翻译： JULIA 来源： Julia法规翻译
ViaUPS
Warning Letter 320-17-47
Return Receipt Requested
August 11, 2017
Mr. Tao Yang, General Manager
Bicooya Cosmetics Limited
No. 17, Yan Hu Road
Shangxi Town
Yiwu Zhejiang 322006
China
Dear Mr. Yang:
The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Bicooya Cosmetics Limited at No. 17, Yan HuRoad, Shangxi Town, Zhejiang, from May 22–25, 2017.
美国FDA于2017年5月22-25日检查了你们位于中国浙江义乌市上溪镇岩湖路17号的生产场所义乌市碧蔻雅化妆品有限公司。
This warning letter summarizes significant violationsof current good manufacturing practice (CGMP) regulations for finishedpharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了药品生产严重违反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 theFederal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你们的药品生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的药品根据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 31, 2017, response in detail andacknowledge receipt of your subsequent correspondence. Your cursory responsedid not provide adequate corrective actions for any of the observations madeduring the inspection.
我们详细审核了你们公司2017年5月31日及之后的回复。你们草率的回复未对检查期间所发现缺陷给出充分的纠正措施。
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 failed to keep thebuildings used in the manufacture, processing, packing, or holding of a drugproduct free of infestation by rodents, birds, insects, and other vermin (21CFR 211.56(a)).
你们的公司未能保持药品生产、加工、包装和存贮所用建筑不受啮齿动物、害鸟、昆虫和其它有害动物的侵入(21 CFR 211.56(a))。
Our investigator observed rodent feces throughout yourfacility:
我们调查人员在你们整个场所都有发现啮齿动物的粪便：
in direct proximity to the filling machine where you manufacture OTC drug products
在生产OTC药品紧邻灌装机的地方
in direct proximity to the (b)(4) system, which produces (b)(4) incorporated in your drug products
在生产要加入你们药品中的XX紧邻XX系统的地方
throughout the warehouse, around both raw materials and finished drug products
整个仓库，原料和药品成品周围
Your over-the-counter (OTC) drug products include (b)(4)ointments and (b)(4).
你们的OTC药品包括XX膏和XX。
2. Your firm failed to clean,maintain, and, as appropriate for the nature of the drug, sanitize and/orsterilize equipment and utensils at appropriate intervals to preventmalfunctions or contamination that would alter the safety, identity, strength,quality, or purity of the drug product beyond the official or other establishedrequirements (21 CFR 211.67(a)).
你公司未能以适当的时间间隔清洁、维护，以及当药品属性适当时，消毒和/或灭菌设备，以防止故障或污染改变药品的安全性、均一性、含量、质量或纯度使其超出官方或其它既定要求(21 CFR 211.67(a))。
For example, our investigator observed residuebuild-up in the (b)(4) tanks you use to manufacture OTC drug products,and damaged transfer hoses held together with plastic wrap. When an employeeattempted to open a (b)(4) tank lid during the inspection, a hingebroke.
例如，我们的调查人员在你们用于生产OTC药品的XX罐内发现累积残留，损毁的传输软管用塑料扎带绑在一起。当检查期间一位员工试图打开XX罐口时，一个铰链断掉了。
3. Your firm failed to have, foreach batch of drug product, appropriate laboratory determination ofsatisfactory conformance to final specifications for the drug product,including the identity and strength of each active ingredient, prior to release(21 CFR 211.165(a)).
你公司未能在放行前对每一批药品均进行化验室检测，确定其符合最终的药品质量标准，包括每种活性成分的鉴别和含量(21 CFR 211.165(a))。
You did not test all lots of your drug products foractive ingredient content prior to release. You also failed to conductmicrobial testing (i.e., total count, objectionable microorganisms) for eachbatch of drug product you release.Your firm stated that your customer onlyrequires microbiological tests to be performed (b)(4). Because you lackmicrobiological testing, there is insufficient assurance that the products youdistribute are safe and sanitary.
你们未在放行药品之前测试你们所有批次药品中活性成分含量。你们也未在放行前对每批药品进行微生物检测（例如，总计数，致病菌）。你公司声称你们的客户只需要对XX进行微生物检测。由于你们缺少微生物检测，因此不能充分确保你们销售的药品的安全性和卫生。
4. Your firm failed to prepare batchproduction and control records with complete information relating to theproduction and control of each batch of drug product produced (21 CFR 211.188).
你公司未能制订批生产和检验记录，在其中记录与每批药品生产相关的生产和检测的完整信息(21 CFR 211.188)。
Our investigator requested batch records for OTC drugproduct lots distributed to the United States, including (b)(4) Ointmentand (b)(4). You were unable to provide batch records.
我们的调查人员要求查看销售至美国的OTC药品，包括XX药膏和XX的批记录时，你们未能提供批记录。
In addition, analytical testing records were missingdata, dates, and signatures. Our investigator observed your staff alteringinformation in analytical test reports during the inspection. For example, yousignificantly altered the analytical testing report for (b)(4) Ointmentlot (b)(4), although this lot had already been distributed to the U.S.market.
此外，分析检测记录中缺失数据、日期和签名。我们的调查人员发现你们的员工在检查期间修改分析检测报告上的信息。例如，你们对XX批XX药膏的分析测试报告进行了重大修改，而该批已经销售到了美国市场。
CGMP consultant recommended CGMP顾问建议
Based upon the nature of the violations we identifiedat your firm, we strongly recommend engaging consultants qualified as set forthin 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use ofconsultants does not relieve your firm’s obligation to comply with CGMP. Yourfirm’s executive management remains responsible for fully resolving alldeficiencies and ensuring ongoing CGMP compliance.
根据我们在你们工厂发现的违规情况，我们强烈建议你们聘请一位有能力评估你们操作的顾问，协助你们符合CGMP要求。你们聘用顾问并不能免除你们公司符合CGMP的义务。你们公司的执行管理人员仍保有全面解决所有缺陷，确保持续符合CGMP要求的职责。
Data Integrity Remediation 数据完整性弥补措施
Yourquality system does not adequately ensure the accuracy and integrity of data tosupport the safety, effectiveness, and quality of the drugs you manufacture. Weacknowledge that you are using a consultant to audit your operation and assistin meeting FDA requirements. In response to this letter, provide the following.
你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。我们知道你们聘请了顾问来审计你们的操作，协助符合FDA要求。在回复此函时，提供以下资料：
A. A comprehensive investigation into the extent of the inaccuracies in datarecords and reporting. Your investigation should include: 一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括：
A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
详细的调查方案和方法学；对评估所覆盖的所有化验室、生产操作和系统的总结，以及对你们意在排除的操作中所有部分的论证。
Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
与现有的和已离职的员工进行面谈，找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
An assessment of the extent of data integrity deficiencies at your facility. 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.
你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。描述你们工厂操作中发现数据完整性问题的所有部分。
A comprehensive retrospective evaluation of the nature of the data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
B. A current risk assessment of the potential effects of the observed failures onthe quality of your drugs. Your assessment should include analysesof the risksto patients caused by the release of drugs affected by a lapse of dataintegrity, and risks posed by ongoing operations.
对你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。
C. A management strategy for your firm that includes the details of your globalcorrective action and preventive action plan. Your strategy should include:
你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：
A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.
详细的CA计划，描述你们如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。
A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
一份完整的描述你们数据完整性问题的根本原因的描述，包括认定当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
临时描述，描述你们已采取的行动，或即将采取用以保护患者确保你们药品质量的努力，例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。
Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。
A status report for any of the above activities already underway or completed.
对上述活动已开展或已经完成的状态报告。
Conclusion 结论
Violations cited in this letter are not intendedas an all-inclusive list. You are responsible for investigating theseviolations, for determining the causes, for preventing their recurrence, andfor preventing other violations in all your facilities.
在此函中所引用的偏差并不是全部。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 on June 29,2017.
FDA已于2017年6月29日将你们公司放在进口禁令66-40清单中。
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 result inFDA continuing to refuse admission of articles manufactured at BicooyaCosmetics Limited at No. 17, Yan Hu Road, Shangxi Town, Zhejiang, into theUnited States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3). Under the same authority, articles may be subject to refusalof admission, in that the methods and controls used in their manufacture do notappear to conform to CGMP within the meaning of section 501(a)(2)(B) of theFD&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 officein writing within 15 working days. Specify what you have done since ourinspection to correct your violations and to prevent their recurrence. If youcannot complete corrective actions within 15 working days, state your reasonsfor 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 [email protected]or mail your reply to:
请将你们的电子回复发送至上述邮箱或者以下邮箱。
Chelsea Sealey
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 3010671652.
Sincerely,
/S/
Thomas J. Cosgrove
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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