FDA警告信：Mylan（迈兰）制药有限公司

翻江鼠

昨夜，FDA对迈兰（Mylan）制药有限公司发布了警告信，该警告信列举了迈兰（Mylan）制药有限公司包括清洁验证、OOS/偏差调查和变更控制在内的多项CGMP违规，FDA强调该公司应为质量部门提供适当的权力、充足的资源和工作人员来履行其职责；最后，FDA还批评了Mylan多家工厂存在重复缺陷，要求Mylan立即全面评估公司的全球制造业务，缺陷列举如下：

清洁验证不足
多名员工判定设备清洁为干净，但仍发现可见残留
在设备存在可见药物残留的情况下，生产了数批其他产品
清洁验证棉签难以回收清洁剂
清洁验证对设备、位置的选择流程和擦拭样品数量设置不合理，也没有记录
清洁验证执行了6年还未完成，将长期推迟的原因归结为“方案和相关数据遗失”
引入新的高风险活性成分 (例如难以清洁、溶解度低、高活性) 时, 并不总是进行充分的验证或验证研究。
清洁验证样品发现未知峰，结果判定为无效而未进行调查
清洁棉签经常丢失或不报告在数据中
OOS调查不充分
2名质量主管以溶液稳定性超过时限为由判定OOS结果无效，但实际样品和标准品都是稳的
含量偏高和含量均匀性偏大的偏差调查原因为人员未经培训或经验不足，而未调查工艺本身
不合理的物料转移导致物料分层和片剂含量不均匀
偏差改进措施未在批记录中进行规定
发现多个批次存在含量不均匀，但仍被放行
变更未在执行前进行评估
多个存在重大工艺变更的批次未包括在稳定性试验中
某些变更是通过偏差而不是变更控制程序进行授权
多个工厂重复违规

该警告信摘译如下：

Mylan Pharmaceuticals, Inc.
迈兰制药有限公司
1000 Mylan Boulevard Canonsburg, PA 15317
卡农斯堡迈兰大道1000号

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
贵公司未能在适当的时间间隔内对设备和用具进行清洁、维护，并根据药物的性质进行消毒或灭菌, 以防止可能导致药品安全、鉴定、剂量、质量或纯度超过官方或其他既定要求的问题或污染(21 cfr 211.67(a))。

Your cleaning validation and verification program for manufacturing equipment is inadequate to prevent cross contamination.
你们的生产设备的清洁验证和验证程序不足以防止交叉污染。

A. Your firm has had many recurring incidents in which visible drug residues were found on non-dedicated equipment after the equipment was deemed clean by multiple staff.
贵公司的非专用设备在由多名员工判定为清洁干净后进行发现仍有可见药物残留。

For example, on January 10, 2018, your firm opened an investigation after a technician found visible residues of nitrofurantoin in the form of a yellow powder on your encapsulation machine after you had already made (b) (4) batches of another drug, verapamil HCl extended release (ER) capsules, a white powdered drug product.
例如, 在 2018年1月10日, 在你们已经生产了XX批盐酸维拉帕米缓释胶囊（药粉未白色粉末状）后, 一名技术人员在你的封装机上发现了黄色粉末形式的呋喃妥因残留物, 你们展开了调查。

You had cleaned the encapsulation machine after you finished manufacturing the yellow nitrofurantoin and before you started to manufacture the white verapamil HCl ER capsules. The machine was cleaned (b) (4) more times between different capsule dosage strength changes of verapamil HCl ER. Although both manufacturing and quality personnel performed visual inspections after these cleanings, visible yellow powder residue of nitrofurantoin was not detected on the encapsulation machine(b) (4) until many verapamil batches had been exposed to a significant risk of cross-contamination with nitrofurantoin.
在完成黄色硝基呋喃蛋白的生产之后, 开始生产白色盐酸维拉帕米缓释胶囊之前, 你们已经清洁了封装机。该设备还会在不同规格的盐酸维拉帕米缓释胶囊之间清洁数遍以上。虽然生产人员和质量人员在这些清洗后都进行了目视检查, 但仍未能在封装机 (b) (4) 上发现可见黄色呋喃妥因粉末残留, 导致多批维拉帕米严重暴露在与呋喃妥因的交叉污染的风险下。

B. Your firm continued to experience cleaning swab failures related to detergent residue across numerous pieces of non-dedicated equipment and surfaces. In your 2013 cleaning assessment, you noted several cleaning swab failures and difficulties in recovering your detergent, (b) (4), from equipment surfaces. This assessment culminated in the decision to replace (b) (4) with a pharmaceutical-grade detergent. However, our inspection noted that you continued to use (b) (4). You also continued to obtain failing cleaning swab results in 2018 for residual (b) (4) after equipment was deemed visually clean.
贵公司还存在与清洗剂残留有关的清洁擦拭样品不合格，包括多个非专用设备和表面。在2013年的清洁评估中，你们注意到一些清洁擦拭样品不合格以及难以从设备表面回收(b) (4)清洗剂。这一评估最终结论是用医药级清洗剂取代 (b) (4)。但是, 我们的检查发现, 你们还是继续使用 (b) (4)。2018年,在设备被目视判定为清洁干净后，你们还是检测到清洁擦拭样品 (b) (4) 残留的问题。

C. Your cleaning program was insufficient, including, but not limited to, the following.
你们的清洁程序是不充分的，包括但不限于，如下：
The selection process for equipment, location, and number of swab samples collected was not justified or consistently documented (e.g., sufficient pieces of equipment, demonstration of reproducibility).
对设备、位置的选择流程和收集的擦拭样品数量没不合理，也没有一贯的记录 (例如, 足够的设备、可重复性的证明)。
The cleaning procedures used in your validation and verification protocols were not always documented.
验证和确认方案中使用的清洁程序并不总是有文件记录。
Protocols were not consistently followed (e.g., obtaining successful samples from (b) (4)).
方案没有得到一贯的遵循 (例如, 从 (b) (4) 中获取合格的样品)。
For periods as long as 6 years, cleaning validation and verification study reports were not finalized for drug products you deemed “high risk.” The lengthy delay in producing your October 2016 report to evaluate the capability of your cleaning procedures for these critical products was attributed to “misplacement of the protocol and associated data.”
在长达6年的时间里, 对于你们认为 "高风险" 的药品, 清洁验证和验证试验报告尚未最终完成。在编制于2016年10月用以评估这些关键产品的清洁程序有效性的报告中，将长期延迟的原因归结为 "方案和相关数据遗失"。
Adequate validation or verification studies were not always performed when introducing a new high-risk (e.g., difficult to clean, low solubility, potent) active ingredient into the manufacturing operation.
在生产操作中引入新的高风险活性成分 (例如难以清洁、溶解度低、高活性) 时, 并不总是进行充分的验证或验证研究。
Initial equipment surface cleaning swab results with unknown or extraneous peaks were sometimes invalidated (without meaningful investigation) by re-collecting a swab from the failed location after a re-clean, or from another equipment location.
当设备表面清洁擦拭结果显示有未知或外来的峰时, 但常常被判定为无效（没有实质性调查）而通过对不合格位置重新清洁从或从另一设备重新取样。
You lacked a system to trigger timely and effective investigations when multiple visual checks failed to detect visible drug residues remaining on a piece of equipment.
在多次目视检查未能发现设备上残留的可见药物残留时, 你们没有一个系统能够对此发起及时有效的调查。
Cleaning swabs were sometimes lost or not accounted for in your data.
清洁棉签经常丢失或不报告在你的数据中。

Your response was insufficient in that it lacked updated procedures and evidence to support a validated cleaning program. In addition, you provided only partial product impact assessments.
你们的回复是不充分的, 因为它缺乏更新的程序和证据来支持经过验证的清洁程序。此外, 你们仅提供了部分产品的影响评估。

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
贵公司未能彻底调查产品或其任何成分偏离其标准的任何无法解释的差异或失败, 无论批次是否已放行 (21 cfr 211. 192)。

Your investigations into out-of-specification (OOS) results and process deviations were inadequate. Root causes did not consistently include scientifically supported conclusions.
你们对OOS结果和工艺偏差的调查是不充分的。根本原因并不总是包含科学支持的结论。

A. Your firm opened Laboratory Investigation Report 1464472 on March 6, 2018, because of OOS assay test results for three separate batches of the active pharmaceutical ingredient (API) atenolol, USP. You also obtained OOS results during re-analysis. During the inspection, two quality directors stated that the OOS results were dismissed because the values were obtained when solution stability had exceeded the time limit (b) (4). However, our investigators’ review of the data provided by your firm indicated that standards and samples of this API can be stable (b) (4). The unjustified invalidation of failing test results is a repeat violation (b) (4).
贵公司于2018年3月6日因3批不同批次的活性药物成分 (API) 阿替洛尔, USP的OOS结果发起了实验室调查报告1464472。在重新检验的过程中，你们还是得到了OOS结果。在检查过程中, 两名质量主管表示, OOS结果是无效的, 因为该数值是在溶液稳定性超过时限 (b) (4) 时获得的。然而, 我们的检查人员对贵公司提供的数据进行审查发现, 此API的标准品和样品可以是稳定的 (b) (4)。不合理的判定不合格结果无效是重复违规(b) (4)。

B. Your firm opened two manufacturing investigation reports, No. 1071629 on December 12, 2016, and No. 1106258 on January 25, 2017, to investigate atypically high assay and high variability content uniformity results for three batches of prednisolone sodium phosphate 10 mg orally disintegrating tablets (ODT). The investigations identified a root cause of untrained or inexperienced operators (b) (4). The investigation did not fully evaluate the processing factors that contribute to variability in your finished tablets. In particular, it did not evaluate the inherent variability of the (b) (4) method used for charging (b) (4), and identify more robust methods for performing this critical transfer that could prevent blend segregation and tablet dose non-uniformity. It also did not ensure improvements were adequately specified in batch records to enable an ongoing state of control. We acknowledge your firm’s market recall on April 30, 2018, of all batches of prednisolone sodium phosphate ODT within expiry from the U.S. market.
贵公司于2016年12月12日和2017年1月25日发起了两份生产调查报告（No.1071629和No.1210258）, 以调查3批泼尼松龙磷酸钠10mg口崩片的非典型含量偏高和含量均匀性偏大的结果。调查表明根本原因是操作人员 (b) (4)未经培训或经验不足。该调查没有充分评估导致成品片剂变异性的工艺因素。特别是, 它没有评估用于装料的 (b) (4) 方法的固有变异性, 也没有确定更有力的方法来执行这种关键转移, 以防止混合分层和片剂含量不均匀。它也没有确保在批生产记录中充分规定改进措施, 以便能够保持持续的控制状态。我们知道贵公司在2018年4月30日召回所有批次的泼尼松龙磷酸钠口崩片。

C. Your firm opened multiple manufacturing investigation reports and trending assessments from July 2016 to October 2017 related to out-of-trend and OOS content uniformity results for metolazone 2.5 mg tablets. A scientifically justified root cause had not been identified, and effective CAPA plans had not been implemented. Despite substantial non-uniformity observed in multiple batches of metolazone 2.5 mg tablets, you continued to manufacture and release this drug product up to the time of the inspection.
贵公司在2016年7月至2017年10月期间就甲氮酮2.5 毫克片剂的含量均匀性OOT和OOS结果展开了多项生产调查报告和趋势评估。没有确定科学合理的根本原因, 也没有执行有效的 CAPA计划。尽管在多批甲氮酮2.5 毫克片剂中发现含量不均匀, 但你们还是继续生产和放行此产品，直到我们来检查。

3. Your firm failed to follow written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to record and justify any deviations from them (21 CFR 211.100(b)).
贵公司未能遵循用以确保所生产药品具有其声称或应有的鉴定、剂量、质量和纯度的生产和工艺控制的书面程序, 并记录和论证任何偏差(21 cfr 211.100(b))。

Changes in blend size, formulation, and manufacture of your drug products were not evaluated consistently, appropriately, or thoroughly before execution. In many cases, you failed to use your change management system for significant changes. Furthermore, numerous batches with major process changes were not included in your stability program.
有关混合批量、配方和生产方面的变更在其执行之前并没有一致地进行适当或彻底的评估。在许多情况下, 你们未能使用变更管理系统进行重大变更。此外, 许多存在重大工艺变更的批次未包括在你们的稳定性试验中。

During this inspection, our investigators identified numerous major changes that were not adequately managed to prevent substantial risks to drug quality, including, but not limited to, significant changes (b) (4), and significantly modifying (b) (4) from validated production and process control procedures.
在这次检查中, 我们的检查人员发现了许多重大变更, 这些变更没有得到充分的管理, 无法防止对药品质量的重大风险, 包括但不限于对已验证的生产和工艺控制程序的重大变更 (b) (4)。

For example, to avoid potential contamination from a metal washer found (b) (4) carbidopa/levodopa 25 mg/100 mg tablets, Batch 3092534, by (b) (4). You implemented this change without evaluating the effect it would have on your validated process. Following compression, you tested this batch and it failed the finished product dissolution specification.
例如, 为避免3092534 批次(b) (4) 甲基多巴肼\左旋多巴25 mg/100 mg片, , 由 (b) (4) 分列的金属垫圈可能造成的污染。您实施了此变更, 但没有评估它对已验证的工艺的影响。压片后, 你们对该批次进行了检验, 但未通过成品溶出度标准。

Significantly, we note that recently you also submitted a field alert and recalled a batch of Maxide-25 Tablets 37.5 mg/25 mg for which equipment changes had been made to the manufacturing process without first adequately evaluating their impact. The batch (Batch 3087136) failed assay testing at the 3-month stability time point. Your investigation indicated that equipment changes and variability in (b) (4) likely played key roles in the failing assay results.
值得注意的是, 我们注意到, 你们最近还提交了现场警报, 并召回了一批Maxide -25 片 37.5 mg\ 25mg, 其中生产工艺设备进行了变更, 但没有事先充分评估其影响。该批次 (批号：3087136) 3个月稳定性试验检测不合格。你们的调查表明, (b) (4) 中的设备变更和XX的变化可能是含量不合格结果的关键原因。

Your firm lacks an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. Deviations from a validated process increase the likelihood of variation that can lead to product quality failures.
贵公司缺乏充分的持续监控工艺控制以确保稳定的生产操作和一致的药品质量的计划。偏离已验证的工艺增加了导致产品质量失败的变异的可能性。

When significant variability is observed in one or more stages of pharmaceutical production, it is essential for executive management to support and implement effective actions that proactively address the source(s) of the variation and provide for a continued state of control.
当在药品生产的一个或多个阶段观察到显著的变异时, 执行管理层必须支持和实施有效行动, 积极主动地解决差异的根源, 并提供持续的控制状态。

In your response, you state that the combination of equipment controls, in-process testing, and verification of physical attributes (b) (4) provided a high degree of assurance of process control for compression operations. You also note that five batches of solid oral drug products, (b) (4) that were “authorized under a deviation” rather than the change control program, were rejected due to the failure to meet pre-defined quality attributes.
在你们的回复中, 你们说通过设备控制、过程中检测和物理属性(b) (4)确认的组合，为压片操作提供了高度的工艺控制保证。你们还说，有5批通过偏差而不是变更控制程序进行授权的口服固体药物产品(b) (4)因不符合既定质量属性被拒绝。

Quality Unit Authority
质量单位权力

Your inspectional history and significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities. For example, your quality unit failed to ensure that cleaning operations are adequate to prevent cross-contamination; manufacturing changes are appropriately evaluated; manufacturing processes are robust and capable of consistently delivering quality product; and investigations are effective. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.
你们的检查历史和本警告信中的重大缺陷项表明, 你们的质量单位没有充分行使其权力和责任。例如, 你们的质量单位未能确保清洁操作足以防止交叉污染；对生产变更进行适当的评估；确保生产工艺稳健, 能够始终如一地提供高质量产品;并确保有效调查。贵公司必须为质量单位提供适当的权力、充足的资源和工作人员来履行其职责, 并持续确保药品质量。

Repeat Violations at Multiple Sites
多个工厂重复违规

FDA cited similar CGMP violations at this and other facilities in your company’s network. Since 2015, FDA has taken the following actions in response to CGMP violations at Mylan facilities.
FDA列举贵公司该工厂和其他工厂中类似的CGMP违规。自2015年以来, FDA针对Mylan工厂违反CGMP的行为采取了以下行动。

• On August 6, 2015, three Mylan facilities (FEI No. 3003813519, FEI No. 3007512701, and FEI No. 3007648351) were issued a combined Warning Letter for, among other things, inadequate controls for manufacturing sterile drugs; failure to establish scientifically sound and appropriate laboratory controls; and failure to thoroughly investigate unexplained discrepancies.
2015年8月6日, 向三个Mylan工厂 (fei no. 3003813519、fei no. 3003813519 和 fei no. 3007648351) 发出了一封联合警告信, 除其他外, 原因是对无菌药物生产的控制不足;未能建立科学合理和适当的实验室控制;和未能彻底调查无法解释的偏差。

• On April 3, 2017, Mylan Laboratories, Ltd., FEI No. 3005587313, was issued a Warning Letter for, among other things, invalidating numerous initial OOS assay results without sufficient investigations to determine the root cause of the initial failure.
2017年4月3日, Mylan实验室有限公司 (fei no. 3005587313) 被发出警告信, 除其他外, 在没有进行充分调查以确定最初失败的根本原因的情况下,使大量初始OOS检测结果无效。

• (b) (4)
(b) (4). These repeated failures at multiple sites demonstrate that Mylan’s management oversight and control over the manufacture of drugs is inadequate.
(b) (4)。在多个工厂重复违规表明, Mylan对药品生产的管理监督和控制是不足的。

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the products you manufacture, consistently conform to FDA requirements.
你们的执行管理层仍有责任全面解决所有缺陷, 并确保持续的CGMP符合性。你们应该立即全面评估贵公司的全球制造业务, 以确保系统和工艺, 并最终确保你们生产的产品始终符合FDA的要求。

本文摘自GMP办公室

Jackon

老外也有这么烂的工厂

Jackon

老外也有这么烂的工厂

jixia

已阅，不新鲜的缺陷

alber688

昨天看到这篇文章，当时感觉老美的工厂也不啥样，这样的工厂能在FDA下存在，也打击了FDA的威信。

yuansoul

alber688 发表于 2018-11-22 11:03
昨天看到这篇文章，当时感觉老美的工厂也不啥样，这样的工厂能在FDA下存在，也打击了FDA的威信。

发达神教 本来就是 家养鬼子 吹出来滴。

往事随风12

制药企业都一个样，不稀奇。

yc20160802

alber688 发表于 2018-11-22 11:03
昨天看到这篇文章，当时感觉老美的工厂也不啥样，这样的工厂能在FDA下存在，也打击了FDA的威信。

这并非打击FDA的威信，恰恰说明FDA在监管上的原则性和灵活性充分结合。FDA现场检查员只针对现场发现缺陷如实表述，至于该缺陷违反那一条法规及最终处理，由另外的专门小组进行判别。

熔岩巨人

印度的药企确实不过如此 接触过几家

熔岩巨人

不过是仗着不发达国家的特殊专利政策而已  

syhorchid

迈兰公司(Mylan)是一家全球著名的仿制药和制药公司,公司总部位于美国宾夕法尼亚州塞西尔乡。

小刚子

都是习以为常的缺陷，

whx2017

缺项很熟悉啊