We recently reported on the issuance of two FDA Warning Letters, one to a company in Italy and one to a company in the US, which included observations on inadequate root cause analysis (RCA). However, also in other Warning Letters issued in FDA's fiscal year 2024, insufficient root cause analysis is cited and seems to be a frequent finding in FDA inspections.

我们最近报道了两封FDA警告信的发布，一封给意大利的一家公司，另一封给美国的一家公司，其中包括对根本原因分析（RCA）不足的观察。然而，在FDA 2024财政年度发布的其他警告信中，也引用了根本原因分析不足，这似乎是FDA检查中经常发现的问题。

Investigations and Root Cause Analysis are the basis of a compliant pharmaceutical quality system. Quite some GMP violations that lead to FDA Warning Letters (and also EU Non-GMP Compliance Reports) are caused by inadequate investigations. As stated in an FDA Warning Letter, "Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that compromise the ability to manufacture safe and effective drug products" (Glicerinas Industriales, Mexico, January 2024).

调查和根本原因分析是合规药品质量体系的基础。相当多的GMP违规导致FDA警告信（以及欧盟GMP不合规报告）是由于调查不充分造成的。正如FDA警告信中所述，“不充分的调查可能导致无法确定的根本原因、无效的CAPA和反复出现的问题，从而损害生产安全有效药品的能力”（墨西哥某药企，2024年1月）。

Local GMP regulations around the world require sufficient investigations in the case of deviations. In the US, requirements for investigations are for example laid down in the Code of Federal Regulations (CFR):

 

世界各地的GMP法规都要求对偏差进行充分的调查。例如，在美国，联邦法规（CFR）规定了调查的要求：

 

§ 211.180 General Requiremnets: 通用要求

Written procedures shall be established and followed for such evaluations and shall include provisions for (...) (2) A review of complaints, recalls, returned or salvaged drug products, and investigations (...) (f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted" [reg.complaints].

对投诉、召回、退回或回收的药品和调查的审查（…）(f)应建立程序，以确保公司的负责人员，如果他们没有亲自参与或立即意识到这些行为，则应以书面形式通知所进行的任何调查。

 

§ 211.192 Production record review 生产记录审核

"Any unexplained discrepancy (...) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, (...). The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup."

任何无法解释的差异（…）或批次或其任何组分不符合其任何规格，均应进行彻底调查（…）。调查应扩展到同一药品的其他批次以及可能与特定不合格或差异有关的其他药品。调查应当作成笔录，记载调查结论和后续情况。”

 

§ 211.198 Complaint files 投诉文件

(2) "Where an investigation under §211.192 is conducted, the written record shall include the findings of the investigation and followup. (...). (3) Where an investigation under §211.192 is not conducted, the written record shall include the reason that an investigation was found not to be necessary (...).

“如果根据§211.192进行调查，书面记录应包括调查结果和后续调查。(…)。(3)如果没有根据§211.192进行调查，书面记录应包括调查被认为没有必要的原因（…）。

Compliance with these regulations is investigated during FDA inspections. This can often be seen in observations written down in Warning Letters. In the following, findings cited in Warning Letters in the first half of the FDA fiscal year 2024 are listed:

 

在FDA检查期间对这些法规的遵守情况进行调查，这通常可以在警告信中看到。以下列出了FDA 2024财年上半年警告信中关于调查的缺陷：

 

1. Colonial Dames Company, USA (December 2023)

 

"you did not provide a detailed investigation identifying the root cause for the evaporation, nor supporting data to assure your CAPA is adequate."

你们没有提供详细的调查来确定蒸发的根本原因，也没有提供支持数据来确保你们的CAPA是充分的。

 

2. Glicerinas Industriales, Mexico (January 2024)

 

"Failure to document, explain, and investigate any deviation from established procedures"

未能记录、解释和调查任何偏离既定程序的情况

 

"you did not reject the lots and failed to fully identify a clear root cause for the contamination source. Your firm also failed to implement a corrective action and preventive action (CAPA) according to your procedure until after FDA cited your firm.

你们没有拒收这些批次，也没有完全确定污染源的根本原因。你们公司也未能按照你们的程序实施CAPA，直到FDA发现了你们公司的缺陷之后。

 

3. Bell International Laboratories, USA (February 2024)

 

"Your quality unit (QU) lacked adequate control over your over-the-counter (OTC) drug manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to ensure:

 

你们的质量部门对你们的非处方药生产操作缺乏足够的控制，未能确保你们有足够的程序。例如未能确保：

Adequate investigations into non-conformances (21 CFR 211.192).

 

对不符合项进行充分的调查（21 CFR 211.192）。

 

Adequate investigations into complaints (21 CFR 211.198(a))."

 

对投诉进行充分调查（21 CFR 211.198(a)）。”

"Your response is inadequate because you did not address how you will ensure that investigations contain adequate root cause determinations, corrective action and preventive action (CAPA), and effectiveness checks".

 

你们的回复是不充分的，因为你们没有说明你们将如何确保调查包含充分的根本原因确定、CAPA以及有效性检查。

 

4. Sichuan Deebio Pharmaceutical, China (February 2024)

 

"Your firm's quality unit (QU) failed to (...) extend product quality complaint investigations to other batches or APIs potentially associated with the root cause, failure, or deviation".

 

“你们公司质量部门未能将产品质量投诉调查扩展到可能与根本原因、故障或偏差相关的其他批次或原料药”。

 

5. Cosmetic Specialty Labs, USA (February 2024)

 

"For example, your QU failed to ensure: (...) Thorough investigations into out-of-specifications (OOS) results, deviations, and other discrepant results are performed per an adequate written and approved procedure".

 

“例如，你的质量部门未能确保：（…）对OOS结果、偏差和其他不一致的结果进行彻底的调查，并按照适当的书面和批准的程序进行。

 

6. Antaria Pty. Ltd., Australia (March 2024)

 

"The root causes were not clearly defined nor adequately documented"

 

“根本原因没有明确定义，也没有充分的文件记录”

 

"you failed to describe a holistic review of all investigations, root cause analyses and corrective actions for adequacy"

 

“你们未能描述对所有调查、根本原因分析和纠正措施的全面审查。”

 

"ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation".

 

“确保所有其他易受相同或类似根本原因影响的实验室方法都被识别出来进行补救”。

 

7. Cohere Beauty, USA (April 2024)

 

"Your investigation only focused on reviewing formulation and customer complaints but did not adequately investigate the root cause".

 

你们的调查只集中在审查配方和客户投诉上，但没有充分调查根本原因。

 

8. Natco Pharma, India (April 2024)

 

"Your firm's investigations into unexplained discrepancies were inadequate. Your quality unit (QU) failed to thoroughly investigate all finished product batches and components associated with unexplained discrepancies."

 

“贵公司对无法解释的差异的调查是不充分的。你们的质量部门未能彻底调查所有与无法解释的差异相关的成品批次和组分。”

 

"You concluded your investigations without a root cause determination supported by evidence or initiating CAPA."

 

“你们在没有证据支持的根本原因确定或启动CAPA的情况下结束了调查。”

 

中国GMP中关于调查相关的规定如下：

 

第十条：药品生产质量管理的基本要求：（六）生产全过程应当有记录，偏差均经过调查并记录；（十）调查导致药品投诉和质量缺陷的原因，并采取措施，防止类似质量缺陷再次发生。

 

第十二条：质量控制的基本要求：（五）取样、检查、检验应当有记录，偏差应当经过调查并记录；

 

第二十三条：质量管理负责人（二）主要职责：6.确保所有重大偏差和检验结果超标已经过调查并得到及时处理；12.确保所有与产品质量有关的投诉已经过调查，并得到及时、正确的处理；

 

第一百零六条：发现外包装损坏或其他可能影响物料质量的问题，应当向质量管理部门报告并进行调查和记录。

 

第一百三十七条：只有经检查、检验和调查，有证据证明退货质量未受影响，且经质量管理部门根据操作规程评价后，方可考虑将退货重新包装、重新发运销售。

 

第一百七十五条：批生产记录的内容应当包括：（九）对特殊问题或异常事件的记录，包括对偏离工艺规程的偏差情况的详细说明或调查报告，并经签字批准。

 

第一百八十条：批包装记录的内容包括：（九）对特殊问题或异常事件的记录，包括对偏离工艺规程的偏差情况的详细说明或调查报告，并经签字批准；

 

第二百一十四条：因包装过程产生异常情况而需要重新包装产品的，必须经专门检查、调查并由指定人员批准。

 

第二百二十四条：质量控制实验室应当建立检验结果超标调查的操作规程。

 

第二百二十五条:（三）成品的留样：4.如果不影响留样的包装完整性，保存期间内至少应当每年对留样进行一次目检观察，如有异常，应当进行彻底调查并采取相应的处理措施；

 

第二百三十条：产品的放行应当至少符合以下要求：6.所有与该批产品有关的偏差均已有明确的解释或说明，或者已经过彻底调查和适当处理；

 

第二百三十八条：应当对不符合质量标准的结果或重要的异常趋势进行调查。

 

第二百四十八条：企业应当建立偏差处理的操作规程，规定偏差的报告、记录、调查、处理以及所采取的纠正措施，并有相应的记录。

 

第二百五十二条：企业应当建立纠正措施和预防措施系统，对投诉、召回、偏差、自检或外部检查结果、工艺性能和质量监测趋势等进行调查并采取纠正和预防措施。调查的深度和形式应当与风险的级别相适应。

 

第二百七十条：应当主动收集药品不良反应，对不良反应应当详细记录、评价、调查和处理，...