FDA警示药品生产商特定药品中苯污染风险
FDA is evaluating the root cause of benzene contamination in certain drugs and alerting drug manufacturers to the risk of benzene contamination from drug components and other potential risk factors. Benzene is a known human carcinogen that causes leukemia and other blood disorders. Certainhand sanitizersand aerosol drug products have beenrecalleddue to benzene contamination. This contamination may be related to inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons.
FDA 正在评估某些药物中苯污染的根本原因，并提醒药品生产商注意药物成分和其他潜在风险因素造成苯污染的风险。苯是一种已知的人类致癌物，会导致白血病和其他血液疾病。由于苯污染，某些洗手液和气雾剂产品已被召回。这种污染可能与非活性成分有关，例如卡波姆（增稠剂）、异丁烷（喷雾推进剂）或其他由碳氢化合物制成的药物成分。
FDA reminds drug manufacturers they are required to establish scientifically sound and appropriate specifications and test procedures to assure drug components (active and inactive ingredients) and finished drug products conform to appropriate quality specifications (21 CFR 211.84,21 CFR 211.160). This includes testing of raw materials and finished product batches (21 CFR 211.165) prior to release to ensure they meet appropriate specifications for identity, strength, quality, and purity.
FDA 提醒药品生产商，他们必须建立科学合理和适当的质量标准和检测方法，以确保药物成分（活性和非活性成分）和制剂符合适当的质量规范（21 CFR 211.84、21 CFR 211.160），其中包括在放行前对原材料和成品批次 (21 CFR 211.165) 进行测试，以确保它们符合相应的鉴别、含量、质量和纯度标准。
One way manufacturers can meet the requirements of 211.84, 211.160 and 211.165 is by using tools such as risk assessments to determine they have the appropriate specifications, test methods, and controls to ensure drugs are free from contamination. FDA has discussed with manufacturers conducting risk assessments to evaluate the possible presence of benzene in their drug products and components, including active ingredients and inactive ingredients. In particular, FDA has also discussed with manufacturers the need for a special focus on ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons.
生产商满足 211.84、211.160 和 211.165 要求的一种方法是使用风险评估等工具来确定他们具有适当的规格、测试方法和控制措施，以确保药物不受污染。FDA 已与进行风险评估的制造商讨论，以评估其药品和成分（包括活性成分和非活性成分）中可能存在的苯。FDA 还与生产商特别讨论了需要特别关注碳氢化合物或用苯或其他碳氢化合物制造的成分。
Drug manufacturers should avoid using benzene in the manufacturing process
药品生产商应避免在生产工艺中使用苯
Manufacturers should not use benzene in the manufacture of drugs. The International Conference on Harmonization (ICH)Q3C Impurities: Residual Solvents guidanceand companion documentQ3C Tables and Listprovide guidance on limited cases where the presence of benzene may be tolerated. Specifically, the ICH Q3C guidance explains that Class 1 solvents such as benzene should not be employed in the manufacture of drug substances, excipients, or drug products because of their unacceptable toxicity. The guidance notes that if benzene use is unavoidable to produce a drug product with a significant therapeutic advance, then its levels should be restricted to 2 parts per million (ppm), unless otherwise justified.
生产商不应在药品生产中使用苯。ICH Q3C 杂质：残留溶剂指南和配套文件 Q3C 表格和清单提供了关于允许苯存在的有限情况的指南。具体而言，ICH Q3C 指南解释说，苯等 1 类溶剂不应用于生产原料药、辅料或制剂，因为它们具有不可接受的毒性。该指南指出，如果不可避免地要使用苯来生产具有显着治疗进展的药品，则其水平应限制在百万分之二 (ppm)，另有正当理由者除外。
What drug manufacturers should do
哪些药品生产商需要做
Drug manufacturers are required to ensure the safety and quality of their drugs. As FDA works to better understand the potential sources of benzene in drugs, FDA reminds manufacturers of drugs marketed under approved applications and manufacturers of other drugs, including over-the-counter monograph drug products, of their obligation to ensure their products conform to appropriate quality specifications. Consistent with the recommendations of the ICH Q3 guidance, manufacturers should not use benzene in the manufacture of drugs. Ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons may indicate a higher likelihood of benzene contamination.
药品生产商必须确保药品的安全和质量。随着 FDA 努力更好地了解药物中苯的潜在来源，FDA 提醒根据批准申请上市的药品生产商和其他药物（包括非处方药专论产品）的生产商，他们有义务确保其产品符合适当的质量 规格。根据 ICH Q3 指南的建议，生产商不应在药品生产中使用苯。碳氢化合物成分或用苯或其他碳氢化合物制造的成分可能显示出苯污染的可能性更高。
FDA is also aware of ingredients, such as the antifungal preservative sodium benzoate, that may form benzene under certain conditions. The formation of benzoate from benzene can impact the appropriate measurement of benzene if this is not considered and controlled for in the analysis. FDA reminds manufacturers that changes in raw materials throughout the lifecycle of the drug, including changes in raw material suppliers, warrant additional scrutiny for the potential risk of benzene contamination.
FDA 也知道在某些条件下可能会形成苯的成分，例如抗真菌防腐剂苯甲酸钠。如果在分析中没有考虑和控制苯甲酸盐的形成，可能会影响苯测定的适当性。FDA 提醒生产商，在药物的整个生命周期中原材料的变化，包括原材料供应商的变化，均需要对苯污染的潜在风险进行附加审查。
Drug manufacturers with a risk for benzene contamination should test their drugs accordingly and should not release any drug product batch that contains benzene at or above 2 ppm, consistent with the recommendations described in ICH Q3C. If any drug product batches with benzene above 2 ppm are already in distribution, the manufacturer should contact FDA to discuss the voluntary initiation of a recall by contacting the appropriateDivision of Pharmaceutical Quality Operations in the Office of Regulatory Affairs.
有苯污染风险的药品生产商应相应地对其药品进行测试，且不得放行任何苯含量大于等于2 ppm （根据 ICH Q3C 所述建议）的药品批次。如有在售批次苯含量高于 2 ppm ，生产商应联系 FDA，通过联系监管事务办公室的相应药品质量运营部门，讨论自愿发起召回的事宜。
We note that if decisions to not release a drug product or to initiate a recall are likely to disrupt the drug supply, manufacturers should contact CDER’s Drug Shortages Staff immediately atdrugshortages@fda.hhs.gov. Contacting the Drug Shortages Staff in writing allows manufacturers of covered drug products to meet applicable obligations to report discontinuances or interruptions in drug manufacture under 21 U.S.C. 356C(b) and FDA’s associated regulations. This also allows FDA to evaluate the market and determine if additional steps are needed to avoid a supply disruption that may impact public health.
在此提醒，如果不放行药品或发起召回的决定可能会中断药品供应，生产商应立即通过 drugshortages@fda.hhs.gov 联系 CDER 的药品短缺工作人员。以书面形式联系药品短缺工作人员，确保履行适用的义务，根据 21 U.S.C.356C(b) 和 FDA 的相关法规报告药品生产的停产或中断，同时也使 FDA 能够评估市场并确定是否需要采取额外措施来避免可能影响公众健康的供应中断。
FDA reminds manufacturers of NDA and ANDA products of their obligation to submit a Field Alert Report (FAR) if testing reveals their drug products contain benzene at or above 2 ppm (21 CFR 314.81(b)(1)(ii)). FDA’s guidanceField Alert Report Submission: Questions and Answers Guidance for Industryaddresses how to submit a FAR. Manufacturers of NDA and ANDA drug products whose testing reveals their drug products contain benzene below 2 ppm should contact FDA atCDER-benzene@fda.hhs.gov.
FDA 提醒 NDA 和 ANDA 产品的生产商，如果测试显示其药品中苯含量达到或高于 2 ppm (21 CFR 314.81(b)(1)(ii))，他们有义务提交现场警报报告 (FAR)。FDA 的指导现场警报报告提交：行业问答指南说明了如何提交 FAR。NDA 和 ANDA 药物产品的生产商如果测试表明其药物产品中苯含量低于 2 ppm，应通过 CDER-benzo@fda.hhs.gov 联系 FDA。
Manufacturers of nonapplication products, including over-the-counter monograph drug products, should contact FDA using the information in the table below when testing reveals benzene in a product. Manufacturers should also be prepared to provide FDA with test results and any information available on the potential source of the benzene to assist in FDA’s analysis.
非审批上市药品（包括非处方药专论产品）的生产商在检测发现产品中含有苯时，应使用下表中的信息联系 FDA。生产商还应准备好向 FDA 提供测试结果和有关苯的潜在来源的任何可用信息，以协助 FDA 的分析。
The below chart summarizes when and how manufacturers should contact FDA if testing reveals the presence of benzene and the information FDA may request from drug manufacturers when following up:
下表总结了如果检测显示存在苯，制造商应何时以及如何联系 FDA，以及 FDA 在跟进时可能要求药品制造商提供的信息：
（超出2ppm制剂和原料药，应联系ORA召回协调员，发送FAR。检出但低于2ppm者，联系指定工作人员，报告其检测方法和苯来源信息帮助FDA调查）
FindingContact MethodNotesActive pharmaceutical ingredient lotwith benzene above 2 ppmContactappropriate ORA Division Recall CoordinatorsFDA will advise on appropriate next steps such as notifying any entity that received contaminated API.
Benzene limits in drug products药品中的苯限量
As FDA evaluates the root cause of benzene contamination in certain drugs, the agency is taking a stepwise approach to address the potential for benzene contamination in marketed drug products by first identifying products that should be immediately recalled or not released for distribution based on a benzene level in the products above 2 ppm consistent with the considerations described in ICH guidance. Concurrently, the agency will review any Field Alert Reports from drug manufacturers that identify the presence of benzene, in addition to other available information. This information will help inform further updates to FDA’s approach to limiting benzene levels in drug products, as appropriate.
FDA 在评估某些药物中苯污染的根本原因的同时，正在采取分步方法来解决已上市药品中苯污染的可能性，首先苯含量2 ppm（与ICH指南中所述考量一致）以上者应立即召回或不放行销售的产品。与此同时，除了其他可用信息外，FDA还将审查来自药品生产商的所有发现有苯存在的现场警示报告。该信息将有助于进一步更新 FDA 限制药品中苯含量的方法（视情况而定）。
We note that certain United States Pharmacopeia – National Formulary (USP-NF) carbomer monographs allow for levels of benzene of 100 ppm or greater. To eliminate confusion and because of the safety concerns associated with these unacceptable levels of benzene, FDA has asked USP to remove (or “omit”) these monographs from their compendium.
我们注意到，某些美国药典 - 国家处方集 (USP-NF) 卡波姆专论允许苯含量为 100 ppm 或更高。为消除混淆，同时考虑到与这些不可接受的苯含量相关的安全问题，FDA 已要求 USP 从药典中删除这些专论。
In order to ensure their products conform to appropriate quality specifications (21 CFR 211.84,21 CFR 211.160), and consistent with the recommendations in the ICH Q3C guidance, applicants and manufacturers who identify risks of benzene contamination from drug components or confirm the presence of benzene in a drug product should also take steps to use ingredients without benzene, or, if justified, use suppliers that minimize risk of unacceptable benzene impurity levels. FDA intends to issue guidance for manufacturers on recommended test methods and appropriate steps for manufacturers needing to modify their formulation or manufacturing process for a legally marketed drug product. For additional questions, contactCDER-benzene@fda.hhs.gov.
为了确保其产品符合适当的质量标准（21 CFR 211.84、21 CFR 211.160），并符合 ICH Q3C 指南中的建议，申请人和生产商确定药物成分中苯污染的风险或确认苯的存在在药品中还应采取措施使用不含苯的成分，或者（如果有正当理由）使用将不可接受的苯杂质水平风险降至最低的供应商。FDA 准备发布指南，为生产商发布有关推荐测试方法和适当措施，指导需要为其合法销售药品修改配方或生产工艺的生产商。如有其他问题，请联系 CDER-benzo@fda.hhs.gov。
