Nitrosamine Impurities in Medicines: FDA’s Continuing Multidisciplinary Response

藥品中的亞硝胺雜質：FDA的持續多學科響應

In June 2018, the FDA learned that certain generic versions of valsartan, a high blood pressure and heart failure medication, contained unexpected impurities that posed a potential safety concern. These impurities, known as nitrosamines, are probable carcinogens that may increase the risk of cancer in humans. They include N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosomethylphenylamine (NMPA), 1-methyl-4-nitrosopiperazine (MNP), and 1-cyclopentyl-4-nitrosopiperazine (CPNP). There are many reasons why nitrosamines can be present in medications, including a drug’s manufacturing process, its chemical structure, or the conditions in which it is stored or packaged.

2018年6月，FDA了解到有些纈沙坦仿制藥（一種高血壓和心力衰竭治療用藥）中含有非預期雜質，有潛在安全問題。這些雜質已知是亞硝胺，是可能的致癌物，可增加人類患癌風險。亞硝胺包括有NDMA、NDEA、NMBA、NIPEA、NMPA、MNP(1-甲基-4-亞硝基哌嗪)和CPNP(1-環戊基-4-亞硝基哌嗪)。藥品中出現亞硝胺的原因有許多，包括藥品的生產工藝、其化學結構，以及藥品的存貯條件和包裝條件。

Since the initial discovery of NDMA in valsartan, FDA scientists and regulators have investigated nitrosamine impurities in other products, including the heartburn medications ranitidine and nizatidine, the type 2 diabetes medication metformin, and the tuberculosis medications rifampin and rifapentine. The Agency has developed appropriate test methods for testing for these impurities in specific drug products, has tested drug products and drug substances, sent information requests to applicants and manufacturers of drug products suspected of containing nitrosamine impurities, and evaluated the information received from industry. It has assisted industry in initiating voluntary recalls of products when nitrosamines have been found above an acceptable level, and worked with industry when changes to manufacturing processes were appropriate. Throughout this process FDA has kept industry, health practitioners and the public informed of our investigation and regulatory actions. Timely communication o fthis information has provided health care professionals, patients, consumers and other interested persons with access to the most current information concerning the potential risks and benefits of marketed drugs, helping them to make more informed treatment choices.

自從在纈沙坦中首次發現NDMA以來，FDA科學家和監管人員對其它藥品中的亞硝胺雜質進行了調查，包括胃灼燒藥品雷尼替丁和尼扎替丁，II型糖尿病用藥二甲雙胍，以及結核病用藥利福平和利福噴丁。FDA已開發出適當的檢測方法用于特定藥品中這些雜質的檢測，并對制劑和原料藥進行了檢查，要求申報人和疑似含有亞硝胺雜質的藥品生產商提交資料，并評估了企業提供的相關資料。FDA的工作幫助了企業主動召回發現亞硝胺雜質高于可接受水平的藥品。在這些工作中，FDA一直向企業、衛生工作人員和公眾提供我們的調查和監管措施信息。對這些信息的及時溝通使得衛生工作人員、患者、消費者和其它利益相關方可獲得最新的已上市藥品的潛在利弊資料，幫助他們更好了解治療選擇。

Ranitidine雷尼替丁

All of FDA’s 2020 updates and actions on ranitidine are available online. On April 1, FDAannounced it was requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine medications from the market immediately. The Agency determined the NDMA impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity.

所有FDA在2020年的更新和措施均可在線查找。4月1日，FDA宣布要求生產商立即從市場上撤回所有處方和OTC雷尼替丁藥品。FDA檢測發現有些雷尼替丁藥品中的NDMA雜質隨時間而增長，并且在存貯溫度高于室溫時可能會導致使用者暴露于不可接受水平的該雜質中。

Metformin 二甲雙胍

The full timeline of announcements, statements, and actions related to metformin products is available online. Key 2020 actions addressing NDMA impurities in metformin products include:

與二甲雙胍有關的全部公告、聲明和措施時間線可在線查到。二甲雙胍藥品中NDMA雜質在2020年關鍵措施包括：

FEBRUARY 3 | FDA announced that it posted laboratory results showing NDMA levels in some metformin products approved in the United States. The Agency determined that the levels of NDMA in the metformin products tested ranged from not detectable to low levels.

2月3日，FDA宣布發布美國批準的有些二甲雙胍藥品中的NDMA水平的實驗室結果。FDA檢測顯示二甲雙胍藥品中的NDMA從未檢出到較低水平。

MAY 28| FDA alerted patients and health care professionals that laboratory testing revealed levels of NDMA above the Agency’s acceptable intake limit in several lots of the extended release (ER) formulation of metformin.

5月28日，FDA警示患者和衛生工作人員，實驗室檢測顯示幾個批次的緩釋（ER）二甲雙胍制劑中NDMA水平超出FDA認定的可接受攝入限度。

JUNE 11 | FDA named fivecompanies that voluntarily recalled certain ER metformin and updated the Agency’s laboratory test results showing the levels of NDMA it found in samples of metformin to date. FDA also posted a second liquid chromatography-electrosprayionization-high resolution mass spectrometry (LC-ESI-HRMS) testing method to provide an option for regulators and industry to detect eight different nitrosamine impurities in metformin drug substances and products.

6月11日，FDA點名要求5家公司主動召回特定ER二甲雙胍，并更新了FDA實驗室截止當時所檢測出的NDMA水平。FDA亦發布了第二個LC-ESI-HRMS檢測方法，為藥監機構和企業提供檢測二甲雙胍原料藥和制劑中8種不同亞硝胺雜質的方法選擇。

JULY 2 | The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists, published FDA’s manuscript titled, “A Cautionary Tale: Quantitative LC-HRMS AnalyticalProcedures for the Analysis of N-Nitrosodimethylamine in Metformin.” This article assessed the cause for the discrepancy between the NDMA values FDA found in its testing of metformin drug products and the values a private laboratory reported. In summary, FDA found the private laboratory method to be inappropriate for quantifying NDMA in metformin drug products due to presumptive overestimation of NDMA caused by the presence of a substance that interfered with the testing results. This article emphasized the importance of the use of appropriate test methodology. If FDA relied upon the data from inappropriate test methods, drug products approved by FDA may have been removed or voluntarily recalled from the market causing unnecessary disruption to patients and health care providers.

7月2日，APPS雜質（美國藥物科學家官方雜志）發布了FDA題為“警示故事：二甲雙胍中定量檢測N-二甲基亞硝胺LC-HRMS分析方法”的文章。該篇文章評估了FDA在其對二甲雙胍藥品中檢測所得NDMA值與私人實驗室所報告的值之間的差異。簡單地說就是FDA發現私人實驗室的方法并不適合對二甲雙胍制劑中的NDMA進行定量分析，因為存在一種物質影響了檢測結果，所以NDMA結果虛高。該文章強調了使用恰當的檢測方法的重要性。如果FDA依賴于不恰當的檢測方法所得數據，則由FDA批準的數據可能會從市場召回或移除，從而不必要地導致患者和衛生工作人員缺少該藥品。

JULY 13 | FDA announced that several companies voluntarily recalled ER metformin medications due to the possibility they could contain NDMA above the acceptable intake limit. FDA also published a recalled metformin list that included details about metformin products that had been recalled, which has since been updated.

7月13日，FDA宣布幾家公司因其ER二甲雙胍藥品中可能含有NDMA超出不可接受的攝入限度，因此主動召回。FDA還發布了二甲雙胍召回清單，包括已被召回的二甲雙胍藥品，這些均已進行了更新。

Rifampin and Rifapentine 利福平與利福噴丁

AUGUST 26 | FDA announced it was aware of nitrosamine impurities in certain samples of rifampin and rifapentine, which are antibacterial medications used to treat tuberculosis. The Agency identified rifampin containing MNP and rifapentine containing CPNP above the acceptable intake limits. FDA has been investigating this problem and isworking with manufacturers to permit temporary distribution of these drug products to avoid shortages and to help ensure patients continued to have access to these necessary medications, until manufacturers can reduce oreliminate the impurities. FDA announced it would not object if certain manufacturers temporarily distributed rifampin containing MNP below 5 parts permillion (PPM), and rifapentine containing CPNP below 14 ppm.

8月26日，FDA宣布其了解到一些利福平與利福噴丁樣本中含有亞硝胺雜質，該藥品為抗菌藥品，用于治療結核病。FDA發現利福平中含有的MNP和利福噴丁超出了可接受的攝入限度。FDA已對此問題進行了調查，并與生產商一起努力，暫時允許銷售這些藥品，以避免藥品短缺，并幫助確?；颊呃^續獲得這些必要的藥品，直至生產商能夠降低或清除這些雜質。FDA宣布不會對暫時銷售含有NMP低于5ppm的利福平，以及含CPNP低于14ppm的利福噴丁的生產商采取措施。

SEPTEMBER 2 | FDA published a LC-ESI-HRMS testing method to provide an option for regulators and industry to detect nitrosamine impurities in rifampin and rifapentine.

9月2日，FDA發布了一個LC-ESI-HRMS方法，為監管方和企業提供了檢測利福平和利福噴丁中亞硝胺雜質的方法。

OCTOBER 29 | To continue to mitigate or avoid a shortage, FDA announced it would not object to certain manufacturers temporarily distributing rifapentine containing CPNP at or below 20 ppm to help ensure patients had continued access to the medication.

10月29日，為繼續緩解和避免藥品短缺，FDA宣布其不會對臨時銷售含CPNP等于低于20ppm的利福噴丁的生產商采取措施，以幫助確?；颊呃^續獲得該藥品。

FDA Guidance for Industry  FDA的行業指南

On September 1, FDA announced the publication of the guidance “Controlof Nitrosamine Impurities in Human Drugs. ” The guidance recommends steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in their drugs. The guidance also describes conditions that may introduce nitrosamine impurities. On October 2, FDA held a Small Business and Industry Assistance webinar to explain the guidance.

9月1日，FDA發布“人藥中亞硝胺雜質的控制”指南。該指南建議API和制劑生產商應采取的檢測和防止其藥品中亞硝胺雜質達到不可接受水平的措施。該指南亦描述了可能會引入亞硝胺雜質的條件。10月1日，FDA召開了中小企業網絡培訓對該該指南進行了解釋。