FDA警告信：西尔欧（中国）医疗设备有限公司 20181130

翻江鼠

Warning Letter 320-19-05       November 30, 2018

Mr. Dianlong Cao

General Manager, Cao Medical Equipment Co., Ltd.

Number 19 Baihe Road, Langfang Industrial Zone

Langfang, Hebei, 065001, CHINA

Dear Mr. Cao:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cao Medical Equipment Co., Ltd. at Number 19 Baihe Road, Langfang Industrial Zone, Langfang, Hebei, from July 16 to 20, 2018.

美国FDA于2018年7月16-20日检查了你们位于河北省廊坊经济技术开发区百合道19号的西尔欧（中国）医疗设备有限公司生产场所。

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 do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 21U.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 August 3, 2018, response in detail and acknowledge subsequent correspondence.

我们详细审核了你们2018年8月3日的回复，并此告知已收悉你公司后续回复。

During our inspection, our investigator 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：

1.     Your firm failed to perform, 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, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)). 你公司未在放行之前对每批药品进行适当的实验室检测，确定其是否符合药品最终质量标准，包括每种活性成分的鉴别和剂量，未在必要时对每批需要不含致病菌的药品进行适当的实验室检测（21 CFR 211.165(a) and (b)）。

You manufacture (b)(4) drugs intended for use during (b)(4) procedures and applied to (b)(4). Drugs applied to (b)(4) must be free of objectionable microorganisms. However, you failed to test your finished drug products for total aerobic microbial count and objectionable microorganisms prior to release and distribution. In addition, you also failed to test each batch of drug products for identity and strength of active ingredients prior to release and distribution. Without this testing, you do not have scientific evidence that all drug product batches you manufactured meet their established specifications prior to release.

你们生产XX药品，用于XX程序并应用于XX。应用于XX的药品必须不含致病菌。但是你们的未在放行销售之前检测你们的最终药品中的TAMC和致病菌。另外，你们亦未在放行和销售之前检测每批药品中活性成分的鉴别和剂量。没有这些检测，你们就没有科学证据证明你们生产的所有药品批次在放行之前均符合其既定质量标准。

2.     Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR211.84(d)(1) and (2)). 你公司未检查每种成分样品的鉴别，确定其纯度、剂量和质量是否符合适当的书面质量标准。你公司亦未以适当时间间隔验证和建立你们成分供应商检测分析的可靠性（21 CFR 211.84(d)(1) and (2)）。

Your firm failed to test incoming active pharmaceutical ingredients and other components used to manufacture your drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied solely on certificates of analysis (COA) without verification of your suppliers COA, or in other instances, you used components to manufacture drugs without having received a COA.

你公司未检测进厂活性药物成份和其它用于生产你们药品的成分，以确定其鉴别、纯度、剂量和其它适当的质量属性。相反，你们公司仅依赖于你们供应商的COA而并未进行核查，有时候你们用来生产药品的成分甚至并未收到COA。

Your firm also uses glycerin as an ingredient in (b)(4) drug products. Your firm failed to analyze lots of glycerin raw material from your supplier for the presence of diethylene glycol (DEG) and ethyleneglycol (EG) prior to releasing it for use in drug product manufacturing. DEG contamination in glycerin has resulted in various lethal poisoning incidents in humans worldwide.

你公司亦使用了甘油作为XX药品的一种成分。你公司未分析来自你们供应商的数批甘油原料是否含有二甘醇（DEG）和乙二醇（EG）即将其放行用于药品生产。甘油中的DEG污染已导致多起人体中毒死亡事件。

See FDA’s guidance document Testing of Glycerinfor Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin, athttps://www.fda.gov/downloads/Drugs/Guidances/ucm070347.pdf.

参见FDA指南文件“甘油中二甘醇检测”帮助你们符合在药品中使用甘油的CGMP要求。

3.     Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63). 你公司在药品生产、加工、包装或存贮中所用设备未经适当设计、具备足够尺寸并适当安装使得其便于其既定用途操作及其清洁维护（21 CFR 211.63）。

You failed to adequately design, qualify, and control your (b)(4) system used to manufacture drug products. You do not test your source (b)(4) or your production (b)(4) before use in manufacturing. A (b)(4)at your facility is (b)(4) and open to the outdoor environment where it is exposed to vermin, animal waste, and various contaminants.

你们未对药品生产所用XX系统进行充分的设计、确认和控制。你们在将其用于生产之前并未检测你们的源X或你们生产XX。在你们工厂的一个XX是XX并且开放于室外环境，暴露于虫鼠动物废料和不同污染物中。

You lack adequate installation, operational, and performance qualifications to ensure your (b)(4) system is capable of sustainably producing (b)(4) of adequate quality for its intended use indrug products. In addition, you do not protect your (b)(4) from the ingress and proliferation of objectionable microorganisms.

你们缺乏足够的安装、运行和性能确认，无法确保你们的XX系统足以持续生产出XX具备足够质量满足其在药品中的既定用途。另外，你们并未保护你们的XX不受致病菌的侵入和滋长。

4.     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 (21 CFR 211.100(a)). 你公司未能建立书面的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应具备的鉴别、剂量、质量和纯度（21 CFR 211.100(a)）。

You have not validated the processes used to manufacture your drug products, you did not define or identify critical process parameters, and you lack an ongoing program for monitoring process controls to ensure stable manufacturing operations and consistent drug quality.

你们未验证你们用于生产你们药品的工艺。你们未定义或识别关键工艺参数，你们缺乏持续监测工艺控制的计划，无法确保稳定的生产操作和持续的药品质量。

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

参见FDA指南文件“工艺验证：通则与规范”。

Inadequate Response and Recall Initiated 回复不充分和启动召回

Your August 3, 2018, response to FDA’s inspectional observations was inadequate. You failed to evaluate the impact of your lack of controls on the quality and safety of drugs distributed to the United States within expiry. Furthermore, FDA review of import records demonstrated you continued to ship drugs to the United States despite stating in your response that you would immediately stop manufacturing and distributing drugs to the United States.

你们20180803对FDA检查缺陷的回复是不充分的。你们未能评估你们缺乏对销售至美国仍在效期内药品的质量和安全的控制的影响性。另外，FDA也审核了进口记录，记录表明你们在你们回复中声称会立即停止生产和向美国销售药品之后仍在继续发送药品至美国。

We acknowledge that you agreed to recall all drug products in the United States market, within expiry, on November 9, 2018, after FDA discussed with you the CGMP violations at your facility.

我们知悉你们于20181109在FDA与你们讨论了你们工厂的CGMP违规情况之后同意召回在美国市场的所有效期内药品。

CGMP Consultant Recommended CGMP顾问建议

If your firm intends to resume manufacturing drugs for the United States market, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform acomprehensive audit of your entire operation for CGMP compliance and evaluatethe completion and effectiveness of any corrective actions and preventive actions you have implemented before you pursue resolution of your firm’s compliance status with FDA.

如果你公司有意继续为美国市场生产药品，我们强烈建议你们聘用一位有21 CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议该有资质的顾问对你们整体操作情况进行一次全面CGMP合规审计，在你们寻求解决方案达到FDA合规要求之前评估你们已实施的CAPA的完成情况和有效性。

If you intend to resume manufacturing and shipping drugs to the U.S., you should provide comprehensive corrective actions which include systemic remediation of the finished product, raw material, laboratory testing, process validation, and (b)(4) violations listed above as well as global assessment and remediation of all (b)(4) systems of your manufacturing operations.

如果你们有意继续生产和向美国销售药品，你们应提交全面的纠正措施，其中包括对成品、原料、实验室检测、工艺验证和上列XX违规的系统性补救措施，以及全球评估并弥补你们生产运营的所有XX体系。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring 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。

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.

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 on November 26, 2018.

FDA已于2018年11月8日将你公司放入进口禁令清单66-40项下。

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 resultin FDA continuing to refuse admission of articles manufactured at Number 19 Baihe Road, Langfang Industrial Zone, Langfang, Hebei, into the United Statesunder 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 refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning 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 our inspection to correct your violations and to prevent their recurrence. 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 CDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:

LT Matthew Schnupp, PharmD.

Regulatory 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 No.3004475754.

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