警告信缺陷包括：
-
生产工艺评估未能包括亚硝胺等杂质污染
。
-
使用
回收溶剂
，但未能控制回收溶剂带来的污染和交叉污染风险
-
NDEA检测结果标准限度40倍，但仍得出结论是不会导致NDEA的显著水平
。
-
缺乏记录哪个储罐用于存放哪个溶剂的文件
。
-
虽然该公司
坚持认为现行工艺中没有可能产生亚硝胺杂质
，但在
内部溶剂回收的工艺性能确认报告发现溶剂中含有NDMA（高于检测限）和 NDEA （高于标准限）
。
-
尽管承诺了后续将使用新鲜溶剂，但没有说明在放行用于生产之前测试NDMA/NDEA等杂质。
-
检查过程发现，
某非专用被贴上已清洁标签。然而，当用无绒布擦拭凹槽内表面时，观察到残留
。随后检验发现是残留的缬沙坦 API。对此，该公司通过对投诉和OOS调查的回顾，判定对产品质量的影响很小。该公司指出，所有生产的缬沙坦批次和其他药物都经过"外来杂质"的检验，没有报告不合格。FDA表示这种回答是不充分的。
交叉污染的分布不能假定是均匀的，仅靠检验不足以减轻观察到的污染危害
。
-
FDA特别强调
应注意药品生产操作中多个最差情况的组合条件
，如毒性较高的药物、药效较高的药物、在清洁溶剂中溶解度较低的药物、具有使其难以清洁的特性的药物、最难清洁的位置、清洁前的最大保持时间。
该警告信翻译如下：
Dear Ms. Bresch:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited, Unit 8, FEI 3002785310, at G. Chodavaram Village, Vizianagaram, Andhra Pradesh, India, from May 27 to June 5, 2019.
FDA于2019年5月27日至6月5日检查了你们在印度安得拉邦维齐亚纳加拉姆的G.Chodavaram村的药品工厂，Mylan实验室有限公司，8单元，FEI 3002785310。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
此警告信总结了与活性药物成分（API）违反CGMP的重大偏差。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你们生产、加工、包装或保存的方法、设施或控制不符合CGMP，你们的API 根据FD&C Act，21 U.S.C. 351（a）（2）（B）被认定为掺假。
We reviewed your June 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
我们详细审阅了你们2019年6月26日对我们FDA 483表的答复，并确认收到了你们随后的信件。你们的答复是不充分的，因为它没有提供足够的细节或纠正措施证据，以使你们的操作符合 CGMP。
During our inspection, our investigators observed specific deviations including, but not limited to, the following.
在我们的检查过程中，我们的检查人员发现的具体偏差，包括但不限于以下：
1. Failure to have adequate written procedures for the receipt, identification, testing and handling of raw materials.
未能建立用于原辅料接收、鉴定、检验和处理的适当的书面程序。
Your procedures for receiving, identifying, testing, and handling raw materials were inadequate to ensure suitability of materials used in manufacturing, including preventing contamination and cross-contamination with (b)(4) impurities such as (b)(4) and (b)(4). Your firm had not anticipated the presence of (b)(4) impurities based on your assessment of the API manufacturing process.
你们用于原料接收、鉴定、检验和处理的程序不足以确保生产中使用了适当的物料，包括防止污染和与 （b）（4） 杂质的交叉污染，例如 （b）（4） 和 （b）
（4）
杂质。根据你们对API生产工艺的评估，贵公司没有预料到存在 （b）（4） 杂质。
By December 2018, you recalled all your valsartan API batches after tests determined that the majority of batches contained NDEA contamination at levels above the limit. Your investigation dated November 21, 2018, with addendum dated January 1, 2019, concluded that NDEA contamination originated from recovered (b)(4)solvents. Your investigation into nitrosamine contamination also found that another recovered solvent, (b)(4), contained NDEA at levels of 3.38 ppm, more than 40 times your limit of 0.08 ppm. Without adequate scientific justification, you concluded that the recovered (b)(4) solvent containing high levels of NDEA would not result in significant levels of NDEA in your API.
直到2018年12月，在测试确定大多数批次含有超过限度水平的 NDEA 污染后，你们召回了所有缬沙坦 API 批次。你们在 2018 年 11 月 21 日的调查以及 2019 年 1 月 1 日的补充中得出结论，NDEA 污染源自回收的 （b）（4） 溶剂。你们对亚硝胺污染的调查还发现，另一种回收的溶剂（b）（4）含有3.38ppm的NDEA，超过0.08ppm限度的40倍。在没有充分的科学论证的情况下，你们的结论是，回收的（b）（4）溶剂含有高浓度的NDEA不会导致API中NDEA的显著水平。
In addition, your firm found low levels of NDMA in your valsartan API. Your investigation concluded this nitrosamine impurity was introduced via contaminated (b)(4) recovered solvents. Notably, you stated in a Field Alert Report (FAR) submitted to FDA on September 13, 2019, that one likely root cause of the nitrosamine contamination found in rejected batches of valsartan API was recovered (b)(4) solvent containing NDMA at levels as high as 0.629 ppm.
此外，贵公司还在缬沙坦API 中发现了低水平的 NDMA。你们的调查得出结论，这种亚硝胺杂质是通过受污染的（b）（4）回收溶剂引入的。值得注意的是，你们在2019年9月13日提交给 FDA的现场警报报告（FAR）中指出，在已拒批 缬沙坦API 中发现的亚硝胺污染的一个可能来源被回收（b）（4） 溶剂，其浓度高达 0.629 ppm。
Your firm used recovered solvents such as (b)(4) and (b)(4) from multiple external contract manufacturers, including (b)(4). In January 2019 you restricted the procurement of all valsartan-related materials from (b)(4)and in March 2019, you removed (b)(4) from your approved manufacturing list. FDA placed (b)(4) on Import Alert 66-40 on (b)(4), and issued Warning Letter (b)(4) on (b)(4), due to CGMP deficiencies involving inadequate solvent recovery operations resulting in nitrosamine impurity contamination of solvents supplied to their customers.
贵公司使用从多个外部合同生产商（包括（b）（4）））回收的溶剂，如（b）（4）和（b）（4）。2019 年 1 月，你们限制从 （b）（4） 采购所有缬沙坦相关物料，2019 年 3 月，你们从已批准的生产清单中删除了（b）（4）。FDA将（b）（4）列入进口警报66-40中，并在（b）（4）上发布警告信（b）（4），原因是溶剂回收操作不足相关CGMP缺陷导致提供给其客户的溶剂受到亚硝胺杂质污染。
Multiple contract manufacturers supplied solvents that were contaminated with nitrosamines, but your firm lacked documentation of which tanks were used to store these solvents. Although you acknowledged that there was no record of usage for each of the recovered solvent tanks, your response did not provide sufficient information on attempts to retrospectively reconcile the number, identification, and usage of the tanks. Furthermore, you did not provide an adequate investigation to determine whether other API could have been impacted by use of storage tanks that held recovered (b)(4) and other valsartan API process solvents.
多个合同生产商提供的溶剂受到亚硝胺的污染，但贵公司
缺乏记录哪个储罐用于存放这些溶剂的文件
。尽管你们承认每个回收溶剂罐都没有使用记录，但你们的回复没有提供足够的信息，说明尝试回顾性地追溯储罐的数量、身份和使用情况。此外，你们没有提供足够的调查来确定其他API是否可能因为使用存放回收（b）（4）和其他缬沙坦API 工艺溶剂的储罐而受到影响。
After suspending the use of recovered solvents from contract manufacturers for valsartan API, your firm began relying on in-house solvent recovery of (b)(4). While your firm maintained there was no opportunity to produce nitrosamine impurities with your current process, the process performance qualification report for your in-house solvent recovery of (b)(4) found that the solvent contained NDMA above your detection limit and NDEA at levels above your specification limit.
在暂停使用合同制造商回收的溶剂后，贵公司开始依赖内部（b）（4）溶剂回收。虽然贵公司坚持认为，你们现行工艺中没有可能生产亚硝胺杂质，但在内部溶剂回收（b）（4）的工艺性能确认报告发现溶剂中含有NDMA（高于你们的检测限）和 NDEA （高于你们的标准限）。
In your response, you explained the most probable reason for nitrosamine contamination was the use of (b)(4)that had been used to store material intended for destruction. You stated you switched to new (b)(4), but your response did not address whether other similar equipment may also need to be replaced or remediated.
在答复中，你们解释了亚硝胺污染最可能原因是使用了已用于存放待销毁物料的（b）（4）。你们说已更换了新的（b）（4），但你们的回复没有提及其他类似设备是否需要更换或补救。
Furthermore, you stated that you will continue to use fresh solvents until you can validate your in-house solvent recovery process for control of (b)(4) impurities. Your response is inadequate because you did not commit to test fresh and recovered solvents for (b)(4) prior to release for use in API manufacturing.
此外，你们说后续将使用新鲜溶剂，直到内部溶剂回收工艺已验证足以控制 （b）（4） 杂质。你们的回复是不充分的，因为没有承诺在新鲜或回收溶剂放行用于 API 生产之前测试（b）（4）。
See FDA’s guidance document M7 (R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk for approaches to consider where appropriate regarding the presence of mutagenic impurities, at https://www.fda.gov/media/85885/download.
参见 FDA指南M7 （R1）《评估和控制药物中的 DNA活性（突变）杂质以限制潜在的致癌风险》https://www.fda.gov/media/85885/download，以便酌情考虑存在的基因杂质。
In response to this letter, provide the following:
回复此函，请提供以下：
-
An update on investigations involving recovered solvents, including but not limited to (b)(4) and (b)(4), and corrective action and preventive action (CAPA) plans to avert the presence of NDMA, NDEA and other potential mutagenic impurities in all API manufactured at your firm.
-
有关回收溶剂的最新调查情况，包括但不限于（b）（4）和（b）（4），以及纠正措施和预防措施（CAPA）计划，以避免所有生产的原料药中存在NDMA、NDEA和其他潜在的基因杂质。
-
Your program for process performance qualification for API and recovered solvents, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. Include your program for ongoing lifecycle evaluation of impurity profiles for all API.
-
你们的API 和回收溶剂的工艺性能确认程序，以及对批内和批间变异的持续监控以确保持续控制状态。包括用于对所有 API 杂质文件进行持续的生命周期评估的计划。
-
Procedures for controlling incoming raw materials, including but not limited to ensuring that they are not co-mingled. In addition, provide an analysis of storage tanks that held contaminated (b)(4) and (b)(4) solvents, and whether material from those tanks was used to manufacture any other API produced by your firm.
-
进料的控制程序，包括但不限于确保它们不混淆。此外，提供分析储存受污染的 （b）（4） 和 （b）（4） 溶剂的储罐，以及这些储罐中的物料是否用于生产任何其他 API。
-
Specifications, including test methods, used to release fresh and recovered solvents in the API manufacturing process. Your response should address capability to detect and quantify a wide array of potential impurities or contaminants, including but not limited to nitrosamines.
-
用于放行用于API 生产的新鲜和回收溶剂的标准，包括检验方法。你们的回复应包括检测和量化各种潜在杂质或污染物（包括但不限于亚硝胺）的能力。
-
A comprehensive, third-party review of your material system. Provide a report that assesses the adequacy of this system, including but not limited to:
-
一份对你们物料系统的全面的第三方审查。提供一份评估此系统是否充分的报告，包括但不限于：
1、incoming lot controls to prevent use of unsuitable materials
入库批次的控制以防止使用不适当的物料
2、assignment of appropriate expiration or retest dates
分配适当的失效和复验期
3、quality oversight of capability and acceptability of all material suppliers, including qualification standards for initial supplier selection and ongoing lifecycle evaluations to ensure continued supplier acceptability
对所有物料供应商的能力和可接受性进行质量监督，包括初始供应商选择的确认标准和持续的生命周期评估，以确保供应商的持续接受性
4、all CAPA to be implemented, such as improvements to standard operating procedures (SOPs) and management oversight.
所有需要实施的 CAPA，例如改进标准操作程序 （SOP）和管理监督。
2. Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the API beyond the official or other established specifications.
未能清洁设备和器具，以防止污染或残留物料，从而导致API超出官方或其他既定标准。
There is no assurance that your cleaning methods are adequate to clean and prevent contamination or carry-over of drugs manufactured on non-dedicated equipment. Our investigators observed that non-dedicated (b)(4)1102 and (b)(4)1506, were labeled as clean. However, when the interior surfaces of the (b)(4) chutes were wiped with lint-free cloths, (b)(4) stains were observed. Testing you conducted later determined the (b)(4) stains were residual valsartan API.
你们的清洁方法没能保证足以清洁和防止非专用设备上生产的药品的污染或残留。我们的检查人员发现，非专用（b）（4）1102 和（b）（4）1506 被贴上已清洁标签。然而，当用无绒布擦拭（b）（4）凹槽的内表面时，观察到（b）（4）污渍。你们后续进行的测试确定 （b）（4） 污渍是残留的缬沙坦 API。
In your response, you attributed the adherence of residual deposits to rough surfaces on the equipment. Also, as an immediate action, the interior surfaces of the (b)(4) chutes of (b)(4), which were also observed with (b)(4)stains, were ground and polished to smooth surfaces. You also implemented an update to your cleaning procedures.
在你们的回复中，你们将残留归因于设备上的粗糙表面。此外，作为立即行动，同样观察到（b）（4）残留的（b）（4）凹槽内表面，已打磨抛光使表面光滑。你们还更新了清洁程序。
You determined there was minimal impact on product quality based on a review of complaint and out-of-specification investigations. You also stated that all valsartan batches and other drugs manufactured were tested for “extraneous matter” and reported no failures. Your response is inadequate. Cross-contamination cannot be assumed to be uniformly distributed and testing alone is insufficient to mitigate the observed contamination hazards.
你们根据对投诉和OOS调查的回顾，确定对产品质量的影响很小。你们还指出，所有生产的缬沙坦批次和其他药物都经过"外来杂质"的检验，没有报告不合格。你们的回复是不充分的。交叉污染的分布不能假定是均匀的，仅靠检验不足以减轻观察到的污染危害。
In response to this letter, provide the following:
回复此函，请提供以下内容：
-
A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.
-
一份对你们的清洁效果的全面的、独立的回顾性评估，以评估交叉污染危害的范围。包括残留物的鉴定、其他可能未正确清洁的生产设备，以及评估交叉污染产品是否已被放行销售。评估应确定清洁程序和做法的任何不足之处，并涵盖用于多产品生产的每个设备。
As one element of the risk assessment, describe whether you will be testing all API manufactured on non-dedicated equipment for impurities such as nitrosamines due to your deficient systems for cross-contamination prevention and cleaning. The risk assessment should support your response to this item.
作为风险评估的一个要素，描述你们是否将测试所有在非专用设备上生产的 API，以检测由于交叉污染预防和清洁系统不完善而导致的杂质（如亚硝胺）。风险评估应支持你们对此问题的答复。
-
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
-
对清洁验证程序进行适当改进，特别强调在药品生产操作中多个最差情况的组合条件。这应包括但不限于对所有最差情况的识别和评估：
drugs with higher toxicities
毒性较高的药物
drugs with higher drug potencies
药效较高的药物
drugs of lower solubility in their cleaning solvents
在清洁溶剂中溶解度较低的药物
drugs with characteristics that make them difficult to clean
具有使其难以清洁的特性的药物
swabbing locations for areas that are most difficult to clean
最难清洁的位置
maximum hold times before cleaning.
清洁前的最大保持时间。
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
此外，描述在引入新生产设备或新产品之前，在变更管理系统中必须采取的步骤。
