FDA警告信：Fresenius Kabi AG & Prosana Distribuciones S.A. de C.V.

翻译： julia  来源：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 [e-mail], 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 [e-mail] 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

FDA警告信：Prosana Distribuciones S.A. de C.V. 20171218

ViaUPS                                                                             

 Warning Letter 320-18-18

Return Receipt Requested 

December 18, 2017

Mr. Fernando Vidal Millan

Director General

Prosana Distribuciones S.A. deC.V.

Oriente 225 97-1 AgricolaOriental

Iztacalco, Mexico City DF08500

Mexico

Dear Mr. Millan:

The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, ProsanaDistribuciones S.A. de C.V. at Oriente 225 97-1 Agricola Oriental, Iztacalco,Mexico City, from March 6–9, 2017.

 美国FDA于2017年3月6-9日检查了你们位于墨西哥伊斯塔卡尔科的Prosana Distribuciones S.A. de C.V.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 product is 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。

Our investigator alsocollected labeling for Bicaruvas Antacid Effervescent Powder. For the purposeof this letter, we will refer to the product as Bicaruvas. Based on our reviewof the product label, FDA has determined that, as formulated and labeled,Bicaruvas is an unapproved new drug in violation of section 505(a) of theFD&C Act, 21 U.S.C. 355(a), and is misbranded under section 502(c) of theFD&C Act, 21 U.S.C. 352(c).

我们的调查人员还采集了Bicaruvas抗酸泡腾片粉末的标签。在本函中，我们将引用产品Bicaruvas。根据我们对产品标签的审核，FDA已经确定，作为配方和标签完成的药品，Bicaruvas是一个未经批准的新药，违反FDCA第505（a）条和21 U.S.C. 355(a)，依据FDCA502（c）和21 U.S.C. 352(c)是为冒牌药品。

We reviewed your March 29,2017, response in detail.

我们已详细审核了你公司2017年3月29日的回复。

During our inspection, ourinvestigator 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：

CGMP Violations CGMP违规

1.     Your firm failed to have, for each batch of drug product, appropriatelaboratory determination of satisfactory conformance to final specifications forthe drug product, including the identity and strength of each activeingredient, prior to release (21 CFR 211.165(a)).

你们公司未对每批药品进行适当的化验室测试，确保其在放行之前符合药品的最终标准，包括每种活性成分的鉴别和剂量(21 CFR 211.165(a))。

You distributed two batches ofBicaruvas before receiving certificates of analysis (COA) containing thefinished product test results from your third-party testing laboratory, (b)(4).

 你们在从第三方化验室收到成品检验结果COA之前就销售了2批Bicaruvas。

Your management could notlocate the COA for Bicaruvas batches EBU02 and EBU03. During the inspection,you retrieved the COA from your third-party testing laboratory. You had alreadydistributed batches EBU02 and EBU03 to the United States.

 你们的管理人员没找到Bicaruvas批号EBU02和EBU03的COA。在检查期间，你们从你们的第三方化验室重新获得了COA。你们已经销售了EBU02批和EBU03批至美国。

Drugs must be manufactured inconformance with CGMP. FDA is aware that many drug manufacturers useindependent contractors, such as production facilities, testing laboratories,packagers, and labelers. FDA regards contractors as extensions of themanufacturer.

 药品生产必须符合CGMP要求。FDA了解许多药品生产商使用独立的合同方，例如生产场所、化验室、包装商和标签商。FDA认为这些合同方是生产商的延伸。

You are responsible for thequality of drugs you produce, regardless of agreements in place with yourcontract testing laboratory. You are required to ensure that drugs are made inaccordance with section 501(a)(2)(B) of the FD&C Act to ensure safety,identity, strength, quality, and purity. See FDA’s guidance document, ContractManufacturing Arrangements for Drugs: Quality Agreements, athttps://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf

你们对于你们生产的药品质量负有责任，而不论你们是否与合同化验室签订有协议。你们应确保药品依据FDCA第501(a)(2)(B)部分生产和检测。参见FDA指南。

2.     Your firm failed to conduct at least one test to verify the identity of eachcomponent of a drug product. Your firm also failed to establish the reliabilityof component supplier analyses on which you rely in lieu of certain teststhrough appropriate validation of the supplier’s test results at appropriateintervals (21 CFR 211.84(d)(1) and (2)).

   你们公司未能实施至少一项检测来核查药品的每种成分的鉴别。你们公司也没有对每种成分进行检查，确认其符合所有适当的书面纯度、含量和质量标准(21 CFR 211.84(d)(1) & (2))。

You did not test for identityof incoming active pharmaceutical ingredients and other components used tomanufacture over the counter (OTC) drug products. You also failed to establishthe reliability of all your suppliers’ analyses, and to test each component forconformity with all appropriate written specifications for purity, strength, andquality. You relied on unqualified suppliers’ COA. In some instances, youaccepted raw materials without COA.

 你们没有检测OTC药品生产所用进厂API和其它组分的鉴别。你们也未建立你们所有供应商分析情况的可靠性，以及检测每种组份是否符合所有适当的书面纯度、剂量和质量标准。你们依赖于未经确认的供应商的COA。在有些时候，你们接受没有COA的原料。

3.     Your firm failed to prepare batch production and control records for each batchof drug product that include complete documentation of the accomplishment ofeach significant step in the manufacture, processing, packing, or holding ofthe batch, including a statement of the actual yield, and a statement of apercentage of theoretical yield at appropriate phases of processing. (21 CFR 211.188(b)(7)).

 你们公司未能为每批药品准备批生产和批检验记录，包括记录生产、加工、包装和存贮过程中每个重大步骤的完成情况的完整文件，包括一份实际收率的声明，以及在加工的适当阶段的理论收率百分比（21 CFR 211.188(b)(7)）

During the inspection, yourfirm’s management stated that operators “made up” yield results in your batchrecords for processing steps such as weighing, (b)(4), and filling, aswell as for label reconciliation. Management informed our investigator thatoperators falsified batch records because there were no establishedcalculations for determining yields.

 在检查期间，你们公司的管理人员声明操作人员在你们加工步骤例如称量、灌装以及标签数量平衡的批记录上“虚构”收率结果。管理人员告知我们的调查人员说操作人员伪造了批记录，因为没有制订计算方法来确定收率。

4.     Your firm failed to establish adequate written procedures for production andprocess control designed to assure that the drug products you manufacture havethe identity, strength, quality, and purity they purport or are represented topossess (21 CFR 211.100(a)).

 你们公司未能建立充分的生产和工艺控制书面程序，用以确保你们生产的药品具备其所应具备的鉴别、剂量、质量和纯度(21 CFR211.100(a))。

You have not validated theprocesses used to manufacture your drug products. You did not perform processperformance qualification studies, and lacked an ongoing program for monitoringprocess control to ensure stable manufacturing operations and consistent drugquality.

你们未验证用于生产你们药品的工艺。你们未实施工艺性能确认研究，缺乏监测工艺控制的持续计划来确保稳定的生产操作和一致的药品质量。

You also lacked adequatemaster production and control records for Bicaruvas with established processcontrols. For example, you did not have a master batch record for each batchsize that you manufacture. Our investigator noted that you manufacturedBicaruvas batches EBU01, EBU02, and EBU03 with five times the amount of calciumcarbonate specified on the product label. Firm management stated that personnelperformed a calculation on the spot for customer orders of more than (b)(4),and that they used a wrong formula for these three batches.

 你们还缺乏足够的Bicaruvas主生产和检验记录，并在其中包括既定的工艺控制。例如，你们对你们所生产的每个生产批量没有单独的一份主批记录。我们的调查人员注意到你们生产的Bicaruvas批号EBU01、EBU02和EBU03的碳酸钙是产品标签上指定的5倍。公司管理人员声称员工对不止XX客户订单进行抽样计算，他们对这三批计算中用的公式是错的。

See FDA’s guidance document, ProcessValidation: General Principles and Practices, for general principles andelements of process validation at https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf

 参见FDA工艺验证指南。

Inadequate Response 回复不充分

 Your March 29, 2017, responseto FDA’s inspectional observation was inadequate and did not provide sufficientevidence of corrective actions to bring your operations into compliance withCGMP. For example, you failed to provide:

2017年3月29日，你们为FDA检查缺陷提交的回复是不充分的，未提供足够的证据证明纠正措施可以将你们的操作合规化。例如，你们未能提交：

• The quality control test methods and specifications used to analyze each drug product batch prior to a batch release decision, including both chemical and microbial quality attributes.

• 在批放行决策之前用以分析每批药品的质量控制检测方法和质量标准，包括化学和微生物质量属性

• A procedure detailing your batch release program and the responsibilities of your quality unit.

• 详细说明你们的批放行计划的程序，以及你们质量部门的职责

• An evaluation of all batches of Bicaruvas distributed to the U.S. that are still within expiry to ensure they met specifications prior to release. If your evaluation reveals substandard     quality drug products, provide your proposed corrective actions, such as notifying customers or recalling product.

• 对所有销往美国且仍在有效期的Bicaruvas批次的评估，以确保其符合放行前标准。如果你们的评估显示有药品不符合质量标准，请提交你们提议的纠正措施，如通知客户或召回产品

• Specific timelines for process performance qualification for each of your drug products, and a detailed summary of your approach for routinely monitoring intra-batch and inter-batch     variations.

• 你们每种药品的工艺性能确认的时间表，以及你们常规监测批内和批间波动性的方法摘要

• A master batch record with defined process parameters.

• 一份主批记录，在其中定义工艺参数

• A summary of test results obtained from full testing of each of your incoming components to validate vendors’ certificates of analysis. Provide your current incoming raw material batch release specifications for each component. Also include your procedures to ensure that you test for the identity of each incoming lot of components.

• 对你们每种进厂组份的全检所得结果的摘要，以验证供应商的COA。提交你们当前每种组份进厂原料批次放行标准。还请包括你们确保你们鉴别每批进厂组份的程序。

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility's operations in which you discovered data integrity lapses, and evaluate the nature of the data integrity deficiencies.

• 对数据记录和报告不准确性程度的全面调查。找出遗漏、修改、删除、记录损毁、不同步记录和其它缺陷。描述你们工厂操作中发现有数据完整性问题的所有部分，并评估数据完整性缺陷的情况。

CGMP Consultant Recommended CGMP顾问建议

 If your firm resumesmanufacturing drugs for the United States market, based upon the nature of theviolations we identified at your firm you should undertake a comprehensive andglobal assessment to ensure that your systems and processes, and ultimately thedrug products you manufacture, conform to FDA requirements. We stronglyrecommend engaging a consultant, qualified as set forth in 21 CFR 211.34, toassist your firm in meeting CGMP requirements.

如果你们公司继续生产销往美国的药品，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。你们有必要启动对你们公司的生产操作的全面评估，以确保你们的系统和工艺，以及最终，你们所生产的产品，符合FDA的要求。

Your use of a consultant doesnot relieve your firm’s obligation to comply with CGMP. Your firm’s executivemanagement remains responsible for fully resolving all deficiencies andensuring ongoing CGMP compliance.

 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。

Unapproved New Drug Violation 未批准的新药违规

Examples of claims observed onthe product label for Bicaruvas that establish the intended use of your productinclude, but may not be limited to, the following.

在你们Bicaruvas产品标签上发现的 声明样例中，你们注明的产品用途包括但不仅限于：

“FAST RELIEF OF: Heartburn,Acid Reducer, Upset Stomach” and “Uses (sic) for the relief of: Heartburn, Sourstomach, Acid indigestion, upset stomach associated with these symptoms.”

“快速缓解：胃灼热，降酸，胃痛”以及“用于缓解：胃灼热、胃泛酸、胃酸过多、伴有上述症状的胃痛”。

Based on the above claims,Bicaruvas is a drug as defined by section 201(g)(1)(B) of the FD&C Act 21,U.S.C. 321(g)(1)(B) because it is intended for the diagnosis, cure, mitigation,treatment, or prevention of disease, and/or under section 201(g)(1)(C) of theFD&C Act, 21 U.S.C. 321(g)(1)(C) because it is intended to affect thestructure or any function of the body of man.

 依据上述声明，Bicaruvas是一种FDCA第201(g)(1)(B)部分和U.S.C.321(g)(1)(B)所定义的药品，因为其用途是诊断、治愈、缓解、治疗或预防疾病，和/或FDCA第201(g)(1)(C)部分和21 U.S.C. 321(g)(1)(C)规定，因为其用于影响人体的结构或功能。

Specifically, this product isintended as an antacid. OTC drug products intended as antacids, such asBicaruvas, are subject to the Final Monograph for Antacid Drug Products forOver-the-Counter Use. See 21 CFR Part 331. However, this product is notformulated in accordance with this final monograph for the reasons explainedbelow.

 尤其是，该产品用作防酸剂。用作防酸剂的OTC药品，如Bicaruvas，受到OTC用途防酸药品的最终各论约束。参见21CFR第331部分。但是，该产品并未依据此最终各论的要求配方，理由如下。

The product’s labeledconcentration for citric acid does not comply with the required concentrationsfor this active ingredient as specified in the final monograph. Specifically,Bicaruvas is labeled to contain 1.927 grams of citric acid per packet andincludes directions for adults to dissolve one packet every 4 hours with thewarning, “Do not exceed more than 5 packets in 24 hours period (sic).”

产品的标示柠檬酸浓度不符合最终各论中所要求的此活性成分的浓度。尤其是Bicaruvas标示含有柠檬酸1.927克/包装，还有针对成人的指示要每4小时溶解一个包装，其中有警示“24小时内不要超过5包”。

The final monograph requiresthat the maximum daily amount of citric acid not exceed eight grams per day.However, if taken as directed, it is possible for a consumer to exceed theeight-gram daily maximum under the final monograph (21 CFR 331). Thus, as formulated,Bicaruvas does not comply with the final monograph described above.

 最终各论要求最大日服用剂量柠檬酸不超过每天8克。但是，如果按指示服用，则可能消费者会超出各论中所指定的每天8克的数量（21CFR331）。因此，按配方所制的Bicaruvas不符合上述最终各论所述要求。

Furthermore, we are not awareof sufficient evidence to show Bicaruvas, as formulated and labeled, isgenerally recognized as safe and effective. Therefore, this product is a newdrug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p)because it is not generally recognized among scientific experts as safe andeffective for its labeled uses.

 另外，我们并未看到有足够的证据显示Bicaruvas，如其所配方和标示，是公认为安全和有效的。因此，此产品按FDCA第201（p）部分21 U.S.C. 321(p)是一种新药，因为它并未被科学专家公认其标示用途安全和有效。

As a new drug, Bicaruvas maynot be legally marketed in the United States absent approval of an applicationfiled in accordance with section 505(a) of the FD&C Act, 21 U.S.C. 355(a).Bicaruvas is not the subject of an FDA-approved application, and therefore, thecurrent marketing of this product violates section 505(a) of the FD&C Act,21 U.S.C. 355(a). Introduction of such products into interstate commerce isprohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

作为一种新药，Bicaruvas在未依据FDCA第505（a）部分21 U.S.C. 355(a)提交申报并获得批准前提下在美国上市销售可能并非合法。Bicaruvas并不是依据FDA批准申报的药品，因此，当前此药品上市销售违反了FDCA第505（a）和21 U.S.C. 355(a)规定。将此类药品引入州际贸易依据FDCA第301（d）和21 U.S.C. 331(d)是被禁止的。

Misbranding Violation 冒牌违规

Bicaruvas is misbranded underSection 502(c) of the FD&C Act 21 U.S.C. 352(c) because, although thelabeling includes both English and Spanish, some of the information requiredunder authority of the FD&C Act does not appear in both English andSpanish. For example, the Drug Facts panel only appears in English while thePrinciple Display Panel (PDP) appears in both English and Spanish. Under 21 CFR201.15(c)(2) and 201.15(c)(3), if a product’s label or labeling contains anyrepresentation in a foreign language, all words, statements, and otherinformation required by or under authority of the FD&C Act appearing on thelabel shall appear thereon in the foreign language.

依据FDCA第502（c）和21 U.S.C. 352(c)， Bicaruvas是冒牌药品，因为尽管标签包括有英语和西班牙语，有些FDCA所要求的信息并未以英语和西班牙语双语出现。例如，药品信息只有英语显示，而原理显示标签（PDP）则为双语。依据21 CFR 201.15(c)(2) 和 201.15(c)(3)，如果一个产品的标签或标示含有任何外语展示，则所有FDCA法案监管要求的文字、声明和其它信息均应也以外语方式显示。

Bicaruvas also is misbrandedunder section 502(c) of the FD&C Act, 21 U.S.C. 352(c) because neither theouter carton nor the individual packets include a lot or control number andexpiration dating, which are required under 21 CFR 201.18 and 21 CFR 211.137,respectively.

依据FDCA第502(c)条和 21 U.S.C. 352(c) ，Bicaruvas也是冒牌药品，因为其外包纸盒和单个包装都没有批号和控制码以及有效期，而这些信息依据21 CFR 201.18 和21 CFR 211.137都是需要的。

The introduction or deliveryfor introduction of a misbranded drug into interstate commerce is prohibitedunder section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, themarketing of Bicaruvas violates this provision of the FD&C Act.

引入或引入发运一种冒牌药品至州际贸易依据FDCA第301(a)和21 U.S.C. 331(a)是禁止的。因此，Bicaruvas的销售违反了FDCA的此条规定。

We note that the Directionssection in the Drug Facts panel is unclear. The directions state that “adultsand children under 12 years older (sic)” should dissolve one packet every fourhours, but also states that “children under 12 years” consult a doctor.

我们注意到在药品信息的指令部分是不清楚的。指令声称“成人和12岁以下儿童”应每4个小时溶解一包，但也声称“12岁以下儿童”应咨询医生。

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.

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。

FDA placed your firm on ImportAlert 66-40 on July 12, 2017.

2017年7月12日，FDA已将你公司放在了进口禁令66-40清单中。

Until you correct allviolations completely and we confirm your compliance with CGMP, FDA may withholdapproval of any new applications or supplements listing your firm as a drugmanufacturer.

  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 continuing to refuse admission of articlesmanufactured at Prosana Distribuciones S.A. de C.V. at Oriente 225 97-1Agricola Oriental, Iztacalco, Mexico City into the United States under section801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, 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 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 [e-mail] or mail your reply to:

Towanda Terrell

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 3011473501.

Sincerely,

/S/ 

Francis Godwin

Acting Director

Office of ManufacturingQuality

Office of Compliance

Center for Drug Evaluation andResearch