FDA最新警告信：物料免检，评估了没？

11月10日，FDA公布一封针对墨西哥企业(Nartex Laboratorios Homeopaticos)的警告信。主要的缺陷项涉及：缺少验证与确认、物料检验不充分。

在检查期间，该公司向FDA的调查员提供了一份带有签名的书面声明，确认未对分发给美国市场的药品执行任何工艺验证或设备确认。对于进厂物料，该公司依赖于供应商的COA，进行了多项免检，但没有验证供应商的COA。

Warning Letter 320-21-07

November 4, 2020

Dear Mr. Acosta:

警告信320-21-07

2020年11月4日

尊敬的Acosta先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Nartex Laboratorios Homeopaticos, S.A. de C.V., FEI 3009407408, at Calzada Lazaro Cardenas 708-770, Col. Eduardo Guerra, Torreon, Coahuila de Zaragoza, from February 24 to 28, 2020.

2020年2月24日至28日，美国食品药品监督管理局(FDA)检查了你们的药品生产设施Nartex Laboratorios Homeopaticos, SA de CV，FEI 3009407408，位于墨西哥科阿韦拉。

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 201 and 211).

该警告信总结了严重违反制剂CGMP规定的情况。请参阅21CFR第210和211部分。

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，你们的药品被认为是掺假。

We reviewed your March 19, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们详细审查了你们2020年3月19日对FDA 483表格的答复，并确认收到你们的后续信件。

During our inspection, our investigator observed specific violations and deviations 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。

未充分验证工艺
1. Your firm failed to establish adequate 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)).

1.公司未建立用于生产和过程控制的书面程序，以确保你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))。

Your firm did not adequately validate the process and qualify the equipment used to manufacture your drug products. During the inspection, your firm provided our investigator a signed statement acknowledging that your firm had not performed any process validation or equipment validation for a variety of your homeopathic drug products distributed to the United States.

你们公司未充分验证工艺，并对用于药品生产的设备进行确认。在检查期间，你们公司向我们的调查员提供了一份签名声明，确认你们公司未对分发给美国的多种顺势疗法药品执行任何工艺验证或设备确认。

In your response, you provided validation documents for two drug products. You stated you would validate six additional drug products marketed to the United States. You further stated that you do not plan to initiate process validation for the remaining  (b)(4) drug products due to lack of demand or discontinuing the drug product for the United States in 2020.

在答复中，你们提供了两种药品的验证文件。你们说你们将验证另外六种销售到美国的药品。你们还声明，由于需求不足或2020年在美国市场停止生产某些药物，你们不打算针对其余XX药品启动工艺验证。

You response is inadequate. You did not perform a risk assessment for the drugs shipped to the United States without adequate process validation. Given that several of the drug products you produced for the U.S. market contains potentially toxic ingredients (e.g., (b)(4), (b)(4), and (b)(4)), failure to validate processes to identify and control sources of variation could place consumers at risk.

你们的回应不充分。对于未经充分的工艺验证而分销美国的药物，你们没有进行风险评估。鉴于你们为美国市场生产的几种药品都含有潜在的有毒成分(例如XX，XX和XX)，因此未通过验证工艺来识别和确定控制变化的来源，可能会使消费者面临风险。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and drug products. Process qualification studies determine whether an initial state of control has been established.

工艺验证会评估整个流程生命周期中设计的合理性和控制状态。生产工艺的每个重要阶段都必须进行适当的设计，并确保原材料输入、在制品和药品的质量。通过工艺确认研究，可以确定是否已建立初始控制状态。

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

商业放行之前，必须进行成功的工艺确认研究。此后，有必要对过程性能和产品质量进行持续的监督，以确保你们在整个产品生命周期中保持稳定的生产操作。

See FDA guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

请参阅FDA的指南《工艺验证：一般原则和实践》，以获取FDA认为工艺验证适当要素的一般原则和方法。

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.

•有关确保整个产品生命周期中的控制状态的验证项目的详细摘要，以及相关程序。描述你们的程序，以进行工艺性能确认，并持续监控批内和批间变化，以确保持续的控制状态。

• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.

•对每种上市药品执行工艺性能确认(PPQ)的时间表。

• Your process performance protocols, and written procedures for qualification of equipment and facilities.

•包括你们的工艺性能草案，以及书面的设备和设施确认程序。

• Risk assessment for product that remains on the market within expiry. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.

•对到期后仍在市场上销售的产品进行风险评估。指定你们将对风险评估采取的措施，例如客户通知和产品召回。

入厂检验
2. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).

2.你们公司未能检验每个组分样品，已确定是否符合有关纯度、强度和质量的书面质量标准(21 CFR 211.84(d)(2))。

During the inspection, it was observed that you do not adequately test components prior to use in the manufacture of drug product destined for the United States. Although you conduct identity testing on incoming lots of components, you rely on supplier certificates of analysis (COA) for conformity with all other appropriate written specifications for purity, strength, and quality. You did not validate your supplier COA for appropriate written specifications for purity, strength, and quality.

在检查过程中，发现你们在生产用于美国的药品之前，没有充分检验组分。尽管你们对入厂批号进行了鉴别检验，但依赖供应商分析证书(COA)，来确保其纯度、强度和质量符合所有其他适当的书面质量标准。针对纯度、强度和质量的适当书面质量标准，你们没有验证供应商的COA。

In your response, you committed to revise your procedure to include “when verification of the Certificate of Analysis (COA) or certificate of Conformance (COC) for materials is used in our products for the US market that are received from our approved suppliers is necessary.”

在你们的答复中，你们承诺修改程序，以包括“对于美国市场产品中使用物料，当从认可的供应商处获得分析证书(COA)或合格证书(COC)的时，何时有必要进行确认。”

Your response is inadequate in that it lacked sufficient detail for how each component will be tested for conformance with all appropriate written specifications for identity, strength, quality, and purity. Additionally, it is unclear if you plan to rely on your suppliers COA test results (with the exception of identity) in lieu of testing, as you did not provide detail about how you plan to establish the reliability of your supplier COA through appropriate validation of the supplier test results at appropriate intervals.

你们的回答是不够的，因为它没有充分的详细信息，说明如何检验每个组分是否符合有关鉴别、强度、质量和纯度的适当书面质量标准。此外，还不清楚：你们是否打算依靠供应商的COA检验结果(鉴别除外)，来代替自己的检验，因为你们没有提供有关计划：在适当的时间间隔内，如何验证供应商的检验结果，来建立供应商的COA可靠性的详细信息。

In response to this letter, provide the following:

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 suppliers COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers 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.

•说明如何检验每个批次，确定是否符合有关鉴别、强度、质量和纯度质量标准。如果你们打算接受供应商COA的结果，而不是检验每个组分批次的强度、质量和纯度，请指定如何进行初始验证和定期再验证，从而稳健地确定供应商结果的可靠性。此外，还应承诺：对于每个入库的组分批次，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SOP。

结论
Conclusion

The violations and deviation 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 violations and deviations and for preventing their recurrence or the occurrence of violations and deviations.

本信函中引用的违规行为并非旨在列出与你产品相关的所有违规行为。你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。

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.

在你们完全纠正所有违法行为并且我们确认你们遵守CGMP之前，对于将你们公司列为生产商的新药申请或补充申请，FDA可能会拒绝批准。

Failure to correct these violations may also result in the FDA refusing admission of articles manufactured at Nartex Laboratorios Homeopaticos, S.A. de C.V., Mexico, 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拒绝接纳该墨西哥工厂生产的产品，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，你们所做的事情，以纠正你们违规行为，并防止其再次发生。如果你们无法在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 believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

如果你们认为你们产品未违反FD＆C法案(或你们已遵守FDA法规)，请提供你们理由和任何支持信息，以供我们考虑。

Ref.: [FDA][2020-11-10]WARNING LETTER-Nartex Laboratorios Homeopaticos S.A. de C.V.

       文章来源：PharmLink

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