FDA警告信：佛山市朗博医疗救护用品有限公司 20181214

翻江鼠

Warning Letter 320-19-09               December 14,2018

Mr. Zhiyuan Dong

General Manager, Longbow First Aid ProductsManufactory

2/F, A3 Building, Hantian Industrial Park, GuipingRoad, Guicheng, Foshan 528200 CHINA

Dear Mr. Dong:

The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Longbow First Aid ProductsManufactory at 2/F, A3 Building, Hantian Industrial Park, Guiping Road,Guicheng, Foshan, from April 16 to 20, 2018.

美国FDA于2018年4月16-20日检查了你们位于广东佛山市南海区桂城桂平路瀚天科技城A区3号楼二楼的佛山市朗博医疗救护用品有限公司生产场所。

This warning letter summarizes significantviolations of current good manufacturing practice (CGMP) regulations forfinished pharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信总结了制剂生产严重违反CGMP的行为。参见21CFR第210和211部分。

Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrug products are adulterated within the meaning of section 501(a)(2)(B)of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C.351(a)(2)(B).

由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的制剂根据FDCA的501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your May 2, 2018, response in detailand acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2018年5月2日的回复，并此告知已收到后续通信。

During our inspection, our investigator observedspecific violations including, but not limited to, the following.

检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：

1.     Your firm does not have, for each batch of drug product purporting to besterile and/or pyrogen-free, appropriate laboratory determination ofsatisfactory conformance to final specifications for the drug product (21 CFR211.167(a)). 你公司未对每批理应无菌和/或无热原的药品执行适当的实验室检测确保其符合药品的最终质量标准(21 CFR 211.167(a))。

Your firm released your finished over-the-counter(OTC) (b)(4) drug products to the U.S. market without testing each batchfor all appropriate quality attributes. For example, your firm distributedmultiple batches of purportedly sterile (b)(4) without conductingsterility testing. Instead, you conducted microbiological enumeration testswith a specification of < (b)(4) CFU/mL. Microbiological enumerationtesting is insufficient when testing for drug product sterility. Furthermore,you did not test your (b)(4) drugs for particulate matter before theirrelease. Without appropriate testing for these physical and microbiologicalquality attributes, your quality unit lacks the essential safety informationrequired to make suitable release decisions.

你公司未检验每批药品OTC药品XX的所有适当质量属性即将其放行至美国市场。例如，你公司未进行无菌检测即将多批理应无菌的XX药品放行销售。相反，你们进行了微生物计数测定，标准为<XXCFU/ml。微生物计数检测用于检测药品无菌是不够的。另外，你们并未检测你们XX药品的颗粒物即将其放行。由于没有这些物理和微生物质量属性的适当检测，你们质量部门缺少做出适当放行决策的必要安全信息。

Your response stated that you did not conductsterility testing because it was not a customer requirement, and that you will“take retention samples for sterility test and provide it to customer.” Yourresponse is inadequate because it lacked sufficient details, including who willtest these retention samples and what specific test methods will be used onthese drug products.

你们在回复中声称你们未进行无菌检测是因为没有客户提出要求，你们将“取留样进行无菌检测并提交给客户”。你们的回复是不充分的，因为其缺少足够详细的内容，包括谁将检测这些留样，要对这些药品使用什么专用检测方法。

In response to this letter:  在回复此函时：

• Provide your newly established testing methods, such as your methods for particulate testing and sterility testing, and specifications intended for analysis of the physical     properties of the drug products, for each batch of drug products before their release.
• 请提交你们新建的检验方法，如你们的颗粒物检测和无菌检测，以及用于药品物理属性检测的质量标准，在各批次放行之前进行检测。
• Provide all sterility test results for your OTC (b)(4) drug products and indicate whether they conform to United States Pharmacopeia (USP) Sterility Tests <71>.
• 请提交你们XX OTC药品的所有无菌检测结果，说明他们是否符合USP无菌检测<71>的要求。
• For any drug product batch that failed to meet established quality criteria, provide your detailed corrective action plans, including notifying customers or recalling drug products.
• 对所有不符合既定质量标准的药品批次，请提交你们详细的纠正措施计划，包括通知客户或召回药品。
  
  

2.     Your firm failed to establish and follow appropriate written procedures thatare designed to prevent microbiological contamination of drug productspurporting to be sterile, and that include validation of all sterilizationprocesses (21 CFR 211.113(b)). 你们公司未能建立和遵守适当的书面程序，设计用以防止理应无菌的药品受到微生物污染，包括所有灭菌工艺的验证(21 CFR 211.113(b))。

You failed to demonstrate that your asepticprocesses are capable of preventing microbial contamination of your ophthalmicdrug products.

你们未证明你们的无菌工艺能够防止你们眼用药品的微生物污染。

Inadequate EquipmentSterilization设备灭菌不充分

Your firm has not demonstrated that your process iscapable of ensuring the sterility of your (b)(4)equipment. You statedthat you use an (b)(4) mixture that is intended to “sterilize” equipmentbefore manufacturing. When our investigator asked for the concentration of (b)(4)used in this process, you could not provide this information, nor could youprovide any documentation to support equipment “sterilization” beforemanufacturing. Furthermore, you lacked documentation and validation studiesassessing the suitability and reproducibility of this method for sterilizingequipment. Your (b)(4) equipment must be sterilized using an appropriateand robust sterilization method to ensure that your (b)(4) drug productsare safe for use by patients.

你公司未证明你们的工艺能够确保你们的XX设备的无菌性。你们声称你们使用了一个XX混合器，用于生产之前对设备“灭菌”。当我们的调查人员询问此工艺中所用的XX浓度时，你们未能提交此信息，亦未提交任何文件资料支持设备在生产之前的“灭菌”。另外，你们亦缺少评估该设备灭菌方法的适用性和重复性的文件记录和验证研究。你们的XX设备必须使用适当和稳健的灭菌方法进行灭菌，以确保你们的XX药品在患者使用时是安全的。

In your response, you stated that you will“validate the aseptic capacity of the (b)(4) equipment” by June 15,2018. Your response is inadequate. You failed to provide data demonstrating useof appropriate and robust processes to sterilize the entire equipment paththrough which the drug product travels.

在你们的回复中，你们声称你们会在2018年6月15日之前“验证XX设备的无菌能力”。你们的回复是不充分的，你们未能提交数据证明使用了恰当稳健的工艺对药品所经历的整个设备路径进行灭菌。

Your response also stated that “the final sterilitywarranty level is guaranteed by preservatives.” You cannot rely onpreservatives to ensure drug product sterility.

你们的回复还声称“最终无菌性的保障是通过防腐剂来保证的”。你们不能依赖防腐剂来确保药品的无菌性。

Lack of Media Fill Studies 缺乏培养基灌装研究

Your firm has not performed aseptic processsimulations (i.e., media fill studies). During the inspection, our investigatorasked your firm if it had performed process simulations for the (b)(4)machine used to manufacture your OTC (b)(4) drug products. You statedthat no media fill simulations had been conducted, but that you plan to performmedia fill simulatons in the future. To ensure the sterility of productspurporting to be sterile, aseptic filling and closing operations must beadequately validated before manufacture and distribution. Adequate media fillstudies accurately simulate aseptic processing line practices and conditions,including any interventions that may be encountered during actual production.These studies should be conducted at least twice a year (for each shift) toevaluate whether each aseptic processing line remains in control and robustlyyields sterile drugs that are safe for use by patients.

你们公司未能进行无菌工艺模拟（即培养基灌装研究）。在检查期间，我们的调查人员询问你们公司是否对你们XX OTC药品生产用XX设备进行了工艺模拟。你们声称未进行培养基灌装模拟，但你们计划要在将来进行培养基模拟。为确保理应无菌的药品的无菌性，无菌灌装和密闭操作必须在生产和销售前进行足够的验证。充分的培养基灌装研究能准确模拟无菌工艺线实际操作和条件，包括所有在实际生产中可能遭遇的干扰。这些研究应每年至少进行2次（每个班次），以评估是否每条无菌工艺线均能保持受控，并能稳定生产出患者可安全使用的无菌药品。

Your response lacks adequate details about themedia fill program you will use to validate your (b)(4)operations. Forexample, your proposed media fill study does not incorporate all containersizes that you manufacture for the U.S. market. Media fill studies should berepresentative of all container sizes, filling speeds, and other parametersused in your production processes.

你们的回复缺乏关于你们将用来验证你们的XX操作的培养基程序的足够详细的信息。例如，你们所提议的培养基灌装研究未包括你们为美国市场生产所用的所有容器尺寸。培养基灌装研究应代表所有容器尺寸、灌装速度和其它生产工艺所用参数。

Refer to FDA’s guidance document Sterile DrugProducts Produced by Aseptic Processing – Current Good Manufacturing Practicefor recommendations to help you meet CGMP requirements when manufacturingsterile drugs using aseptic processing. This guidance is on the FDA website athttp://www.fda.gov/downloads/Dru ... nces/UCM070342.pdf.

参见FDA指南文件“无菌工艺生产的无菌药品—CGMP”。

In your response to this letter: 在回复此函时

• Describe how you will sterilize the (b)(4) manufacturing equipment. Provide a detailed sterilization method, a list of all equipment sterilized using this method, validation protocols, and validation reports for your processes.
• 请说明你们将如何灭菌XX生产设备。请提交详细的灭菌方法、一份所有采用此方法灭菌的设备清单、你们工艺的验证方案和验证报告。
• Provide a comprehensive summary of your media fill program that ensures an appropriate simulation of the worst-case conditions of commercial manufacturing. In addition, describe in detail how you examine units for presence of growth and how you perform batch yield reconciliation. Include all related standard operating procedures (SOPs).
• 请提交一份确保恰当模拟商业化生产最差情形的培养基灌装程序的综述。另外，要详细说明你们要如何检查是否有菌生长，以及你们如何执行批收率衡算，包括所有相关的SOP。
  
  

3.     Your firm failed to conduct at least one test to verify the identity of eachcomponent of a drug product. Your firm also failed to validate and establishthe reliability of your component supplier’s test analyses at appropriateintervals (21 CFR 211.84(d)(1) and (2)).你公司未能对药品的每种成分执行至少一项鉴定测试。你公司亦未以恰当的时间间隔验证并建立你们组份供应商的检测分析的可靠性(21 CFR 211.84(d)(1) and (2))。

Your firm failed to test your incoming rawmaterials, including (b)(4), for identity, purity, strength, and otherappropriate quality attributes. Instead, your firm relied on certificates ofanalysis (COA) from unqualified suppliers. During our inspection, you told ourinvestigator that you consider a supplier qualified if they are registered andhold a certificate of GMP. FDA requires identity testing for each component lotused in drug product manufacturing, and you can only rely on a COA for othercomponent attributes by appropriately validating the supplier's test results atappropriate intervals.

你公司未能检查进厂原料（包括XX）的鉴别、纯度、剂量和其它适当的质量属性。相反，你们公司依赖于未经验证的供应商的COA。在我们检查过程中，你们告诉我们调查人员说如果一个供应商经过登记并持有GMP证书就认为该供应商是经过验证的。FDA要求对药品生产中所用的每种成分均进行鉴定测试，并且只能依赖于经过适当周期验证的供应商的检测结果中的其它成分属性。

In your response, you stated that you will “entrusta third party to examine each inspection item to confirm its authenticity.”However, you failed to include details about this examination, and you do notdescribe what tests will be performed. Also, you have not described in detailhow you will qualify the third-party laboratory or how you will ensure thatincoming raw materials meet USP testing requirements.

在你们的回复中，你们声称你们将“委托一个第三方检测所有项目以确认其真实性”。但是你们并未包括该检测的详细内容，并且你们亦未说明要执行何种检测。你们亦未详细说明你们将如何确认第三方实验室，或者要如何确保进厂原料符合USP检测要求。

In response to this letter: 在回复此函时

• Provide quality control release specifications for all incoming components, and the tests you perform for each lot.
• 请提交所有进厂组份的质量控制放行标准，以及你们对每个批准执行的检测
• Provide a summary of test results obtained from comprehensive testing of all incoming components, to validate the COA from each manufacturer of raw material.
• 请提交一份对所有进厂组份全面检测获得的检测结果，用以验证每个原料生产商提供的COA
• Provide a summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test incoming components and the drug products you manufacture.
• 请提交一份你们确认和监管负责进厂组份和你们所生产药品检测的合同场所充分性的程序综述
• Provide a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified; whether they are assigned appropriate expiration or retest dates; and whether incoming material lot controls are adequate to prevent the use of unsuitable containers, closures, and components.
• 请提交一份对你们原料体系的全面独立审核，确定是否来自每个供应商的所有容器密闭器和成分均经过足够的验证，是否给定了恰当的有效期或复验期，进厂物料批次控制是否足以防止使用不适当的容器密闭器和组份
  
  

4.     Your firm failed to ensure that its drug product bore an expiration date thatwas supported by appropriate stability testing 21 CFR 211.137(a).你公司未能确保药品具备有效期，并有适当的稳定性检测支持（21 CFR 211.137(a)）。

You firm has not established a stability program.You lack data to demonstrate that the chemical, physical, and microbiologicalproperties of your OTC (b)(4) drug products, including sterility, willremain acceptable throughout their labeled (b)(4) expiry period.

你公司未能建立稳定性程序。你们缺乏数据证明你们XX OTC药品的理化和微生物性质，包括无菌性，在其所标示的XX有效期内能保持在可接受范围。

In your response, you stated that you will“establish the long-term stability testing of OTC (b)(4)drugsimmediately,” and that your laboratory needs to “acquire equipment forlong-term stability testing.” Your response is inadequate. You failed toinclude adequate stability protocols, including all relevant quality attributesand acceptance criteria, and provide assurance that your test methods willindicate adequate stability.

在你们的回复中，你们声称你们将“立即制订XX OTC药品的长期稳定性检测计划”，并且你们实验室需要“申请长期稳定性试验用设备”。你们的回复是不充分的。你们未能包括有足够的稳定性方案，包括所有相关质量属性和可接受标准，并证明你们的检测方法具有稳定性指示性。

In response to this letter: 在回复此函时

• Provide stability data to demonstrate that the chemical, physical, and microbiological properties of your (b)(4) drug products remain acceptable throughout their labeled expiry period.
• 请提交稳定性数据证明你们的XX药品的理化和微生物属性在其所标示的有效期内保持可接受
• Provide a comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but not be limited to, a remediated SOP describing your stability program; stability-indicating methods; stability studies to support each drug     product in its container-closure system before distribution is permitted; an ongoing program that adds representative batches of each product annually to determine if the shelf-life claim remains valid; and specific attributes to be tested at each station.
• 请提交一份全面评估和CAPA计划，确保你们的稳定性程序的充分性。你们的CAPA应包括但不仅限于修改后的SOP，在其中描述你们的稳定性程序、稳定性指示性方法、稳定性研究，在批准销售之前支持各药品在各种容器密闭器包装、每年增加各产品代表性批次的持续稳定性计划，以确定其货架期声明保持有效，以及在各时间点所需检测的具体属性。
  
  

CGMP consultant recommended CGMP顾问建议

Based upon the nature of the violations weidentified at your firm, we strongly recommend engaging a consultant qualifiedas set forth in 21 CFR 211.34, to assist your firm in meeting CGMPrequirements. We also recommend that the qualified consultant: (1) perform acomprehensive audit of your entire operation for CGMP compliance; and (2)evaluate the completion and effectiveness of corrective actions and preventiveactions you have implemented, before you pursue resolution of your firm’scompliance status with FDA.

依据我们在你们工厂发现的违规情况，我们强烈建议你们使用一位有21 CFR211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议由具备资质的顾问（1）对你们全面操作进行CGMP合规性综合审计，以及（2）在你公司寻求符合FDA法规解决方案之前评估你们已实施的所有CAPA的完整性和有效性。

Your use of a consultant does not relieve yourfirm’s obligation to comply with CGMP. Your firm’s executive management remainsresponsible for fully resolving all deficiencies and ensuring ongoing CGMPcompliance.

你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。

Conclusion 结论

Violations cited in this letter are not intended asan all-inclusive list. You are responsible for investigating these violations,for determining the causes, for preventing their recurrence, and for preventingother violations.

此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。

FDA placed your firm on Import Alert 66-40 onAugust 17, 2018.

FDA已于2018年8月17日将你公司置于进口禁令66-40内。

Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug 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 these violations may also resultin FDA continuing to refuse admission of articles manufactured at Longbow FirstAid Products Manufactory at 2/F, A3 Building, Hantian Industrial Park, GuipingRoad, Guicheng, Foshan, 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 thisoffice in writing within 15 working days. Specify what you have done since our inspectionto correct your violations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons fordelay 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:

Bryce Hammer

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3006102089.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

本文摘自 Julia法规翻译

syhorchid

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