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April 23, 2020
Dear Mr. Singh:The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Kumar Organic Products Limited, FEI 3009167769, at Plot No. 379, Canal Road, Maitri Marg, Village Luna,Taluka-Padra District, Vadodara, Gujarat, from November 11 to 14, 2019.美国FDA于2019年11月11日至14日检查了你们位于印度的Kumar Organic Products Limited生产场所。This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts210 and 211 (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与211部分。Our inspection noted that your firm produces theactive pharmaceutical ingredient (API) (b)(4). The(b)(4) by definition an in-process material for a finished drug product under Title 21, Code of Federal Regulations section 210.3(b)(9), and therefore subject to the CGMP regulations at 21 CFR 211.我们检查中注意到你公司生产原料药（API）XX。该原料药根据21CFR210.3(b)(9)定义为制剂的中间体，因此受GMP法规21CFR211监管。Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is 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 December 5, 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2019年12月5日对我们FDA483表的回复，并此告知已收到后续通信。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 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 CFR211.63). 你公司在生产、加工、包装或保存药品时未使用经过适当设计、具备足够尺寸并适当定位安装的设备，便于其既定用途和清洁与维护（21 CFR 211.63）。Your firm manufactures an over-the-counter topical drug product intended to treat (b)(4). You use(b)(4) produced at your facility as a component in manufacturing this drug product. Your firm’s (b)(4) system was not adequately designed, maintained, or monitored to ensure that it consistently produces (b)(4) suitable for its intended use.你公司生产治疗XX用的OTC局部用药品。你们在你们工厂使用XX作为组份生产该药品。你们公司的XX系统未进行充分的设计、维护或监测，无法确保其能持续生产出适合其既定用途的XX。Inadequate (b)(4) System Design Features and MaintenanceXX系统设计特性和维护不够Your (b)(4) distribution system had multiple design deficiencies and also lacked proper maintenance, both of which can foster the development of biofilms. For example:你们的XX分配系统有多个设计缺陷，缺少适当的维护，这会导致生物膜生长。例如： #8226; You informed our investigator that you turn off your (b)(4) system when not in use. #8226; 你们告诉我们的检查员说你们在不用的时候关闭了XX系统 #8226; Your maintenance records indicate that the (b)(4) were last changed in August of 2014. #8226; 你们的维护记录显示XX最后修改日期为2014年8月 #8226; Your (b)(4) were found actively leaking when in use. #8226; 你们的XX在使用时有泄漏 #8226; Your cleaning procedures did not adequately addres show your storage tanks are sanitized. #8226; 你们的清洁程序未能说明你们的贮罐是如何消毒的 Inadequate (b)(4) System Monitoring XX系统监测不够Your procedures for testing your (b)(4) system required (b)(4) point-of-use sampling for chemical analysis and (b)(4) sampling for microbiological analysis. Your (b)(4) sampling intervals were inadequate to ensure your (b)(4) meets its specifications before using it for production activities.你们检测XX系统的程序要求在使用点取样进行化学分析，XX取样用于微生物分析。你们的XX取样间隔不足以确保在用于生产活动之前你们的XX符合其质量标准。In your response, you submitted drug product microbial test results. Your response is inadequate. Your results for microbial release testing of your drug product cannot be used to compensate for a poorly designed and maintained (b)(4) system.在你们的回复中，你们提交了一份药品微生物检测结果。你们的回复是不充分的。你们的药品微生物放行检测结果不能用于补偿XX系统的设计和维护不良。Further, you stated that you have not designed your system to control bioburden. However, you also stated that you rely on the (b)(4) system’s filtration components and (b)(4) sanitization program to control the microbial load. You also committed to evaluate your (b)(4) system to identify needed design changes, implement the changes, and revalidate the system.另外，你们声称你们并未设计你们的系统来控制生物负载。但是你们亦声称你们依赖于XX系统的过滤部件和XX消毒程序来控制微生物负载。你们亦承诺会评估你们的XX系统，找出设计所需的变更，执行变更并重新验证系统。Your response is inadequate. Your response did not address leaks from your (b)(4) or the lack of continuous circulation.Your response also lacked scientific details of your overall maintenance program including but not limited to your sanitization program.你们的回复是不充分的。你们的回复并未解决你们的XX的泄漏问题，亦未解决缺乏连续循环的问题。你们的回复亦缺乏你们整体维护计划的科学性细节，包括但不仅限于你们的消毒计划。You also stated that your (b)(4) is tested on a (b)(4) basis. However, the revised sampling procedure included in your response did not revise your microbial monitoring interval. Your sampling intervals remain inadequate. Significantly more frequent microbial monitoring at all points of use for your (b)(4) system is necessary to ensure your (b)(4) meets its established limits before using it as a component for your drug product.你们声称你们的XX检测周期为XX。但是你们回复中修订后的取样程序并未修订你们的微生物监测时间间隔。你们的取样时间间隔仍是不充分的。有必要对你们XX系统的所有使用点均进行更为频繁的微生物监测，以确保你们的XX作为一种组份用于你们的药品生产之前符合其既定限度。In response to this letter, provide the following: 在回复本函时请提交以下内容： #8226; A comprehensive remediation plan for the design, control, and maintenance of the (b)(4)system. #8226; 一份对你们XX系统的设计、控制和维护全面补救计划 #8226; A (b)(4) system validation report. Also include the summary of all improvements made to system design (e.g., newly installed equipment, elimination of deadlegs) and to the program for ongoing control and maintenance. #8226; XX系统验证报告。还要包括对系统设计（例如新安装的设备、清除死管）的所有改进总结，以及持续控制和维护计划的改进总结 #8226; Your total microbial count and objectionable microbes limits to monitor whether this system is producing (b)(4) suitable for the intended uses for each of your products and API. #8226; 你们的总微生物计数和致病菌限度，监测该系统是否能为你们的制剂和API生产出适合其既定用途的XX #8226; A detailed risk assessment addressing the potential effects of your inadequate monitoring on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in responseto the risk assessment, such as customer notifications and product recalls. #8226; 一份说明你们监测不足对所有目前在美国销售的药品批次质量的可能影响的详细风险评估。写明你们应对风险评估结果准备采取的措施，例如通知客户和召回产品 #8226; A procedure for your (b)(4) system monitoring that specifies routine microbial testing of (b)(4)points of use to ensure its acceptability for use in each batch of drug products produced by your firm. #8226; 一份你们XX系统的监测程序，在其中说明XX使用点常规的微生物检测，确保其可用于你公司所生产的每批次药品 #8226; A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits. #8226; 一份持续控制、维护和监测的管理程序，确保补救后的系统能持续产出符合XX、USP各论标准和适当微生物限度的XX #8226; A comprehensive, independent assessment of your laboratory practices and competencies, with special focus on (b)(4) testing methods. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system. #8226; 一份对你们实验室规范和能力的全面独立评估，特别要关注XX的检测方法。根据该审核，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 test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)). 你公司未检测每种组份样品的鉴别和相关项目，确保其符合所有书面的纯度、含量和质量标准。你公司亦未以适当时间间隔验证和建立你们组份供应商的检测分析可靠性(21 CFR 211.84(d)(1) and (2))。Your failed to test incoming components (e.g., (b)(4)) for identity. Identity testing is required for each component lot before use in drug product manufacturing. For example, you did not conduct a specific identity test for (b)(4) used in the manufacture of (b)(4).你公司未对你们的进厂组份XX进行鉴别检测。每种组份在用于药品生产之前应进行鉴别检测。例如，你们并未对XX生产所用XX进行鉴别检测。In addition, your firm used a technical grade of (b)(4) as a component in your drug product. You failed to analyze incoming lots of (b)(4) for the presence of diethylene glycol (DEG) and (b)(4)before use in the manufacture of your drug product. Your (b)(4) supplier’s certificate ofanalysis (COA) did not include testing for DEG (b)(4).另外你们公司使用了工业级的XX作为你们药品的组份。你们在将其用于你们药品生产之前未分析进厂XX批次的DEG和XX。你们的XX供应商COA中没有DEG的检测。DEG contamination has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing for Glycerin for Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin athttps://www.fda.gov/media/71029/download.DEG污染已导致全球多次人类因毒致死事件。参见FDA指南“丙三醇中EG检测”，有助于你们满足CGMP要求前提下生产含有丙三醇的药品。In your response, you stated that you reviewed all raw material specifications and committed to revise the specifications to include identity testing. You also revised the specifications for (b)(4) to include impurity testing for DEG and (b)(4) impurities with a specification limit of Not More Than (NMT) (b)(4). In addition, you committed to evaluating batches distributed to the U.S. for “this impurity” along with related substances. Lastly, you revised your vendor qualification procedure to require qualification of all raw material (component) manufacturers and associated suppliers to verify the reliability of the received COAs.在你们的回复中，你们声称你们审核了所有原料质量标准，承诺会修订质量标准在其中加入鉴别检测。你们还修订了XX的质量标准，在其中包括了DEG和XX杂质的检测，标准限度规定为不得过（NMT）XX。另外，你们还承诺要评估已销售至美国的批准中“该杂质”和有关物质。最后，你们还修订了你们的供应商确认程序，要求对所有原料（组份）生产商和相关供应商均进行确认，核查所收到COA的可靠性。Your response is inadequate. You did not commit to testing all component lots from your retain samples to ensure each were of expected quality for drug product batches within expiry. In addition, you did not provide a plan of action for any lots of components that failed to meet specifications. Lastly, your specifications for DEG and (b)(4) differed from the current USP monograph of NMT (b)(4).你们的回复是不充分的。你们并未承诺对你们留样的所有组份进行检测，以确保效期内的所有药品批次具备预期质量。另外，你们亦未对不满足质量标准的组份批次采取的行动计划。最后，你们的DEG标准和XX与当前USP各论中NMT XX是有差异的。In response to this letter, provide the following: #8226; 在回复本函时请提交以下内容： #8226; A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures. #8226; 一份对你们原料系统的全面独立审核，以确定是否所有组份、容器和密闭器的供应商均经过了确认，且物料有给定适当的有效期或复测期。审核后应确定进厂物料控制是否足以防止使用不适当的组份、容器和密闭器。 #8226; The chemical and microbiological quality control specifications you use to determine disposition of each incoming lot of components before use in manufacturing. #8226; 你们用于检测和放行每批生产所用进厂组份的化学和微生物质量控制标准 #8226; A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. #8226; 说明你们准备如何检测每种组份的每个批准，确保其符合所有适当的鉴别、含量、质量和纯度标准。如果你们准备接受你们供应商的所有COA结果，取代你们对每批进厂物料的含量、质量和纯度检测，则需说明你们准确如何通过初始验证和定期再验证稳固地建立你们供应商结果的可靠性。另外，在其中包括一份承诺，保证会一直对每批进厂物料执行至少一项特定鉴别项目。 #8226; A summary of test results obtained from comprehensive testing of all incoming components to validate the COA from each manufacturer of raw material. #8226; 一份所有组份检测所得结果的汇总，以评估来自每个组份生产商的COA的可靠性，其中要包括你们阐述该COA验证程序的SOP。 #8226; A commitment that you will use only pharmaceutical-grade components going forward. #8226; 承诺你们往后只会使用药用级的组份 #8226; Results of tests for DEG and (b)(4) in retain samples of all (b)(4) lots used to manufacture your drug products. #8226; 你们药品生产所用的所有XX批次中的留样中XX和DEG检测结果 #8226; A full risk assessment for drug products that contain (b)(4) and are within expiry in the U.S. market. Take prompt corrective actions and preventive actions, and detail your future actions to ensure appropriate selection of your suppliers, ongoing scrutiny of their supply chain, and appropriate incoming lot controls. #8226; 一份对含有XX的药品在美国仍在效期内批次的全面风险评估。采取立即纠正措施和预防措施，以及详细说明你们未来的措施，以确保对供应商的适当选择，对其供应链的持续严格审查，以及对进厂批次的适当控制 #8226; A full risk assessment for drug products manufactured with component lots that did not include testing for identification that are within expiry in the U.S. market. Take prompt corrective actions and preventive actions, and detail your future actions to ensure appropriate selection of your suppliers, ongoing scrutiny of their supply chain, and appropriate incoming lot controls. #8226; 对于采用未检测鉴别项的组份批次生产的销往美国且在有效期内的药品的全面风险评估。立即采取纠正和预防措施，详细说明你们未来的措施，以确保对供应商的适当选择，对其供应链的持续严格审查，以及对进厂批次的适当控制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 qualifiedas set forth in 21 CFR 211.34 to 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.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。Conclusion 结论The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility.You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of 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。Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug 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。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 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 toCDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to: Michael Klapal
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response with FEI 3009167769.Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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