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FDA警告信:吉林舒兰合成药业股份有限公司

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【导读】美国FDA于2017年11月7-10日检查了你们位于中国吉林省舒兰市人民大路2066号的吉林舒兰合成制药有限公司生产场所。本警告信总结了原料药生产严重违反CGMP的行为。......
TAG标签: FDA 警告信 吉林舒兰合成药业 FDA警告信

翻译: JULIA 来源:Julia法规翻译

 

Warning Letter 320-18-51

May 14, 2018

Mr. Daqian Li, Genera lManager

Jilin Shulan Synthetic Pharmaceutical Co., Ltd.

No. 2066 People’s Main Road, Shulan City, Jilin Province, 132600 China

 

Dear Mr. Li:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Jilin Shulan Synthetic Pharmaceutical Co., Ltd., at No. 2066 People’s Main Road,Shulan City, Jilin Province, from November 7 to 10, 2017.

美国FDA2017117-10日检查了你们位于中国吉林省舒兰市人民大路2066号的吉林舒兰合成制药有限公司生产场所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

 本警告信总结了原料药生产严重违反CGMP的行为。

Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your API are adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21U.S.C. 351(a)(2)(B).

由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求,你们的原料药根据FDCA501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your November 27, 2017, response in detail.

我们已详细审核了你公司20171127日的回复。

During our inspection, our investigators observed specific deviations including, but notlimited 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. Failure to document known deviations and out-of-specification results and conduct a thorough investigation. 未能记录已知偏差和OOS结果并实施彻底调查。

Undocumented manufacturing deviation

未记录的生产偏差

You failed to ensure that manufacturing process deviations are documented, and any critical process deviations are investigated, and resolved. Specifically, the (b)(4). Our investigator found a note in your batch record stating that the (b)(4)(which violated the process) and the operator was to be fined 50 yuan. There was noformal deviation report documented. You failed to investigate the effects ofthis deviation on product quality, nor did you evaluate the criticality of this process parameter.

你们未能确保记录生产工艺偏差,并调查和解决所有关键工艺偏差。具体来说,我们调查人员在你们的批记录中发现一张便条写着XX(违反工艺)和操作人员罚款50元。没有正式的偏差报告记录。你们未对此偏差对产品质量的影响进行调查,也没有评估此工艺参数的关键程度。

In your response, yousaid the operator violated your procedure for (b)(4). Your response was inadequate because you did not explain why the operator did not follow the procedure. Also, you did not explain how you will ensure all deviations are documented and critical deviations are investigated as required.

在你们的回复中,你们说操作人员违反了你们的XX程序。你们的回复是不充分的,因为你们未解释为何操作人员并未遵守程序。还有你们亦未解释你们要如何确保会记录所有偏差,并按要求对关键偏差进行调查。

Dual sets of laboratory records and uninvestigated OOS results

2套化验室记录和未经调查的OOS结果

Our investigator also found that you failed to document, investigate, and resolve out-of-specification (OOS) results in your laboratory. The investigator identified two sets of laboratory testing records for four (b)(4) batches and five (b)(4) batches: one set of records included OOS results; the second set included results within specifications. You could not provide evidence to support the passing results. You also failed to conduct investigations for the OOS results. Your quality department acknowledged this practice during the inspection.

我们的调查员发现你们未记录、调查和解决你们化验室中的OOS结果。调查员发现4批次XX5批次XX均有2套化验室检验记录:一套记录中有OOS结果,第二套记录里的结果则符合标准。你们未能提供证据支持合格结果。你们亦未对OOS结果进行调查。你们的质量部门知晓了检查中发现的这些事情。

In your response, you stated that the failure to investigate these deviations was due to the staff’slack of CGMP knowledge. You provided retest results and your updated “Out-Of-Trend (OOT) Manage Procedure.” Your response was inadequate because you addressed OOT results instead of OOS results; you did not provide your investigations into the original OOT/OOS results. You also failed to identify the root causes of the OOS results.

在你们的回复中,你们声称未调查这些偏差是因为员工缺乏CGMP知识。你们提供了复测结果,以及你们更新后的“OOT管理程序”。你们的回复是不充分的,因为你们处理了OOT结果而不是OOS结果。你们亦未提供你们的对原始OOT/OOS结果的调查。你们亦未找到OOS结果的根本原因。

For more information about handling failing, OOS, OOT, or other unexpected results and documentationof your investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, at https://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

关于处理失败、OOSOOT或其它非预期结果以及记录你们调查情况的更多信息,参见FDA指南文件。

2. Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to have adequate controls to prevent omission of data. 未对计算机化系统进行充分控制以防止未经授权进入或修改数据,亦未进行充分控制以防止数据遗漏。

Our investigator found that audit trails in your standalone instruments ((b)(4) high-performance liquid chromatography systems, (b)(4) gas chromatography systems, and (b)(4) infrared radiation system) were not enabled. You also did not have other mechanisms for recording and monitoring any changes to data generated on these instruments. Your firm backed up electronic data from these instruments to a portable drive (b)(4). However, the drive was not password-protected, and itwas stored in an unlocked drawer in an unlocked office.

我们调查员发现你们单机仪器(XX HPLC系统里的审计追踪,XX气相系统,以及XX红外系统)未激活。你们亦无其它机制记录和监测对所这些仪器所生成的数据所做的变更。你公司将这些仪器中的电子数据备份至移动硬盘XX。但是,该硬盘并未有密码保护,并且放置在一个未上锁的办公室里一个未上锁的抽屉中。

Our investigator also found that operators had full system permissions, including the ability tomodify and delete files. For example, our investigator found files related to system suitability tests for (b)(4) in the recycle bin folder on the computer connected to high performance liquid chromatography system.

我们的调查员还发现操作人员具有全面的系统权限,包括可以修改和删除文件。例如,我们调查员在连接HPLC系统的计算机回收站里发现了与系统适用性有关的文件。

In your response, you committed to upgrading your chromatography computer systems to a software version with audit trails. Your response was inadequate because you did not provide appropriate procedures or details on your updated computer systems to demonstrate how you will restrict access or changes to your data.

在你们的回复中,你们承诺要升级你们的色谱计算机系统至带审计追踪的软件版本。你们的回复是不充分的,因为你们并未提供你们更新后计算机系统的适当程序或详细信息以证明你们要如何限制进入或修改你们的数据。

3. Failure to record activities at the time they are performed. 未能在实施活动时即记录之。

Our investigator found numerous examples of your failure to record manufacturing operations contemporaneously with their performance. For example, our investigator discovered blank batch production records that were pre-signed by your operator, partially-completed batch records, and batch records with data changes in pencil without any justification. Our investigator also identified two process batch records for the same operation for (b)(4) batch (b)(4); one record was partially filled out by one operator and the second record was completed by a different operator.

我们的调查员发现大量你们未能在操作时同步记录生产操作的例子。例如,我们调查员发现已经由你们操作人员提前签名好的空白批记录、部分完成的批记录以及用铅笔修改数据而没有任何论证的批记录。我们调查员还发现2本批记录都是XX产品XX批次的相同操作,一份记录由一个操作员填写了一半,另一份则由另一个操作员填写完成了。

In your response, you indicated that these deficiencies were due to the lack of oversight by your quality assurance department. Your response was inadequate because you did not explain why your quality unit did not ensure contemporaneous documentation or exercise adequate oversight.

在你们的回复中,你们说这些缺陷是因为缺乏QA部门监管。你们的回复是不充分的,因为你们未能解释为何你们质量部门未能确保同步记录或实施充分监管。

Data Integrity Remediation 数据完整性弥补措施

Significant findingsin this letter indicate that your quality unit is not able to fully exerciseits authority and/or responsibilities. Your firm must provide the quality unitwith the appropriate authority, sufficient resources, and qualified staff to carry out its responsibilities and consistently ensure drug quality. Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We strongly recommend that you retain a qualified consultant to assist in your remediation.

此函中的严重缺陷显示你们的质量部门不能全面履行职权。你们公司必须为质量部门提供适当的权力、充分的资源和有资质的人员来履行其职责,持续确保药品质量。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。我们强烈建议你们聘请有资质的顾问来协助你们进行弥补。

In response to this letter, provide the following.

在回复此函时,提供以下资料:

A. A comprehensive investigation into the extent of the inaccuracies in data records 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

Ÿ  A detailed investigation protocol and methodology; a summary of all laboratories,manufacturing operations, and systems to be covered by the assessment; and ajustification for any part of your operation that you propose to exclude.

Ÿ  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。

Ÿ  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.

Ÿ  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。

Ÿ  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.

Ÿ  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。

Ÿ  A comprehensive retrospective evaluation of the nature of the testing, manufacturing and other 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.

Ÿ  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 on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, 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 global corrective 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:

Ÿ  A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate, including analytical data,manufacturing records, and all data submitted to FDA.

Ÿ  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。

Ÿ  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.

Ÿ  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。

Ÿ  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.

Ÿ  临时措施,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。

Ÿ  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.

Ÿ  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。

Ÿ  A status report forany of the above activities already underway or completed.

Ÿ  对上述活动已开展或已经完成的状态报告。

Conclusion 结论

Deviations cited inthis letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.

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 March 1, 2018.

FDA已于201831日将你公司放在了进口禁令66-40清单中。

Until you correct all deviations 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 correctthese deviations may also result in FDA refusing admission of articles manufactured at Jilin Shulan Synthetic Pharmaceutical Co., Ltd., at No. 2066 People’s Main Road, Shulan City, Jilin Province, into the United States undersection 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 methodsand 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FDCA801(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 receivethis letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your deviations 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.gov or mail your reply to:

 

Mr. Lixin (Leo) Xu

Compliance Officer, U.S.Food and Drug Administration

White Oak Building51, Room 4212, 10903 New Hampshire Avenue

Silver Spring, MD20993, USA

 

Please identify yourresponse with FEI 3003091092.

 

Sincerely,

/s/

Francis Godwin, ActingDirector

Office ofManufacturing Quality, Office of Compliance, Center for Drug Evaluation andResearch

(本文来源:蒲公英 )

(责任编辑:子豪)

TAG标签: FDA 警告信 吉林舒兰合成药业 FDA警告信
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