FDA警告信：杭州中波实业有限公司 20181127

翻江鼠

Warning Letter 320-19-02        November 27, 2018

Mr. Guokang Li
President, Hangzhou Zhongbo Industrial Co., Ltd.
Yuhang District, Changle Industrial Zone, Hangzhou, Zhejiang, 311123 CHINA

Dear Mr. Li:

The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Hangzhou Zhongbo Industrial Co.,Ltd. at Yuhang District, Changle Industrial Zone, Hangzhou, Zhejiang, fromApril 23 to 27, 2018.

美国FDA于2018年4月23-27日检查了你们位于浙江杭州市余杭区径山镇长乐村的杭州中波实业有限公司生产场所。

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 product is 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 18, 2018, response in detail.

我们已详细审核了你公司2018年5月18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. Your firm failed to have,for each 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)). 你公司未在放行前对每批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，包括每种活性成分的鉴定和含量(21 CFR 211.165(a))。

You released over the counter (OTC) drug productsto the U.S. market without conducting finished product quality testing. Youreceived a testing report from your contract laboratory, (b)(4), datedMarch 23, 2018, for your (b)(4). This testing was carried out on a smallbatch of your drug product. You used the results from this report to releaseBatch No. (b)(4) of your (b)(4). Your records show that you beganmanufacturing Batch No. (b)(4) on April 2, 2018, more than a week afterthe date of your contract laboratory’s report. Further, this report containedresults for microbial enumeration but not for assay testing.

你们未对OTC药品执行成品质量检测即将其放行至美国市场。你们从你们合同实验室XX收到了签署日期为2018年3月23日的XX药品检测报告，检测的是你们药品的一个小批次。你们使用该报告的结果放行了批号XX的药品。你们的记录显示你们开始生产批号XX是2018年4月2日，是你们合同实验室报告签发日期超过一周之后。另外，该报告中有微生物计数结果，但没有含量检测。

In your response, you stated that you will reviseyour procedure and ship batches after you complete production and after “a[n]overall inspection.” However, you did not indicate whether you will ship your productonly after completing all required finished product tests using arepresentative sample.

在你们的回复中，你们声称你们会修订你们的程序，在完成生产和“全面检查”之后再发货。但是你们并未说明你们是否会使用代表性样品完成成品检测之后再发货。

In response to this letter, provide your revisedfinished product release procedure. Your procedure should include thecompletion of manufacturing and product quality release testing beforeshipping. It should specify appropriate release tests of finished drug productsamples that are taken at statistically appropriate intervals.

在回复此函时，请提交你们修订后的成品放行程序。你们的程序应包括完成生产和产品质量放行检测，然后才可发货。其中应指明使用统计学合理间隔采样进行恰当的放行检测。

In addition, provide testing by an independentCGMP-qualified laboratory of each finished product distributed to the UnitedStates within expiry, to demonstrate if they met established quality criteriabefore release. For any product that failed to meet established qualitycriteria before release, provide your detailed corrective action plan includingnotifying customers or recalling drug products.

此外，请提交由一个独立的具备CGMP资质的化验室对每个发至美国且仍在效期内的药品批次所执行的检测，以证明其在放行之前是否符合既定的质量标准。对所有放行前不符合既定质量标准的药品，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 toestablish and follow an adequate written testing program designed to assess thestability characteristics of drug products and to use results of such stabilitytesting to determine appropriate storage conditions and expiration dates (21CFR 211.166(a)). 你公司未能制订并遵守足够的书面检测程序，用于评估药品的稳定性特性，并使用此稳定性检测的结果来确定适当的存贮条件和有效期(21 CFR 211.166(a))。

You do not have long-term stability testing data tosupport your (b)(4) expiration dates for your finished product. Youbased the expiration dates on only three months of accelerated stabilitytesting. The accelerated stability testing does not have written justificationfor the number of lots tested, the number of units sampled and tested, thestorage conditions, the testing interval, or the critical quality criteria,including assay.

你们没有长期稳定性检测数据用于支持你们成品的XX有效期。你们的有效期依据的仅仅是3个月加速稳定性试验的数据。加速稳定性试验没有书面论证所测批数、取样和检测单位数量、存贮条件、检测间隔以及关键质量标准，包括含量。

In your response, you said that you plan to testretention samples from product manufactured two years ago. You did not indicatethat your retention sample testing will include testing of all criticalattributes, including assay. You did not explain where you will obtain thesesamples for testing, as, during the inspection, you said that you retainsamples for (b)(4). Further, your response did not provide a planfor establishing and executing written stability protocols, including long-termstability testing. You stated that your customer and their third-party testinglaboratory determine the stability program for your products. However, youmaintain responsibility for the quality of your drugs, including your stabilitytesting program, regardless of agreements with your customer or any third-partytesting laboratory.

在你们的回复中，你们说你们计划对2年前生产的药品留样进行检测。你们并未说明你们的留样检测是否会包括对所有关键属性的检测，包括含量。你们并未解释你们要从何处获得这些样品进行检测，因为在检查过程中你们说你们留样是为了XX。另外，你们的回复并未提交一份制订和执行书面稳定性方案的计划，包括长期稳定性检测。你们声称你们的客户和他们的第三方检测化验室检测了你们产品的稳定性计划。但是无论你们与你们客户或任何第三方检测实验室是否有协议，你们仍对你们的药品质量负有义务，包括你们的稳定性检测计划。

In response to this letter, provide a comprehensiveassessment and CAPA to ensure the adequacy of your stability program. Your CAPAshould include, but should not be limited to, a remediated standard operatingprocedure describing your stability program; stability-indicating methods;stability studies to support each drug product in its container-closure systembefore distribution is permitted; an ongoing program in which representativebatches of each product are added each year to the program to determine if theshelf-life claim remains valid; and specific attributes to be tested at eachstation.

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。

3. Your firm failed to testsamples of each component for identity and conformity with all appropriatewritten specifications for purity, strength, and quality (21 CFR 211.84(d)(1)and (2)). 你公司未能对药品的每种成分样品进行鉴别测试，并确保其符合所有适当的书面纯度、含量和质量标准 (21 CFR 211.84(d)(1) and (2))。

Your firm failed to test incoming raw materials fortheir identity, purity, strength, and other appropriate quality attributes.There is no assurance that the (b)(4) used to manufacture your finisheddrug product conforms to appropriate quality attributes, includingmicrobiological specifications. During the inspection, you indicated that youdo not test your (b)(4) inactive ingredients for identity or otherquality attributes, and that you accept test results based on your suppliers’certificate of analysis (CoA).

你公司未检测进厂物料的鉴别、纯度、含量和其它恰当的质量属性，不能保证用于生产你们制剂的XX符合适当的质量属性，包括微生物质量标准。在检查期间，你们说你们并不检测你们的XX非活性成分的鉴别和其它质量属性，你们会接受你们供应商的COA中的检测结果。

In your response, you said that you will use athird-party laboratory to conduct microbial tests (b)(4) for the(b)(4)used to manufacture your finished drug product, and that you will work with athird party on testing inactive ingredients. However, you did not: (1) providescientific rationale to support the frequency of your(b)(4) testing;(2) specify the (b)(4) attributes you will test; (3) state when thetesting will start; or (4) state when you will implement inactive ingredienttesting.

在你们的回复中，你们声称你们会使用第三方实验室来执行你们制剂生产所用XX原料的XX微生物检测，你们会找一个第三方检测非活性成分。但是，你们并未（1）提交科学理由支持你们检测XX的频次，以及（2）说明你们会检测的XX属性，（3）声明何时开始进行检测，亦未（4）说明你们何时开始对非活性成分进行检测。

In response to this letter, provide: 在回复此函时，请提交

• A detailed plan, including all relevant procedures and implementation dates, to ensure the quality of the water used in your manufacturing operations. This plan should include scientific justification for your chosen testing frequency.
• 一份详细的计划，包括所有确保你们生产操作用水质量的相关程序和实施日期。此计划应包括对你们所选检测频次的科学论证。
• Describe in detail how you plan to test each incoming component lot for conformity with all appropriate written specifications for purity, strength, and quality. If you intend to accept     your suppliers’ CoA in lieu of testing each component lot for purity, strength, and quality, describe how you plan to establish the reliability of your suppliers’ test results for these attributes at regular intervals. Regardless of your plans for CoA verification, include a commitment to test every incoming component lot (both active and inactive ingredients)     for identity. Also provide your revised procedure remediating these deficiencies and your timeline for implementation.
• 详细说明你们计划如何检测每种进厂组份的批次，保证其符合所有适当的书面纯度、剂量和质量标准。如果你们想要接受你们供应商的COA，替代你们自己对每个组份批次的纯度、剂量和质量检测，则请说明你们计划如何定期建立你们供应商的这些属性的检验结果的可靠性。无论你们是否计划对COA进行验证，请包括一份执行每批进厂组份鉴定测试的承诺（活性和非活性成分）。亦请提交你们弥补这些缺陷的修订后程序以及你们的实施时间表。
  
  

Responsibilities as a Contractor作为合同生产方的职责

Drugs must be manufactured in conformance withCGMP. FDA is aware that many drug manufacturers use independent contractors,such as production facilities, testing laboratories, packagers, and labelers.FDA regards contractors as extensions of the manufacturer.

药品生产必须符合CGMP。FDA了解许多药品生产商会使用独立的委托方，如生产场所、检测实验室、包装商和贴标商。FDA将合同生产商视为生产商的延伸。

You are responsible for the quality of drugs youproduce as a contract facility, regardless of agreements in place with productowners. You are required to ensure that drugs are made in accordance withsection 501(a)(2)(B) of the FD&C Act for safety, identity, strength,quality, and purity. See FDA’s guidance document Contract ManufacturingArrangements for Drugs: Quality Agreements athttps://www.fda.gov/downloads/drugs/guidances/ucm353925.pdf.

无论你们与药品所有方是否有协议，作为受托场所，你们对你们所生产的药品质量负有义务。你们要确保药品生产符合FDCA第501(a)(2)(B)条款中对安全、鉴定、剂量、安全和纯度的要求。参见FDA指南文件。

Quality Unit Authority 质量部门权力

Your inspectional history indicates that yourquality unit is not able to fully exercise its authority and/orresponsibilities. Your firm must provide the quality unit with the appropriateauthority, sufficient resources, and staff to carry out its responsibilitiesand consistently ensure drug quality.

你们的检查历史显示你们质量部门无力全面履行其权力和/或职责。你们公司必须为质量部门提供适当的权力、足够的资源和员工使得其可履行其义务，持续确保药品质量。

Repeat observations atfacility 重复缺陷

In a previous inspection, dated July 18 to 21,2016, FDA cited similar CGMP observations. These repeated failures demonstratethat your facility’s oversight and control over the manufacture of drugs isinadequate.

在之前2016年7月18-21日的检查中，FDA引用了类似的CGMP缺陷。这些重复失败证明你们工厂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 weidentified at your firm, we strongly recommend engaging a consultant qualifiedas set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.We also recommend that the qualified third party perform a comprehensive auditof your entire operation for CGMP compliance, and that they evaluate thesufficiency, completion, and effectiveness of any corrective actions andpreventive actions you have implemented, before you pursue resolution of yourfirm’s compliance 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 onSeptember 28, 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 HangzhouZhongbo Industrial Co., Ltd. at Yuhang District, Changle Industrial Zone,Hangzhou, Zhejiang, 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 ourinspection to correct your violations and to prevent their recurrence.

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。

If you cannot complete corrective actions within 15working days, state your reasons for delay and your schedule for completion.

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:
Jason F. Chancey
Consumer Safety 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.3008229416.

Sincerely,

/S/

Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

Cc: (b)(4)

本文摘自 Julia法规翻译

meiya

这家也是做湿巾产品的。

syhorchid

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？