FDA关于无菌生产的警告信学习

20160303 FDA关于无菌生产的警告信学习  

   

Warning Letter

VIAUPS                                                                              

WL: 320-16-08

                                    

March 3, 2016

Mr. Satish Mehta

Chief Executive Officer

Emcure Pharmaceuticals Ltd.,

Plot No. P-1, IT BT Park Phase II, MIDC,Hinjwadi

Pune 411 057, Maharashtra

India

Dear Mr. Mehta:

From January 27 to February 4, 2015, theU.S. Food and Drug Administration (FDA) inspected your pharmaceuticalmanufacturing facility, Emcure Pharmaceuticals Limited, located at Plot No.P-1, IT BT Park Phase II, MIDC, Hinjwadi, Pune 411 057, Maharashtra, India.

We identified significant violations ofcurrent good manufacturing practice (CGMP) regulations for finishedpharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.These violations cause your drug products to be adulterated within the meaningof Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (theFD&C Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or thefacilities or controls used for, their manufacture, processing, packing, orholding do not conform to, or are not operated or administered in conformitywith, CGMP.

We reviewed your February 25, 2015,response in detail. We acknowledge receipt of subsequent responses.

Our investigators observed specificviolations during the inspection, including, but not limited to, the following.

1.    Your firm failed toestablish and follow appropriate written procedures that are designed toprevent microbiological contamination of drug products purporting to besterile, and that include validation of all aseptic and sterilization processes(21 CFR 211.113(b)).

你公司未能建立和遵守适当的书面程序，用以防止应为无菌的药品的微生物污染微生物，包括所有无菌和灭菌工艺的验证（21CFR211.113(b)）。

Poor Aseptic Processing Techniques 无菌工艺技术低下

Our investigators observed poor asepticprocessing techniques during the manufacture of (b)(4)injection USP(aseptically filled for U.S. market) batch (b)(4), and (b)(4) injection(aseptically filled for U.S. market) batch (b)(4). These poortechniques, which may compromise the sterility of injectable products, includedthe following.

我们的调查员发现注射剂USP（无菌灌装，目的市场为美国）的生产中无菌工艺技术低下。这些低下的技术可能会使得注射级药品产生无菌问题，包括以下：

a.    Your operatorplaced a (b)(4) cup on the floor of an ISO 7 area (Grade B) tocollect water (b)(4)from a (b)(4) unit. Asoperators set up ISO 5 (Grade A) filling line, they used the cup contents towet the mechanical assembly in the piston drive.

     你们的操作工将一个XX茶杯放在ISO7级（B级）区域地板上，收集从XX单元出来的水。由于操作工人在ISO5级（A级洁净区）操作灌装线，他们使用了杯子里的东西来润湿活塞驱动的机械装配。

b.    Operators crawledon the floor on their hands and knees under the filling line during routineaseptic filling operation activities.

日常无菌灌装操作中，操作工用手和膝盖趴在灌装线下面的地板上。

c.    An operatordirected vials to the (b)(4) with his hand located directlyabove open vials.

一个操作工人用手从开口的西林瓶上方将西林瓶导入XX。

d.    During set up, anoperator moved un-bagged sterilized tools from the ISO 7 to the ISO 5 area,which he placed in the filling area near the stoppering equipment.

在设置期间，一个操作工人将未装袋灭菌的工具从ISO7级移到ISO5级区域，将工具放在灌装区内加塞的设备附近。

e.    During (b)(4) unloadingin the ISO 7 area, an operator dropped a sterilized lid from a (b)(4)containeronto the floor, which he then picked up and placed it back on the container.

在XX于ISO7级区域的灌装中，一个操作工人将一个灭过菌的盖子从XX容器掉到地上，然后他捡起来放回到容器上。

f.    Before performingaseptic filling activities in the filling room during aseptic setup, operatorswore goggles on their foreheads and exposed skin.

在灌装室里进行无菌灌装之前，无菌装配中，操作工人将眼镜戴在前额上，皮肤暴露出来。

g.    Operators opened (b)(4) barrier (b)(4) toadjust or remove vials from the line with bare hands, instead of wearingRestricted Access Barrier Systems (RABS) (b)(4).

操作工人打开XX屏障XX用裸手调节或从生产线上移动西林瓶，没有使用限制进入屏障系统（RABS）XX。

h.    Operators carriedunprotected sterilized RABS (b)(4) from the (b)(4) ISO5 area, to the ISO 7 area, and then to the mobile Laminar Air Flow (LAF) ISO 5area.

操作工人将不受保护的灭过菌的RABS 某某从某某ISO5级区域拿进ISO7级区域，然后再拿进移动的层流（LAF）ISO5级区域。

Your procedure BRD/GEN/011/08, Behaviorand Aseptic Practices in Classified Areas, restricts operators fromtouching the floor or leaning over opened vials. The above examples show thatyour operators engaged in these practices.

你们的程序BRD/GEN/011/08，在洁净区里的操作和无菌规范，限制操作工接触地板或俯身向开口的西林瓶。上述例子显示你们的操作工实际是这么做的。

Poor Sterilization Practices 灭菌规范不充分

Although your Validation Report PRD/PQ/107-04REP-07 references the RABS (b)(4) loading pattern that shouldhave been followed, the inspection also documented that operators did notfollow the validated loading pattern configuration for RABS (b)(4) duringthe (b)(4) cycle. For example, the RABS(b)(4) were (b)(4) insidea (b)(4) and not properly configured in the (b)(4) toensure appropriate sterilization of the (b)(4) surfaces, asdescribed in the procedure.

尽管你的验证报告 PRD/PQ/107-04REP-07 使用了RABS某某的灌装模式，这是需要遵守的，但检查报告也记录了操作工在XX生产中没有遵守经过验证的RABS灌装模式参数设置。例如，RABS某某里面一个XX没有进行适当的参数设置，以确保按程序中所述的对XX表面进行适当的灭菌。

Facility Design 设施设计

Your facility design may represent anadditional contamination risk to the products you manufacture. For example, weobserved an employee crawling under filling equipment to get to the area wherehe performed other critical operations. Collecting (b)(4) waterfrom the bottom of the filling machine to lubricate equipment, as mentionedabove, also raises concerns about the design and qualification of yourequipment.

你们的设施设计可能会对生产的产品有增加的污染风险。例如，我们观察到一个雇员在灌装设备下爬行到实施其它关键操作的区域。从灌装机器的底部接XX水来润滑设备，如上所提到的，也引起的对于你们设备的设计和确认的担心。

Your response is inadequate because itis limited to a review of video recordings reviewed by FDA and referenced onthe FDA Form 483. Your response does not include an evaluation of all availablevideos to identify all batches that could be affected by poor aseptic practicesand associated risks.

你们的回复是不充分的，因为它仅限于了对FDA审核过的视频记录的审核，以及FDA的483表上所提到的内容。你们的回复没有包括对所有可以获取的视频的评估，以找出可能受到不充分的无菌规范影响的所有批次以及相关风险。

In response to this letter, list thebatches manufactured from November 2014 to the end of the inspection. Includeyour independent third party’s evaluation of these recordings, and their findings.Also include a detailed action plan describing the revisions made to yourprocedures, the content of employee training, and how video recordings areevaluated and by whom.

在对此信进行回复时，请列出从2014年11月开始至检查结束时所有生产的批次。包括你们独立第三方对这些记录的评估，以及他们发现的问题。还应包括一个详细的行动计划，在其中描述对你们程序做出的修订，员工培训内容，以及对视频记录评估的过程，由谁做的评估。

2.    Your firm failed toestablish laboratory controls that include scientifically sound and appropriatespecifications, standards, sampling plans, and test procedures designed toassure that drug products conform to appropriate standards of identity,strength, quality, and purity (21 CFR 211.160(b)).

你们公司未能建立化验室控制，其中包括科学合理性和适当的规范、质量标准、取样计划，以及检测程序，用来确保药品符合适当的鉴别、剂量、质量和纯度标准（21 CFR 211.160(b)）。

Unreliable Environmental and PersonnelMonitoring 环境和人员监测不可靠

Your environmental monitoring (EM) andpersonnel monitoring (PM) data are not reliable because of the materials andprocedures you use to conduct EM and PM tests. Multiple elements of theseprograms are scientifically unsound, including the following.

你们的环境监测（EM）和人员监测（PM）数据不可靠，因为你们用来实施EM和PM测试的原料和程序有问题。这些程序中的多个要素不具有科学合理性，包括以下：

a.    Our investigatorsobserved dried media plates you used for surface and personnel monitoring inthe (b)(4) facility incubators. We documented that 36 of (b)(4) platesinside the Plant (b)(4) incubator showed signs of dryness anddesiccation.

我们的调查员观察了你们用于XX设施培养器表面和人员监测的干培养碟。我们记录下XX碟中36个在工厂的XX培养器中显示出过干和失水。

Your response indicated that youinitiated a study to assess the signs of desiccation in (b)(4) plates.You committed to switch to outsourcing (b)(4) and (b)(4) platesupplies. However, your use of dried (b)(4) plates in priortesting was not scientifically sound, and compromised your results.

你们的回复说你们启动了一个研究来评估在XX碟中的失水迹象。你们承诺要换成外包XX和YY碟供应商。但是，你们在之前的测试中使用了干的XX碟，这是不科学合理的，你们的结果有问题。

In response to this letter, indicatesteps you have taken to determine whether products made under these conditionsmeet limits. Also explain how you will improve laboratory controls to preventuse of unsuitable media in the future.

在对此信回复时，请指出你们要采取的措施，来确定是否在此条件下生产的产品符合限度。还要解释你们将如何来加强对化验室控制，以防止在将来使用不适当的培养基。

b.    Your EM data forthe filling areas did not specify the sampling location of the RABS (b)(4) usedduring filling and (b)(4) operations. SOP QCD/MIC/034-10 Procedureof Surface Monitoring by Swabdoes not require sampling from predetermined (b)(4) locationsidentified as critical risk points of your filling and (b)(4) operations.Instead, the procedure permits individual operators to determine the locationto be sampled. Additionally, you only collected a (b)(4) swabsample from (b)(4), and failed to sample other (b)(4) usedin daily aseptic operations.

你们的灌装区域EM数据没有说明在RABS里的取样位置，该RABS用于灌装和XX操作。SOP QCD/MIC/034-10擦拭取样表面监测程序不要求从预先确定的XX位置取样，该位置在你们的灌装和XX操作中被鉴别为关键风险点，而是允许操作人员自己来确定取样位置。另外，你们只是收集了一个从XX位置的XX擦拭样品，没有在日常无菌操作中所用的其它XX中取样。

According to your response, you willincrease the sampling frequency for your RABS (b)(4) tests.However, you failed to specify whether you will ensure sampling of (b)(4) usedin daily aseptic operations.

根据你们的回复，你们会增加取样频次，进行你们RABS的XX测试。但是，你们未能说明你们是否能确保用于日常无菌操作的XX的取样。

In response to this letter, specify (b)(4) locationsin the RABS and your improved sampling procedures.

在对此信回复时，请指明在RABS中的XX位置，以及你们改进后的取样程序。

c.    Your firm lackedpersonnel monitoring data for aseptic operations on line (b)(4).Documents generated in the laboratory for personnel monitoring did not identifyspecific employees involved in filling operations.

你们公司缺乏生产线XX无菌操作的人员监测数据。在化验室里的人员监测文件中没有找到灌装操作参与人员的。

According to your response, it wasdifficult to accurately locate plates corresponding to specific operators,because the plates were not uniquely identified. You indicated that operatorswere trained in aseptic practices; practices we observed were “deviations” thatyou “considered serious lapses by the facility management.” Furthermore, youacknowledged serious gaps “especially with respect to the suspected dataintegrity and falsification” in data generated in your environmental monitoringprogram.

根据你们的回复，很难准确对应特定的员工放置采样碟，因为碟子没有唯一的识别。你们说操作工按无菌规范进行了培训，但我们观察到的做法“偏差”要求，你们“认为严重脱离工厂管理”。另外，你们环境监测程序中产生的数据“特别疑似有数据完整性问题以及数据造假”。

Your response is inadequate. Despiteyour claim that your operators were appropriately trained, video recordings ofyour manufacturing operations clearly showed that your employees were not followingproper aseptic techniques.

你们的回复不够充分。尽管你们声明你们的操作人员经过适当的培训，你们生产操作的视频记录清楚显示你们员工没有遵守适当的无菌技术要求。

These violations posed a significantrisk to the sterility of your products. You may wish to review FDA’s guidancewww.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072171.htm tohelp you improve your manufacturing of sterile products. You are responsiblefor ensuring that your quality and production management organizations overseecritical operations in your facility. We acknowledge your decision to ceaseproduction during the FDA inspection and (b)(4).

这些违规行为对你们药品的无菌性有严重的风险。你们可能会希望查看FDA指南帮助你们改进无菌产品的生产。你们有责任确保你们的质量和生产管理组织监督你们工厂的关键操作。我们已知晓你们在FDA检查期间停止生产的决定。

Inadequate Visual Inspection Program 目视检查程序不充分

In addition to the inadequacies of yourEM and PM programs, our inspection documented that your visual inspectionprogram is unreliable. Your qualification and re-qualification of operators didnot include determining the operator’s ability to detect and identify knownproduct defects for (b)(4)products or products filled in ambervials.

除了你们EM和PM程序的不充分外，我们检查中记录了你们的目视检查程序是不可靠的。你们对操作工的资格确认和再确认没有包括对操作工是否具备发现和识别未知产品缺陷或在琥珀色西林瓶中产品缺陷识别能力的确定。

For example, one inspector failed tocorrectly identify major defects as defined in your SOP PRD/VAL/003 -05 Qualificationof Visual Inspection Operators. Your inspector incorrectly identified threeof (b)(4) vials containing fiber material, one of (b)(4) vialscontaining particles, and one of (b)(4)vials that had the incorrectvolume from the Kit (b)(4) challenge set. A second inspectoralso failed to correctly identify two of (b)(4) unitscontaining fiber, 2 of (b)(4) units containing particles, andone of (b)(4) units that had the incorrect fill volume fromthe (b)(4) Kit (b)(4) challenge set.

例如，一个检查员未能正确识别出你们SOP “PRD/VAL/003 -05目视检查操作人员资格确认”中定义的主要缺陷。你们的检查员错误地识别了三个含有纤维物料的XX西林瓶，其一个有颗粒物，一个是容积不对。第二个检查员也没能正确找出有纤维的两支，有颗粒物的两支，以及灌装体积不正确的一支。

Your SOP PRD/OPN/065-09 VisualInspection of Vials permits inspectors to classify defects such asfragmented glass subjectively, as critical or major. Your SOP has no objectivecriteria for these classification decisions.

你们的SOP“PRD/OPN/065-09 西林瓶目视检查”允许检查员自主将缺陷进行分级，例如，玻璃开裂，可以作为关键，也可以作为主要问题。你们的SOP没有客观的分级标准。

According to your response, you willrevise the qualification procedure for visual inspections and requalify yourinspectors. However, you did not include the revised SOP or your schedule forcompleting re-qualification.

根据你们的回复，你们会修订目视检查确认程序，重新对检查员进行资格确认。但是，你们没有提供修订后的SOP，或者你们重新进行资格确认的时间计划。

In your response to this letter, providea detailed summary of improvements you have made to your visual inspectionqualification program. Include training you have provided and will continue toprovide to your visual inspectors. Also indicate how you will determine theeffectiveness of your visual inspection training program, how you will improveyour defect classification, and what you will do if visual inspectors areunable to correctly discriminate between critical and major defects.

在你们对此信的回复中，请提供一份详细的总结，关于你们已经对目视检查资格确认程序所做的改善。在其中包括你们已为你们的目视检查员提供的培训，将要持续提供的培训。还要说明你们要如何确定你们目视检查培训项目的有效性，你们如何改善你们的缺陷分级，如果目视检查员不能在关键和主要缺陷之间进行正确分级，你们要怎么做。

In addition to details on the trainingand re-qualification of your visual inspectors, indicate how you will ensurethat no batches with critical defects were released to the market, given thatyour visual inspection program relied on subjective determinations ofcriticality by visual inspectors who were unable to correctly classify defectsduring the inspection. Conduct and provide the results of a risk assessment ofproducts that were visually inspected by unqualified employees and released fordistribution. Indicate steps you have taken to ensure that patients have notbeen, or will not be, exposed to products with critical defects.

除了你们目视检查员的培训和资格重新确认以外，还要说明你们要如何确保有会有存在关键缺陷的批次放行用于市场销售，因为你们的目视检查程序依赖于目视检查员对缺陷关键程度的主观决定，而检查员在检查中并不能正确地对缺陷进行分级。对由资格有问题的员工进行目视检查并放行销售的产品执行风险评估，并提供评估结果。说明你们已采取的措施来确保不会有患者被，或将被暴露于具有关键缺陷的药品之下。

3.    Your firm failed toensure that laboratory records included complete data derived from all testsnecessary to assure compliance with established specifications and standards(21 CFR 211.194(a)).

你们公司未能确保包括所有测试中产生的完整数据的实验室必须数据，以确保符合既定规格和标准(21 CFR 211.194(a))。

During our inspection, we observedmultiple examples of incomplete, inaccurate, or falsified laboratory records.

在我们的检查中，我们发现多个不完整、不准确或假造化验室记录的例子。

a.    EM records for activeair monitoring of the aseptic filling area reported samples as being collectedwhen they were not actually collected, and some records documented purported EMresults of zero colony forming units (CFU) even when the samples for whichthose results were reported were not actually collected. Contemporaneous videorecordings that FDA reviewed during the inspection showed that such EM sampleshad not been collected, even though your laboratory records reported resultsfor those samples. Our investigators observed your firm’s practice offalsifying EM results for samples that were not collected for multiple drugs,including (b)(4) injection USP lot (b)(4) and (b)(4)injectionlot (b)(4).

      无菌灌装区域里主动空气监测EM记录报告了已收集的样品，而实际上这些样品没有被采集过，有些文件记录报告了零CFU的EM结果，而实际上这些所谓的报告结果的样品根本都没有被采集过。FDA在检查期间审核过的同步录制视频记录显示这些EM样品并没有被采集过，即使你们的实验室记录报告了这些样品的检测结果。我们的调查员发现你们公司假造多个药品中未采集过的样品的EM结果，包括XX注射剂USP批号和XX注射剂批号XX。

Although your laboratory records forthese products and lots indicated that you collected active air samples, thevideo we reviewed during the inspection demonstrated that operators did notactually collect the samples. During the inspection, your microbiologistconfirmed that these EM samples were never collected. Additionally, twomicrobiologists informed the investigator that media plates were labeled andsubmitted for incubation as though they had been exposed to the environment.However, these media plates were never actually exposed to the environment.Your microbiologist indicated that this practice was routine and due to “workpressure.” Because the EM results for samples were falsely reported as havingbeen collected and/or as having produced no CFU growth, you lack assurance thatthe injectable drugs your firm produced in this area were sterile at the end ofthe aseptic filling process.

尽管你们的化验室里对这些药品和批次的记录显示你们收集了主动空气样品，我们在检查期间审核的视频证明你们操作人员并没有实际地取样。在检查期间，你们的微生物化验员确认这些EM样品从来都没有被采集过。另外，有两个微生物化验员告诉调查员说，这些培养基碟子有标签，放进去培养，弄好好像是真的在环境中暴露采过样似的。但是，这些培养基的真的从来没有实际地暴露在环境过。你们的微生物化验员说因为“工作压力”一直都是这么做的。由于EM结果是假造的，并没有CFU生产，你们不能确保你们公司在此区域生产的注射剂药品在无菌灌装工艺结束时是无菌的。

b.    Our review of EM recordsfrom January 2014 through September 2014 found that no samples had exceeded theaction levels for any of the (b)(4) filling lines in your (b)(4) plant,or for the filling line in Plant (b)(4). However, we observed 12microbiological plates in the incubator showing EM results that requiredfurther action during our inspection of your laboratory.

我们对2014年1月至2014年9月期间EM记录的审核发现，在XX车间XX灌装线和YY车间的灌装线没有样品曾经超出过行动限。但是，在我们对你们化验室的检查期间，我们发现培养箱里有12个微生物碟，显示EM结果需要进一步行动。

These EM records provide critical dataon environmental trends and whether environmental control is maintained duringaseptic filling of a batch. Environmental monitoring should promptly identifypotential routes of contamination, allowing for implementation of correctionsbefore product contamination occurs.

这些EM记录提供了环境趋势的关键数据，以及环境控制在一个批次的无菌灌装期间是否维持良好。环境监测可以主动识别出潜在的污染途径，在药品污染发生之前即可以采取措施纠正。

In your response, you stated “there havebeen serious gaps in the management, oversight and execution of theenvironmental monitoring program, especially with respect to the suspected dataintegrity and falsification of data concerns.” Your response also indicatedthat you revised procedures, provided training, and reviewed documents fromMarch 2013 to January 2015. Your investigation confirmed that EM samples werenot collected and “the data was fraudulent.” You acknowledged these problems inyour response and took some corrective actions. However, your response isinadequate because you have not demonstrated how you can ensure that EM recordsgenerated before the inspection were reliable and accurate, or how thefalsification of some of your reported EM data may have affected the quality ofyour products.

在你们的回复中，你们声明“在管理、监管和执行环境监测程序中有严重差距，尤其是可疑的数据完整性的数据造假问题”。你们的回复也指出了你们已修订的程序，提供了培训，审核了2013年3月至2015年1月的文件。你们的调查确认了EM样品并没有被采集过，“数据是伪造的”。你们在回复中说明了这些问题，采取了一些纠正措施。但是，你们的回复是不充分的，因为你们没有说明你们要如何确保在检查之前产生的EM记录是准确可靠的，或者你们报告的一些EM数据的伪造行为可能对你们药品质量的影响。

We acknowledge your (b)(4) afterthe inspection, your management changes, and your engagement with consultants.However, your investigation was not extended to all systems and areas that mayhave been affected by your questionable practices. You have not provided datasufficient to demonstrate that all products released for distribution weremanufactured with the appropriate environmental controls in place duringaseptic filling operations.

我们在检查后收到了你们的XX，你们管理层的变更，以及你们聘用顾问的情况。但是，你们的调查没有延伸至所有可能受到你们被质疑的做法影响的系统和区域。你们没有提供足够的数据来证明所有放行销售的药品其无菌灌装操作过程都是在适当的环境控制中生产的。

Furthermore, data falsification andmanipulation, and your reliance on incomplete records to release product to themarket, are repeat violations. A February 2014 inspection of solid (b)(4) dosageoperations at this same facility also reported data manipulation andfalsification of test results generated by your firm, along with otherdeficient laboratory practices that also resulted in products being recalledfrom the U.S. market.

另外，数据造假和篡改，以及你们依赖不完整记录放行产品用于销售，是重复的违规行为。在2014年2月对相同工厂固体制剂生产的检查也报告了数据篡改和检验结果伪造，以及其它的化验室规范缺陷，当时引起了对美国市场药品的召回。

In your 2014 response, you made a similarcommitment to hire a third party auditor to conduct a comprehensive audit ofall laboratory electronic and hard copy data for tests conducted for allrelease and stability finished product. Our 2015 inspection found continuingpractices of data falsification and manipulation at your facility, indicatingthat previous corrections were ineffective.

在你们2014年的回复中，你们做出了类似的承诺，要聘请第三方审计员对所有实验室电子和纸质量数据实施综合审计，包括所有放行和稳定性制剂的测试。我们2015年检查发现数据伪造和篡改行为在你们工厂仍在持续，说明之前的纠正措施是没有效果的。

c.    Our investigatorsobserved poor documentation practices during production and in-process testing.

我们的调查员发现你们生产和中控测试中文件记录规范不充分。

i.    Media fill batch (b)(4) documenteda “check by” operation performed by an operator who was not present at thefacility. This operator signed “checked by” for 63 out of (b)(4) individual (b)(4).In addition, during this media fill, a Quality Assurance (QA) individual signed“checked by” for observing the intervention “(b)(4) of conveyorbelt” from (b)(4) to (b)(4) on December 2,2014, but the QA individual was not present in the filling room when thisintervention was performed, and did not view it.

培养基灌装批XX记录中显示由一个操作工进行了“复核”，这个操作工当时根本不在工厂。这个操作工“复核”了XX个记录中的63个。另外，在此次培养基灌装中，一个QA人员签署了“复核”2014年12月XX批号至YY批号“传送带的XX”调整中观察复核，但该QA人员在此调整过程中根本都没有出现在灌装间，也没有查看。

Your response admitted that theindividual signing the QA “checked by” column was not present during that portionof the media fill (b)(4) to (b)(4) onDecember 2, 2014.

你们的回复承认签署QA“复核”的人员在2014年12月XX批至YY批培养基灌装期间并没有出现在现场。

ii.    Disinfection of the fillingmachine was not completed before filling of (b)(4) injectionUSP batch (b)(4) (aseptically filled, (b)(4), anddistributed to the U.S. market). Records were made for cleaning on November 13,2014, from (b)(4) to (b)(4), but review of videosshow that cleaning did not match records.

在注射级USP批号XX（无菌灌装，已销售至美国市场）开始灌装前，灌装机的消毒不完全。清洁记录写的是在2014年11月13日做清洁，从XX时间到YY时间，但对视频的审核显示清洁操作与记录不符合。

Your response confirms that the cleaningand disinfection did not occur on November 13, 2014.

你们的回复确认了清洁和消毒并不是在2014年11月13日。

iii.    On January 29, 2015,an operator performed in-process weight checks for (b)(4) duringthe filling operation performed at 13:30. This activity was not documenteduntil 14:15. In addition, another weight check operation performed at (b)(4) hadnot been documented on the record when reviewed at (b)(4)by theinspector.

在2015年1月29日，一个操作工在13：30灌装操作中进行了中控重量复核。此动作直到14：15才被记录下来。另外，另一次重量复核操作是在XX时进行的，当检查员对XX进行审核时并没记录在记录上。

Your response indicated that activitiesthat occurred on January 29, 2015, are deviations.

你们的回复说发生在2015年1月29日的活动确实是偏差。

iv.    Cleaning of the (b)(4) andparts of the filling machine was not completed before filling (b)(4)injectionUSP batch (b)(4) (aseptically filled, (b)(4), anddistributed to the U.S. market). Records were made for cleaning on November 26,2014, from 08:57 to 09:26, but videos show that cleaning did not match records.

在注射级USP批号XX（无菌灌装，销往美国市场）开始灌装之前，灌装机的XX和部件的清洁不完整。清洁记录写的是2014年11月26日清洁，从8：57至9：26，但视频显示清洁与记录不符。

Your response indicates that thecleaning and sanitization of the conveyor (b)(4) was missed onone side.

你们回复说传送XX的清洁和消毒缺失。

Your investigation into this issue isinadequate because it did not consider other in-process tests, or whether theoperator(s) have been involved in the same poor documentation practices forothers batches. Your response lacks an assessment of your documentationpractices to determine the extent of the problem in your facility.

你们对此问题的调查不够充分，因为没有考虑其它中控测试，或者是否操作工也参与了其它批次中相同的记录规范问题。你们的回复缺乏对你们的文件规范的评估，不能确认你们工厂问题的程度。

Conclusion

Violations cited in this letter are notintended to be an all-inclusive list. You are responsible for investigating anddetermining the causes of the violations identified above, for preventing theirrecurrence, and preventing other violations.

If, as a result of receiving thiswarning letter or for other reasons, you are considering a decision that couldreduce the number of finished drug products produced by your manufacturingfacility, FDA requests that you contact CDER's Drug Shortages Staffimmediately, as you begin your internal discussions, atdrugshortages@fda.hhs.gov so that we can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), andallows FDA to consider, as soon as possible, what actions, if any, may beneeded to avoid shortages and protect the health of patients who depend on yourproducts. In appropriate cases, you may be able to take corrective action withoutinterrupting supply, or to shorten any interruption, thereby avoiding orlimiting drug shortages.

Until all corrections have beencompleted and FDA has confirmed corrections of the violations and your firm’scompliance with CGMP, FDA may withhold approval of any new applications orsupplements listing your firm as a drug product manufacturer. In addition, yourfailure to correct these violations may result in FDA continuing to refuseadmission of articles manufactured at Emcure Pharmaceuticals Limited, Plot No.P-1, IT BT Park Phase II, MIDC, Hinjwadi, Pune 411 057, Maharashtra, India,into the United States. Under Section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3), articles may be refused admission because manufacturing methods andcontrols 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).

Within 15 working days of receipt ofthis letter, please notify this office in writing of the specific steps thatyou have taken to correct and prevent the recurrence of violations. In additionto the specific requests noted above, supporting documentation should includeyour third party assessment of the following.

1.    A comprehensiveevaluation of the extent of the inaccuracy of your recorded and reported data.Include a detailed action plan to fully investigate the extent of yourdeficient documentation and data management practices.

2.    A risk assessmentof the potential effects of observed failures on the quality of your drugproducts, including the effects of deficient documentation and data managementpractices, aseptic processing breaches, and inadequate environmental monitoringprogram. Determine the effects of your failures on the quality of drug productsreleased for distribution and the data supporting all associated submissions.

3.    A managementstrategy for your firm that includes the details of your corrective action andpreventive action plan. Describe the actions you will take, such as contactingyour customers, recalling drugs, conducting additional testing and/or addinglots to your stability programs, or other steps to assure the quality of yourdrugs manufactured under the deficient conditions discussed above. Alsoindicate measures you will take, such as revising procedures, implementing newcontrols, training or re-training personnel, or other actions to prevent therecurrence of CGMP violations, including breaches of data integrity.

Provide copies of supportingdocumentation. If you cannot complete corrective actions within 15 workingdays, state the reason for the delay and the date by which you will havecompleted the corrections. Additionally, if you no longer manufacture ordistribute the drug products at issue, provide the date(s) and reason(s)you ceased production. Send your reply to:

Maan Abduldayem

Compliance Officer

U.S. Food and Drug Administration

Center for Drug Evaluation and Research

Office of Manufacturing Quality

Division of Drug Quality I

White Oak Building 51, Room 4212

10903 New Hampshire Ave.

Silver Spring, MD 20993

USA

Please identify your response with FEI#3005151215.

                                                                     

Sincerely,

/S/                              

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

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