FDA警告信：你们对XX偏差的调查不充分

翻译：JULIA 来自：Julia法规翻译

Warning Letter 320-19-29 July 9, 2019

Mr. Suresh G. Kare

Chairman, Indoco Remedies Limited

Indoco House, 166 CST Road, Santacruz (E), Mumbai 400 098 India

Dear Mr. Kare:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Indoco Remedies Limited (Plant I) at L-14 IDC Verna Industrial Road, Vasco Da Gama, Goa, from January 17 to 25, 2019.

美国FDA于2019年1月17日至25日检查了你们位于印度果阿邦的Indoco Remedies Limited (PlantI)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与211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not 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&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 February 15, 2019, response indetail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2019年2月15日的回复，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 toprepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR211.188). 你公司未制订批生产和检验记录，在其中包括与所生产每批药品的生产和检验有关完整信息（21 CFR 211.188）。

Compression machine process control values were not adequately reported in your batch production records during the manufacture of (b)(4) mg tablets intended for the U.S. market. Your quality unit used these deficient records to release batches of this drug product.

准备在美国销售的XX片剂生产过程中压片机工艺控制值在你们的批生产记录报告不充分。你们质量部分使用这些有缺陷的记录放行了这些药品批次。

While multiple batch records of (b)(4)mg tablet included handwritten values routinely within process parameters, the values recorded by the programmable logic controller (PLC) of your compression machine were frequently outside your established process parameters. For example, (b)(4)mg batch (b)(4)had compression force valuesh and written (b)(4)in the batch record ranging from (b)(4)(your limit was (b)(4)).

虽然多批XX片剂生产记录中有手写值均在工艺参数范围内，但你们压片机PLC所记录的值频繁超出你们设定的工艺参数。例如，批记录中手写的XX片剂的压力值为XX（你们的限度为XX）。

However, the PLC data recorded individual values ranging from (b)(4)for the same time period. In addition to compression force values, handwritten values for filling depth and automatic weight control (AWC) did not accurately reflect the values within the PLC data.

同一时间段内PLC数据所记录单值从XX至XX。除了压力值外，自动重量控制（AWC）和充填高度的手写值亦不能准确反映PLC数据中的值。

An inspection conducted by the (b)(4)in March 2018 found similar discrepancies between the compression force values in batch records and PLC data.

2018年3月由XX执行的检查中发现类似缺陷，看到批记录中和PLC中的压力值有差异。

Your response acknowledged discrepancies including missing data, “mis-matched data,” non-contemporaneous entries, and other inconsistencies in your batch records. It also acknowledged inadequate procedures for compression machine setup and adjustments during operations intended to maintain process control, and a lack of documentation of these critical activities.

你们的回复讲了这些情况，包括数据缺失、“不匹配的数据”、未同步录入和其它批记录中的不一致情况，还承认用于维护工艺控制的压片机设置和操作过程中调整程序不够充分，缺乏对这些关键动作的文件记录。

Your response is insufficient. The integrity of all data within your manufacturing records is called into question by the actions of your staff involved in compression operations. You did not commit to perform a comprehensive retrospective evaluation of the integrity of data throughout your manufacturing operation. You also did not adequately address how you will ensure that AWC is consistently maintained and documented throughout compression by providing detailed procedures for setup and changing of parameters during a batch, and address how all associated parameters will be controlled.

你们的回复是不充分的。你们生产记录中所有数据的完整性因为你们压片操作员工的动作而引起质疑。你们未承诺对整个生产操作中的数据完整性进行全面回顾性评估，亦未充分说明你们要如何通过提供在一批生产过程中详细的参数设置和修改程序确保AWC在整个压片过程中得到一致维护和记录，亦未说明如何对所有相关参数进行控制。

It is essential that you use appropriate continuous process controls to promptly respond to variation in your process, and prevent sporadic loss of control during processing. Additionally, you did not sufficiently detail your batch record changes for each strength of (b)(4) tablets.

使用适当的连续工艺控制以对你们工艺波动进行快速响应，防止生产过程中偶发性失控是非常有必要的。另外你们亦未足够详细地说明你们对每个剂量XX片剂的批记录修改情况。

In response to this letter, provide: 在回复此函时请提交

Procedures that establish use of appropriate AWC and other control procedures in your compression operation. This includes but is not limited to detailed procedures for batch setup and subsequent adjustments for AWC; identification of all parameters that can impact consistency of compression; and complete documentation of all batch production activities.
建立适当AWC和其它压片操作控制程序，其中包括但不仅限于AWC的批设置和后续调整详细程序、识别出所有可能影响压片一致性的参数，以及所有批生产活动的完整记录。
Your updated master production and control batch records for drug products that fully document each manufacturing operation. Also submit your most recent executed batch production and control record with full machine printouts for each strength of your (b)(4) tablet drug product.
更新后的药品主生产和检测记录，可完整记录每个生产操作。亦请提交你们最近执行的批生产和检测记录，包括你们XX片剂每个剂量的完整设备打印件。
An independent review of all your process parameters for the manufacture of your (b)(4)dosage form drug products to ensure adequacy of ranges, setup parameters, and in-process monitoring for detecting variation in your process.
一份对你们XX剂型药品生产的所有工艺参数的独立审核，以确保范围、设置参数的精密度，以及发现工艺波动的过程监测。
A data-driven and scientifically sound program that identifies and controls variability, to ensure production and packaging processes consistently meet appropriate manufacturing standards and parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.
由数据支持的发现和控制波动的科学合理程序，以确保生产和包装过程能一直符合适当的生产标准和参数。其中包括但不仅限于评估设备是否适合其既定用途、确保输入物料的质量，以及确定每个生产工艺步骤和控制的能力与可靠性。
Your corrective action and preventive action (CAPA) plan as requested in the Data Integrity Remediation section of this letter below. As one facet of the comprehensive CAPA plan, an independent reviewer(s) should provide a thorough retrospective assessment of manufacturing data validity since February 1, 2016, and perform thorough interviews of production staff (both operators and supervisors). This assessment should augment the internal investigation that you have performed and include but not be limited to an independent review of the integrity of (b)(4)in-process checks (b)(4)and disintegration testing, and evaluate any missing compression operation data. The retrospective assessment should fully determine the degree to which this in-process testing data has information gaps (whether due to omissions or lost data), personnel sign-offs occurred at times where staff were not present, and to what extent current data can be relied upon for this product and other products.
本函以下数据完整性补救措施部分中要求的CAPA计划。作为CAPA计划的一部分，应由一位独立审核人员提交一份对2016年2月以来的生产数据有效性的彻底回顾性评估，并对生产员工进行深入面谈（操作员和主管）。此项评估应在你们之前已执行调查的基础上进行扩展，包括但不仅限于对中控检查XX和崩解试验完整性的独立审核，以及对所有缺失压片操作数据的评估。回顾性评估应全面确定该中控测试数据资料缺失的程度（是否由于疏忽或数据丢失）、员工不在场时的签名情况，以及该产品和其它产品当前数据可依赖的程度。

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). 你公司未能彻底调查已销售或未销售的批次及其组份偏离或不符合质量标准的情况（21 CFR 211.192）。

Your investigation into discrepancies found within (b)(4) mg tablet batch records was inadequate.

你们对XX片剂批次记录偏差的调查是不充分的。

Specifically, document DEV-G1-18-033 provided the details of your investigation into multiple batch record discrepancies between compression force values written in (b)(4)mg batch records and the data electronically recorded in the PLC of compression equipment. Your investigation was inadequate because it lacked the following:

具体来说，偏差DEV-G1-18-033中讲了你们对多批次生产记录中手动记录的压力值与压片机PLC中电子数据不一致的调查详情。你们的调查是不充分的，其中缺乏以下内容：

A review of the integrity of the data by contrasting handwritten and electronic data for all process control values recorded by your PLC during (b)(4)tablets manufacture to determine if other discrepancies had occurred.
对比XX片剂生产期间手书和PLC记录的电子数据中所有工艺控制值，从而对数据完整性进行回顾，以确定是否曾发生过其它偏差。
A sufficient extension of your investigation to other strengths of (b)(4)batches and other products manufactured at your facility.
将调查充分扩展至你们工厂生产的其它剂量批次和其它药品。
A substantive root cause for the significant variability of compression machine process control values throughout the manufacturing of (b)(4)tablets.
在XX片剂生产过程中压片机工艺控制值严重波动的实质性根本原因。
A CAPA plan to resolve the root causes of this variability.
解决此波动根本原因的CAPA计划。

In your response, you stated the deviation was aresult of your staff’s belief that it was acceptable to proceed with compression operations and overlook aberrant equipment control values (e.g.,compression force, fill depth, AWC) if all key tablet attributes were within specification.

在你们的回复中，你声称该偏差是因为你们员工相信如果关键片剂属性在质量标准范围内，则继续压片操作是可接受的，忽视了设备控制值异常（例如压力、充填高度、AWC）。

Your response acknowledged that your original investigation was limited and not holistic, and as a result it did not sufficiently determine the scope of the data integrity issues and the causes. Your response is inadequate because you did not provide an adequate root cause of the high variability of process parameters such as fill depth and compression force, and why these values contrasted with the far tighter control demonstrated throughout compression of your validation batches. You did not adequately address the impact of the atypical values on batch quality.

你们在回复中承认你们原来的调查是有局限的，不够全面，因此未能充分确定数据完整性问题的范围以及偏差原因。你们的回复是不充分的，因为你们并未提交工艺参数（如充填高度和压力）严重波动的足够的根本原因，以及为何这些值与你们验证批次的压片过程中所展示的严格很多的控制完全不一样。你们未充分解决异常值对批质量的影响问题。

In response to this letter, provide: 在回复此函时请提交

A retrospective, independent evaluation comparing process control values manually recorded within the batch records and the values recorded electronically within the PLC for all strengths of (b)(4)batches manufactured for the U.S. market. For example, this evaluation should identify any time periods of tablet compression in which the AWC was set to the “off” position and address the quality of those tablets manufactured during those periods.
比较为美国市场生产的XX产品所有剂量批次的批记录中手动记录的工艺控制值和PLC内电子记录数据值，提交一份回顾性独立评估。该评估中应识别出如AWC设置为“关”的所有压片时间段，并说明在此期间所生产片剂的质量情况。
A detailed risk assessment for drug products within expiry in the U.S. market that were compressed under these poorly documented production conditions. Take appropriate corrective actions based on the risk assessment.
一份对美国市场仍在效期内的在这不良记录生产条件下压片的药品的详细风险评估。根据风险评估采取适当的纠正措施。
A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification (OOS) results, and failures. Your 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.
对你们偏差、异常事件、投诉、OOS结果和失败情况进行调查的整体系统的独立全面评估。你们的CAPA应包括但不仅限于提高调查能力、改进根本原因分析、改进书面程序以及强化质量部门监管，亦要包括你们评估CAPA有效性的流程。

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). 你公司未能确保实验室记录中包括的所有为确保符合既定质量标准而执行的检测中生成的完整数据（21 CFR 211.194(a)）。

On several occasions, you conducted a new analysis after obtaining an initial OOS test result. These analyses included water content tests on a Karl Fischer instrument and an assay test on an auto titrator instrument. We reviewed the electronic data on these instruments and found OOS testing results which were not reported in the analytical records. Only passing results were ultimately included in the data presented for batch review and disposition decisions.

在几种情形下，你们在获得初始OOS检测结果之后进行了新的检测。这些检测包括KF水含量和自动滴定仪的含量检测。我们审核了这些仪器上的电子数据，发现有OOS检测结果在分析记录中未报告，只放入了最终合格的结果呈交批审核和处置决策。

Additionally, your laboratory failed to maintain basic raw laboratory data (e.g., original raw data sheets, original chromatograms, instrument usage logs, original weight printouts) in many instances.

另外，你们化验室有许多未能维护基本的实验室原始数据（即原始数据表、原始图谱、仪器使用日志、原始称重打印件）的例子。

For example, the initial assay tested using the auto titrator instrument for the active pharmaceutical ingredient (b)(4), batch (b)(4), was conducted on December 29, 2018, at 13:50. The initial result was OOS at (b)(4)% (specification (b)(4)%). The official release data for the assay testing was reported as within specification at (b)(4)% on December 29, 2018, at 15:00. The official release package did not include the initial OOS result of (b)(4)%. No investigation was performed.

例如，20181229 13:50采用自动滴定仪检测的XX原料药含量初始结果是OOS（结果为XX%，标准为XX%）。20181229 15:00正式的放行数据中含量报告为符合标准。正式放行包中未包括初始OOS结果，未进行调查。

In your response, you indicated that 10 additional cases of unreported OOS results were found, in addition to the nine observed during the inspection. You also discovered 23 instances where the initial results were not OOS but you had repeated testing without justification for the additional analysis.

在你们的回复中，你们说除了检查中发现的9起外，另外有10起未报告OOS的案例。你们还发现有23起案例初始结果并非OOS，但没有进行论证即重复了检测。

Your response is inadequate because it did not address the disposition of lots affected by these OOS results discovered during the inspection.

你们的回复是不充分的，因为你们并未说明如何处置受这些检查中所发现OOS结果影响的批次。

In response to this letter, provide: 在回复此函时请提交

A retrospective, independent review of all invalidated OOS (in-process and finished testing) results for all products since June 1, 2016. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that establish laboratory root cause, ensure that you identify other laboratory methods vulnerable to the same root cause for remediation.
一份对2016年6月1日以来所有产品宣布无效OOS（中控和成品）结果的回顾性独立审核。对于已确定实验室根本原因的调查，确保你们已识别出其它受相同根本原因影响的实验室类似方法，并进行补救。
A thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, batch failure history) for any OOS results with inconclusive or no root cause identified. A CAPA plan should identify manufacturing root causes and specify meaningful improvements.
对生产进行彻底审核（例如，批生产记录、生产步骤的充分性、原料、工艺能力、偏差历史、批失败历史），查看是否有不支持结论的或未找到根本原因的OOS结果。应有CAPA计划识别出生产根本原因，并制订实质性改进措施。
A risk assessment for any drug products in the U.S. market within expiration date for which an OOS result was obtained. Take appropriate actions, including customer notifications or recalls, if drug quality may be impacted.
一份对所有在美国市场仍在效期内有OOS结果的药品的风险评估。采取适当的措施，包括通知客户或召回（如果药品质量受到影响）。
A review and remediation of your system for investigating OOS results. Provide a CAPA plan to improve OOS handling. Your CAPA plan should ensure that your revised OOS investigations procedure includes:
对你们OOS结果调查系统进行回顾和补救。提交一份CAPA计划改进OOS处理程序。你们的CAPA计划应确保你们修订后的OOS调查程序包括：

Enhanced quality unit oversight of laboratory investigations
强化质量部门对实验室调查的监管
Identification of adverse laboratory control trends
识别出不良QC趋势
Resolution of causes of laboratory variation
解决实验室波动原因
Investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified
如果未发现可支持结论的实验室原因时，调查潜在生产原因

A comprehensive, independent review of your laboratory practices, procedures, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to remedy your laboratory system. Your plan should include the process you will use to evaluate the effectiveness of the implemented CAPA plan.
一份对你们实验室规范、程序、方法、设备和化验员资质的全面独立审核。根据该审核报告，提交一份详细的CAPA计划，补救你们的实验室系统。你们的计划应包括你们用于评估所执行CAPA计划有效性的流程。

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, andquality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance with Drug CGMPfor guidance on establishing andfollowing CGMP compliant data integrity practices at https://www.fda.gov/downloads/drugs/guidances/ucm495891.pdf

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 you retain 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：

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

A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
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
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.
对在职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。
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.
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。
A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with expertise in the area where potential breaches were identified, evaluate all data integrity lapses.
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 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.

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：

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.
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。
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.
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。
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.
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、召回产品、执行额外检测、增加批次至稳定性计划以确保稳定性、药品申报措施和加强投诉监测。
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.
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。
A status report for any of the above activities already underway or completed.
对上述活动已开展或已经完成的状态报告。

Process Controls 工艺控制

Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document Process Validation:General Principles and Practicesfor general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

你公司没有足够的持续计划用以监测工艺控制，从而确保稳定的生产操作和一致的药品质量。参见FDA指南文件“工艺验证通则与规范”。

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 highly qualified in data integrity as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.

根据我们在你们公司发现的违规情况，我们强烈建议你们聘请具备21CFR211.34要求资质的顾问协助你们符合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.

你们聘用顾问并不能免除你公司的CGMP合规义务。你公司的高级管理人员仍有义务全面解决所有缺陷和系统瑕疵，确保持续CGMP合规。

Quality Systems 质量体系

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulationsfor help 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.

你们公司的质量体系是不充分的。参见FDA指南文件：药品CGMP质量体系，以帮助你们实施质量体系和风险管理方法，符合21CFR第210和211部分的要求。

Conclusion 结论

Violations cited in this letter are not intended asan 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。

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 Staffalso allows you to meet any obligations you may have to report discontinuances 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。

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 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 violations may also resultin FDA refusing admission of articles manufactured at Indoco Remedies Limited (Plant I) at L-14 IDC Verna Industrial Road, Vasco Da Gama, Goa, 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, inthat 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 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.govor mail your reply to:

Joseph Lambert, Pharm.D.

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3006644152.

Sincerely,

/S/