无效OOS成为检查重点

岁寒三友

近期，美国FDA发布了关于德国Fresenius Kabi Oncology Ltd.的警告信，FDA于2017年5月24日对其进行了检查，发现其API生产存在严重违反CGMP的行为。

检查缺陷

1.    Failureto adequately investigate and document out-of-specification results accordingto a procedure.

未能依据程序充分调查和记录OOS结果。

Our review of yourout-of-specification (OOS) investigations found that you did not use adequateOOS procedures, and lacked scientific justification to invalidate initial OOSresults. For example:

我们对你们的OOS调查审核发现你们并未使用充分的OOS程序，缺乏科学论断来判定初始OOS结果无效。例如：

a.  Investigation reportOOS/2015/098 was initiated for an initial OOS result in your related substancestest, where (b)(4)% and (b)(4)% (specification: not more than (b)(4)%)was obtained for Impurity (b)(4) in (b)(4) API batches (b)(4)and (b)(4), respectively. Your investigation concluded thatover-sonication might have increased the temperature of the water bath andcaused degradation of the sample solution.

调查报告OOS/2015/098由于一个有关物质检测的初始OOS结果启动，某API批次检测的杂质结果分别为XX（质量标准为不得过YY）和ZZ。你们的调查结论是超声过度可能会增加水浴温度，导致样品溶解降解。

However, your investigationlacked evidence to support this possible root cause. Instead, yourinvestigation found that the analyst only briefly sonicated the solution (forabout (b)(4)) at (b)(4) temperature. In addition, degradationstudies conducted as part of high performance liquid chromatography (HPLC)validation showed that heat degradation was minimal even after (b)(4) atextremely high ((b)(4)o C) temperatures.

但是，你们的调查缺乏证据来支持该可能的根本原因。相反，你们的调查发现化验员对溶液的超声时间很短（大约XX时间），温度为XX。另外，作为HPLC验证的一部分所实施的降解研究显示即使在极高温度XX下其热降解仍非常之小。

Although your investigationwas inconclusive, you did not proceed to Phase 2 and investigate potentialcauses of the OOS result relating to deficient manufacturing and productquality.

尽管你们的调查并无法得出结论，你们并未进入第二阶段，调查与生产缺乏和产品质量有关的潜在OOS结果原因。

b.  Investigation reportOOS 50989 was initiated following initial OOS results for “relatedsubstances–unspecified impurities” for (b)(4) API stability batches (b)(4)and (b)(4). You concluded that the most probable cause of the OOSresult was contamination, although the source of the contamination was notidentified or confirmed through your hypothesis study. You invalidated the OOSresults (as well as an additional failing retest from a fresh sample preparationby a second analyst for batch (b)(4)) and reported the average of sixretests. You failed to expand the investigation to review potential causes ofthe OOS result relating to deficient manufacturing and product quality.

调查报告OOS50989启动是因为XX原料药稳定性批准XX和YY的“有关物质—未知杂质”初始结果为OOS。你们得出结论说该OOS结果最可能的原因是污染，虽然污染来源并未识别出来，也未通过你们的假设性研究得到证实。你们宣布该OOS结果无效（由第二个化验员对XX批制备新鲜样品进行复测，结果仍不合格），报告了6次复测结果的平均值。你们未能扩大调查审核与生产缺乏和产品质量有关的潜在OOS结果原因。

c.  Your OOSinvestigation procedure 036/—/QS/QA permits an analyst to abort achromatographic run if an apparent OOS is observed prior to completing analysisof all samples scheduled to be injected in the sequence. Your quality control(QC) manager confirmed that analysts abort HPLC analyses if they “expect toinvalidate” them later for an assignable cause. For example, you aborted theHPLC sequence of (b)(4) API batch (b)(4) while observing thechromatographic run on the screen (“online monitoring”) in which an individualunknown impurity tested at (b)(4)% (specification: NMT (b)(4)%).There was no machine malfunction (e.g., unstable system) that would justifyaborting the automated analysis.

你们的OOS调查程序0366/—/QS/QA允许化验员在发现明显OOS结果但尚未完成该序列中所有样品分析之前中断色谱运行。你们的QC经理确认化验员如果他们“期望之后由于可归结的原因宣布无效”则中断HPLC分析。例如，你们在屏幕上（在线监测）发现色谱运行中出现一个单一未知杂质达到XX%（标准为不得过YY%）时，你们中断了XX原料药批次的HPLC序列。没有设备故障（例如，系统不稳定）支持中断自动分析过程。

Our investigators documentedapproximately 248 instances of aborted sequences.

我们调查人员记录下了约248次中断的序列。

Your SOP was inadequate. Whenperforming a sample preparation, it may be possible to identify an obviousmanual error at the time of the mistake. In such a limited instance, it can beappropriate to discontinue the sample preparation, immediately document thedeviation, and justify a new sample preparation. However, it is not appropriateto stop an in-progress automated analysis because of an assumption that anearlier error may be causing an OOS result. Obtaining an unexpected result doesnot constitute an “assignable cause” and the assumption of such a cause is nota valid basis for interrupting an analysis. The automated analytical sequenceshould be allowed to proceed to completion, irrespective of the appearance ofundesirable analytical results on the computer screen.

你们的SOP是不充分的。在执行一个样品制备时，发生错误时可能会发现明显的人为错误。在此类有限情形下，中止样品制备是恰当的，立即记录下偏差，论证新的样品制备。但是，由于假定更早的一个错误可能导致一个OOS结果从而停止一个正在进行的自动化分析则是不恰当的。得到一个非预期的结果并不构成一个“可归结的原因”，此类原因的假设并不是中断分析的有效基础。应允许自动化分析序列继续直到完成，而不管计算机屏幕上出现的是否所想要的分析结果。

We acknowledge your commitmentto correct this deficient SOP. Your response was inadequate because yourcorrections did not ensure that lab investigations will be started immediatelyafter obtaining an OOS result. You acknowledged that in about nine of theexamples referenced by the investigator, the original samples were notre-injected due to sample solution stability. Notably, your method validationdata show that some of these sample solutions are stable for up to (b)(4) atroom temperature. Prompt re-testing of the actual stock, working, and HPLC vialsolutions is essential to determine if mechanical error or preparation errormay have occurred. Timely investigations of potential original laboratorysample preparations are essential to provide clear evidence and credibility forlaboratory error hypotheses.

我们了解你们承诺要纠正该有缺陷的SOP。你们的回复是不充分的，因为你们的纠正措施并不能确保化验室调查会在得到OOS结果之后立即开始。你们说在调查员引用的大概9个例子中，由于样品溶液稳定性原因，原始样品并未重新进样。显然，你们的方法验证数据显示有些样品溶液在室温下稳定长达XX时间。立即重新检测实际贮备溶液、工作液和HPLC小瓶中的溶液对确定是否有可能发生机械性错误或制备错误是很基本的。对可能的原始化验室样品制备进行及时调查对于提供清楚证据和化验室错误假设可信度是很重要的

2.    Failureto ensure that all test procedures are scientifically sound and appropriate toensure that your raw materials, intermediate and API conform to establishedstandards of quality and purity.

未能确保所有检测程序科学合理，适合于确保你们所有原料、中间体和API符合既定的质量和纯度标准。

The inspection documented thatyour test methods were not robust. For example:

检查中记录下了你们的检验方法耐受性不强。例如，

a.  Investigation reportOOS/2015/037, related to an OOS assay result for (b)(4) intermediate API,concluded that the standard preparation degraded because the HPLC autosamplertemperature was held at (b)(4)° C. According to your response, the testmethod was revised to incorporate the (b)(4) of the autosampler at (b)(4)°C, because your method previously lacked the needed specificity. Your CAPA didnot extend to specificity of your laboratory’s other test methods to ensuretheir parameters were sufficient.

调查报告OOS/2015/037是关于一个中间体API的OOS含量结果，调查结论说标准制备降解了，因为HPLC自动进样器的温度保持在XX度。根据你们的回复，该检验方法进行了修订，写入了对自动进样品要求在XX度的要求，因为你们的方法之前缺乏所需的专属性。你们的CAPA并未延伸至你们化验室的其它检验方法的专属性，以确保其参数是足够的。

b.  Investigation reportOOS/2015/124, related to an OOS assay in stability batches of (b)(4)API, concluded that the vials of a specific brand were interacting with thesample and the analysis, although these vials had been used in your laboratoryfor at least six months prior to the OOS results. Your assay method for (b)(4)API had not specified the use of a particular brand of vial. Your firm changedthe method to exclude use of Waters vials in response to the OOS. We also notethat an OOS for another product (RSD for (b)(4)) had similarly beenattributed to a specific brand of vials.

调查报告OOS/2015/124是关于XX原料药稳定性批准中OOS含量的，调查结论说指定品牌的进样瓶与样品和分析有反应，但这些进样瓶在OOS结果之前已经在你们实验室使用了至少6个月之久。你们的XX原料药含量方法并未指定要使用特殊品牌的进样瓶。在回复该OOS时，你们公司修改了方法，要求不能使用WATERS的进样瓶。我们也注意到另一个产品（XX的RSD）的一个OOS也类似地归因于某个品牌的进样瓶。

Your firm’s CAPA wasinsufficient. It did not require that your other analytical methods be assessedto determine if their robustness is also adversely affected by a specific vial(e.g., Waters).

你们公司的CAPA是不充分的。它未要求对你们其它的分析方法进行评估以确定其耐用性是否也会受到特定进样瓶（例如WATERS）的不良影响。

Your response was inadequatebecause it only addressed the specific examples cited in the inspection but didnot include the review of other methods and laboratory equipment that also mayhave been affected by the same deficiency. In addition, you did notsufficiently address improvements in your quality system to ensure that flawsin written laboratory procedures will be corrected.

你们的回复是不充分的，因为它只是说明了检查中所引用的特定例子，但并未包括对可能受到相同缺陷影响的其它方法和化验室设备的审核。另外，你们也未充分改进你们的质量体系，以确保会纠正书面化验室程序中的瑕疵。

Repeat Deviations at Facility场所内重复偏差

In a previous warning letter(WL 320-13-20), FDA cited similar CGMP deviations. You proposed specificremediation for these deviations in your response.

在之前的警告信（WWL 320-13-20）中，FDA引用了类似的CGMP偏差。你们在回复中提议了对这些偏差的特定弥补措施。

These repeated failuresdemonstrate that your facility’s oversight and control over the manufacture ofdrugs is inadequate.

这些重新的失败说明你们工厂对药品生产的监管和控制是不充分的。

转自：Julia法规翻译

原文：https://www.fda.gov/ICECI/Enforc ... 2017/ucm589941.html

zysx01234

就是假的呗，怎么造圆

z412710502

学习一下英文

豚鼠

OOS也是技术活

xqliu

虚浮不可取，应该尽快完善。

beiwei5du

2018.12.04号对Fresenius Kabi Oncology的West Bengal（检查时间：May 15 to May 24, 2017）工厂发了警告信，2018.12.18号对Fresenius Kabi Oncology的baddi（检查时间from April 6 to 14, 2017）工厂发了警告信。同时都涉及到OOS调查，并且都是印度工厂，这个显示了跨国企业如何管控子公司合规性的挑战啊！

FDA警告信：Fresenius Kabi AG 20171218

原创 2018-01-03 julia Julia法规翻译

ViaUPS                                                                                Warning Letter 320-18-19

Return Receipt Requested

December 18, 2017

Mats Henriksson

Chief Executive Officer

Fresenius Kabi AG

Else-Kröner-Straß 1

61352 Bad Homburg

Germany

Dear Mr. Henriksson:

The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, Fresenius KabiOncology Limited Baddi at Kishanpura Village, Baddi, Gurumajra, HimachalPradesh, India, from April 6 to 14, 2017.

美国FDA于2017年4月6-14日检查了你们位于印度喜马偕尔邦的Fresenius Kabi Oncology Limited Baddi生产场所。

注：警告信320-18-12是FDA于2017年5月24日检查的孟加拉邦的Fresenius Kabi Oncology Ltd.生产场所

This warning letter summarizessignificant 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 for manufacturing, processing, packing, or holding donot conform to CGMP, your drug products are adulterated within the meaning ofsection 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&CAct), 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 10, 2017,response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2017年5月10日的回复。

During our inspection, ourinvestigators observed specific violations including, but not limited to, thefollowing.

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：

Your firm failed to thoroughlyinvestigate any unexplained discrepancy or failure of a batch or any of itscomponents to meet any of its specifications, whether or not the batch hasalready 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组份不符合其质量标准的没有解释的差异或不合格。(21 CFR 211.192)

You failed to adequatelyinvestigate the sterility failure of (b)(4) injection (lot (b)(4)).This test, performed in January 2017 as part of routine stability testing,reported Bacillus subtilis, Pseudomonas putida, andPseudomonasentomophila growth. Microbiological growth was observed in both the (b)(4)and (b)(4) media canisters.

你公司未能充分调查注射剂批号XX的无菌不合格。该检测是2017年1月作为常规稳定性测试执行的，报告在有枯草芽胞杆菌、恶臭假单胞菌、假单胞菌生长，XX和XX培养基罐中检出微生物。

According to yourinvestigation, the most probable root cause was laboratory error. Specifically,your May 10, 2017, response states that an analyst failed to immerse sterilitytest sample vials and other materials in sporicidal solution before transferringthem from the Grade C to the Grade B sterility testing room. Instead, theanalyst performed a spray disinfection. You indicated that spraying with asporicide will disinfect the top and sides of samples, but that the bottom ofunits might not be fully decontaminated.

根据你们的调查，最可能的根本原因是化验室错误。具体来说，你们的2017年5月10日回复中声称一个化验员未将无菌测试样品管和其它材料浸入杀孢子溶液中就将之从C级区转移到了B级区无菌测试间。化验员只是做了喷淋消毒。你们说采用杀孢子剂喷淋能对样品的顶部和旁边消毒，但是底部可能无法完全消毒。

However, during the transferstep, the exterior of the units were spray-disinfected with the validatedsporicidal disinfectant solution and held for a specified contact time. Theunits were also placed on a (b)(4), which is intended to facilitateexposure of the bottom of units to the sporicide. Further, following thistransfer to the sterility testing room, the vials were exposed to an aggressivesporicidal agent two more times. These additional sporicidal disinfections wereperformed as part of the (b)(4) staging and transfer steps, and occuredbefore the vials were used in the sterility test. The disinfections includedexposure to a (b)(4) cycle in the sterility testing room for (b)(4),followed by a another spray disinfection with (b)(4). One or moreextensive sporicidal disinfections, such as these, normally ensure suitabilityof samples for use in the sterility test.

但是，在转移步骤中，单位的外部经过了有验证的杀孢子剂溶液喷洒消毒，并放置了指定的接触时长，还放在一个XX里，就是为了将底部暴露在杀孢子剂中。另外，在转移至无菌测试间后，样品管还暴露于一种较强的杀孢子剂中2次。这些额外的杀孢子消毒是作为XX阶段和转移步骤的一部分来执行的，是在样品管用于无菌测试之前做的。消毒操作包括暴露于无菌测试间XX循环中YY时长，然后采用XX进行再一次喷洒消毒。像这样多次深入的杀孢子消毒操作通常可以确保样品适合于无菌测试用途。

In addition: 另外

• The sterility test was performed using a (b)(4) filtration system. This (b)(4) testing system was used inside an ISO-5 closed restricted access barrier system (cRABS). Both provisions significantly minimize the potential for introduction of adventious contamination during a sterility test.
• 无菌测试中使用的是XX过滤系统。此XX测试系统是在ISO-5级密闭限制进入隔离系统（cRABS）中使用的。这两个条件都大大减少了无菌测试中引入外源污染的可能性。
• No microbiological contamination was observed in the negative controls.
• 在阴性控制中未发现微生物污染
• No aseptic breaches were observed during thesterility test.
• 在无菌测试期间未观察到无菌异常
• Environmental monitoring data did not indicate that the sterility testing cRABS had a loss of control.
• 环境监测未显示无菌测试cRABS失控
• Other materials used in performing thesterility test were also subjected to additional sporicidal disinfections.
• 用于实施无菌测试的其它材料也经过了其它的杀孢子剂消毒
  
  

Your investigation wasdeficient in that it did not sufficiently address these factors and thoroughlyinvestigate potential manufacturing root causes. Your manufacturinginvestigation substantively assessed environmental data for only the weekbefore and the week after the product’s December 2015 manufacture date. It didnot sufficiently address whether adverse trends or related incidents hadoccurred in the manufacturing area over a longer period and did not address theatypical findings of gram negative bacteria (e.g., Pseudomonas, spp.)earlier in the year in the production cRABS. Your review of environmental datawas insufficient as it only addressed near term data trends and relied tooheavily on cumulative contamination rates in assessing the potential routes ofcontamination in your manufacturing operation.

你们的调查是有缺陷的，在调查中，你们没有充分说明这些因素并彻底调查潜在的生产根本原因。你们的生产调查实际只评估了产品在2015年12月生产日期前后各一周的环境监测数据。其中没有充分说明是否有不良趋势，或者在生产区域较长一段时期内是否有发生过相关的事件，也没有说明在生产用cRABS该年度早些时间段是否有异常发现革兰阴性菌（例如绿脓杆菌属）的情况。你们对环境数据的审核是不充分的，因为它只是针对近期的数据进行了趋势分析，在评估你们生产操作污染的潜在来源时过多依赖于积累的污染频率。

In response to this letter,provide:

在回复此函时请提交：

• Your plans and procedures to ensure that     future sterility failure investigations include
• 你们确保未来无菌不合规调查的计划和程序，包括
• a more thorough review of longterm trends,
• 对长期趋势分析的更彻底审核
• sufficient investigation ofpotential vulnerabilities in the manufacturing operation
• 对生产操作中潜在弱点的充分调查
• potential correlations withpast incidents (e.g., your extensive history of attributing sterility positivesto poor material disinfection; gram negatives detected in the ISO 5 or otherclean areas)
• 与过去事件的可能关联性（例如，你们历史上常常将无菌阳性归因于材料消毒不够，在ISO5级或其它洁净区发现革兰氏阴性菌）
• An assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. Your corrective action and preventive action (CAPA) plan should include, but not be limited to,  improved rigor in reviewing the sources of variation in your operation that may cause deviations, failures, or defects.
• 对你们偏差、异常事件、投诉、OOS结果和不合格调查系统的全面评估。你们的纠正措施和预防措施（CAPA）计划应包括但不仅限于，改进审核你们可能引发偏差、不合格或缺陷的操作波动性来源的严格度
• A detailed explanation of how (b)(4) sterility samples and other sterility testing materials are immersed in a sporicidal disinfectant, whether these materials are completely immersed, and a CAPA if the latter is done.
• 详细解释如何将无菌样品和其它无菌测试材料浸入杀孢子剂，是否这些材料完全浸入，以及做到后者的CAPA
• A review of your aseptic processing operation. Provide a formal assessment of microbiological contamination risks in your current process, equipment, and facility, and a CAPA plan to address identified hazards.
• 对你们无菌工艺操作的审核。提交一份对你们当前工艺、设备和设施微生物污染风险的正式评估，以及解决所发现危害的CAPA计划
  
  

Repeat Observations 重复缺陷

In an inspection from May 14to 22, 2015, FDA cited a similar CGMP observation in which you invalidatedsterility test failures without adequately investigating the root causes, andfailed to take timely and appropriate corrective actions. Although you proposedremediations in your responses following the 2015 inspection, and discussedthese plans during a 2016 regulatory meeting with the Agency, our currentinspection found that your facility’s oversight and control over themanufacture of drugs remains deficient.

在2015年5月14-22日的检查中，FDA发现了类似的CGMP缺陷，该缺陷中，你们宣布了无菌测试不合格结果无效，但没有对根本原因进行充分调查，也没有采取及时恰当的纠正措施。尽管你们在对2015年检查之后的回复中拟定了弥补措施，并在2016年与FDA的注册会议中讨论了这些计划，但我们现在的检查却发现你们工厂对药品生产的监管和控制仍有缺陷。

Inadequate investigations intoout-of-specification results is a recurring issue in your company’s network.Warning Letter 320-18-12 was issued to you on December 4, 2017.

对于OOS结果的不充分调查在你们公司网络2017年12月4日签发的警告信320-18-12中是重复缺陷。

Your executive managementremains responsible for fully resolving all deficiencies, and ensuring ongoingCGMP compliance. You should immediately and comprehensively assess yourcompany’s global manufacturing operations to ensure that systems and processes,and ultimately, the products manufactured, conform to FDA requirements.

你们的高级管理层对于解决所有缺陷，确保持续符合CGMP负有职责。你们应立即全面评估你们公司的全球生产运营以确保体系和工艺，最终确保所生产的产品符合FDA要求。

CGMP Consultant Recommended CGMP顾问建议

Based upon the nature ofthe violations we identified at your firm, we strongly recommend engaging aconsultant qualified as set forth in 21 CFR 211.34 to assist your firm inmeeting CGMP requirements.

依据违规情况，我们强烈建议你们使用一位符合21CFR211.34要求的顾问来协助你们公司符合CGMP要求。

In particular, the consultantshould comprehensively assess risks in your manufacturing operation,retrospectively review all sterility failure investigations since 2014,retrosepctively evaluate chemistry out-of-specification investigations todetermine their adequacy, and assist with improvements to your investigationsystems. Your use of a consultant does not relieve your firm’s obligation tocomply with CGMP. Your firm’s executive management remains responsible forfully resolving all deficiencies and ensuring ongoing CGMP compliance.

你们的顾问尤其应该全面评估你们生产操作中的风险，回顾性审核2014年以来所有无菌失败调查，回顾性评估所有化学OOS调查以确定其充分性，协助提升你们的调查体系。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 thisletter are not intended as an all-inclusive list. You are responsible forinvestigating these violations, for determining the causes, for preventingtheir recurrence, and for preventing other violations in all your facilities.

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 anaction that is likely to lead to a disruption in the supply of drugs producedat your facility, FDA requests that you contact CDER’s Drug Shortages Staffimmediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on themost effective way to bring your operations into compliance with the law.Contacting the Drug Shortages Staff also allows you to meet any obligations youmay have to report discontinuances or interruptions in your drug manufactureunder 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, whatactions, if any, may be needed to avoid shortages and protect the health ofpatients 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。

Until you correct allviolations completely and we confirm your compliance with CGMP, FDA maywithhold approval of any new applications or supplements listing your firm as adrug manufacturer.

在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP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。

Failure to correct theseviolations may also result in FDA refusing admission of articles manufacturedat Fresenius Kabi Oncology Limited Baddi, Kishanpura Village, Baddi, Gurumajra,Himachal Pradesh, India, into the United States under section 801(a)(3) of theFD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may besubject to refusal of admission, in that the methods and controls used in theirmanufacture do not appear to conform to CGMP within the meaning of section501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。

After you receive this letter,respond to this office in writing within 15 working days. Specify what you havedone since our inspection to correct your violations and to prevent theirrecurrence. If you cannot complete corrective actions within 15 working days,state your reasons for 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 CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Brooke K. Higgins

Compliance Officer

U.S. Food and DrugAdministration

White Oak Building 51, Room4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your responsewith FEI 3006210232.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of ManufacturingQuality

Office of Compliance

Center for Drug Evaluation andResearch

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1、Your SOP was inadequate. When performing a sample preparation, it may be possible to identify an obvious manual error at the time of the mistake. In such a limited instance, it can be appropriate to discontinue the sample preparation, immediately document the deviation, and justify a new sample preparation. However, it is not appropriate to stop an in-progress automated analysis because of an assumption that an earlier error may be causing an OOS result. Obtaining an unexpected result does not constitute an “assignable cause” and the assumption of such a cause is not a valid basis for interrupting an analysis. The automated analytical sequence should be allowed to proceed to completion, irrespective of the appearance of undesirable analytical results on the computer screen.
这个说的在理，preparation操作中发现错误，终止重来是可以允许的，但是为什么都是在 in-progress automated analysis过程中终止呢？？如果有这种情况，也应该很少（因为设备都是自动操作的），况且还有248个终止操作。这个换成任何人都不可能相信；
2、另一个层面的问题就是在于CAPA不仅仅限于在检查中特定的observations，还应该推广到其他相关的问题上，对于像Fresenius Kabi这样的集团公司（25 plants）,更应该推广到所有的子公司去【其中在warning letter中建议就有要求： Provide a CAPA to improve quality of OOS investigations in all Fresenius Kabi facilities. 】