China News Service Client, Beijing, June 3 (Reporter Zhang Ni) Recently, the US Food and Drug Administration issued a document saying that in some metformin sustained-release preparations, the content of carcinogenic nitrosamine impurities exceeds the standard, and some companies are recommended to volunteer recall. Coincidentally, such impurities have also been detected in some antihypertensive drugs and stomach medicines earlier, causing public concern.
In response to the problem of drug impurities, the domestic drug regulatory department has recently issued a document requesting pharmaceutical companies to control the level of nitrosamine impurities below the safety limit. At the same time, out of risk prevention, some companies have also started self-examination.
Data map (not related to the text) She Xinshe reporter Tong Yushe
Metformin is exposed to carcinogenic impurities
Recently, the US Food and Drug Administration (FDA) official website stated that in some metformin sustained-release preparations, the content of N-nitrosodimethylamine (NDMA), a carcinogenic nitrosamine impurity, has exceeded the standard and has been recommended5 A pharmaceutical company voluntarily recalled the diabetes drug metformin sustained-release agent.
In the treatment of diabetes, metformin is the first choice and the full-course drug for the treatment of type 2 diabetes. It is also the first choice for monotherapy and combination therapy. It has a wide audience and is also called "diabetic medicine" by some patients.
The ninth edition of the Global Diabetes Map released by the International Diabetes Federation shows that there are currently an estimated 463 million adults worldwide with diabetes, while China has more than 116.4 million diabetic patients.
According to the official website of the independent inspection laboratory Valisure in March this year, the agency analyzed 22 companies selling metformin and a total of 38 batches of products, and found that 16 batches and 11 companies had higher NDMA levels. The upper limit of the acceptable daily intake of 96ng.
Clinically, metformin mainly has ordinary dosage form, enteric solution type and sustained-release dosage form. The drugs involved in this over-standard are mainly sustained-release dosage forms.
According to foreign media reports, last year, about 21 million prescription drugs in the United States used metformin sustained-release dosage forms, accounting for about a quarter of all metformin prescriptions in the United States. In addition, metformin has high sales in the Chinese market.
Among domestic companies, Baiyang Pharmaceutical, Shiyao Ouyi, Hisun Xuantai and other metformin sustained-release tablets have previously received FDA approval. However, the aforementioned impurity storm has not yet affected Chinese pharmaceutical companies selling in the United States.
Data map (not related to pictures and photos).
What is NDMA?
N-nitrosodimethylamine, also known as dimethylnitrosamine, is abbreviated as NDMA in English. Currently, it is mainly used for scientific research in medicine and food analysis. Industrial sectors such as tanning, pesticide production, rubber and tire manufacturing, alkylamine production and use sites, fish processing, casting and dye production, soap production, detergents and surfactant manufacturing all generate and emit NDMA.
According to the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization, NDMA is a category 2 carcinogen, meaning that there is limited evidence of carcinogenicity to humans and sufficient evidence of carcinogenicity to laboratory animals.
In daily life, NDMA is not uncommon, such as common in various preserved, smoked barbecue products and other foods. The US Food and Drug Administration limits the acceptable intake of NDMA in pharmaceutical preparations to 96 ng per day.
So, why does NDMA exist in metformin preparations?
A person in charge of a pharmaceutical company revealed to reporters that the existing test results cannot specify the source of genotoxic substances. It is currently speculated that the NDMA excess may be due to the metformin API and formulation prescription process, the formation of genotoxic impurities and the synthesis of API Steps, solvents, preparation methods and so on.
Data map (not related to the picture) Photo by Zhang Xinfu, reporter of China News Service
Impurity issues frequently cause patients to worry
It is worth noting that it is not the first time that NDMA has exceeded the standard. Many drugs are still commonly used.
As early as July 2018, according to the European Medicines Agency (EMA) regulations, the Italian Medicines Regulatory Authority (AIFA) had ordered the recall of some valsartan blood pressure lowering drugs containing NDMA.
In 2019, the US Food and Drug Administration found suspicious NDMA impurities in drugs such as ranitidine.
During this period, a number of pharmaceutical companies at home and abroad have actively recalled the problematic drugs, and the widespread use of the "sacred medicine" by the public has been questioned to be at risk, and it has also caused public concern.
Since 2019, the US Food and Drug Administration and the European Medicines Agency have investigated whether metformin contains NDMA and whether NDMA exceeds the daily acceptable intake limit.
However, even so, professional institutions do not advise patients to stop the drug because of it.
The US Food and Drug Administration has made it clear that even if some of the drugs have recall problems, patients should continue to take metformin until health care professionals find other alternatives for them. Once a patient stops taking drugs, they may face health risks.
In addition, the US Food and Drug Administration still recommends that healthcare professionals continue to prescribe metformin for patients when there is clinical need.
Data map (not related to the text) Guo Jiashe
Domestic regulatory authorities require strict control of toxic impurities in drugs
The problem that the drug may contain NDMA impurities has also attracted great attention from domestic drug regulatory authorities.
As early as August 2018, the State Food and Drug Administration announced the "Revised Draft of Valsartan National Standards" of the National Pharmacopoeia Commission.
According to this public draft, the 2015 edition of the Chinese Pharmacopoeia will increase the production requirements for valsartan, including "the production process must be evaluated to determine the possibility of forming N-nitrosodimethylamine", and it is also proposed The first-come-first-served limit for this substance is “not to exceed three ten millionths”.
In May this year, the State Drug Administration's Drug Evaluation Center issued the "Guiding Principles for the Research of Nitrosamine Impurities in Chemical Drugs (Trial)".
The document clearly states that drug marketing license holders/pharmaceutical manufacturers should effectively fulfill the main responsibility of drug quality management, carry out full life cycle management of drug safety and quality, and avoid the introduction of nitrosamine impurities as much as possible. If it cannot be avoided completely, the risk of nitrosamine impurities in the drug should be fully evaluated, and the level of nitrosamine impurities should be controlled below the safety limit.
Although the NDMA incident of metformin has not yet reached domestic enterprises, some enterprises have carried out corresponding self-examination work.
For example, Lei Jifeng, a director of Baiyang Pharmaceutical, told the media recently that since the European Medicines Agency disclosed that metformin contained NDMA in December last year, the company conducted an investigation and evaluation of the new metformin drug Nida, and tested both NDMA in raw materials and preparations. , NDMA was not detected. Baiyang Pharmaceutical has sent the NDMA evaluation report to the US sales agency.
Although there are many types of enterprises and medicines involved after the strengthening of supervision, industry analysis shows that this move is not to allow enterprises to have "nowhere to go", but to enable capable enterprises to improve control of product risks and control backward production capacity. Eliminate and improve the quality and safety of medicines. (Finish)