FDA警告信：483信回复太草率

9月15日，FDA公布一封针对印度企业的警告信，包括了制剂和API违反GMP的情况。制剂主要的违规项包括检验问题、未能有效执行工艺验证、系统设计存在死角等问题；API的违规主要集中于清洁及清洁验证问题。

值得注意的一个细节是，公司的回复时指出已按照要求修改了清洁程序。但FDA表示，该回复中提供的清洁程序，与检查期间FDA收集的程序是相同的，表明FDA认为该公司的回复工作不充分、不细致。

September 4, 2020

Dear Mr. Chimthanawala:

2020年9月4日

尊敬的Chimthanawala先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mayons Pharmaceuticals, Pvt. Ltd., FEI 3010910756, at Old Kamptee Road, Behind Octroi Naka No. 4, Kalamna, Nagpur, Maharashtra from February 17 to 20, 2020.

2020年2月17日至20日，美国FDA检查了您的药品生产设施Mayons 制药(FEI 3010910756)，位于(印度)马哈拉施特拉邦。

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

该警告信总结了严重违反制剂CGMP规定的情况，见21CFR第210和211部分;同时也总结了有效活性成分(API)GMP的偏移情况。

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).

由于您用于生产、加工、包装或储存的方法、设施或控制措施不符合CGMP，因此根据FD＆C法案501(a)(2)(B)条及21 U.S.C.351(a)(2)(B) 条的规定，您的药品被认为是掺假。

We reviewed your March 14, 2020, response and subsequent responses to our Form FDA 483 in detail.

对于您2020年3月14日对FDA 483表格的回复及之后的回复, 我们进行了审查。

During our inspection, our investigator observed specific violations including, but not limited to, the following.

在我们的检查过程中，调查员发现了具体的违规行为，包括但不限于以下行为。


Finished Drug Violations成品药违规

检验问题
1. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to test each component for conformity with all appropriate specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and (2)).

1.公司未进行至少一项检验来确认药品中每种成分的鉴别。公司也没有检验每个组分是否符合纯度、强度和质量方面适当的质量标准(21 CFR 211.84(d)(1)和(2))。

Your firm failed to test incoming components used to manufacture your in-process homeopathic materials and finished homeopathic drug products to determine identity, purity, strength, and quality. For example, you did not test (b)(4), which contains (b)(4), used in your (b)(4), for identity. You also failed to perform appropriate identity testing of (b)(4) used in products such as (b)(4).

公司未能检验入厂组分，来确定鉴别，纯度，强度和质量，这些组分用于顺势疗法中间体和最终顺势疗法药品。例如，您没有检验XX(其中包含在XX中使用的XX)的鉴别。您也未能执行适当的鉴别检验XX在产品中使用，如XX 。

Furthermore, you failed to determine whether each component, such as (b)(4), conformed with all appropriate specifications for purity, strength, and quality before using them. Your firm did not qualify the suppliers of the components used in your products and you could not provide scientific evidence that your components are compliant with appropriate specifications. Your drug products have been used in the development of (b)(4) homeopathic (b)(4) products.

此外，在使用它们之前，您无法确定每个成分(例如XX)是否符合纯度、强度和质量的所有适当质量标准。对于产品所用组分供应商，公司没有进行资质确认，并且您无法提供科学证据证明您的组分符合适当的质量标准。您的药品已用于开发XX顺势疗法XX产品。

In response to this letter, provide:

针对此信，请提供：

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

•用于检验和放行每批入厂组分的化学和微生物QC质量标准（组分用于生产目的）。

• 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 Certificates Of Analysis (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.

•就是否符合有关鉴别、强度、质量和纯度的适当质量标准，说明如何检验每个批号。如果您接受供应商的分析证书(COA)的任何结果，而不是检验每个组分的强度、质量和纯度，请说明：如何通过初始验证和定期再验证，来稳健地确定供应商结果的可靠性。此外，还应承诺始终对每个入厂的组分批次，至少进行一个特定的鉴别检验。

• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your Standard Operating Procedure (SOP) that describes this COA validation program.

•结果摘要：对所有组分进行检验，以评估每个组分生产商的COA可靠性。包括描述此COA验证程序的标准操作程序(SOP)。

• A summary of your program for qualifying and overseeing contract facilities that test raw material you use and the drug products you manufacture.

•确认和监督合同设施的计划摘要，这些设施对原物料和所生产的药品进行检验。

生产和过程控制
2. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

2.公司未建立用于生产和过程控制的书面程序，以确保您所生产的药品具有其声称或代表拥有的鉴别、强度、质量和纯度(21 CFR 211.100(a))。

You released numerous batches of drugs, some of which contain ingredients with toxic components, without validating your manufacturing process. For example, you manufactured and distributed (b)(4) to the United States without data that supports the product quality and homogeneity.

您放行了许多批次的药物，其中有些包含具有毒性成分，而没有验证您的生产工艺。例如，您在没有支持产品质量和同质性的数据的情况下，将XX生产和分发到美国。

Your response stated you developed a process validation master plan, but you provided only a validation protocol for your (b)(4) products. You did not provide a timeline or detailed plan to ensure all products are manufactured using validated processes.

您的答复表明您制定了工艺验证总体计划，但仅提供了XX 产品的验证草案。您没有提供时间表或详细计划，来确保所有产品都是使用经验证的工艺生产的。

In response to this letter, provide the following:

针对此信，请提供：

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

•验证计划的详细摘要、相关程序：如何确保整个产品生命周期中的控制状态。描述您的计划，以进行工艺性能确认，并持续监测批内和批间变化，以确保持续的控制状态。

• A timeline for performing appropriate process performance qualification for each of your marketed drug products. Include your process performance protocols, and written procedures for qualification of equipment and facilities.

•对每种上市药品执行适当的工艺性能确认(PPQ)的时间表。包括您的工艺性能草案，以及用于设备和设施确认的书面程序。

系统设计问题

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).

3.公司未在生产、加工、包装或保存药品过程中，使用设计合理、尺寸适当且位置合适的设备，以实现预期用途及清洁和维护操作(21 CFR 211.63) )。

Your (b)(4) system, which provides (b)(4) for the formulation of some of your homeopathic drug products, was not designed to consistently produce (b)(4). Our investigator observed dead legs, dripping (b)(4), and threaded piping. There should be no threaded fittings in a pharmaceutical (b)(4) system.

您的XX系统为某些顺势疗法药品的配方提供XX，但设计不能保证始终如一地生产XX。我们的研究人员观察到了死角，滴水XX和螺纹管道。药物XX系统中不应有螺纹接头。

In your response, you provided photographs showing adjustments to your (b)(4) system design that appear to lessen the severity of the design flaws, but do not resolve them. You also stated that you initiated a detailed gap and impact assessment but did not provide supporting documentation.

在您的答复中，您提供了显示对XX系统设计进行调整的照片，这些调整似乎可以减轻设计缺陷的严重性，但不能解决这些缺陷。您还说过，您已经开始了详细的差距和影响评估，但是没有提供支持文档。

In response to this letter, provide:

针对此信，请提供：

• A comprehensive remediation plan for the design, control, and maintenance of the (b)(4) system.

•有关XX系统的设计、控制和维护的综合补救计划。

• Validation report for the (b)(4) system obtained after all identified design issues have been fully corrected and any maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report.

• 在完全纠正所有已识别的设计问题、并且完成所有维护维修之后，获得XX系统的验证报告。包括系统验证草案、完整的检验结果和最终的验证报告。

• A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

•进行详细的风险评估，就观察到的XX系统故障，解决对目前在美国分销的所有药品批次质量的潜在影响。说明您将对风险评估采取的措施，例如客户通知和产品召回。

• The current action/alert limits for total counts and objectionable organisms used for your (b)(4) system. Ensure that the total count limits for your (b)(4) are appropriately stringent in view of the intended use of each of the products produced by your firm.

•就XX系统所使用的微生物总计数和有害微生物，提供当前行动限和警戒限。考虑到公司生产的每种产品的预期用途，请确保您XX的总计数限度适当严格。

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that is suitable for its intended use.

•控制程序的程序，以进行持续的控制、维护和监视，以确保修复的系统始终产生适合其预期用途的XX。

API Deviations API偏差

清洁问题
1. Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the API beyond the official or other established specifications.

1.未能清洁设备和用具，以防止污染或残留会改变API质量、以至超出了官方或其他既定质量标准。

Your firm manufacturers homeopathic in process materials and (b)(4) from various raw materials. Our investigator observed unidentified debris in the (b)(4) of your (b)(4) equipment, which is used to process multiple raw materials for homeopathic (b)(4), including (b)(4) containing (b)(4). This equipment was marked as clean.

公司使用各种原材料，生产顺势疗法中间体和XX。我们的 调查员在XX设备的XX中，观察到未识别的碎片，该设备用于处理顺势疗法XX的多种原材料，其中包括XX。该设备被标识为“已清洁”。

Your response states that you filed a deviation and re-trained your staff. This response is inadequate because you failed to identify the observed debris and perform an impact assessment for the drugs that were manufactured using this dirty equipment.

您的答复指出，您启动了偏差、并重新培训了员工。由于您没有鉴别观察到的碎片、且没有对使用此肮脏设备生产的药物进行影响评估，因此此响应不充分。

In response to this letter, provide:

针对此信，请提供：

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product, including both API and finished products.

•对清洁效果进行全面、独立的回顾性评估，以评估交叉污染危害的范围。包括残留物的鉴别、可能未正确清洁的其他生产设备，以及评估交叉污染产品是否可以放行和分销。评估应确定清洁程序和实践的任何不足之处，并涵盖用于生产多产品(包括原料药和成品)的每台生产设备。

• A corrective and preventive action plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning execution for all products and equipment, and all other needed remediations.

•基于回顾性评估的CAPA计划：其中包括清洁工艺和实践的适当补救措施，以及完成时间表。就设备清洁的生命周期管理，提供其流程漏洞的详细摘要。描述您的清洁程序的改进，包括增强清洁效果；就对所有产品和设备正确执行清洁，提供持续确认的改进；以及所有其它需要的补救措施。

清洁验证
2. Failure to establish adequate written procedures for cleaning equipment and its release for use in manufacture of API.

2.没有建立充分的书面程序来清洁设备、及放行设备用于API的生产。

You do not have adequate cleaning procedures for the equipment you use to manufacture multiple homeopathic products. You did not validate the methods you used to clean your equipment. Inadequate removal of raw materials and residues from manufacturing equipment during cleaning can lead to cross-contamination of material used in your homeopathic (b)(4).

针对生产多种顺势疗法产品所用的设备，您没有充分的清洁程序。您没有验证用于清洁设备的方法。在清洁过程中，如果从生产设备中去除原料和残留不充分，会导致顺势疗法XX中使用的物料存在交叉污染。

Your response states that you revised your cleaning procedure, but the cleaning procedure provided in your response is the same as the one collected during our inspection and is not indicative of any revisions. You also failed to provide a plan or supporting documentation for a cleaning validation program. This response is inadequate because it does not establish systemic procedures and controls for your cleaning program to prevent cross-contamination.

您的回复指出您已修改清洁程序，但您的回复中提供的清洁程序与我们检查期间收集的清洁程序相同，也没有表示发生了任何修订。您还没有提供清洁验证程序的计划、或支持文档。该响应是不充分的，因为它没有为您的清洁程序建立系统性程序和控制措施，以防止交叉污染。

In response to this letter, provide:

针对此信，请提供：

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

•对清洁验证程序进行了适当的改进，特别着重于纳入在药品生产工艺中确定为最差情况的条件。最差情况的识别和评估，应包括但不限于：

o products with higher toxicities

o products with higher potencies

o products of lower solubility in your cleaning solvents

o products with characteristics that make them difficult to clean

o swabbing locations for areas that are most difficult to clean

o maximum hold times before cleaning

o具有较高毒性的

o产品具有较高活性的

o产品在清洁溶剂中溶解度较低的产品

o具有使其难以清洁的特性的产品

o 清洁最困难区域的擦拭位置

o清洁前的最长放置时间

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

另外，描述在引入新的生产设备或新产品之前，变更管理系统必须采取的步骤。

• A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.

•更新的SOP的摘要，以确保制定适当的程序，来验证和确认产品、工艺和设备的清洁程序。

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

本信函中引用的违规行为并非旨在列出与您的产品相关的所有违规行为。您有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。

FDA placed your firm on Import Alert 66-40 on July 13, 2020.

FDA于2020年7月13日将公司置于进口警报66-40上。

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.

在您完全纠正所有违规行为、且我们确认您遵守CGMP之前，对于新药申请或补充申请，FDA可能会拒绝批准将公司列为药品生产商。

Failure to correct these violations may also result in the FDA refusing admission of articles manufactured at PT. MegaSurya Mas, J1 Tambak Sawah 32, Sidoarjo 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).

根据FD＆C法案21 801(a)(3)条与USC 381(a)(3) 条，不纠正这些违规行为也可能导致FDA拒绝接纳该工厂生产的产品，无法进入美国。对于该法案授权下的产品，可能会被拒绝入境，因为其生产使用的方法与控制不符合CGMP，CGMP是在FD＆C法案21(501)(a)(2)(B) 条与USC 351(a)(2)(B) 条中被要求的。

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.

收到这封信后，请在15个工作日内以书面形式答复FDA办公室。说明自我们检查以来，您所做的事情，以纠正您的违规行为，并防止其再次发生。如果您无法在15个工作日内完成纠正措施，请说明延误原因和完成时间表。

If you have evidence or information that you believe demonstrates that your products are not in violation of the FD&C Act and FDA regulations, include that evidence or information for our consideration.

如果您有证据或信息证明您认为自己的产品未违反FD＆C法案和FDA法规，请提供该证据或信息供我们考虑。

       文章来源：PharmLink

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