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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.

我們最近報道了兩封FDA警告信的發(fā)布，一封給意大利的一家公司，另一封給美國的一家公司，其中包括對根本原因分析（RCA）不足的觀察。然而，在FDA 2024財政年度發(fā)布的其他警告信中，也引用了根本原因分析不足，這似乎是FDA檢查中經(jīng)常發(fā)現(xiàn)的問題。

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).

調(diào)查和根本原因分析是合規(guī)藥品質(zhì)量體系的基礎(chǔ)。相當(dāng)多的GMP違規(guī)導(dǎo)致FDA警告信（以及歐盟GMP不合規(guī)報告）是由于調(diào)查不充分造成的。正如FDA警告信中所述，“不充分的調(diào)查可能導(dǎo)致無法確定的根本原因、無效的CAPA和反復(fù)出現(xiàn)的問題，從而損害生產(chǎn)安全有效藥品的能力”（墨西哥某藥企，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法規(guī)都要求對偏差進行充分的調(diào)查。例如，在美國，聯(lián)邦法規(guī)（CFR）規(guī)定了調(diào)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].

對投訴、召回、退回或回收的藥品和調(diào)查的審查（…）(f)應(yīng)建立程序，以確保公司的負責(zé)人員，如果他們沒有親自參與或立即意識到這些行為，則應(yīng)以書面形式通知所進行的任何調(diào)查。

 

§ 211.192 Production record review 生產(chǎn)記錄審核

"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."

任何無法解釋的差異（…）或批次或其任何組分不符合其任何規(guī)格，均應(yīng)進行徹底調(diào)查（…）。調(diào)查應(yīng)擴展到同一藥品的其他批次以及可能與特定不合格或差異有關(guān)的其他藥品。調(diào)查應(yīng)當(dāng)作成筆錄，記載調(diào)查結(jié)論和后續(xù)情況。”

 

§ 211.198 Complaint files 投訴文件

(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 (...).

“如果根據(jù)§211.192進行調(diào)查，書面記錄應(yīng)包括調(diào)查結(jié)果和后續(xù)調(diào)查。(…)。(3)如果沒有根據(jù)§211.192進行調(diào)查，書面記錄應(yīng)包括調(diào)查被認(rèn)為沒有必要的原因（…）。

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檢查期間對這些法規(guī)的遵守情況進行調(diào)查，這通?？梢栽诰嫘胖锌吹?。以下列出了FDA 2024財年上半年警告信中關(guān)于調(diào)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."

你們沒有提供詳細的調(diào)查來確定蒸發(fā)的根本原因，也沒有提供支持?jǐn)?shù)據(jù)來確保你們的CAPA是充分的。

 

2. Glicerinas Industriales, Mexico (January 2024)

 

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

未能記錄、解釋和調(diào)查任何偏離既定程序的情況

 

"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.

你們沒有拒收這些批次，也沒有完全確定污染源的根本原因。你們公司也未能按照你們的程序?qū)嵤〤APA，直到FDA發(fā)現(xiàn)了你們公司的缺陷之后。

 

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:

 

你們的質(zhì)量部門對你們的非處方藥生產(chǎn)操作缺乏足夠的控制，未能確保你們有足夠的程序。例如未能確保：

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

 

對不符合項進行充分的調(diào)查（21 CFR 211.192）。

 

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

 

對投訴進行充分調(diào)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".

 

你們的回復(fù)是不充分的，因為你們沒有說明你們將如何確保調(diào)查包含充分的根本原因確定、CAPA以及有效性檢查。

 

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".

 

“你們公司質(zhì)量部門未能將產(chǎn)品質(zhì)量投訴調(diào)查擴展到可能與根本原因、故障或偏差相關(guān)的其他批次或原料藥”。

 

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，你的質(zhì)量部門未能確保：（…）對OOS結(jié)果、偏差和其他不一致的結(jié)果進行徹底的調(diào)查，并按照適當(dāng)?shù)臅婧团鷾?zhǔn)的程序進行。

 

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

 

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

 

“根本原因沒有明確定義，也沒有充分的文件記錄”

 

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

 

“你們未能描述對所有調(diào)查、根本原因分析和糾正措施的全面審查。”

 

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

 

“確保所有其他易受相同或類似根本原因影響的實驗室方法都被識別出來進行補救”。

 

7. Cohere Beauty, USA (April 2024)

 

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

 

你們的調(diào)查只集中在審查配方和客戶投訴上，但沒有充分調(diào)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."

 

“貴公司對無法解釋的差異的調(diào)查是不充分的。你們的質(zhì)量部門未能徹底調(diào)查所有與無法解釋的差異相關(guān)的成品批次和組分。”

 

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

 

“你們在沒有證據(jù)支持的根本原因確定或啟動CAPA的情況下結(jié)束了調(diào)查。”

 

中國GMP中關(guān)于調(diào)查相關(guān)的規(guī)定如下：

 

第十條：藥品生產(chǎn)質(zhì)量管理的基本要求：（六）生產(chǎn)全過程應(yīng)當(dāng)有記錄，偏差均經(jīng)過調(diào)查并記錄；（十）調(diào)查導(dǎo)致藥品投訴和質(zhì)量缺陷的原因，并采取措施，防止類似質(zhì)量缺陷再次發(fā)生。

 

第十二條：質(zhì)量控制的基本要求：（五）取樣、檢查、檢驗應(yīng)當(dāng)有記錄，偏差應(yīng)當(dāng)經(jīng)過調(diào)查并記錄；

 

第二十三條：質(zhì)量管理負責(zé)人（二）主要職責(zé)：6.確保所有重大偏差和檢驗結(jié)果超標(biāo)已經(jīng)過調(diào)查并得到及時處理；12.確保所有與產(chǎn)品質(zhì)量有關(guān)的投訴已經(jīng)過調(diào)查，并得到及時、正確的處理；

 

第一百零六條：發(fā)現(xiàn)外包裝損壞或其他可能影響物料質(zhì)量的問題，應(yīng)當(dāng)向質(zhì)量管理部門報告并進行調(diào)查和記錄。

 

第一百三十七條：只有經(jīng)檢查、檢驗和調(diào)查，有證據(jù)證明退貨質(zhì)量未受影響，且經(jīng)質(zhì)量管理部門根據(jù)操作規(guī)程評價后，方可考慮將退貨重新包裝、重新發(fā)運銷售。

 

第一百七十五條：批生產(chǎn)記錄的內(nèi)容應(yīng)當(dāng)包括：（九）對特殊問題或異常事件的記錄，包括對偏離工藝規(guī)程的偏差情況的詳細說明或調(diào)查報告，并經(jīng)簽字批準(zhǔn)。

 

第一百八十條：批包裝記錄的內(nèi)容包括：（九）對特殊問題或異常事件的記錄，包括對偏離工藝規(guī)程的偏差情況的詳細說明或調(diào)查報告，并經(jīng)簽字批準(zhǔn)；

 

第二百一十四條：因包裝過程產(chǎn)生異常情況而需要重新包裝產(chǎn)品的，必須經(jīng)專門檢查、調(diào)查并由指定人員批準(zhǔn)。

 

第二百二十四條：質(zhì)量控制實驗室應(yīng)當(dāng)建立檢驗結(jié)果超標(biāo)調(diào)查的操作規(guī)程。

 

第二百二十五條:（三）成品的留樣：4.如果不影響留樣的包裝完整性，保存期間內(nèi)至少應(yīng)當(dāng)每年對留樣進行一次目檢觀察，如有異常，應(yīng)當(dāng)進行徹底調(diào)查并采取相應(yīng)的處理措施；

 

第二百三十條：產(chǎn)品的放行應(yīng)當(dāng)至少符合以下要求：6.所有與該批產(chǎn)品有關(guān)的偏差均已有明確的解釋或說明，或者已經(jīng)過徹底調(diào)查和適當(dāng)處理；

 

第二百三十八條：應(yīng)當(dāng)對不符合質(zhì)量標(biāo)準(zhǔn)的結(jié)果或重要的異常趨勢進行調(diào)查。

 

第二百四十八條：企業(yè)應(yīng)當(dāng)建立偏差處理的操作規(guī)程，規(guī)定偏差的報告、記錄、調(diào)查、處理以及所采取的糾正措施，并有相應(yīng)的記錄。

 

第二百五十二條：企業(yè)應(yīng)當(dāng)建立糾正措施和預(yù)防措施系統(tǒng)，對投訴、召回、偏差、自檢或外部檢查結(jié)果、工藝性能和質(zhì)量監(jiān)測趨勢等進行調(diào)查并采取糾正和預(yù)防措施。調(diào)查的深度和形式應(yīng)當(dāng)與風(fēng)險的級別相適應(yīng)。

 

第二百七十條：應(yīng)當(dāng)主動收集藥品不良反應(yīng)，對不良反應(yīng)應(yīng)當(dāng)詳細記錄、評價、調(diào)查和處理，...