警告信

xqliu

Warning Letter

警告信

CERTIFIED MAIL                                                                    
RETURN RECEIPT REQUESTED

WL: 320-15-08

March 31, 2015



Mr. Michael Ball
Chief Executive Officer
Hospira S.p.A.
275 N. Field Drive
Lake Forest, IL 60045
USA

Dear Mr. Ball:

During our May 5-9 and 12-13, 2014 inspection ofyour pharmaceutical manufacturing facility, Hospira S.p.A., located at ViaFosse Ardeatine 2, Liscate, Italy, investigators from the U.S. Food and DrugAdministration (FDA) identified significant violations of current goodmanufacturing practice (CGMP) regulations forfinished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and211. These violations cause your drug products to be adulterated within themeaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act(the 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.

在5月5-9日、12-13日对贵公司（Hospira S.p.A.）的审计中，FDA审计员发现制剂产品严重违反cGMP ，这些违规使得贵公司的制剂从联邦法规的定义上来说是掺假产品。其中使用的方法，厂房，控制，生产，工艺，包装以及仓储不符合cGMP要求。

We have conducted a detailed review of yourfirm’s response dated June 4, 2014 and note that it lacks sufficient correctiveactions. We acknowledge receipt of your firm’s correspondence dated August 4,2014, October 2, 2014, December 4, 2014, and February 9, 2015

我们已经对你们2014年6月4日的回复进行了详细的审核，并且认为该回复缺少足够的纠正措施。我们收到了贵公司14年8月4日，10月2日，12月4日及15年2月9日的信件。

Our investigators observed specific violationsduring the inspection, including, but not limited to, the following:

审计员在审计中看到了包括但不限于如下缺陷：

1.    Your firm failed to establishand follow appropriate written procedures that are designed to preventmicrobiological contamination of drug products purporting to be sterile, andthat include validation of all aseptic and sterilization processes (21 CFR211.113(b)).

贵公司没有建立并遵守合适的书面程序，来防止无菌制剂的微生物污染，其中包括没有对灭菌消毒工艺进行验证。

Your firm did not evaluate all criticaloperations during dynamic airflow studies to determine risk to productsterility.

贵公司在动态气流研究中没有评估所有的关键操作来确定产品无菌性的风险。

a)    Your firm did not evaluatesignificant aseptic interventions during dynamic airflow studies (smokestudies) to determine how the movement of air and personnel during aseptic operationscould pose risks to product sterility. For example,

贵公司没有在动态气流研究（烟雾测试）中评估重要的灭菌步骤，来确定灭菌操作时空气和人员的流动会对产品无菌性产生的风险。例如：

i.    Your smoke studies did notevaluate the impact of operators pushing (b)(4) vials down a chutewhile simultaneously removing a (b)(4) located (b)(4) the chute to load vialsin the designated (b)(4).  Theinspection documented that (b)(4) from the vials duringthis (b)(4) vial transfer operation, potentially exposing theproduct in the vials to contaminants from personnel or the surroundingenvironment.  In addition, during our inspection, the investigatorobserved operators reaching over the (b)(4) vials during thisoperation, an action which could compromise product sterility by introducingmicrobiological contaminants.

贵公司的烟雾测试没有评估操作工把药瓶推下斜坡同时把斜坡转移到指定的位置来装载这些药瓶的影响。审计记录了在药瓶转移操作中可能将产品暴露在人员及环境中从而造成污染。另外，在审计中，审计员观察到操作员在这些操作中接触到了药瓶，这会造成微生物污染，破坏产品的无菌性。

Your investigation on February 18, 2013,documented that you were aware of problems caused by the (b)(4) vial loading operation. Exception reportrecord, PR ID 119409, noted that the (b)(4) vial loading operationfrequently results in rough aseptic transitions. However, our investigatorobserved operators continuing this practice over a year after you closed PRID119409. It did not appear that you had acted on your findings to correct thisproblem or prevent its recurrence, and the sterility of your products may havebeen compromised in the meantime.  

贵公司在13年2月18日的调查记录了你们已经意识到在药瓶转移操作中存在的问题。报告中记录了药瓶转移操作经常导致无菌问题。然而我们的审计员观察到操作员在这报告之后超过一年的时间里还在继续这样的操作。这表明了贵公司并没有采取措施，来纠正这个问题并防止它再次发生，并且贵公司产品的无菌性仍面临威胁。
ii.    You did not perform smokestudies to demonstrate unidirectional airflow for set-up activities of the asepticfill line or for the (b)(4) transfer of (b)(4) vials from the vialholding area to the (b)(4).  Your smokestudies also did not show unidirectional airflow above the un-stoppered vialsthat pass (b)(4) the stopper loading chute.Without smoke study data to demonstrate that air flows unidirectionally overthese critical operations and processing steps, you cannot show that yourprocesses are designed to prevent microbiological contamination of yourproducts or provide adequate assurance of product sterility.

贵公司没有进行烟雾测试，来证明无菌分装线上装配操作或药品从保存区转移到指定区域时气流的单向性。并且贵公司的烟雾研究也没有显示在药瓶去塞步骤时的气流单向性。在没有烟雾测试数据来证实这些关键操作时气流单向性的时候，并不能说明贵公司的流程可以防止微生物污染，或者说并不能对产品的无菌性提供充足的保障。

iii.    We also note that your stopper (b)(4) creates air turbulencein the area around the stopper loading chute, which could lead to additionalopportunities for microbiological contamination.

我们还记录下了贵公司的瓶塞，在瓶塞装载斜坡附近区域引起了空气扰动，这可能微生物污染。

The examples listed above show how disruptionsto the unidirectional flow of air could lead to the contamination of product inexposed vials. We acknowledge your response that you have performed smokestudies, and made limited modifications to the operation in an effort to reducerisks posed by the design deficiencies identified in our inspection. Forexample, we note that you made some minor changes to reduce rocking of the (b)(4) during the(b)(4)vial transfer operationdescribed above in 1. a) 1. However, your response is inadequate because youhave not committed to provide a thorough design assessment.  You alsofailed to provide a video of the new smoke studies you indicated that youperformed.

上述例子表明单向气流的混乱可能导致敞口瓶中产品的污染，我们收到了贵公司的回复说你们已经进行了烟雾测试，并对操作进行一些修改来降低设计缺陷引起的风险。例如：你们进行了一些微小变更，来减小药品转移操作中的振动（如1所述）。然而，你们的回复是不充足的，因为你们并没有承诺提供一个详尽的设计评估。并且你们没有提供新的烟雾测试的录像。

In response to this letter, please describefurther design modifications you will make to mitigate the contaminationhazards in your operation, including, but not limited to, the examplesdiscussed above in examples 1. a)1-3. Also, provide a copy of the video/DVD depictingsmoke studies you performed to demonstrate unidirectional airflow during themanufacturing operations described above.

在这封信件的回复中，请进一步描述你们将进行的设计修改，来降低操作中的污染风险。包括但不限于上述例子。并且提供一份烟雾测试的录像来证实上述生产操作中的气流单向性。

b)    Your firm rejected possible integral units (i.e., units withintact container/closure systems) from media fills without a writtenjustification or explanation. For example, during media fill batch (b)(4) (June 2012), yourejected 5 vials as “tilted” and you also rejected 250 vials during the (b)(4) process withoutexplanation or justification. Similarly, during media fill batch (b)(4) (December 2013), yourejected 21 vials as “tilted” and you also rejected 30 vials during the (b)(4) process withoutexplanation or justification. During the inspection, your management told theinvestigator that the vials you rejected as “tilted” would likely be fullystoppered and integral. Your media fill batch records did not include anyfurther rationale for rejecting these vials, although many of them were likelyintegral.

贵公司在没有任何书面证明或解释的情况下，在培养基灌装时拒绝可能的完整药瓶。例如在2012年6月的一批培养基灌装中，你们因为“倾斜”拒绝了5个药瓶，并且在那个批的生产中你们拒绝了250个药瓶但没有任何解释。相似的，在2013年12余的一批培养基灌装中，你们因为“倾斜”拒绝了21个药瓶，并且在生产中在没有任何解释的情况下拒绝了30个药瓶。在审计中，你们管理层告诉审计员，标注“倾斜”的药瓶可能是塞好的并且完整的。你们的培养基灌装批记录中没有进一步写明任何拒绝这些药瓶的理由，尽管其中很多药瓶是完整的。

When you perform a final product inspection ofunits immediately following a media fill run, all integral units should proceedto incubation.  Units found to have defects not related to integrity(e.g., cosmetic defects) should be incubated; units that lack integrity shouldbe rejected. Erroneously rejected units should be returned promptly forincubation with the media fill lot. After incubation is underway, any unitfound to be damaged should be included in the data for the media fill runbecause the units might be representative of drug product released to themarket. Any decision to exclude non-integral units from the final run tallyshould be fully justified and you should fully explain the deviation in yourmedia fill report.  If a correlation emerges between difficult todetect damage and microbial contamination, you should conduct a thoroughinvestigation to determine its cause.

在贵公司进行最后的产品检查后，立即进行了培养基灌装，所有完整的单位应该进一步培养。应该培养那些有缺陷但完整的单位，那些不完整的单位则应该被拒绝。被错误拒绝的单位应该立刻取回并与培养基灌装批培养。培养时，任何损坏的单位应该记录在培养基灌装的数据中，因为这些单位可能代表了进入市场的制剂成品。任何从最后灌装排除不完整单位的决定都应该有正当的理由并且在培养基灌装报告中对偏差做出详尽的解释。如果难以检测损坏和微生物污染之间有关联，应该进行彻底的调查来确定它的原因。

We acknowledge that you completed a media fillperformance qualification. However, your protocol, Shut Down Media FillQualification Protocol KC4103-PQ, is inadequate becauseit does not provide criteria that adequately defines when vials are to berejected.  In your response to this letter, provide yourcategorization criteria and justification for rejection of vials from a mediafill.

贵公司完成了培养基灌装的性能确认。然而你们的方案是不充分的，因为它并没有提供充足的标准对于何时药瓶应该被拒绝。在这封信的回复中，你们应该为培养基灌装中药瓶拒绝提供分门别类的标准和理由。

These violations are similar to those found during the October 2012 inspectionof your Irugattukottai, Sriperumburdur, India manufacturing site. Dynamicairflow study and media fill deficiencies were noted in Warning Letter (WL:320-13-18), issued May 28, 2013. Your response to that warning letter statedthat you implemented your Global Quality Strategy and Global Quality Plan in February 2013foryour manufacturing facilities. Provide evidence of the effectiveness of yourimplemented global corrective actions and preventive actions.

这些违规行为与2012年在你们印度厂区发现的行为相似。动态气流研究和培养基灌装缺陷都记录在13年5月28日的警告信中，对那封警告信的回复中说道你们在2013年2月对你们的生产厂区实施全球质量策略和全球质量计划。请提供你们实施的全球纠正预防措施效果的证据。

2.    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).

贵公司没有对不符和不合格批或者物料不合格进行彻底的调查，无论这个批是否已经被分发。

For example, your firm failed to conduct athorough investigation for 103 complaints for (b)(4) injection related todiscoloration of (b)(4) or (b)(4) solution betweenNovember 1, 2011 and October 31, 2013, and a more recent complaint on April 3,2014. Many customer complaints have stated that the product changed to a (b)(4) color, rather than thenormal “(b)(4)” appearance.  You concluded that theroot cause for the discoloration was the (b)(4) of the product. Yourinvestigation is inadequate because you failed to evaluate the impact that (b)(4) may have on the qualityof the product and to correlate the level of (b)(4) degradant with theamount of discoloration observed. Your investigation also failed to considerthat the discoloration might have been caused by the failure to perform a stepin the manufacturing process in an (b)(4) environment.Specifically, you mention that some vials may have(b)(4) as a result of them (b)(4) shelf during thestoppering manufacturing phase. You state that the unloading of the vials fromthe (b)(4) to (b)(4) is not performed (b)(4) and that there is apotential for (b)(4)ingress.

例如：贵公司没有对103投诉进行一个彻底的调查，投诉是关于产品在2011年11月1日到2013年10月31日之间发生变色，以及最近的一个在2014年4月3日的投诉。许多客户投诉产品变色。你们认为变色的原因是由于产品中的b4成分。你们的调查是不充分的，因为你们没有评估b4可能对产品造成的影响以及降解程度和变色程度之间的联系。你们的调查也没有考虑到变色可能由于生产工艺中的一个步骤没有完成。而且，你们说在加塞的生产过程中b4成分可能进入到一些药瓶中。

We acknowledge your commitment to continue theinvestigation of (b)(4) levels in (b)(4) vials per protocolKC3601-ENG. However, your response does not adequately address the impact ofthe effect of (b)(4) in that your medicalassessment lacks an evaluation of whether the degradant poses a risk topatients.   

我们收到了贵公司对继续调查药瓶中b4水平的承诺，然而你们的回复并没有充分说明b4的影响，因为在药品评估中没有评估降解产物对病人的风险。

In addition, your firm has not adequatelyaddressed vulnerabilities in your manufacturing process that can be addressedto prevent the potential ingress of (b)(4).

另外，贵公司没有充分说明你们生产过程中的缺陷，认识到这个缺陷可以防止b4进入。

Please provide a protocol and timeline for the assessment of your manufacturingprocess to control the level of(b)(4) in the vial (b)(4). Also, include yourscientific rationale that the level of the (b)(4) degradant has nomeaningful impact on product quality.

请提供一个方案和时限评估你们的生产工艺来控制药瓶中b4成分的含量。并为b4降解产物不会对药品质量产生影响提供你们的科学依据。

Pleasealso explain whether your firm will be identifying and quantifying the (b)(4) degradant, and anyother major degradants, and if you have determined that appropriatespecification limits should be established.

请解释贵公司将来是否会定量定性地检测b4降解产物，以及其他一些降解产物，以及你们是否已经建立了合适的质量标准。

In your response, you indicate that yourappearance specification ((b)(4)) is subjective. Pleaseexplain how you intend to qualify the appearance specification for the (b)(4) finished product.

在你们的回复中，你们指出外观标准是凭经验的，请解释你们打算怎样判断b4最终产品的外观是合格的。

3.    Your firm failed to exerciseappropriate controls over computer or related systems to assure that onlyauthorized personnel institute changes in master production and controlrecords, or other records (21 CFR 211.68(b)).

贵公司没有对计算机和相关系统实行合适的控制，来保证只有经授权的人员才能修改生产主记录和控制记录以及其他记录。

Specifically, your high performance liquidchromatography (HPLC) and gas chromatography (GC) data acquisition software,TotalChrom®, did not have sufficient controls to prevent the deletion oralteration of raw data files. During the inspection, the investigator observedthat the server that maintains electronic raw data for HPLC and GC analyses(the J drive) contains a folder named “Test,” and that chromatographic methods,sequences, and injection data saved into this folder can be deleted byanalysts.  The investigator also found that data files initiallycreated and stored in the “Test” folder had been deleted, and that back-upfiles are overwritten(b)(4).

特别你们没有足够地控制HPLC和GC数据采集软件，来防止原始数据文件的删除和修改。审计中，审计员发现储存HPLC和GC原始数据的服务器中有一个名为“测试”的文件夹，而且储存在那个文件夹的色谱方法，顺序和进样数据可以被检测人员删除。审计员还发现“测试”文件夹下的初始数据已经被删除，而且备份文件被覆盖过。

In addition, because no audit trail function wasenabled for the “Test” folder, your firm was unable to verify what types ofinjections were made, who made them, or the date or time of deletion. The useof audit trails for computerized analytical instrumentation is essential toensure the integrity and reliability of the electronic data generated.

另外，由于“测试”文件夹并没有追查功能，贵公司无法证明曾经做过何种进样，谁进的样以及数据删除的日期和时间。计算机化的分析仪器的追查功能是必不可少的，可以保证电子数据的完整性和可靠性。

Your response indicates that you have addedcomputer controls to prevent the deletion of folders and files in the J drivefor electronic raw data. However, you provide no evidence demonstrating howyour firm will prevent deletion of newly created folders and files in each ofyour computer systems. We acknowledge your commitment to hire a third partyconsultant to address the inadequacies of your data systems. However, yourresponse is inadequate as it fails to address how you will enable and reviewaudit trail functions for all of your analytical computer systems.

你们的回复指出你们已经增加了计算机控制来防止删除原始数据的文件夹和文件。然而，你们没有提供任何证据证明你们如何防止删除电脑系统中新建的文件夹和文件。我们收到了你们将雇佣第三方顾问来处理数据系统不足的承诺。然而你们的回复并不充分，因为它并没有说明你们将如何建立以及检查所有分析电脑系统的追查功能。

In response to this letter, provide specificdetails about the comprehensive controls in place to ensure the integrity ofelectronic raw data generated by all computer systems used to support themanufacture and testing of drug products. Your response should demonstrate anunderstanding of your processes and the appropriate controls needed for eachstage of manufacture that generates electronic raw data, as well as for yourlaboratories.

在这封信的回复中，请提供关于综合控制的具体细节，来保证生产、检测中所有的计算机系统中电子原始数据的完整性。你们的回复中应该证明你们对过程的理解以及对生产的每一个阶段和实验室生成的电子原始数据的合适控制。

We identified a similar inspectional findingduring the December 2013 inspection of your Irugattukottai, Sriperumburdur,India, manufacturing facility and noted this finding in an Untitled Letter,issued April 16, 2014. Explain how your firm will implement global correctiveactions and preventive actions concerning computer controls and provide atimeline for implementation.

我们在2013年对你们印度厂区的审计中发现了一个相似的的缺陷，并将它记录在2014年4月16日的一封无标题信件中。请解释你们将如何对你们的计算机控制实施全球纠正预防措施，并提供一个实施时限。

4.    Your firm failed to ensure thatlaboratory records included complete data derived from all tests necessary toassure compliance with established specifications and standards (21CFR 211.194(a)).

贵公司无法保证实验室记录包括检测中产生的计算机数据能够满足已经建立的质量标准。

a)    Our investigators identifiedyour practice of performing trial sample injections for HPLC analyses. Forexample, trial injections of (b)(4) stability samples (lot (b)(4) and (b)(4)) were acquired in the“Test” folder prior to official testing. Immediately after the trial injectionswere completed, the official samples were analyzed. The trial injection rawdata, captured in the back-up files, were deleted from the test folder.

我们的审计员指出你们在进行HPLC供试品进样时的操作不符合要求。例如：b4稳定性样品进样的数据在正式测试前先进入到“测试”文件夹。紧接着供试品进样完成后，分析了官方标准品。备份中供试品进样的原始数据被删除了。

b)    You retested analytical sampleswithout reporting original results in laboratory records. Because of thispractice, you are unable to assure that all raw data generated is included andevaluated when you review analytical test results to determine whether yourproducts conform with their established specifications and standards.

你们重新检测了分析样品，但是在实验室记录中没有记录原始结果。由于这个操作，你们无法保证当你们检查分析测试结果来去顶你们的产品是否满足质量标准时，你们记录并评估了所有生成的原始数据。

For example, (b)(4) lot #(b)(4) failed the contentuniformity test, where sample #8 of (b)(4) resulted with a value(b)(4)%. Your firm proceededto retest the sample on a different instrument without initiating anout-of-specification (OOS) investigation, as required by your chemistrylaboratory investigation standard operating procedure, SOP QAG-097. Theseinjections were not reported as part of the original data or included in yourlaboratory investigation report. Subsequently, the electronic raw data fileswere deleted. Moreover, there is no procedure describing the use ofre-injections for standards or samples on a different system to verify anoriginal result.

例如：b4批没有通过均匀性检测，8号样品不合格。你们在另外一台仪器上重新测试了样品，但没有做OOS调查，这个调查在你们的“实验室调查SOP”中是需要的。这些进样数据没有记录在原始数据中，也没有记录在实验室调查报告中。随后，电子原始数据被删除了。而且你们没有一个程序描述在一个不同的系统中重新进样标准品和样品来证明一个原始结果。

Your response indicates that the “Test” folderswere used to equilibrate the analytical columns and to determine when thesystem was ready for analysis. It is your responsibility to follow validatedmethods that include specific procedures to assess the suitability of yourinstruments. Neither the ICH document Q2R, "Validation of AnalyticalProcedure: Text and Methodology," nor the United States Pharmacopoeia(USP), General Chapter <1058>, "Analytical InstrumentQualification," provides for use of “trial” injections as part of avalidated method. Your rationale that you retested failing samples on differentanalytical instrumentation to evaluate system suitability is inadequate. SeeUSP General Chapter <621>, “Chromatography,” which discusses systemsuitability tests and the use of replicate injections of a standard preparationor other standards to determine if the requirements for precision aresatisfied.

你们的回复中指出“测试”文件夹是用来平衡色谱柱和确定系统何时可以开始分析用的。遵守经过验证的方法以及特定的程序来评估系统适用性是你们的职责。无论是ICHQ2R还是USP中都没有说可以将尝试性的进样作为经验证过的方法的一部分。你们对于你们在不同的分析仪器上测试不合格样品来评估系统适用性的理由是不充分的。参照USP“色谱”，讨论了系统适用性测试和重复进样工作对照品以及其他标准品来确定精密度是否满足要求。

Theseare serious CGMP violations that demonstrate that your quality system does not adequatelyensure the accuracy and integrity of the data you generate to support thesafety, effectiveness, and quality of the drug products you manufacture. Weacknowledge your commitment to work with a third party consultant to conduct acomprehensive assessment of your firm’s manufacturing, laboratory, and qualityoperations. However, it is your responsibility to ensure that the third partyaudit includes a full evaluation of sophisticated electronic systems and thepotential for manipulation of such systems. In response to this letter, providethe following to the Agency:

这些都是严重违反cGMP的行为，表明你们的质量系统并不能确保那些支持安全性、有效性和产品质量的数据是精确的和完整的。我们收到了你们将和第三方顾问合作对你们的生产、实验室和质量操作进行一个综合评估的承诺。然而确保第三方审计中包括对复杂的电子系统以及操控这样一个系统的可能性的全面评估是你们的职责。在这封信的回复中请将如下内容提供给代理：

1.    A comprehensive evaluation ofthe extent of the inaccuracy of the reported data. As part of yourcomprehensive evaluation, provide a detailed action plan to investigate theextent of the deficient documentation practices noted above;

不准确数据的范围的综合评估。作为你们综合评估的一部分，请提供一个详细的行动计划来调查上述缺陷文件操作的范围。

2.    A risk assessment regarding the potential effect on the qualityof drug products. As part of your risk assessment, determine the effects ofyour deficient documentation practices on the quality of the drug productreleased for distribution; and

产品质量潜在影响的风险评估。作为风险评估的一部分，请确定缺陷文件操作对分发的产品质量的风险。

3.    A management strategy for yourfirm that includes the details of your global corrective action and preventiveaction plan.

对你们公司的管理策略，包括详细的全球纠正预防措施计划。

a)    As part of your correctiveaction and preventive action plan, describe the actions you have taken or willtake, such as contacting your customers, recalling product, conductingadditional testing and/or adding lots to your stability programs to assurestability, monitoring of complaints, or other steps to assure the quality ofthe product manufactured under the violative conditions discussed above.

在你们的纠正预防措施中请描述你们已经采取或将要采取的措施，比如联系你们客户，召回产品，进行额外的测试或者在稳定性试验中增加批次来确保稳定性，对投诉的监督，或者其他措施来保证在如上所述的违规条件下生产出的产品的质量。

b)    In addition, as part of yourcorrective action and preventive action plan, describe the actions you havetaken or will take, such as revising procedures, implementing new controls,training or re-training personnel, or other steps to prevent the recurrence ofCGMP violations, including breaches of data integrity.

另外纠正预防措施计划中，请描述你们已经采取或将要采取的措施，比如修改操作规程，实施新的控制，培训或重新培训员工，或者其他措施来防止cGMP违规行为的再次发生，其中包括数据完整性的违规行为。

The violations cited in this letter are notintended to be an all-inclusive list of violations that exist at your facility.You are responsible for investigating and determining the causes of theviolations identified above and for preventing their recurrence and theoccurrence of other violations.

本警告信中引用的违规行为并不包括贵公司中发现的所有违规行为。你们有职责调查并确定产生上述违规行为的原因，并防止它们再次发生以及其他违规行为的发生。
If, as a result of receiving this warning letteror for other reasons, you are considering a decision that could reduce thenumber of finished drug products produced by your manufacturing facility, FDArequests that you contact CDER's Drug Shortages Program immediately, as youbegin your internal discussions, at drugshortages@fda.hhs.gov so that we can workwith you on the most effective way to bring your operations into compliancewith the law. Contacting the Drug Shortages Program also allows you to meet anyobligations you may have to report discontinuances in the manufacture of yourdrug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon aspossible, what actions, if any, may be needed to avoid shortages and protectthe health of patients who depend on your products. In appropriate cases, youmay be able to take corrective action without interrupting supply, or toshorten any interruption, thereby avoiding or limiting drug shortages.

如果由于受到这封警告信或其他原因，你们考虑减少制剂产品，FDA建议你们立即联系CDER，当你开始决定的结果你内部讨论，在   drugshortages@fda.hhs.gov   ，这样我们就可以在最有效的方式与您合作，使你们的操作符合法律规定。  在适当的情况下，贵公司可以采取的纠正措施不中断药品供应，从而避免或限制的药物短缺。

Until all corrections have been completed andFDA has confirmed corrections of the violations and your firm’s compliance withCGMP, FDA may withhold approval of any new applications or supplements listingyour firm as a drug product manufacturer. In addition, your failure to correctthese violations may result in FDA refusing admission of articles manufacturedat Hospira S.p.A located at Via Fosse Ardeatine 2, Liscate,Italy  into the United States under Section 801(a)(3) of the Act, 21U.S.C. 381(a)(3). The articles may be subject to refusal of admission pursuantto Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).

直至所有的纠正措施完成，FDA确认了偏差的纠正措施和你的公司符合cGMP，FDA保留批准你公司作为生产者的任何新的申请或补充。另外，纠正这些偏差措施的失败导致FDA拒绝位于意大利的S.p.A公司生产的药品进入美国。物药品拒绝进入的依据801(a)(3) of the Act [21 U.S.C. § 381(a)(3)]，生产方法和控制不符合cGMP 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].部分

Within fifteen working days of receipt of this letter, please notify thisoffice in writing of the specific steps that you have taken to correct andprevent the recurrence of violations, and provide copies of supportingdocumentation. If you cannot complete corrective actions within fifteen 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) youceased production. Please identify your response with FEI # 3004640070.

在收到这封信的十五个工作日内，请将你纠正偏差的具体步骤以书面的形式通知本部门。包括防止偏差再发生的每个步骤的解释和支持性文件的复印件。如果十五个工作日内贵公司不能完成纠正措施，注明延迟的原因和措施将完成的日期。此外，你的答复应该注明你是否不再生产或发放上述事件中生产的药品，提供你中断产品的日期和原因。请识别你的答复FEI # 3003887583。

Please send your reply to:
Christina Alemu-Cruickshank
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 4233
10903 New Hampshire Ave.
Silver Spring, MD 20993

叶非

FDA警告信值得很多中国企业学习，因为FDA警告信中，不单单会指明缺陷项目是什么，还会提到风险点或者说为什么提出这个缺陷，而这些是我们日常中，应当避免的！