about 30%, and the impurities of the isomers have also been effectively controlled. Based on the above reasons, the company began to change the process into the existing process in accordance with the regulatory requirements of the pharmaceutical regulatory authorities of the relevant countries in 2012.
Eight. How did enterprises discover the presence of impurity NDMA in valsartan?
In June 15, 2018, in the process of optimizing the production process of valsartan, one of the unknown impurities was found to be N- nitroso two methylamine (NDMA). NDMA is an unexpected trace impurity produced during the production process of the current registration process. Before the incident, drug regulatory agencies in various countries did not detect the impurity.
The detection of unknown impurities in drugs depends mainly on the level of cognition and cognition and the development level of detection methods. The guidelines for the control of genotoxic impurities, ICHM7, formally proposed by the ICH Management Committee in 2010, were finalized in 2013, and this has gradually aroused the attention of the pharmaceutical industry. The company has developed valsartan since 2004. The research on genotoxic impurities is a gradual process, from the initial study of azide residues to the residue of the later bromide series, and to the discovery and verification of this NDMA. In view of the level of research and cognition at the time, the study of genotoxic impurities is based on the guidelines for potential genotoxicity warning structures, and risk assessment and control are carried out on the main line of starting materials, intermediates, principal components, main reaction byproducts and direct reagents. Because this NDMA is produced by the reaction of the solvent lowering 4/4 substance with the latter reaction reagent, and the residue in the product is minimal.
The approved analytical method can not be detected, and it is impossible to control the genotoxic impurity. Therefore, the impurity of NDMA is newly discovered with the deepening of product scientific cognition, the development of science and technology and the improvement of detection methods.
In July 11, 2018, the company received a technical communication letter from the European Pharmacopoeia Committee of EMA (EDQM), which indicated that the toxicity of NDMA impurities would be further evaluated. At present, the acceptability limit of the impurity in valsartan was tentatively designated as 0.3ppm according to the requirements of ICHM7, and further assessment was still being conducted by EMA. The final acceptable limit index has not been determined, so the company did not disclose it in the early stage. In July 29, 2018, the State Drug Administration issued information. According to the toxicological data, the maximum daily intake limit of NDMA was calculated to be 0.1 mu g, equivalent to the EMA temporary reference limit of 0.3ppm (according to daily use of 320mg valsartan).
According to the information issued by the State Administration of drug administration, the NDMA impurities in valsartan raw materials in other domestic valsartan enterprises are lower than the limit value or not detected in other domestic valsartan raw materials, in addition to the limit of the value of the impurities in the Valsartan raw material of the company. After checking other products of the company, no NDMA impurity was found. The company will further improve the evaluation system of gene toxicity in the stage of R & D and process change, and improve the guidance document of potential genotoxic impurity research and risk assessment, which will effectively guide the research and control of toxic impurities containing warning structures, improve product quality and avoid similar events again. The company will continue to pay close attention to the follow-up development of the matter, and in strict accordance with relevant laws and regulations timely fulfillment of information disclosure obligations. The information about the company is subject to the announcement by the company to disclose the media of China Securities, the Shanghai Securities Daily, the securities times, the Securities Daily and the Shanghai stock exchange website. We ask the investors to pay attention to the risk of investment. This is hereby announced. Zhejiang Huahai pharmaceutical Limited by Share Ltd board July 2018 30 Japanese language source: surging news editor: Qiao Jing _NN6607
According to the information issued by the State Administration of drug administration, the NDMA impurities in valsartan raw materials in other domestic valsartan enterprises are lower than the limit value or not detected in other domestic valsartan raw materials, in addition to the limit of the value of the impurities in the Valsartan raw material of the company. After checking other products of the company, no NDMA impurity was found. The company will further improve the evaluation system of gene toxicity in the stage of R & D and process change, and improve the guidance document of potential genotoxic impurity research and risk assessment, which will effectively guide the research and control of toxic impurities containing warning structures, improve product quality and avoid similar events again.
The company will continue to pay close attention to the follow-up development of the matter, and in strict accordance with relevant laws and regulations timely fulfillment of information disclosure obligations. The information about the company is subject to the announcement by the company to disclose the media of China Securities, the Shanghai Securities Daily, the securities times, the Securities Daily and the Shanghai stock exchange website.
This is hereby announced.
Zhejiang Huahai pharmaceutical Limited by Share Ltd