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[FDA药事] 转载:FDA警告信:MYLAN美国 20181109

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发表于 2018-12-14 18:23:10 | 显示全部楼层 |阅读模式

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WARNING LETTER
CMS # 557903
November 9, 2018
Ms. Heather Bresch
Chief Executive Officer
Mylan Pharmaceuticals, Inc.
1000 Mylan Boulevard
Canonsburg, PA 15317
Dear Ms. Bresch:
The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Mylan Pharmaceuticals, Inc. at 781Chestnut Ridge, Morgantown, West Virginia, from March 19, 2018, to April 12,2018.
美国FDA于2018年3月19日至4月12日检查了你们位于西弗吉利亚的MYLAN生产场所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了制剂生产严重违反CGMP的行为。参见21CFR第210和211部分。
Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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).
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求,你们的制剂根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your May 3, 2018, response in detail and acknowledge receipt of your subsequent correspondence.
我们详细审核了你们2018年5月3的回复,并此告知已收到后续通信。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
检查期间,我们的调查人员发现的具体问题包括但不仅限于以下:
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)). 你公司未能按适当时间间隔清洁、维护以及根据药品特性消毒和/或灭菌设备与工器具,以防止发生故障或污染导致改变药品的安全性、鉴别、剂量、质量或纯度超出官方或其它既定要求(21 CFR 211.67(a))。
Your cleaning validation and verification program for manufacturing equipment is inadequate to prevent cross contamination.
你们的生产设备清洁验证和核查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. 你公司多次发生多名员工检查后认可清洁的非专用设备上有目视药品残留的事件。
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,2018年1月10日,你公司在技术人员发现在胶囊灌装机上发现呋喃妥因黄色粉末状可见残留,而该机器已被用于生产另一药品几个批次维拉帕米盐酸盐缓释(ER)胶囊,一种白色粉末药品。
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.
在黄色呋喃妥因生产后,白色维拉帕米盐酸盐ER胶囊开始生产之前你们已将胶囊灌装机进行了清洁,在不同胶囊剂量维拉帕米盐酸盐ER切换时又清洁了几次。尽管生产和质量人员在这些清洁之后进行了目视检查,却没有发现胶囊灌装机上的呋喃妥因可见黄色粉末残留,使得多批维拉帕米暴露于与呋喃妥因的严重交叉污染风险之下。
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. 你公司不断经历大量非专用设备和表面与清洁剂残留有关的清洁擦拭取样失败情形。在你们2013年清洁评估中,你们注释说有几个清洁擦拭取样失败,难以从设备表面回收你们的清洁剂XXX。此评估最后得出结论采用药用级别清洁剂取代了XXX。但是我们检查中注意到你们仍在继续使用XX。你们在2018年目视清洁后的设备中发现残留XX清洁擦拭样品结果不合规。
C.   Your cleaning program was insufficient, including, but not limited to, the following. 你们的清洁程序不足,包括但不仅于以下:
•      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).
•      擦拭取样的设备、位置和数量选择过程未经论证,亦未全部记录(例如,足够多的设备,证明可重复性)
•      The cleaning procedures used in your validation and verification protocols were not always documented.
•      你们验证和核查方案中所用的清洁程序并未全部记录
•      Protocols were not consistently followed (e.g., obtaining successful samples from (b) (4)).
•      未完全遵守方案(例如,从XX成功取得样品)
•      For periods aslong as 6 years, cleaning validation and verification study reports were not finalized for drug products you deemed “high risk.” The lengthy delay inproducing 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.”
•      长达6年之久你们认为“高风险”药品的清洁验证和核查研究报告仍未完成。2016年10月这些关键药品清洁程序能力的评估报告的长期延误部分导致“方案和相关数据放错位置”
•      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.
•      在引入新的高风险(如难以清洁、低溶解度、效价)活性成分至生产操作时未全部执行充分验证或核查
•      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.
•      设备表面清洁后擦拭结果有未知峰或外来峰,有时未经有意义的调查就通过对重新清洁后的不合格位置重新采集擦拭样品或从另一设备位置取样检测,从而宣布原始结果无效
•      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.
•      你们缺乏体系在多次目视检查未能发现可见药品残留于设备上时及时启动有效调查
•      Cleaning swabs were sometimes lost or not accounted for in your data.
•      你们数据中的清洁擦拭样品时有缺失或不可靠
Your response was insufficient in that it lacked updated procedures and evidence to support a validated cleaning program. Inaddition, you provided only partial product impact assessments.
你们的回复是不充分的,其中缺少更新后的程序和证据用以支持有效的清洁程序。另外,你们只提供了部分药品影响性评估。
In response to this letter: 在回复此函时请
•      Provide evidenceof a validated program in which cleaning procedures used to remove active ingredients and detergents from production equipment can consistently meet predetermined and scientifically sound specifications.
•      提交经验证的程序证据,证明用于将活性成份和清洁剂从生产设备中清除的程序可持续满足科学合理的预定标准
•      Justify the number, location, timing, and frequency of cleaning swabs on equipment, and the selection of products and equipment types for your cleaning matrix validation/verification activities.
•      论证在设备采集清洁擦拭样品的数量、位置、时间和频次,以及你们清洁矩阵验证/核查活动中药品和设备类型的选择
•      Assess all equipment ((b) (4)) in which drug product residues were discovered during manufacturing or cleaning operations at your facility.
•      评估你们工厂里所有在生和清洁操作中发现有药品残留的设备(XX)
•      Provide a retrospective investigation into all cleaning swab failures and identify the root cause of the failures. Specify any swab failures for which the corrective action was to re-clean without investigating the root cause of the failure. Provide your corrective action and preventive action (CAPA) plan that details improvements to procedures for cleaning and equipment inspection that will be implemented as a result of your investigation.
•      提交一份回顾性评估,对所有清洁擦拭样品不合格情形进行调查,识别出不合格的根本原因。列出纠正措施为重新清洁而未调查不合格根本原因的擦拭样品不合格情形。提交你们的CAPA计划,详细说明作为你们调查结果将实施的清洁和设备检查程序改进情况
•      Describe your updated cleaning training program for your production and quality assurance employees. Include any objective competency and proficiency results to assess training effectiveness.
•      说明你们更新后的对生产人员和质量保证人员的清洁培训程序,包括所有评估培训效果的客观资格和专业结果
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). 你公司未能彻底调查已销售和未销售的产品批次或其成分所有未经解释的差异情形或不符合其质量标准的情形(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。根本原因并未全部包括有科学支持的结论。
A.   Your firm opened Laboratory Investigation Report 1464472 on March 6, 2018, because of OOS assaytest 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 timelimit (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).你公司于2018年3月6日启动了实验室调查报告164472,原因是3个单独的API批次阿替洛尔USP规格OOS含量结果。你们在复验中亦得到了OOS结果。在检查期间,2位质量总监声称因为得到检测结果时溶液稳定性超出了时间限度XX,所以OOS结果被忽略。但是我们调查员审核了你们公司提供的数据后发现该API的对照液和样品溶液在XX时间内是稳定的。未经论证即宣布不合格检测结果无效是XX的重复缺陷。
B.   Your firm opened two manufacturing investigation reports, No. 1071629 on December 12, 2016, and No. 1106258 on January 25, 2017, to investigate a typically 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. 你公司于2016年12月12日启动了生产调查报告号1071629,2017年1月25日报告号1106258,调查3批泼尼松龙磷酸钠10mg口服崩解片(ODT)含量异常偏高和含量均匀度异常偏高波动。调查识别出根本原因为操作员XX未经培训或没有经验。调查并未全面评估对你们最终片剂波动产生影响的工艺因素,尤其是并未评估你们用于XX投料的XX方法的内在波动性,亦未寻找更为稳健的方法进行此项关键的转移操作,从而防止混合分层和片剂量不匀,且未能确保在批记录中充分指明改进方法,使得其持续受控。我们知悉你们公司于2018年3月30日召回了美国市场上所有效期内批次泼尼松龙磷酸钠10mg口服崩解片(ODT)。
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 notbeen identified, and effective CAPA plans had not been implemented. Despite substantial non-uniformity observed in multiple batches of metolazone 2.5 mgtablets, you continued to manufacture and release this drug product up to the time of the inspection. 你公司在2016年6月至2017年10月期间启动了多个与美托拉腙2.5mg片剂OOT和OOS含量均一性结果有关的生产调查报告和趋势评估。该报告未识别出经过科学论证的根本原因,未实施有效CAPA计划。尽管在多批美托拉腙2.5mg片剂中发现有严重的不均一性,你们仍继续生产并放行此药品直到现场检查。
Your response is inadequate because it lacked a comprehensive retrospective evaluation of all your investigations to ensure implementation of appropriate CAPA. Also, while you indicated that you are implementing controls to remediate your investigation system, you lacked a sufficient interim plan to ensure adequate oversight of investigations of manufacturing and quality issues.
你们的回复是不充分的,因为其中缺乏对你们所有调查的全面回顾性评估,以确保执行适当的CAPA。并且当你们说你们正在实施控制用以弥补你们的调查体系时,你们缺乏足够的临时计划来确保对生产和质量问题调查进行充分的监管。
In response to this letter, provide:
在回复此函时请提交
•      A retrospective, independent review of all OOS (raw materials, in-process testing, and finished testing) results obtained for drug products currently within expiry. Assess whether the scientific justification and evidence were conclusive for each invalidated OOS result. For investigations that establish laboratory root cause conclusively, determine effectiveness of the CAPA and ensure that all laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS results with inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, batch failure history). Provide a CAPA plan that identifies manufacturing root causes and specifies meaningful improvements.
•      一份对所有目前仍在效期的药品中得到的OOS(原料、中控检测和成品检测)的独立回顾审核。评估是否每个宣布无效的OOS结果均有科学论证和证据支持得出此结论。对于可得出实验室根本原因结论的调查,确定CAPA的有效性,确保识别出所有受到相同根本原因影响的实验室方法并进行弥补。对于所有不能支持结论或未识别出实验室根本原因的OOS结果,提交对生产的彻底审核(例如批生产记录、生产步骤的充分性、原料、工艺能力、偏差历史、批失败历史)。提交一份CAPA计划,说明生产根本原因以及建设性改进措施。
•      A retrospective, independent evaluation of the adequacy of major manufacturing investigations (e.g., deviations, rejects) performed for products currently within expiry.
•      对仍在效期内的药品进行的主要生产调查(例如偏差、拒收)的充分性的独立回顾评估
•      A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, OOS results, and failures. Your CAPA should include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.
•      一份对你们偏差、异常事件、投诉、OOS结果和失败调查全面系统的独立全面评估。你们的CAPA应包括但不仅限于调查资质、根本原因分析、书面程序和质量部门监管方面的改进。亦需包括你们评估CAPA有效性的流程。
For more information about handling OOS results and conducting appropriate investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, at https://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.
OOS结果处理和执行适当调查的更多信息参见FDA官网指南。
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)). 你公司未能遵守设计用以确保你们生产的药品具备其既定鉴别、剂量、质量和纯度,并记录和论证偏差的书面生产和工艺控制程序(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.
你们药品混合批量、处方和生产变更在执行之前未全部经适当或彻底评估。许多案例中,你们未使用你们的变更管理系统进行重大变更。另外,许多重大工艺变更批准未放入稳定性考察计划。
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.
在此次检查期间,我们的调查员发现大量重大变更没有足够的管理以防止药品质量的重大风险,其中包括但不仅限于经过验证的生产和工艺控制程序的重大变更XX和重大修订XX。
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,为避免潜在金属垫圈污染,你们未评估其对你们经验证工艺的影响即实施了此变更。在压片之后,你们检测了该批次,结果成品溶出不合格。
Significantly, we note that recently you also submitted a field alert and recalled a batch of Maxide-25 Tablets 37.5 mg/25 mgfor 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.
我们注意到最近你们还提交了工厂警报并召回了一批氨苯蝶呤/氢氯噻嗪-25片剂-37.5mg/25mg,该批次生产工艺中有设备变更但未充分评估其影响。该批次(批号3087136)3个月稳定性含量不合格。你们的调查显示设备变更和XX波动可能对含量结果不合格有着关键作用。
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.
你公司缺乏持续方案监测工艺控制,确保稳定的生产操作和持续的药品质量。偏离经过验证的工艺增加了导致产品质量不合格变化的可能性。
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.
当在一个或多个药品生产阶段发现重大波动时,高层管理人员有必要支持并实施有效的措施提前解决变化根源问题,确保持续受控状态。
In your response, you state that the combination ofequipment 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 adeviation” 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,你们声称设备控制、中控检测和物理属性核查相结合为压片操作的工艺控制提供了高水平保证。你们还提到有5批固体口服制剂XXX,“在偏差情况下放行”而不是变更控制程序,由于不符合既定质量属性而被拒收。
Your lack of rigorous oversight of manufacturing changes continues to be a major factor in the unexpected variation observed in your drug products. In response to this letter, provide the following:
你们缺乏强有力的生产变更监管,它仍是在你们药品中所发现的非预期变化的主因。在回复此函时请提交以下
•      A comprehensive, independent evaluation of your change management system. This review should include, but not be limited to, a review of your procedure(s) to ensure that changes are sufficiently justified, adequately reviewed, and approved by your quality unit. The change management program should include such elements as adding lots to the stability program when there is a significant manufacturing change; provisions for qualification and validation; and a process for determining change effectiveness.
•      一份对你们变更管理体系的全面独立评估。该审核应包括但不仅限于对你们程序的审核,以确保变更经过充分论证、足够的审核并由你们质量部门批准。变更管理计划应包括如在重大生产变更时增加批次至稳定性考察计划、确认和验证条款以及确定变更有效性流程等要素。
•      An independent, retrospective review of any changes that may have significantly increased variation in manufacturing for all batches within expiry. This would include,but not be limited to, changes to your equipment, facility, materials, measurements, and process. Provide explanations and conclusions regarding how changes may have affected the identity, strength, quality, or purity of your drug products. This retrospective review should afford particular attention to all drug products (b) (4).
•      一份对所有可能大大增加仍在效期内批次产品生产变化的所有变更的回顾性独立审核。其中包括但不仅限于你们设备、设施、物料、测量和工艺的变更。提交解释和结论说明变更可能会对你们药品的鉴别、剂量、质量或纯度产生何种影响。此回顾性审核应特别关注XX所有药品。
•      An assessment of the reliability of your manufacturing operations, with an emphasis on variationintroduced by (b) (4). Describe your plans to improve equipment and facility design (b) (4), and to mitigate or eliminate human error.
•      一份对你们生产操作可靠性的评估,重点要关注XX引入的变更。说明你们改进设备和设施设计XX的计划,以及降低或消除人为错误的计划。
•      Detail your validation plan for ensuring a state of control throughout the product lifecycle. This should include, but not be limited to, a description of your program for vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control.
•      详细说明你们的验证计划,确保在产品在生命周期中的受控状态。其中应包括但不仅限于描述你们对批内和批间波动的警戒监测,以确保受控。
Quality Unit Authority 质量部门权力
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.
你们的检查历史和在本函中的严重缺陷显示你们的质量部门并未全面履行其权力和/或职责。例如,你们的质量部门未能确保清洁操作足以防止交叉污染、生产变更得到恰当评估、生产工艺稳健并能确保持续生产具备质量的产品和调查有效。你们公司必须为质量部门提供恰当的权力、足够的资源以及人员履行其职责,持续确保药品质量。
Quality Systems Guidance 质量体系指南
Your firm’s quality systems are inadequate. For guidance on establishing and following CGMP compliant quality systems to establish and maintain an ongoing state of control, see FDA’s guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 Quality Risk Management at https://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and Q10 Pharmaceutical Quality System at https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.
Also see FDA’s guidance document Process Validation: General Principles andPractices athttps://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
你公司的质量体系不充分。建立和执行CGMP合规质量体系以建立和维护持续受控状态请参见FDA指南Q8(R2)、Q9以及Q10,亦请参见FDA工艺验证指南。
Repeat Violations at MultipleSites 多场所重复违规
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在这里和你公司网络其它场所发现有类似的CGMP违规现象。自2015年以来,FDA已对MYLAN的场所采取了如下CGMP违规有关的措施:
•      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,3家MYLAN工厂(FEI号3003813519、3007512701和3007648351)被签发联合警告信,其中有生产无菌药品控制不足、未建立科学合理和适当的实验室控制,以及未能彻底调查未经解释的不符合情形。
•      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实验室公司FEI号3005587313被签发警告信,其中缺陷有未经充分调查确定初始OOS根本原因即宣布大量OOS含量结果无效
•      (b) (4)
(b) (4). These repeated failures at multiple sites demonstrate that Mylan’smanagement oversight and control over the manufacture of drugs is inadequate.
这些多场所重复失败证明MYLAN对药品生产的管理监督和控制是不充分的。
Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. Youshould immediately and comprehensively assess your company’s globalmanufacturing operations to ensure that systems and processes, and ultimately,the products you manufacture, consistently conform to FDA requirements.
你们的高级管理层负有义务全面解决所有缺陷,并确保持续CGMP符合性。你们应立即全面评估你公司的全球生产运营以确保系统和工艺持续符合FDA要求,并最终确保你们所生产的药品持续符合FDA要求。
CGMP consultant recommended CGMP顾问建议
Because you failed to correct repeat violations, westrongly recommend engaging an independent third party qualified as set forthin 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use ofa consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving alldeficiencies and ensuring ongoing CGMP compliance.
由于你们未能纠正重复违规情形,我们强烈建议你们使用一位有21 CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷,确保持续CGMP符合性。
Conclusion 结论
Violations cited in this letter are not intended asan all-inclusive list. You are responsible for investigating these violations,for determining the causes, for preventing their recurrence, and for preventingother violations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查,确定原因,防止其再次发生,防止其它偏差的发生。
If you are considering an action that is likely tolead to a disruption in the supply of drugs produced at your facility, FDArequests that you contact CDER’s Drug Shortages Staff immediately, atdrugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring youroperations into compliance with the law. Contacting the Drug Shortages Staffalso allows you to meet any obligations you may have to report discontinuancesor interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allowsFDA to consider, as soon as possible, what actions, if any, may be needed toavoid shortages and protect the health of patients who depend on your products.
如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断,FDA要求你立即联系CDER药品短缺负责人员,这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足你可能必须报告你们药品中止或中断的义务,让FDA尽快考虑是否需要采取何种措施来避免短缺,保护依赖于你们药品的患者健康。
Correct the violations cited in this letterpromptly. Failure to promptly correct these violations may result in legalaction without further notice including, without limitation, seizure andinjunction. Unresolved violations in this warning letter may also prevent otherFederal agencies from awarding contracts.
立即改正此函中所指出的违规。未能及时纠正这些违规现象可能会导致不经通知的无限强制措施,包括没收与扣留。不解决本警告函中的违规亦可能使得联邦机构不再进行合同采购。
Until these violations are corrected, we maywithhold approval of pending drug applications listing your facility. We mayre-inspect to verify that you have completed your corrective actions. We mayalso refuse your requests for export certificates.
在贵公司纠正所有违规行为之前,FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。我们可能会重新进行现场检查,核查你们已完成的纠正措施。我们亦可能拒绝你们的出口证明申请。
After you receive this letter, respond to thisoffice in writing within 15 working days. Specify what you have done since ourinspection to correct your violations and to prevent their recurrence. If youcannot complete corrective actions within 15 working days, state your reasonsfor delay and your schedule for completion.
在收到此函后,请在15个工作日内回复至本办公室。在回复中说明自从检查后,你们做了哪些工作来纠正你们的偏差,防止其再次发生。如果不能在15个工作日内完成纠正措施,说明延迟的原因以及完成计划。
Send your electronic reply to ORAPharm1_responses@fda.hhs.gov or mail your reply to:
Maya Davis
Compliance Officer
FDA/OPQ Division I
One Montvale Avenue, Fourth Floor
Stoneham, MA 02180
Please identify your response with FEI No. 1110315.
Sincerely,
/S/
Diana Amador-Toro
Program Division Director/OPQ Division I
New Jersey District Office

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药徒
发表于 2018-12-14 20:30:38 | 显示全部楼层
底层无知,高层麻痹,引以为戒
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药师
发表于 2018-12-15 11:10:34 | 显示全部楼层
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求,你们的制剂根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。

长达6年之久你们认为“高风险”药品的清洁验证和核查研究报告仍未完成。
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药士
发表于 2018-12-15 23:15:47 | 显示全部楼层
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药圣
发表于 2022-8-4 20:01:52 | 显示全部楼层
感谢分享。
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