FDA警告信：印度 Goran Pharma 20180424

一沙一叶

Julia法规翻译

Dear Mr. Dholakia:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Goran Pharma Private Limited at GDIC-I, Bhavnagar Road, Sihor, Gujarat, from November 13 to 15, 2017.

美国FDA于2017年11月13-15日检查了你们位于印度古吉拉特邦的Goran Pharma Private Limited.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和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding donot 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&CAct), 21 U.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 December 15,2017, response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2017年12月15日的回复，并知会已收到后续通信。

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 ensure the identity of components, including your activeingredients and excipients from various suppliers (21 CFR 211.84(d)(1) and(2)).你公司未能确保对来自不同供应商的组份包括你们的活性成分和辅料的识别（21 CFR 211.84(d)(1) and (2)。

You failed to test incoming components you use in manufacturing drug products to determine their conformance to identity, purity, strength, and other appropriate specifications. Your firm released components for use in drug product manufacturing based on certificates of analysis (COA) from your supplier without establishing the reliability of the suppliers’ analyses through appropriate validation. For example, your firm did not test each lot of glycerin used as a component of your drugs to determine whether diethylene glycol (DEG) or ethylene glycol (EG) was present. Because you did not test each glycerin lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of lots used in drug product manufacture. DEG contamination in pharmaceuticals has resulted in variousle thal poisoning incidents in humans worldwide.

你们未检测你们用于制剂生产的进厂组份以确定其符合鉴别、纯度、剂量及其它适当的质量标准。你们公司依据供应商的分析报告（COA）放行了组份用于制剂生产，而未通过适当的验证建立对供应商分析结果的可靠性。例如，你们公司并未检测用作你们药品的一种组份甘油（丙三醇）的所有批次批号，以确定其中是否含有二甘醇（二乙二醇DEG）还是甘醇（乙二醇（EG）。因为你们没有使得USP鉴别方法测试每批甘油发现这些危害性杂质，你们无法确保用于药品生产的所有批次的可接受度。DEG污染药品已导致了世界许多死亡事件。

Your response indicated thatyou will compare your laboratory results with the supplier’s COA to confirm there liability of testing for all lots, and you provided a revised standard operating procedure (SOP) Purchasing, Supplier Approval, Monitoring, andRisk Analysis (SOP No. GPPL/PUR/01). The revised SOP, provided with your response as Annexure 30, also discusses adding suppliers to an “approved vendor list.”

你们的回复说你们将比较你们化验室的结果与供应商的COA以确认所有批次检测的可靠性，你们还提供了一份修订后的标准操作规程（SOP）“采购、供应商批准、监测和风险分析”（SOP编号GPPL/PUR/01）。修订后的SOP是作为你们回复的附录30提交的，其中也讨论了增加供应商至一份“已批准供应商清单”。

Your response is inadequate because it is not clear whether you will indefinitely test each incoming component lot for all attributes to verify the accuracy of your suppliers’ COA, or you will instead qualify your suppliers’ test results through an initial round of testing as well as ongoing testing at appropriate intervals. Additionally, your response did not address whether your firm conducted retrospective DEG and EG testing for products distributed to the United States.

你们的回复是不充分的，因为没说清楚你们是否会检测每批进厂组份的所有属性以确认你们供应商COA的准确性，还是会通过初始一轮检测来确认你们供应商的检测结果然后以隔一定时间定期检测。另外，你们的回复并未说明你们公司对销往美国的药品进行回顾性DEG和EG检测。

In response to this letter,provide the following:

在回复此函时，请提交以下内容：

• a detailed description of how you will ensure that components (e.g., ingredients) used in the manufacture of your drug products will be withheld from use until the lot has been tested in accordance with the current United States Pharmacopoeia (USP) and released for use by the quality unit;
• 详细描述你们要如何确保你们药品生产所用组份（例如成分）在经检测确定其符合当前USP标准并由质量部门放行使用之前不得用于生产；
• an improved procedure that describes how you qualify your suppliers’ COA both initially and on an ongoing basis. Explain whether you intend to test each lot of incoming components for all attributes instead of relying on the suppliers’ COA. Alternatively, if you intend to rely on the supplier’s COA, provide specifics on how you will verify each supplier’s test results at regular intervals and include a commitment to test at minimum every incoming component lot for USP identity requirements.
• 改进后的程序说明你们要如何在最初以及持续确认你们供应商的COA。解释你们是否会检测每批进厂组份的所有属性，而不是依赖于供应商的COA。相应地，如果你们想要依赖于供应商的COA，请提交具体说明你们将如何定期确认每个供应商的检测结果，并承诺至少会测试每个进厂成分批准中USP鉴别项。
• a detailed risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. As part of your risk assessment, immediately test retained samples of all lots for DEG and EG, and take appropriate market action if the testing yields any aberrant     results.
• 一份详细的风险评估，对含有甘油销往美国且在效期内的药品。作为风险评估的一部分，请立即检测所有留样中DEG和EG含量，如果检测结果发现任何异常，即应采取适当的市场措施。
• a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to remediate your laboratory systems.
• 一份对你们化验室做法、方法、设备和化验室资质的全面独立审核。基于此审核，提交一份详细的CAPA计划来弥补你们的化验室系统。
  
  

See FDA’s guidance document, Testing of Glycerin for 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“甘油中二甘醇的检测”帮助你们产在生产含有甘油的药品时符合CGMP要求。

2.     Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)). 你公司未能建立充分的质量部门，使其具备权力和职责来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)）。

Your quality unit releasedbatches without reviewing all production and control records. You shipped the (b)(4) batch (b)(4) prior to completion of microbiological testing. Your SOP IssueBatch No., Issue, Entry, Review and Control of BMR and Batch Release (SOPGPPL/QC/04) allows this practice.

你们质量部门未审核所有生产和检验记录即放行了多批产品。你们在微生物检测完成之前即发运了XX产品XX批号。你们的SOP“批号签发、BMR签发、录入、审核和控制以及批放行”（SOP GPPL/QC/04）允许你样如此操作。

Your response is inadequate because your revised SOP, supplied with your response as Annexure 31, statesthat in cases of “emergency” you will transfer the product to the shipping agent’s warehouse with a “not for sales” [sic] COA. This indicates that finished product may still be distributed prior to completion of testing andreview by your quality unit. Your SOP continues to state that if a failing result is obtained you will conduct a “recall/withdrawal” from the shipping agent.

你们的回复是不充分的，因为你们作为回复附件31所提供的修订后SOP中说如果“情况紧急”，你们会将产品转移至货代仓库，配以“不得销售”的COA。这表示成品仍在检测完成以及你们质量部门审核之前即被销售了。你们的SOP继续声称如果检测结果不合格，你们会从货代处“召回/撤回”产品。

In response to this letter, submit updated procedures and corrective actions to ensure that your qualityunit will review complete records prior to making a finished product batch disposition decision. Additionally, provide a CAPA that establishes an adequate quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

在回复此函时，请提交更新后程序和纠正措施，确保你们的质量部门在做出成品批次处置决定阐明会审核完整的记录。另外请提交一份CAPA，建立足够的质量部门，具备足够的权力和充分的资源来履行其职责，持续确保药品质量。

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、包装和存贮过程中未能使用经适当设计、具备足够尺寸、适当定位的设备以便于按其既定用途操作并进行清洁和维护（21 CFR 211.63）。

Your (b)(4) system was not appropriately designed. The system, which you indicated was “sterilized” (b)(4), contained (b)(4) piping with dead legs. This inappropriate system design fosters the development of biofilms. Moreover, due to the deficiencies noted in laboratory controls during the inspection, such as inappropriate storage of media, lack of growth promotion testing, and lack of positive controls, it is not certain you would be able to reliably detect bioburden or microbial limits failures.

你们的XX系统设计不恰当。该系统显示为“已灭菌”XX，其管道有死管。该不当设计会滋长生物膜。另外，由于在检查过程中在化验室看到的缺陷，例如，培养基存贮不当，缺少促生长试验，缺少阳性控制，因此无法确定你们能够可靠地检出生物负载和微生物限度失败情况。

In your response you stated you have procured an improved (b)(4)system. Your response is inadequate because it lacks detail on how you will validate the new (b)(4) system.You stated that you will “sterilize” the new (b)(4) system (b)(4) with (b)(4) for (b)(4), but you did not provide scientific rationale for the proposed frequency, (b)(4), or duration. Lastly, your response did not include a risk assessment for products within your control or that have been distributed to the United States that were manufactured using the previous (b)(4) system.

在你们的回复中，你们声称你们已经采购了更好的XX系统。你们的回复是不充分的，因为其中缺少你们将如何验证新的XX系统的详细信息。你们声称你们会对新的XX系统在XX“灭菌”XX时间，但你们并未为所拟频次、XX或时长提供科学合理性。最后，你们的回复并未包括对采用之前XX系统生产的仍在你们控制下产品和已销往美国产品的风险评估。

In response to this letterprovide the following:

在回复此函时请提交以下信息：

• a detailed plan for validation of the new (b)(4) system 新的XX系统的详细验证计划
• procedures for routine monitoring of the (b)(4) system as well as system control and maintenance XX系统以及系统控制和维护的日常监测程序
• scientific justification for the frequency, (b)(4), and duration that you will use to sanitize the (b)(4) system XX系统消毒所用频次、XX和时长的科学论证
• a risk assessment for products manufactured prior to installation and validation of the new (b)(4) system 新的XX系统安装和验证之前所生产产品的风险评估
• your rationale for relying on past data to characterize the (b)(4)system’s state of control,     given the microbiology laboratory deficiencies noted during the inspection.  考虑到在检查期间发现的微生物化验室缺陷，你们依赖于之前数据定义XX系统的控制状态的合理性
  
  

4.     Your firm failed to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR211.46(b)). 你公司未能提供设备用于充分控制空气压力、微生物、灰尘、湿度和温度使其适合于药品的生产、加工、包装和存贮（21 CFR 211.46(b)）。

You lacked an air handling system as well as control and monitoring of temperature and humidity in the manufacturing (e.g. filling, packaging) and warehouse areas. You confirmed thatyour drug products may be exposed to temperatures over 30°C (86°F) and that temperatures in your facility can reach 50°C (122°F) during hot weather months.

你们的生产（例如灌装和包装）和仓库区域缺乏空气处理系统以及温湿度控制和监测系统。你们确认你们的药品可能会暴露于高于30°C (86°F)温度之下，在最热的几个月你们场所的温度可能会高达50°C (122°F)。

It is unacceptable to manufacture drug products without an air handling system that has control over temperature, humidity, and air cleanliness. Your lack of air handling systems and control has the potential to adversely affect the quality of your raw materials, in-process materials, and finished products.

在没有空气处理系统控制温湿度和空气洁净度的情况下生产药品是不可接受的。你们缺乏空气处理系统和控制可能会对你们的原料、中间体和成品质量产生不良影响。

In response to this letter,provide the following:

在回复此函时，请提交以下信息：

• a detailed action plan for ensuring adequate control and monitoring of temperature, humidity, and air cleanliness in your facility 一份详细的行动计划，确保对你们场所内温湿度和空气洁净度有足够的控制和监测
• a comprehensive, independent assessment of your facilities and equipment. This assessment should include a full evaluation of the suitability of the design, control, and maintenance of your equipment and facilities. Based on this review, provide a detailed CAPA plan. 一份对你们设施和设备的全面独立评估。此评估应包括对你们设备和设施的设计、控制和维护适当性的全面评估。基于此审核，请提交一份详细的CAPA计划。
  
  

Quality Unit Authority 质量部门权力

Significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority, sufficient resources and staff to carry out its responsibilities and consistently ensure drug quality.

在此函中的严重缺陷表明你们的质量部门并未全面履行其权力和/或职责。你们公司必须为质量部门提供适当的权力、足够的资源和人员来履行其职责，持续确保药品质量。

CGMP consultant recommended CGMP顾问建议

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. The third-party consultant should comprehensively audit your entire operation for CGMP compliance, with special emphasis on the materials, laboratory, facility, and production systems, as well as your overall quality assurance program. Your CAPA should be evaluated by the third party to help ensure thorough and systemic remediation before you pursuere solution of your firm’s compliance status.

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 CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议具备资质的第三方对你们全面操作进行综合审计，包括质量保证体系、物料体系、设施和设备系统、化验室系统、生产系统和包装标签系统。你们的CAPA应经由第三方评估以在你们寻求符合性状态解决方案之前协助确保系统补救措施有效。

Your use of a consultant doesnot 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 as an 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，防止你们设施内其它偏差的发生。

FDA placed your firm on Import Alert 66-40 on March 5, 2018.

FDA已于2018年3月5日将你公司放在了进口禁令66-40清单中。

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 adrug 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 theseviolations may also result in FDA continuing to refuse admission of articles manufactured at Goran Pharma Private Limited, GDIC-I Bhavnagar Road, Sihor,Gujarat, into the United States under section 801(a)(3) of the FD&C Act, 21U.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 notappear to conform to CGMP within the meaning of section 501(a)(2)(B) of theFD&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21U.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 havedone since our inspection to correct your violations and to prevent theirrecurrence. 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:

LCDR Catherine Gould, Pharm.D.,Compliance Officer

U.S. Food and DrugAdministration

White Oak Building 51, Room4359

10903 New Hampshire Avenue

Silver Spring, MD 20993, USA

Please identify your responsewith FEI 3009336980.

syhorchid

了解一下

蓝色星期六

serious violations.
FDA’s guidance document, Testing of Glycerin for Diethylene Glycol,这个让我想到了齐二药事件

歪打正着

信息量很大。慢慢看