FDA警告信：印度 Lantech 20190808

罗伊鲱

Warning Letter 320-19-34                    August 8, 2019

Mr. V. Prakash Reddy

Managing Director, Lantech Pharmaceuticals Limited

H. No. 7-2-1735 & 1813/5/A1, Flat 101, SBH Building, CZECH Colony, Street No. 2, Sanath Nagar, Hyderabad - 500 018,Telangana, India

Dear Mr. Reddy:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Lantech Pharmaceuticals Limited, FEI 3012390454, at Sy. No. 78, 79, 80, & 145, Chittivalasa, Pydibhimavaram, Ranastalam, Andra Pradesh, from March 6 to 15, 2019.

美国FDA于2019年3月6日至15日检查了你们位于印度的Lantech Pharmaceuticals Limited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 do not conform to CGMP, your API are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food,Drug, and Cosmetic Act (FD&C Act), 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21 U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your April 5, 2019, response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2019年4月5日的回复，并此告知已收到后续通信。

During our inspection, our investigators observed specific deviations 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.    Failure of your quality unit to ensure that quality-related complaints are investigated and resolved. 你们质量部门未能确保调查和解决与质量有关的投诉。

Our inspection found that your firm acts as acontract solvent recovery facility for your customer’s valsartan API manufacturing operations; and as contract manufacturer for the API intermediate, lamivudine coupled ester (LVC). In December 2018, your firm was notified by your customer, (b)(4), that (b)(4) solvent recovered by your firm contained the potential mutagenic impurity, N-Nitrosodiethylamine(NDEA).

我们检查发现你们公司为你们客户的缬沙坦生产操作溶剂回收合同生产厂，作为API中间体、拉米夫定偶联酯（LCV）的合同生产商。在2018年12月，你公司客户通知你们说你公司回收的XX溶剂含有潜在基因毒性杂质NDEA。

Your firm opened an investigation in response to (b)(4) findings as part of their investigation into contaminated valsartan API. However, your investigation was inadequate for the following reasons:

你公司启动调查，回复XX作为客户对受污染缬沙坦API的一部分。但是你们的调查不够，原因如下：

• Your investigation focused on NDEA, although (b)(4) notified your firm that they had also identified the potential mutagenic impurity N-Nitrosodimethylamine (NDMA) in samples collected from your equipment used to recover (b)(4).
• <span 虽然客户通知你们公司说他们在从你们用于回收XX的设备中所采集样品里也检出了NDMA，但你们的调查集中在NDEA上
• The scope of your investigation failed to include non-dedicated storage, receiving, and charging tanks used in your solvent recovery operations. Given that your firm does not maintain logbooks or documentation demonstrating product use or cleaning associated     with the use of these tanks, there is a potential for all products manufactured at your facility to contain nitrosamines through mix-ups or cross contamination.  
• 你们的调查范围未包括溶剂回收操作中所用的非专用存贮、接收和投料罐。考虑到你公司没有日志或文件记录证明产品用途或这些罐用途相关的清洁，因此认为你们工厂生产的所有产品均有可能通过混淆或交叉污染而含有亚硝胺类杂质。
• Your firm manufactures angiotensin II receptor blockers (ARBs) including valsartan, telmisartan, and olmesartan API and intermediates for non-U.S. supply chains. Your firm failed to adequately evaluate the potential of these ARBs to form nitrosamines and identify     potential cross contamination risks for drugs manufactured made using non-dedicated equipment and shipped into the U.S. supply chain.
• 你公司生产的ARB包括非美国供应链的缬沙坦、替米沙坦和奥美沙坦API以及中间体。你公司未充分评估这些ARB生成亚硝胺类杂质的可能性，识别使用非专用设备所生产以及销往美国供应链的药品的潜在交叉污染风险。
  
  

In your response, you stated that you were unaware of specific aspects of your customer’s valsartan API manufacturing process which were important for predicting nitrosamine formation in the solvent recovery process. Your response is inadequate because it is your responsibility to understand all the potential risks associated with the drug manufacturing processes conducted at your facility.

在你们的回复中，你们声称你们不知道你们客户的缬沙坦API生产工艺中哪些方面对预测在溶剂回收工艺中形成亚硝胺类比较重要。你们的回复是不充分的，因为你们有义务了解你们工厂所执行的与药品生产工艺相关的所有潜在风险。

We acknowledge that you suspended processing recovered solvents for customers, indicating that additional controls will be put in place should you decide to resume operations in the future. However, your firm has not provided sufficient details or procedures to demonstrate acapability of predicting, controlling, and preventing impurities or cross contamination associated with your solvent recovery processes.

我们被告知你们暂停了为客户所做的溶剂回收工艺，如果你们在未来决定继续操作时会增加额外控制。但是你公司并未提交足够详细的内容或程序来证明你公司有能力预测、控制和预防与你们溶剂回收工艺有关的杂质或交叉污染。

In response to this letter, provide the following:

在回复此函时请提交以下资料：

• A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. Your corrective action and preventive action (CAPA) should include but not be limited to     improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA effectiveness.
• 一份对你们偏差、异常事件、投诉、OOS结果和失败调查全面系统的全面独立评估。你们的CAPA应包括但不仅限于改进调查专业性、根本原因分析、书面程序以及质量部门监管。亦要包括你们对CAPA有效性的评估流程。
• An updated nitrosamine investigation to include a detailed risk assessment for all materials produced at your site and the potential to form nitrosamines. The investigation should not be limited to NDMA and NDEA but include a broader evaluation of nitrosamine formation.     
• 一份更新后的亚硝胺杂质调查，包括对在你们工厂生产的所有物料的详细风险评估，以及形成亚硝胺类杂质的可能性。调查不应局限于NDMA和NDEA，而应扩大至所有亚硝胺类杂质的形成。
• An assessment of all non-dedicated equipment used to manufacture materials for the U.S. supply chain, including API, intermediates, solvents, and starting materials. For all shared equipment, provide details of potential impurities in non-U.S. materials and your controls to prevent cross contamination.
• 一份对美国供应链物料生产所用非专用设备的评估，包括API、中间体、溶剂和起始物料。对所有共用设备，要提交非美国物料中的潜在杂质详细信息，以及你们预防交叉污染的控制措施。
• A list of all customers for whom you have processed recovered solvents in the previous three years. Include a risk assessment for all customer-recovered solvents with emphasis on those solvents which may have originated from high-risk manufacturing operations and pose a safety concern.
• 一份你们在过去3年为其回收溶剂的客户清单。包括一份对所有受托回收溶剂的风险评估，重点关注来自高风险生产操作和具有安全关切的那些溶剂。
  
  

2.    Failure to have adequate cleaning procedures to prevent contamination or carry-over of a material that would alter the quality of the API. 没有足够的清洁程序防止可能改变API质量的物料污染或残留。

Your firm does not maintain logbooks for productuse and cleaning of non-dedicated storage, receiving, and (b)(4) solvent recovery tanks. Additionally, during our inspection, solid and liquid materialof unknown origin was noted pooling at the bottom of a non-dedicated receiving tank, (b)(4)-402. Unknown residue was also observed in the external view glasses, a product contact surface, of non-dedicated receiving tanks (b)(4) RT-401,(b)(4)RT-402,(b)(4)RT-403, and (b)(4)RT-410.  

你公司没有日志记录非专用存贮、接收和XX溶剂回收罐的产品用途和清洁。另外，在我们的检查期间，发现非专用接收罐XX-402底有未知来源固体和液体物料沉积。在外视镜产品接触表面亦看到非专用接收罐XXRT-401/402/403/410中有看到未知残留物。

In your response, you stated that the tanks will becleaned (b)(4) or after (b)(4) batches. Your response is inadequate. No scientific justification was provided for these cleaning frequencies. Additionally, your response did not discuss probable cross contamination or potential mix-up risks associated with these non-dedicated tanks.  

在你们的回复中，你们声称这些罐会在XX或XX批次后进行清洁。你们的回复是不充分的。你们未提交科学论据支持这些清洁频次。另外，你们的回复中未讨论这些非专用罐的潜在交叉污染或潜在混淆风险。

Your cleaning validation associated with LVC intermediate production on non-dedicated equipment is also inadequate as you could not provide justification for the swab sample location taken near the (b)(4).

你们非专用设备与LCV中间体生产有关的清洁验证亦不充分，因为你们未能提交接近XX处擦拭取样位置的论证。

Your response included updates to your cleaning validation procedure. However you failed to commit to revalidating your cleaning procedure for LVC production in accordance with your new procedure.

你们的回复包括有对你们清洁验证程序的更新。但是你们未能承诺根据你们的新程序重新验证你们LVC生产的清洁程序。

In response to this letter, provide the following:

在回复此函时请提交以下资料

• A comprehensive plan to evaluate the adequacy of cleaning procedures, practices, and validation studies for each piece of non-dedicated manufacturing equipment.
• 一份对每台非专用生产设备的清洁程序、做法和验证研究充分性进行评估的全面计划
• Scientific rationale for your cleaning validation strategy to ensure that the efficacy of your cleaning procedures is adequately assessed.
• 你们清洁验证策略的科学理由，以确保你们清洁程序的有效性经过足够评估
• A summary of updates to your cleaning validation protocol to better incorporate conditions identified as worst case. This should include but not be limited to evaluating drugs and     materials that are of highest toxicity; that are lowest solubility intheir cleaning solvents or that have characteristics that make themdifficult to clean; and swabbing of various equipment locations that aremost difficult to clean.
• 一份对你们清洁验证方案的更新，以更好结合识别为最差情形条件。其中应包括但不仅限于评估具有最高毒性的、在其清洁溶剂中溶解度最低的、或具有难以清洁特性的物料和药品，以及不同设备中最难清洁位置的擦拭取样点
• A summary of SOP that have been updated to ensure an appropriate program for verification and validation of cleaning procedures for new products, processes, and equipment.
• 一份你们为确保程序适合于新产品、工艺和设备的清洁程序确认与验证而更新的SOP的摘要
  
  

3.    Failure to controland monitor procedures to recover solvents to ensure that they meet appropriate standards before reuse. 未对回收溶剂程序进行控制与监测以确保其在重新使用之前符合适当的标准。

Your firm failed to implement procedures to evaluate and control impurity risks associated with your solvent recovery operations done under contract to API manufacturers. This includes adequate testing to confirm their suitability for manufacturing processes in which theymay be used, establishing an impurity profile for solvents to ensure that they meet appropriate standards and maintaining an ongoing program for monitoring process controls to ensure stable manufacturing and prevent unanticipated impurities.

你公司未执行程序评估和控制与你们受API生产商委托所做溶剂回收操作有关的杂质风险。其中包括为确认可能使用这些溶剂的生产工艺适合性所做的充分测试，为溶剂建立杂质概况以确保其符合适当的标准，以及持续监测工艺控制以确保生产稳定，防止非预期杂质。

Your firm also failed to implement a procedure for investigating unknown peaks in recovered solvent chromatograms observed during analytical testing. Unknown peaks observed in chromatograms may represent unanticipated impurities and should be thoroughly investigated.  

你公司亦未执行程序调查分析检测中发现的回收溶剂色谱图中的未知峰。在色谱图中发现的未知峰可能代表非预期杂质，应进行彻底调查。

Your firm stated that while you “overlooked” conducting process validation for solvent recovery operations either for customers or internal use, no batch failed release specifications. Your response is inadequate. We remind you that nitrosamines were detected insolvents recovered by your firm; and note that you had not implemented procedures for identifying and investigating unknown peaks in recovered solvent analytical testing.

你公司声称你们“忽略”了针对客户或内部用途进行溶剂回收操作工艺验证，没有批次不符合放行标准。你们的回复是不充分的。我们提醒你们你公司所回收的溶剂中检出了亚硝胺物质，我们注意到你们未执行程序识别和调查回收溶剂分析检测中发现的未知峰。

In response to this letter, provide the following:

在回复此函时请提交以下资料

• A detailed plan describing how you will implement an ongoing program for monitoring process control to ensure stable manufacturing and prevention of unanticipated impurities during solvent recovery operations.
• 一份详细的计划说明你们要如何执行持续监测工艺控制的程序，以确保稳定生产，防止溶剂回收操作过程中产生非预期杂质
• A procedure requiring an impurity profile analysis and risk assessment for all solvent recovery operations. The scope of the procedure should include recovered solvents for internal and external use.   
• 一份程序要求对所有回收溶剂操作进行杂质概况分析和风险评估。程序落雷应包括内部和外部使用的回收溶剂。
• An updated procedure for evaluating unknown peaks in chromatograms.
• 一份更新后的对色谱图中未知峰进行评估的程序。
  
  

4.  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. 未能对计算机化系统进行足够的控制以防止未经授权进入或修改数据，未能进行充分控制以防止数据遗漏。

Your firm failed to implement adequate controls to ensure the integrity of data generated at your facility. For example, the Senior General Manager of Quality is also the Administrator for chromatographic data system software on your Quality Control laboratory instrumentation. The Administrator has full access privileges to computerized systems, including editing, deleting, modifying data, and audit trails. Additionally, your firm admitted to routinely deleting recovered solvents gas chromatography (GC) data older than three months permanently, without any backup.

你公司未能执行足够控制以确保你工厂所生成数据的完整性。例如，质量部高级总经理亦是你们QC实验室仪器色谱数据系统软件的管理员。管理员具备计算机化系统的全部权限，包括编辑、删除、修改数据以及审计追踪。另外，你公司承诺经常永久性删除3个月前的回收溶剂GC数据，也未做备份。

In your response, you committed to maintain GC solvent data electronically for six years and to establishing unique user namesand assigned access levels. Your response is inadequate as it did not include a comprehensive evaluation of your data integrity controls. Your firm also stated that all the chromatograms are available as hard copies. This is not acceptable. Electronic records from laboratory instrumentation such as GC are dynamic: for example, they can have the scale adjusted to provide additional detail in a region. A printout or a static record does not preserve the dynamic record format that is part of the complete original record.

在你们的回复中，你们承诺要保存电子GC溶剂数据6年，建立唯一的用户名并指定权限分级。你们的回复是不充分的，其中并未包括对你们数据完整性控制的全面评估。你公司亦声明所有色谱均有保存纸质记录。这是不可接受的。实验室仪器如GC的电子记录是动态数据，例如他们可进行标尺调整以提供更为详细的局部内容。打印件或静态记录无法保存作为完整原始记录一部分的动态记录格式。

Data Integrity Remediation 数据完整性补救措施

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. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry.

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。参见FDA指南文件“数据完整性和药品GMP合格”指导建立和遵守CGMP合格数据完整性规范。

We strongly recommend that youretain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

我们强烈建议你们聘请一位有资质的顾问协助你们进行补救。在回复此函时，请提交以下资料：

• A comprehensive investigation into the extent of the inaccuracies in data records and     reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
• 一份对已销往美国药品的数据记录和报告不准确性程度的全面调查。其中包括对你们数据完整性问题的范围和根本原因说明。
• 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 analyses of the risks posed by ongoing operations.
• 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。
• A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
• 你们公司的管理策略，包括你们全球CAPA计划详细情况。详细整改计划应说明你们要如何确保你公司所有生成数据的可靠性和完整性，包括微生物和分析数据、生产记录以及提交给FDA的全部数据。
  
  

CGMP Consultant Recommended CGMP顾问建议

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S.market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

根据在你们公司发现的偏差情况，如果你公司希望继续生产药品销往美国市场，我们强烈建议你们使用一位有21CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。我们亦建议有资质的顾问对你们整体操作进行一次全面GMP合规审计，在你公司寻求FDA合规解决方案前由顾问评估你们CAPA的完成情况和有效性。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你们使用顾问并不能解除你们公司符合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。

Solvent Recovery Operations Suspended 暂停溶剂回收操作

We acknowledge your commitment to suspend “contract solvent recovery processes” at this facility for the U.S. market. If you plan to resume producing recovered solvents for the U.S. supply chain, notify this office in writing.

我们收到你们承诺在你们工厂暂停将“合同溶剂回收工艺”用于美国市场。如果你们计划继续生产回收溶剂用于美国供应链，请书面通知我们办公室。

Conclusion 结论

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility/in connection with your product(s). You are responsible for investigating and determining the causes of these deviations and for preventing their recurrence or the occurrence of 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，防止你们设施内其它偏差的发生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to reportdis continuances or interruptions in your drug manufacture under 21 U.S.C.356C(b) and allows FDA to consider, as soon as possible, what actions, if any,may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。

FDA placed your firm on Import Alert 66-40 on June 27, 2019.

FDA已于2019年6月27日将你公司置于进口禁令66-40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 correct these deviations may also resultin FDA continuing to refuse admission of articles manufactured at Lantech Pharmaceuticals Limited at Sy. No. 78, 79, 80, & 145, Chittivalasa, Pydibhimavaram, Ranastalam, Andra Pradesh into the United States under 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 themeaning 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 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<span 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。

墨石

这么好的资料，咋没人呢。

清晨的太阳

进来参观一下，顺便看看情况。