翻译：JULIA 来源：Julia法规翻译
Warning Letter 320-19-18 April 4, 2019
Mr. Tham Chew Thor
Director, Luen Fook Medicine Sdn., Bhd.
203 Henderson Road #05-08/09 (Wing B), HendersonIndustrial Park 159546, Singapore
Dear Mr. Tham Chew Thor:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Luen Fook Medicine Sdn., Bhd., at Taman Perindustrian Sri Plentong, No 6, Jalan Sri Plentong 5, Masai, Johor,81750 Malaysia, from December 10 to 14, 2018.
美国FDA于2018年12月10日至14日检查了你们位于马来西亚的Luen Fook Medicine Sdn.,Bhd.生产场所。
This warning letter summarizes significant 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与211部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products is 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。
In addition, as formulated and labeled, African“SEA-COCONUT” Sore Throat Syrup is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction of such aproduct into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d). This violation is described in more detailbelow.
另外，根据其配方和标识，非洲“海底椰”润喉糖浆是一种未经批准的新药，违反了FDCA第505(a)条款21 U.S.C. 355(a)。将该产品引入州际贸易是FDCA第301(d)条款21 U.S.C. 331(d)所禁止的，该违规情况将在以下具体说明。
We reviewed your January 7, 2019, response indetail. Your response was inadequate because it did not provide sufficientdetail or evidence of corrective actions to bring your operations into compliance with CGMP.
我们已详细审核了你公司2019年1月7日的回复。你们的回复是不充分的，因为其中未提交详细的纠正措施信息或证据使得你们的操作符合CGMP要求。
During our inspection, our investigators observed specific 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：
CGMP Violations CGMP违规
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory 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)). 你公司未在放行前对每批制剂进行适当的实验室检测，确定其符合药品的最终质量标准，包括每种活性成分的鉴别和剂量（21 CFR 211.165(a)）。
You do not test your finished drug product, African “SEA-COCONUT” Sore Throat Syrup, to determine the identity and strength of the active ingredient prior to release.
你们在放行之前未检测你们制剂，非洲“海底椰”润喉糖浆，以确定活性成分的性质和数量。
In response to this letter, provide a summary of results obtained from testing retain samples of all drug products within expiry that have been distributed in the United States. Include results for identity and strength of active ingredients, including any ingredient in your drug product that may have pharmacological activity, and all other appropriatechemical and microbial quality attributes. Also evaluate your formulation to identify all active ingredients intended to furnish pharmacological activity.
在回复此函时，请提交一份所有销售至美国仍在有效期内的制剂留样复测结果的汇总，包括活性成分鉴别和剂量，包括你们制剂中任何可能具有药物活性的成分，以及其它适当的化学和微生物质量属性。亦请评估你们的配方以识别出所有意在提供药学活性的活性成分。
2. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)). 你公司未制订书面生产和工艺控制程序，设计用以确保你们生产的药品具备其理当具备或声称的鉴别、剂量、质量和纯度，并且你公司质量部门并未审核和批准这些程序，包括其中所有变更（21 CFR 211.100(a)）。
Your firm failed to validate the manufacturing process for your African “SEA-COCONUT” Sore Throat Syrup. Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drug products. Process qualification studies determine whether an initial state of control has been established.
你公司未能验证你们非洲“海底椰”润喉糖浆的生产工艺。工艺验证是评估整个生命过程中工艺的设计合理性和受控状态。一个生产工艺的每个重要阶段均必须进行恰当设计，并确保原料输入、中间体和制剂成品的质量。工艺确认研究确定是否建立了初始受控状态。
In your response, you provided a validation master plan. However, it lacked adequate detail and only listed pieces of equipment that you intended to qualify as a part of your validation program.
在你们的回复中，你们提交了一份验证主计划。但是，该计划不够详细，只是列出了你们准备作为你们验证计划一部分进行确认的几台设备。
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. SeeFDA’s guidance for industry, Process Validation: General Principles andPractices, at:https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf
商业销售之前有必要进行成功的工艺确认研究。之后则应对工艺性能和产品质量进行持续警觉监管，以确保你们在产品生命周期中均维持稳定的生产操作。参见FDA行业指南“工艺验证：通则与规范”。
In response to this letter, provide a validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification for each of your drug products. Describe your program for monitoring batch-to-batch variation to ensure an ongoing state of control. Also include your process performance protocol(s) and your written procedures for qualification of equipment and facilities.
在回复本函时请提交一份验证计划，确保在整个产品生命周期中的受控状态。包括对你们每个药品实施适当的工艺性能确认的时间表，在其中描述你们监测批间波动以确保持续受控状态的计划。亦请包括你们的工艺性能方案和书面的设备与设施确认程序。
3. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)). 你公司未能按恰当的时间间隔清洁、维护和根据药品属性在适当时消毒和/或灭菌设备与工器具，从而防止可能改变药品安全性、鉴别、剂量、质量或纯度的故障或污染超出官方或其它既定要求（21 CFR 211.67(a)）。
You failed to perform cleaning validation for the equipment used in the production of your African “SEA-COCONUT” Sore Throat Syrup. In addition, your current cleaning procedures do not include a sanitizer. You clean and rinse only with (b)(4).
你们未对你们非洲“海底椰”润喉糖浆生产所用设备进行清洁验证。另外，你们当前的清洁程序并未包括消毒剂。你们仅使用了XX进行清洁和淋洗。
In your response, provide the following. 在你们的回复中请提交以下
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A comprehensive plan to evaluate cleaning procedures and practices and validation studies for each piece of manufacturing equipment used to manufacture more than one product
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一份评估用于生产多个药品的每台生产设备的清洁程序和做法以及验证研究的全面计划
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Scientific rationale for your cleaning validation strategy to ensure your cleaning procedures are effective
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你们清洁验证策略的科学合理性，以确保你们的清洁程序是有效的
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A summary of updates to your cleaning validation protocol incorporating conditions identified as worst case. This should include, but not be limited to:
-
清洁验证方案更新总结，包括被识别为最差情形的条件。其中应包括但不仅限于：
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Evaluating drugs of the highest toxicity
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评估毒性最高的药品
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Assessing drugs of the lowest solubility in their cleaning solvents
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评估在其清洁溶剂中最难溶的药品
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Evaluating drugs with characteristics that make them difficult to clean
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评估具有难清洁特性的药品
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Swabbing equipment locations that are most difficult to clean
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擦拭设备中最难清洁点
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你公司未建立足够的质量部门，赋予其职责和权力批准或拒收所有组份、药品容器密闭器、中间体、包材、标签和成品（21 CFR 211.22(a)）。
During the inspection, our investigator observed that your quality unit (QU) lacks adequate oversight for the manufacture ofyour drug product. For example, your QU failed to ensure that:
在检查过程中，我们调查人员发现你们质量部门对你们药品生产缺乏足够的监管。例如你们的质量部门未能确保：
-
Appropriate finished product specifications for strength and identity were developed, and that each lot of drug product met all specifications prior to distribution in the U.S. market
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建立适当的成品剂量与鉴别标准，确保每批成品在销售至美国市场之前均符合所有质量标准
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Process validation was reviewed and approved by the QU prior to distributing drug products to the U.S. market
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药品销售至美国市场之前其工艺验证由质量部门审核和批准
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Cleaning validation was performed, reviewed, and approved to ensure your firm can prevent the potential of cross contamination from other drug products manufactured on the same shared equipment
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实施、审核和批准清洁验证以确保你们公司可防止在相同共用设备中生产的其它药品导致潜在交叉污染
Your firm’s quality systems are inadequate. For help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211, see FDA’s guidancedocument, Quality Systems Approach to Pharmaceutical CGMP Regulations,athttps://www.fda.gov/downloads/Drugs/Guidances/UCM070337.pdf
你公司的质量体系是不充分的。为帮助实施质量体系和风险管理方法以符合CGMP法规21CFR第210和211部分的要求，请参见FDA指南文件“药物CGMP法规质量体系方法”。
In response to this letter, provide a comprehensive assessment with corrective and preventive actions to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
在回复此函时，请提交一份全面评估和CAPA，以确保你们质量部门被赋予权力和资源有效履职。评估亦应包括但不仅限于：
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A determination of whether procedures used by your firm are robust and appropriate
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确定你公司所用程序是否稳健和恰当
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Provisions for QU oversight throughout your operations to evaluate practices
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质量部门对你们整体操作的监管情况，对做法进行评估
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A complete and final review of each batch and its related information before the QU disposition decision
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质量部门批处理决策之前对每个批次及其相关信息的完整和最终审核
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Oversight and approval of investigations, and discharging all other QU duties to ensure identity, strength, quality, and purity of all products
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对调查的监管和批准，以及执行所有其它质量部门职责以确保所有药品的鉴别、剂量、质量和纯度
Repeat Violations 重复违规
In a May 2015 inspection, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response.
在2015年5月的检查中，FDA给出了类似的CGMP缺陷。你们在回复中针对那些缺陷拟定了补救措施。
Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
重复缺陷说明高级管理层对药品生产的监管和控制是不充分的。
CGMP Consultant Recommended CGMP顾问建议
Based upon the nature of the violations we identified at your firm, if your firm intends to resume manufacturing drugs forthe U.S. market we strongly recommend engaging a consultant qualified as setforth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.
基于我们在你们公司发现的违规情况，如果你们公司想要恢复为美国市场生产药品，我们强烈建议你们使用一位有21CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。
We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your correctiveactions and preventive actions before you pursue resolution of your firm’scompliance status with FDA.
我们亦建议该位具备资质的顾问对你们整个操作进行全面CGMP合规审计，并在你公司寻求公司符合FDA规定解决方案之前由顾问对你们CAPA的完成情况和有效性进行评估。
Your use of a consultant does not relieve yourfirm’s obligation to comply with CGMP. Your firm’s executive management remainsresponsible for resolving all deficiencies and systemic flaws to ensure ongoingCGMP compliance.
你们使用顾问并不能解除你们公司符合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 未批准新药违规（以下省略464字）
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 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，防止你们设施内其它偏差的发生。
FDA placed your firm on Import Alert 66-40 on March 29, 2019.
FDA已于2019年3月29日将你公司置于进口禁令66-40中。
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications 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 in FDA continuing to refuse admission of articles manufactured at Luen Fook Medicine Sdn., Bhd., at Taman Perindustrian Sri Plentong, No 6, Jalan Sri Plentong 5, Masai, Johor, 81750 Malaysia 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 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 CDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:
Carla Norris
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 3001321832.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
