FDA警告信：韩国Dasan E&T

翻译：JULIA  来源： Julia法规翻译

ViaUPS

Warning Letter :320-17-52

Return Receipt Requested

September 22, 2017

Ms. Jeong Soo Ahn

Chief Executive Officer

Dasan E&T Co., Ltd.

98, Samdo-Ro, Yangchon-Eup, Gimpo-Si, Gyeonggi-Do

Gimpo, Kyonggi-do 421808

Republic of Korea

Dear Ms. Jeong Soo Ahn:

The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Dasan E&T Co., Ltd., Inc. at 98,Samdo-Ro, Yangchon-Eup, Gimpo-Si, Gyeonggi-Do Gimpo, Kyonggi-do, from January 23–26, 2017.

美国 FDA 于 2017 年 1 月 23-26 日检查了你们位于韩国京畿道的生产场所 Dasan E&T Co., Ltd., Inc 。

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 February 16, 2017, response indetail.

我们详细审核了你们公司 2017 年 2 月 16 日的回复。

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.    Yourfirm failed to have, for each batch of drug product, appropriate laboratorydetermination of satisfactory conformance to final specifications for the drugproduct, including the identity and strength of each active ingredient, priorto release (21 CFR 211.165(a)).

你公司未在放行每批药品之前经由适当的化验室检测确定其符合该药品的最终质量标准，包括每种活性成分的鉴别和剂量（ 21 CFR211.165(a) ）。

You released your (b)(4) drug products,including (b)(4) Cream (lot (b)(4) ), without testing each activeingredient for identity and strength. You also released your drug products,including (b)(4) , without testing for conformance with the establishedlevels of (b)(4) .

你们放行了你们的 XX 药品，包括 XX 膏（批号 YY ），但没有检测所有活性成分的鉴别和剂量。你们还放行了你们的药品，包括 XX ，但没有测试其符合既定的 XX 水平。

Your response stated that you “will test the . . .labeling ingredients and (b)(4) content in the final product test.” Youalso provided your firm’s procedure.

你们的回复中声称你们“会在最终产品测试中检测……标识成份和 XX 含量”。你们还提供了你们公司的程序。

Your response is inadequate because the procedure youprovided lacks specific details, such as a complete list of testing attributesand methods used by your firm to test each batch.

你们的回复是不充分的，因为你们所提交的程序缺乏具体的详细信息，例如完整的检测属性清单和用于检测所有批次时使用的方法。

In response to this letter, provide the following:

在回复此函时，请提交以下内容：

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

• 一份用于批放行前分析每种药品每个批次的 QC 检测方法和质量标准，包括化学和微生物质量属性。

• A list of all quality control tests and specifications (both chemical     and microbiological) you currently use as part of your stability program.

• 一份你们当前用作稳定性计划一部分的所有QC检测和质量标准清单（化学和微生物）

• An action plan and timelines for conducting tests of retain samples     to determine the identity and strength of active ingredients and (b)(4) content in all drug products distributed to the U.S. that are within     expiry. If such testing reveals substandard quality drug products, provide     your proposed corrective actions, such as notifying customers and product     recalls.

• 一份执行留样检测的行动计划和时间表，以确定所有销售至美国仍在效期内的药品的活性成分鉴别和剂量以及XX含量。如果此检测发现药品质量不符合标准要求，请提交你们所拟的纠正措施，如通知客户和召回药品。

2.    Yourfirm failed to establish laboratory controls that include scientifically soundand appropriate specifications, standards, sampling plans, and test proceduresdesigned to assure that components, drug product containers, closures,in-process materials, labeling, and drug products conform to appropriatestandards of identity, strength, quality, and purity (21 CFR 211.160(b)).

你公司未能建立包括科学合理且适当规格、标准、取样计划和检测方法的化验室控制，用以确保药品组份、药品容器、密闭器、中间体、标签和药品符合适当的鉴别、剂量、质量和纯度标准（ 21 CFR211.160(b) ）。

You failed to demonstrate that the microbial limits testmethod is suitable to detect microorganisms in the presence of your drugproduct, (b)(4) . Method suitability testing demonstrates that drugproducts will not inhibit the growth and detection of microorganisms.

你们未能证明微生物限度检测方法适合于检出你们 XX 药品中出现的微生物。方法适用性测试是用以证明药品不会抑制微生物生长和检出。

Your response stated that you will conduct suitabilitytesting. Your response is inadequate because you did not provide sufficientdetail or evidence of corrective actions.

你们的回复中声称你们会实施适用性测试。你们的回复是不充分的，因为你们没有提供足够详细的纠正措施和证据。

In response to this letter, provide the following:

在回复此函时，请提供以下信息：

• The protocol and timeline for completing suitability testing for each     of your products. If such testing reveals a deficient method, provide your     CAPA plan.

• 完成你们每个产品方法适用性测试的方案和时间表。如果此测试显示出方法有缺陷，则请提交你们的 CAPA 计划。

• A comprehensive review of the adequacy of laboratory controls,     including procedures, practices, testing, and staff competencies.

• 一份全面的化验室控制充分性审核，包括程序、规范、检测、和员工资质。

3.    Yourfirm failed to establish written procedures for production and process controldesigned to assure that the drug products you manufacture have the identity,strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).

你 们公司未能建立书面生产和工艺控制程序，以确保你们生产的药品具备其既定鉴别、剂量、质量和纯度（ 21 CFR211.100(a) ）。

Poor control of manufacturing processes 生产工艺控制不良

You have not validated the processes used tomanufacture your (b)(4) drug products. You did not perform processperformance qualification studies, and also lack an ongoing program formonitoring process control to ensure stable manufacturing operations andconsistent drug quality. See FDA’s guidance document, Process Validation:General Principles and Practices , for general principles and elements ofprocess validation at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf .

你们没有验证用于生产你们的 XX 药品的工艺。你们没有实施工艺性能确认研究，也没有持续计划监测工艺控制以确保适当的生产操作和一致的药品质量。参见 FDA 指南文件“工艺验证：通则和规范”。

Inadequate control of (b)(4) system XX 系统控制不充分

You also have not performed validation studies on your (b)(4) system to evaluate whether you can effectively maintain,sanitize, monitor, and control the system to ensure it consistently produces (b)(4) that meets the (b)(4) USP monograph specifications and appropriatemicrobial limits. You use (b)(4) from this unvalidated system as acomponent in your drug products (b)(4) .

你们也没有对 XX 系统进行性能确认研究以评估你们是否能够有效维护、消毒、监测和控制系统以确保其持续生产出符合 XXUSP 各论标准以及适当微生物限度的 XX 产品。你们在你们的药品 XX 中使用了此未经验证的系统作为一个部件。

In addition, you lacked sufficient testing of the (b)(4) produced by this system. Pharmaceutical (b)(4) must be suitable for itsintended use, and adequately tested with sufficient frequency to ensure ongoingconformance with appropriate chemical and microbiological attributes.

此外，你们对此系统生产的 XX 缺乏足够的检测。药用 XX 必须适合其既定用途，采用足够的频率进行充分的检测以确保持续符合适当的化学和微生物属性。

Your response stated that you will validate your (b)(4) system. Your response is inadequate because you did not provide sufficientdetail or evidence of corrective actions.

你们的回复中声明你们会验证你们的 XX 系统。你们的回复是不充分的，因为你们没有提交足够详细的纠正措施和证据。

In response to this letter, provide an action planwith detailed timelines.

在回复此函时，请提交行动计划和详细的时间表：

• Timelines for process performance qualification for your (b)(4) drug     products, and a detailed summary of your approach for routinely monitoring     intra-batch and inter-batch variation.

• 你的 XX 药品的工艺性能确认时间表，以及你们日常监测批内和批间差异的方法的详细总结。

• Detailed procedures for validating, maintaining, controlling, and     monitoring your (b)(4) system.

• 详细的验证、维护、控制和监测你的 XX 系统的程序。

• A thorough assessment to determine insufficiencies in microbiological     analytical methods established for testing (b)(4) produced by your     system. Include a full remediation plan with appropriate analytical     methods to be used for testing.

• 一份彻底的评估，确定用以检测你们系统所生产的 XX 检测用微生物分析方法的不足。在其中包括一份全面补救计划，以及将用于检测的适当的分析方法。

4.    Yourfirm failed to conduct adequate testing of each lot of component (21 CFR211.84(d)(1)) for conformance with appropriate specifications, including atleast one identity test.

你们公司未能对每批组分进行足够的检测（ 21 CFR 211.84(d)(1) ），证明其符合适当的质量标准，包括至少一个鉴定测试。

Your firm failed to analyze glycerin raw material fromyour supplier prior to the quality unit releasing the glycerin for use in drugproduct manufacturing. Glycerin is an ingredient in multiple drug products youmanufacture. Your firm did not test each lot to determine if diethylene glycol(DEG) or ethylene glycol (EG) was present. DEG contamination in pharmaceuticalshas resulted in various lethal poisoning incidents in humans worldwide.

你们公司在质量部分放行甘油原料用于药品生产之前未对甘油进行分析。甘油是你们生产的多个药品中使用的一个成分。你们公司未检测每个批次以确定是否含有二甘醇（ DEG ）或乙二醇（ EG ）。 DEG 对药品的污染曾导致全球多起患者致命毒害事件。

Your response stated that you will conduct DEG and EGlimit testing according to the USP standards for glycerin.

你们的回复中声称你们会依据 USP 的甘油标准执行 DEG 和 EG 限度检测。

Your response was insufficient. You did not addresswhether your firm tested all lots of drug product that you distributed to theUnited States for DEG and EG.

你们的回复是不充分的。你们没有说明你们公司是否检查了你们销售往美国的所有药品的所有批次中的 DEG 和 EG 。

In response to this letter, provide an updateregarding implementation of DEG and EG testing for all lots of glycerin. Alsoprovide a detailed risk assessment for drug products that contain glycerin andare within expiry in the U.S. market. In addition, test retain samples of all lotsfor DEG and EG.

在回复此函时，请提交更新后的对所有批次甘油均执行 DEG 和 EG 检测的文件。还请提交一份详细的风险评估，对销往美国市场仍在效期内且含有甘油的药品进行评估。此外，应对所有批次的留样检测其中 DEG 和 EG 。

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

参见 FDA 指南文件“甘油中 DG 检测”以帮助你们在生产含有甘油药品时符合 CGMP 要求。