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Shriram Institute for Industrial Research MARCS-CMS 597629 — April 15, 2020


Warning Letter 320-20-33


April 15, 2020


 Dear Dr. Chacko:


The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Shriram Institute for Industrial Research, FEI 3002808145, at 19 University Road, University Campus, Delhi, from October 15 to 22, 2019.


美国FDA于2019年10月15日至22日检查了你们位于印度的Shriram Institute for Industrial Research生产场所。


This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, 21 CFR parts 210 and 211, and significant deviations from CGMP for active pharmaceutical ingredients (API).


本警告信总结了制剂生产严重违反CGMP, 21CFR第210与211部分,以及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 drugs 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 November 7, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.


我们已详细审核了你公司于2019年11月7日对FDA 483表格的回复,并此告知已收到后续通信。


During our inspection, our investigators observed specific violations and deviations including, but not limited to, the following.




Finished Drug Violations 制剂药品违规


1. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(a)). 你公司未对计算机或相关系统实施适当的控制,确保只有经过授权的人员才可修改主生产和检测记录,或其它记录(21 CFR 211.68(a))。


Your firm serves as a contract testing laboratory analyzing both API and drug products. Your firm had not enabled the audit trail function on high-performance liquid chromatography (HPLC) units until on orabout October 11, 2019, when this FDA inspection was announced. Your analyst acknowledged during the inspection that the audit trail function on the HPLCs units was not enabled until October 2019. This was a repeat observation of your August 2016 FDA inspection.




Despite written commitments after that inspection to install audit trails, you failed to enable audit trail functions on multiple analytical instruments, including your HPLC units.




Customers rely on the integrity of the laboratory data that you generate to make decisions regarding drug quality. It is important to maintain strict control over CGMP electronic data to ensure that all additions, deletions, or modifications of information in your electronic records are authorized and appropriately documented.




In your response, your only corrective action was to designate an instrument engineer “to perform the routine inspection to proper performance of the equipment.” Your response is inadequate because it failed to describe specific controls you will implement to ensure audit trails remain enabled and the integrity of your data is not compromised.




In response to this letter, provide: 在回复本函时请提交


•      A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.


•      一份对你们实验室规范、程序、方法、设备、文件记录和化验员能力的全面独立评估。根据该评估,提交一份详细的补救计划,并评估你们实验室系统的有效性。


2. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)). 你公司未能制订并遵守书面的质量部门适用职责与程序(21 CFR 211.22 (d))。


Your Quality Unit (QU) failed to ensure that your laboratory personnel follow written procedures. For example, our investigators observed at least (b)(4) samples tested between March 2019 and September 2019 in which out-of-specification (OOS) results were not investigated as required in your procedures. Your head of Quality Assurance informed our investigator during the inspection that failures are investigated only upon customer request. Additionally, our investigators observed procedures not followed for review of analytical logbooks and results.




These observations included: 这些缺陷包括:


•      Documentation errors covered by adhering new paper over the original value.


•      文件错误时在上面贴一张新纸盖住原始值


•      Tests not recorded contemporaneously.


•      未同步记录检测情况


•      Sample identification not entered into your “Sample Record Register.”


•      样品编号未录入你们的“样品记录登记本”


•      Electronic data supporting analytical laboratory packets were not reviewed before you released final laboratory results.


•      在最终放行实验室结果之前未审核支持分析实验室包的电子数据


In your response, you stated that the procedure for OOS was not followed, but going forward all OOS results will be investigated to identify root causes. Additionally, you committed to conduct further CGMP documentation practice training for your analysts. Your response is inadequate because you failed to perform a risk assessment of your lack of following OOS procedures and poor documentation practices on products you tested for commercial release.




In response to this letter, provide: 在回复本函时请提交


•      A retrospective, independent risk assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Includea detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneousrecords throughout your operation. Specify actions you will take in response tothe risk assessment, such as customer notifications.


•      一份对你们生产和实验室操作所用文件记录系统的回顾性独立风险评估,以确定哪些文件规范是不足的。要包括一份详细的CAPA计划,全面补救你公司的文件规范,确保你们会保存可追溯的、清晰的、完整的、原始的、准确的和同步的所有操作记录。说明你们对风险评估结果准备采取的措施,如通知客户。


•      A retrospective, independent review of all OOS results for all tests. Identify any products which may be intended for the United States for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each OOS:


•      一份对所有OOS检测结果的回顾性独立审核报告。找出所有在检查开始日之前三年内可能销售给美国的所有药品,汇总分析发现的问题,包括每个OOS的以下内容:


For all OOS results found by the retrospective review, identify any potential root cause and indicate if your customer was notified of the failure. Include the original test, date of test, testing result, customer, and reason for initiating an investigation.




•      The written response from your customers when notified of the testing failure(s).


•      在告诉你们客户检测不合格时,客户的书面回复


•      A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function.The assessment should also include, but not be limited to:


•      一份全面的评估和补救计划,确保你们QU被授予权力和资源可有效运作。评估亦应包括但不仅限于以下:


A determination of whether procedures used by your firm are robust and appropriate




Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices




A complete and final review of each batch and its related information before the QU disposition decision




Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products




Test Results Out-of-Specification 检测结果OOS


For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download.




Quality Systems 质量体系


Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and211 at https://www.fda.gov/media/71023/download.




API Deviations API偏差


3. Failure to ensure that all test procedures are scientifically sound and appropriate to ensure that your raw materials and API conform to established standards of quality and/or purity. 未能确保所有检测方法均科学合理恰当,能确保你们的原料和API符合既定质量标准和/或纯度要求。


Our investigators observed many examples of United States Pharmacopeia (USP) labeled material which were tested on your analytical instruments without the completion of system suitability testing prior to analysis. For example, a sample of (b)(4) USP, batch (b)(4), was tested using an atomic absorption spectrometer on January 15, 2019, without confirming system suitability testing. This was a repeat observation from the August 2016 FDA inspection.


我们的检查员发现许多标有USP的物料在你们分析仪器上检测时未完成系统适用性测试就开始进样。例如,一个XX USP样品批号为XX,在2019年1月15日采用原子吸收光谱进行检测,检测前未进行系统适用性测试。这是2016年8月FDA检测中发现的重复缺陷。


After the previous inspection, your firm committed to performing system suitability testing on all analytical instruments “wherever required, prior to analysis” of USP tests. Additionally, your firm failed to document the testing method within laboratory records before issuing a certificate of analysis. You lacked adequate documentation to support that the USP labeled drug products were tested with USP methods.




System suitability testing determines whether requirements for precision are satisfied and ensures that the analytical instrument is fit for the intended testing before analyzing samples. It is critical that your system be demonstrated as suitable for use to avoid the possibility of samples erroneously passing when an instrument is not working properly.




Customers rely on your laboratory data for critical information about the quality of drugs and their components. Thus, it is important that your analytical instruments are suitable for their intended use,and that you use appropriate test methods to enable your customers to make proper decisions (e.g., batch disposition).




In your response, you committed to perform system suitability testing on your laboratory equipment prior to analysis. Additionally, you committed to inform your clients of the need to performmethod verification before conducting analysis. Your response lacked sufficient interim measures to ensure equipment is suitable and methods are robust while you continue to test drug products. Additionally, you did not conduct a risk assessment for USP tests performed without system suitability testing.




In response to this letter, provide: 在回复本函时请提交


•      A retrospective, independent risk assessment addressing the hazards posed by providing USP test results of active pharmaceutical ingredients and drug products to clients without documenting the test method or performing system suitability testing on analytical instruments prior to testing. Specify actions you will take in response to the risk assessment, such as customer notifications.


•      一份回顾性独立风险评估,说明向客户提供API和制剂的USP检测结果却没有记录检测方法或检测前在仪器上执行系统适用性测试的危害。说明你们应对风险评估结果准备采取的措施,如通知客户。


•      A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system. This assessment should include, but not be limited to:


•      一份对你们实验室规范、程序、方法、设备、文件记录和化验员能力的全面独立评估。根据此次审核,提交一份详细的补救计划,同时评估你们实验室系统的有效性。该评估应包括但不仅限于


Your procedure for carrying out system suitability testing prior to analysis on your laboratory equipment




Your procedure for method verification for current and new methods performed within your laboratory




Your procedure for establishing responsibility for performing method verification between you and your clients




Repeat Observations at Facility 工厂重复缺陷


In a previous inspection, dated August 2-5, 2016, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response.




Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.




CGMP Consultant Recommended CGMP顾问建议


Based upon the nature of the violations and deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations as set forth in 21 CFR 211.34to assist your firm in meeting CGMP requirements.


鉴于我们在你公司所发现的违规情况,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。


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.




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/media/119267/download.




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




A.   A comprehensive investigation into the extent of theinaccuracies 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


l  A detailed investigation protocol and methodology; a summary of alll aboratories and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.


l  详细的调查方案和方法学,所有实验室、生产操作和评估所覆盖的系统的总结,如有除外部分请论证


l  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.


l  对现有和已离职员工进行面谈,找出数据不准确的程度、范围和根本原因。我们建议这些面谈由有资质的第三方进行。


l  An assessment of the extent of data integrity deficiencies at yourfacility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe allparts of your facility’s operations in which you discovered data integrity lapses.


l  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。说明你们已发现的数据完整性问题所涉及的工厂操作。


l  A comprehensive retrospective evaluation of the nature of the testing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluateall data integrity lapses.


l  一份对检测和生产数据完整性缺陷情况的全面回顾性评估。我们建议由具备在已发现可能有问题的领域的专业能力的有资质的第三方对所有数据完整性问题进行评估。


B.   A current risk assessment of the potential effects of the observed failures on the quality of drugs you tested for commercial release. 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.




C.  A management strategy for your firm that includesthe 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:


l  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, and all data submitted to FDA.


l  详细的CA计划,描述你们准备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。


l  A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action planis commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related data at your firm.


l  一份对你们数据完整性问题根本原因的全面描述,包括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。说明负责数据完整性的人员是否还有能力影响你公司与CGMP有关或药品申报数据。


l  Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of drugs, such as notifying your customers and conducting additional testing.


l  临时措施,描述你们已采取或将采取用来保护患者和确保你们药品质量的措施,如通知你们的客户、执行额外检测。


l  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.


l  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。


l  A status report for any of the above activities already underway or completed.


l  对上述活动已开展或已经完成的状态报告。


Conclusion 结论


The violations and deviations cited in this letterare not intended to be an all-inclusive list of violations and deviations that exist at your facility. You are responsible for investigating and determining the causes of these violations and deviations and for preventing their recurrence or the occurrence of other violations and deviations.




Until you correct all violations and deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a contract testing laboratory.




Failure to correct these violations and deviationsmay also result in the FDA refusing admission of articles manufactured by your clients and tested at Shriram Institute for Industrial Research, 19 University Road, University Campus, Delhi into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority 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 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 violations and 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.




Send your electronic reply toCDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:


Joseph Lambert, Pharm.D.

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4235

10903 New Hampshire Avenue

Silver Spring, MD 20993



Please identify your response with FEI 3002808145.





Francis Godwin


Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research