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FDA问答:ARB药品中杂质

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药士
发表于 2018-11-29 10:45:13 | 显示全部楼层 |阅读模式

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Questions and Answers: Impurities found in certain generic angiotensin II receptor blocker (ARB) products
问答:特定仿制ARB药品中发现的杂质
20181123

  • What is an angiotensin II receptor blocker  (ARB)?什么是ARB?

The term “ARB” is used to describe drugs in the angiotensin II receptor blocker (ARB) class. ARBs are also called “sartans,” a term derived from aportion of their names that they all share. Examples of ARBs include the drug scandesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. ARBs are commonly used to treat high blood pressure and heart failure.
术语“ARB”用于表示血管紧张素II受体拮抗剂类别的药品。ARB亦称为“沙坦”类药品,该词来源于这些药品共有名称的一部分。ARB药品包括有如坎地沙坦、依普罗沙坦、厄贝沙坦、氯沙坦、奥美沙坦、替米沙坦和缬沙坦。ARB通常用于治疗高血压和心力衰竭。
  • What are the impurities found in some ARBs?在一些ARB中发现的杂质是什么?

Beginning in late June 2018, the FDA found that some generic versions of the prescription drug valsartan contained unexpected impurities that posed as afety concern. The impurities in these products, N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) are probable human carcinogens (cancer-causing). NDMA was the first impurity to be discovered in some valsartan products. During our investigation of valsartan products, the agency learned of a second impurity, NDEA. Upon testing that now includes other ARBs, NDEA has also been found in some irbesartan and losartan products. All products found to contain these impurities have been recalled and are no longer available in the U.S. market. Our investigation and testing activities are ongoing.
2018年6月下旬开始,FDA发现一些含缬沙坦的仿制处方药含有非预期的可能引起安全关注的杂质。这些药品中的杂质NDMA和NDEA是可能的致癌物质。在一些缬沙坦药品中首先发现了NDMA,在对缬沙坦药品的调查期间,FDA知晓了第二种杂质NDEA。通过对其它ARB的检测,发现一些厄贝沙坦和氯沙坦药品中亦有NDEA。所有发现含有这些杂质的药品均已被召回,在美国市场上不再销售。我们调查和检测活动仍在继续。
  • Are all ARB products affected?是否所有ARB药品均受到影响?

We have posted a list of valsartan products affected by the recall and a separate list of irbesartan products affected by the recall on the FDA’s website for health care professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc.’s losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. Our investigation and testing activities are ongoing, and we will be updating the lists as new information develops.
我们已发布了受召回影响的含缬沙坦药品清单,以及另外一份受召回影响的厄贝沙坦药品清单,供患者和卫生专业人员查看。截止目前,有一批氯沙坦药品受到影响,即山德士的氯沙坦钾氢氯噻嗪,100mg/25mg片剂,NDC号0781-5207-10,批号JB8912,有效期2020-06。我们的调查和检测活动仍在进行中,有新消息时将及时更新。
  • How did the impurities get into the ARBs? 此类杂质是如何进入ARB的?

The FDA’s ongoing investigation has determined that these impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the starting materials, intermediates or finished API.  The presence of these impurities in other processes may also be caused when the FDA’s current Good Manufacturing Processes (cGMPs) are not appropriately followed.
FDA的持续调查已确定了这些杂质可能是在起始物料、中间体或API成品生产工艺中特定化学物质和反应条件下生产的。这些杂质在其它工艺中出现可能亦是未恰当遵守FDA的CGMP要求所致。
  • Could the impurities be in other ARBs?其它ARB中可能有此类杂质否?

The FDA is testing samples of other ARBs to help inform the ongoing investigation. We encourage patients who take an ARB to regularly check online for updates to our lists of valsartan andirbesartan products affected by the recall or to see if any other products besides the one currently known lot of losartan product have been affected. Patients should continue taking their current medicine until a doctor or pharmacist gives a replacement. The FDA will continue to work with manufacturers to ensure all affected products are quickly removed from the market.
FDA正在检测其它ARB的样品,获得更多调查信息。我们鼓励正在服用ARB的患者定期检查我们网站的更新信息,查看所服用药品是否受到影响。患者在医生或药师提供替代方案之前应继续服用其当前药品。FDA将继续与生产商一起工作,确保所有受影响药品快速清出美国市场。
  • What is the risk to patients who have taken the affected product? 已服用受影响药品的患者有何风险?

NDMA was the first impurity discovered, and FDA pharmacologists, toxicologists and chemists have taken measures to assess its risk. Our scientists estimate that if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA, for four years (the amount of time we believed the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among Americans. Most patients who were exposed to the impurity through the use of affected valsartan received less exposure than in the scenario described above. Since there are many manufacturers of valsartan API and finish drug product, and sources can vary whenever a patient refills a prescription, it is very likely that a patient using valsartan for four years would not have always received one of the relatively few affected drug products that contained these impurities. We are still seeking to similarly quantify the risk to patients from NDEA and will communicate our findings as soon as possible.
NDMA是发现的第一个杂质,FDA的药理学家、毒理学家和化学家们已采取措施对其风险进行评估。我们的科学家预计如果有8000人服用最高日用剂量(320mg)含有NDMA的药品4年(我们认为受影响药品在美国市场上存在的时长),则可能会在美国平均患癌水平上增加一例癌症患者。大多患者通过使用受影响缬沙坦药品所受到杂质暴露量低于上述情形。由于存在有许多缬沙坦API和制剂生产商,患者补药时来源可能会不同,因此非常可能患者服用4年缬沙坦药品时并不会一直都是服用的含有这些杂质的相对少数受影响药品。我们仍在努力确定患者遭受NDEA风险的近似数量,一旦有所发现将立即发布。
  • Why didn’t the FDA identify the risk of these impurities earlier?FDA为何未能早些识别出这些杂质风险?

The FDA reviews information on impurity testing provided in product applications and when inspecting manufacturing facilities. Manufacturers are required to test for impurities that may be introduced or developed during their manufacturing processes. We review that information in product applications, including requests to change the manufacturing process. We employ organic chemists to review applications and referenced information to look forsteps – and manufacturing changes – where these risks could be introduced. TheFDA also inspects manufacturing facilities across the world, and in routinecurrent good manufacturing practices inspections, we can review a manufacturer’s records regarding impurity testing. However, the review of records depends on manufacturers conducting appropriate tests that are capable of detecting the impurity. Tests are selected based on assessments of what impurities may develop based on the manufacturing process. In other words, it needs to be recognized that there is a risk of an impurity occurring to know that it should be tested for. Before we undertook this analysis, neither regulators norindustry fully understood how NDMA or NDEA could form during this process.
FDA会审核药品申报资料中所提交的杂质检测资料,并在生产现场检查时进行审核。FDA要求生产商检查可能引入其生产工艺或在生产工艺中可能生成的杂质。我们审核了药品申报资料中的该信息,包括生产工艺变更的申请。我们聘请了有机化学专家审核申报资料和相关资料查看可能引入这些风险的步骤和工艺变更。FDA亦会检查全球的生产场所,并常规地执行CGMP检查,我们可以审核生产商关于杂质检测的记录。但是,对记录的审核是建立在生产商所执行的检验可以检出杂质的基础上的,而检验方法是根据生产工艺可能产生的杂质来评估并选择的,换句话说,需要了解知道有什么杂质风险,然后才能进行检测。在我们进行此项分析之前,无论是药监机构还是制药企业均完全不知道在此工艺中会生成NDMA或NDEA。
  • What is the FDA doing to ensure all affected products are quickly removed from the market?FDA做了些什么来确保尽快将所有受影响药品清除出市场?

The FDA is working with manufacturers to recall affected products. Lists of valsartan andirbesartan products affected by the recall are available on the FDA website for healthcare professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets,NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. We will update our website if any otherproducts are recalled due to these impurities. We are also working with makersof API to ensure they remediate their manufacturing processes and their API does not contain these impurities.
FDA与生产商合作召回受影响产品。受召回影响的缬沙坦和厄贝沙坦药品清单在FDA官网公布,卫生工作者和患者均可监控。截止今日,有一批山德士的氯沙坦药品(氯沙坦钾氢氯噻嗪,100mg/25mg片剂,NDC号0781-5207-10,批号JB8912,有效期2020-06)受到影响。如有其它药品因此类杂质召回,我们将及时更新网页。我们亦与API生产商使用以确保其对生产工艺进行改进,使得其API不再含有此类杂质。
  • Will pharmacies run out of valsartan, irbesartan and losartan now that many of the products are recalled?现在有许多沙坦类药品被召回,药房缬沙坦、厄贝沙坦和氯沙坦会短缺吗?

The number of affected products has grown since the FDA’s initial findings,however, there is still sufficient supply of unaffected products available. Other medications may also be suitable as replacements. Patients who need to switch medications because of the recall should consult with their doctors to determine the best alternative therapy.  
受影响药品数量自FDA发现此事后已有增加,但仍有足够数量未受影响药品,另外还有其它的替代性治疗方法。患者如因召回而需要更改治疗方式,需要咨询其医生以确定最佳替代疗法。
  • What is the FDA doing to make sure this does not happen again?FDA怎么防止今后再次发生此类事情?

The FDA has identified factors in manufacturing processes that may contributeto the formation of NDMA and NDEA. As part of our investigation, we are working to ensure that other manufacturing conditions do not contribute to NDMA, NDEA,or related impurities in finished drug products. We will use the information we have learned about these impurities when reviewing applications, assessing manufacturing changes, and conducting inspections. Manufacturers using processes at risk for formation of these impurities will be required to test for them to ensure that the resulting drug product is safe for patients.
FDA已识别出可能导致NDMA和NDEA形成的生产工艺因素。作为调查的一部分,我们亦致力于确保其它生产条件不会导致制剂中生成NDMA、NDEA或相关杂质。我们在审核申报资料、审评生产变更及进行现场检查时会利用此间获得的资料。我们要求使用可能产生这些杂质的工艺的生产商对这些杂质进行检测以确保其生产的药品对患者来说是安全的。
  • What is the agency doing to keep the public informed?FDA如何保持信息公开?

The FDA routinely posts updates on the investigation and the affected products on our website as new information becomes available.
FDA会在官网上及时更新调查进展和受影响药品信息。
  • How is the FDA working with other regulatory agencies around the world? FDA与其它全球药监机构如何合作?

The FDA is working very closely with global regulatory agencies, including the European Medicines Agency and Health Canada. The FDA’s task force overseeing this investigation exchanges information with regulatory counterparts around the world, including inspection findings, laboratory test methods and results, and our scientific assessment of the problem’s cause and its impact on patients.
FDA与全球药监机构紧密合作,包括EMA和加拿大卫生局。FDA监管此调查的工作组与全球合作药监机构交换信息,包括检查发现的缺陷、实验室检测方法和结果,以及我们对问题原因的科学评估及其对患者的影响。
Not every manufacturing site produces valsartan, irbesartan, or losartanfor all countries, but we believe sharing this information is vital to advancing our ongoing investigations. It enables us to address emerging issues quickly to benefit U.S. patients. This includes monitoring actions other regulators are taking as part of their investigations.
并不是每个缬沙坦、厄贝沙坦或氯沙坦生产场所均销往所有国家,但我们相信共享这些信息对于推进我们的持续调查是很重要的,它让我们能尽快解决新发现的问题从而为美国患者服务,其中亦包括其它药监机构作为其调查的一部分所采取的监测措施。
  • How do I find out more information?我在哪里能找到更多信息?

The FDA website contains the mostcurrent information about the affected products. Please send us questions or comments by email to druginfo@FDA.hhs.gov or by phone to 855-543-3784.
FDA官网有受影响药品的最新信息。如有问题或建议请发送邮件或打电话。
Consumers and health care professionals should report any adverse reactions with valsartan-containing products to the FDA’s MedWatch program to help the agency better understand the scope of the problem:
卫生工作人员应向上述机构报告所有缬沙坦类药品的不良反应,以帮助FDA更好了解问题的范围。

    • Complete and submit the report online at www.FDA.gov/medwatch/report.htm or
    • 在线填写并提交报告
    • Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178.
    • 下载并填写表格,通过传真提交

What should patients know? 患者须知

    • Not all lots of valsartan, irbesartan and losartan products are affected and being recalled. Other ARBs including candesartan, eprosartan, olmesartan and telmisartan have not been affected by a recall.
    • 并不是所有批次缬沙坦、厄贝沙坦和氯沙坦药品均受到影响从而需要召回。其它ARB包括坎地沙坦、依普罗沙坦和替米沙坦并不受召回影响
    • Continue taking your current medicine until a doctor or pharmacist gives a replacement.
    • 在医生或药师提供替代药品之前请继续服用目前药品
    • If you are taking any medication containing an ARB, compare the information on your prescription bottle with this valsartan list and this irbesartan list to determine if your current medicine has been recalled. If you take an ARB with losartan, ensure it is not this affected product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. If you are not  certain, contact your pharmacist.
    • 如果正在服用含有ARB的药品,请将官网上缬沙坦和厄贝沙坦清单与你药瓶上的信息进行比较,确定你目前所用药品是否已被召回。如果正在服用含有氯沙坦的ARB,确保其不是受影响的药品:山德士的氯沙坦,氯沙坦钾氢氯噻嗪,100mg/25mg片剂,NDC号0781-5207-10,批号JB8912,有效期2020-06。如果不能确定,请联系你的药师。
    • If you have medicine included in a recall, contact your pharmacist. The pharmacist may be able to provide you with an unaffected ARB made by another company. If not, contact your doctor immediately to discuss other treatment options.
    • 如果你有药品在召回清单中,请联系你的药师。药师可能会为你提供未受影响的由另一公司生产的ARB。如果不能,请立即联系你的医生讨论其它治疗选择。

What should health careprofessionals know? 卫生专业人员须知
  • The FDA has determined the recalled lots of valsartan, irbesartan, and losartan products pose an unnecessary risk to patients. The agency recommends that pharmacists provide a replacement product not affected by the recall or prescribers consider other available treatment options for their patient’s medical condition.
  • FDA已确定被召回的缬沙坦、厄贝沙坦和氯沙坦药品对患者有着不必要的风险。FDA建议药师提供未受召回影响的替代药品,或由处方开具者考虑为其患者提供其它治疗选择
  • Lists of valsartan and irbesartan products affected by the recall are available on the FDA website for healthcare professionals and patients to monitor. To date, there is one affected lot of losartan product: Sandoz Inc. losartan potassium hydrochlorothiazide, 100 mg/25 mg tablets, NDC 0781-5207-10, Lot number JB8912; Exp. Date 06/2020. The FDA suggests health care professionals check regularly for updates.
  • 受召回影响的缬沙坦和厄贝沙坦药品清单公布在FDA官网上。截止目前,有一批氯沙坦受到影响山德士的氯沙坦药品(氯沙坦钾氢氯噻嗪,100mg/25mg片剂,NDC号0781-5207-10,批号JB8912,有效期2020-06。FDA建议卫生专业人士定期检查更新信息。
  • Samples can also be affected and part of the recall. Be certain to check samples to ensure affected products are not given to patients.
  • 样品可能亦受到影响被召回。请对样品进行检查以确保受影响药品不会再发放给患者。



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