近日，F(xiàn)DA發(fā)布了Global Calcium Pvt. Limited的警告信，其中提及各類(lèi)記錄造假、廠房維護(hù)和雜質(zhì)控制問(wèn)題：

FDA檢查該公司批記錄和設(shè)備日志，發(fā)現(xiàn)兩個(gè)產(chǎn)品的生產(chǎn)活動(dòng)在同一設(shè)備上同時(shí)發(fā)生。

在檢查期間刪除了多個(gè)電子記錄。例如，在檢查的第一天早上，檢查人員在工廠的某生產(chǎn)辦公室的臺(tái)式計(jì)算機(jī)上看到了 Microsoft Excel 文件：包括但不限于“XX清潔驗(yàn)證樣品”、“XX生產(chǎn)詳細(xì)信息-2024”、“2024 年 6 月 工廠-XX生產(chǎn)報(bào)告”和“2024 年 6 月-計(jì)劃”。第二天，檢查人員返回該生產(chǎn)辦公室審查這些文件。但是，所有文件都已被刪除，并且在檢查期間無(wú)法恢復(fù)。

該公司承認(rèn)生產(chǎn)主管指示偽造生產(chǎn)記錄來(lái)編排 API 生產(chǎn)活動(dòng)，以便可以就XX工廠的生產(chǎn)索取獎(jiǎng)勵(lì)。

該公司表示刪除 Microsoft Excel 文件是為了“避免與檢查人員進(jìn)行不必要的對(duì)話(huà)”，并補(bǔ)充說(shuō)有問(wèn)題的計(jì)算機(jī)是“個(gè)人使用以記錄日常活動(dòng)”。

檢查人員觀察到一個(gè)房間地板有一個(gè)洞，里面中裝有XX液體。類(lèi)似的液體從這個(gè)房間的天花板管道連接處滴落。液體滴落在標(biāo)已清潔和待使用的生產(chǎn)設(shè)備上。

未能對(duì)制造過(guò)程進(jìn)行全面評(píng)估以識(shí)別所有潛在雜質(zhì)。某API的雜質(zhì)概況僅列出了USP中描述的那些雜質(zhì)，而沒(méi)有考慮特定于工藝和物料來(lái)描述典型批次中的其他雜質(zhì)。此外，未能對(duì)每個(gè)已識(shí)別的雜質(zhì)進(jìn)行充分分類(lèi)。在穩(wěn)定性研究期間沒(méi)有監(jiān)測(cè)雜質(zhì)。

警告信缺陷翻譯如下：

1. Failure of your quality unit to prepare, review, and approve documents related to the manufacturing of APIs in accordance with written procedures.

質(zhì)量部門(mén)未能按照書(shū)面程序準(zhǔn)備、審查和批準(zhǔn)與 API 制造相關(guān)的文件。

You provided production records for two different APIs that showed manufacturing activities occurred simultaneously on the same equipment. For example, your batch records and equipment logbooks show the same equipment including, but not limited to,(b)(4) were used at the same time to manufacture (b)(4) USP and (b)(4) USP.

你們?yōu)閮蓚€(gè)不同的 API 提供了生產(chǎn)記錄，其中顯示：這兩個(gè)API的生產(chǎn)活動(dòng)在同一設(shè)備上同時(shí)發(fā)生。例如，你們的批記錄和設(shè)備日志顯示相同的設(shè)備，包括但不限于（b）（4） 同時(shí)用于制造XX USP 產(chǎn)品和xx USP產(chǎn)品。

Additionally, you deleted multiple electronic records during the inspection. For example, on the initial morning of the inspection, investigators observed Microsoft Excel documents on a desktop computer in the Plant (b)(4) production office including, but not limited to, “(b)(4) Cleaning validation samples,” “(b)(4) Production Details-2024,” “Plant-(b)(4) production Report Jun-2024,” and “Planning June-2024.” On the second day, investigators returned to the production office to review these files. However, all files had been deleted and could not be recovered during the inspection. Without access to the files, the investigators were unable to determine their purpose and adequately evaluate your adherence to CGMP.

此外，你們?cè)跈z查期間刪除了多個(gè)電子記錄。例如，在檢查的第一天早上，檢查人員在工廠 的某生產(chǎn)辦公室的臺(tái)式計(jì)算機(jī)上看到了 Microsoft Excel 文件：包括但不限于“XX清潔驗(yàn)證樣品”、“XX生產(chǎn)詳細(xì)信息-2024”、“2024 年 6 月 工廠-XX生產(chǎn)報(bào)告”和“2024 年 6 月-計(jì)劃”。第二天，檢查人員返回該生產(chǎn)辦公室審查這些文件。但是，所有文件都已被刪除，并且在檢查期間無(wú)法恢復(fù)。由于無(wú)法訪(fǎng)問(wèn)這些文件，檢查人員無(wú)法確定其目的并充分評(píng)估你們的CGMP 符合性。

In your response, you acknowledge your production head directed the creation of falsified manufacturing records to misrepresent API production activities so incentives could be claimed regarding production in plant (b)(4). Additionally, you state a lack of training and other factors resulted in deficient documentation control, then explain you have revised your SOP for document issuance and control. You also state Microsoft Excel files were deleted to “avoid unwanted conversation” with the investigators, and add the computers in question are for “personal use to record day to day activities” so there is no impact on product quality. We also acknowledge you performed a product quality impact assessment.

在你們的回復(fù)中，你們承認(rèn)生產(chǎn)主管指示偽造生產(chǎn)記錄來(lái)編排 API 生產(chǎn)活動(dòng)，以便可以就XX工廠的生產(chǎn)索取獎(jiǎng)勵(lì)。此外，你們指出缺乏培訓(xùn)和其他因素導(dǎo)致文件控制不足，然后解釋你們已經(jīng)修改了文件發(fā)布和控制的 SOP。你們還表示刪除 Microsoft Excel 文件是為了“避免與檢查人員進(jìn)行不必要的對(duì)話(huà)”，并補(bǔ)充說(shuō)有問(wèn)題的計(jì)算機(jī)是“個(gè)人使用以記錄日常活動(dòng)”，因此不會(huì)影響產(chǎn)品質(zhì)量。我們還知道你們執(zhí)行了產(chǎn)品質(zhì)量影響評(píng)估。

Your response is inadequate. Your product quality impact assessment relies, in part, on data generated by your facility’s deficient documentation practices, and therefore is inherently unreliable. Furthermore, you do not adequately evaluate how widespread the practice of record fabrication extends throughout your facility, and you do not share in sufficient detail how you will prevent, detect, and investigate non-contemporaneously prepared records. You also do not adequately explain which, if any records were legitimate and pertain to actual product produced on your equipment. Considering your response states you created records that “falsely attributed” production activities to claim incentives, FDA is concerned about the adequacy of your remediation efforts given you have not sufficiently reconciled all CGMP records.

你們的回復(fù)是不充分的。你們的產(chǎn)品質(zhì)量影響評(píng)估在一定程度上依賴(lài)于你們的工廠有缺陷的文件實(shí)踐所產(chǎn)生的數(shù)據(jù)，因此本質(zhì)上是不可靠的。此外，你們沒(méi)有充分評(píng)估記錄偽造在整個(gè)設(shè)施中的泛濫程度，并且你們沒(méi)有足夠詳細(xì)地分享你們將如何預(yù)防、檢測(cè)和調(diào)查非同步準(zhǔn)備的記錄。你們也沒(méi)有充分解釋哪些記錄（如有）是合規(guī)并與你們?cè)O(shè)備生產(chǎn)的實(shí)際產(chǎn)品相關(guān)的。考慮到你們的回復(fù)表明你們偽造記錄“編排”生產(chǎn)活動(dòng)以申請(qǐng)獎(jiǎng)勵(lì)，鑒于你們沒(méi)有充分核對(duì)所有 CGMP 記錄，F(xiàn)DA 擔(dān)心你們的補(bǔ)救工作是否充分。

2. Failure to properly maintain buildings and facilities used in the manufacture of APIs.

未能妥善維護(hù)用于制造 API 的廠房和設(shè)施。

You failed to maintain your facility in an acceptable state of repair. For example, investigators observed a room with (b)(4) liquid in a floor cavity surrounding the exit pipe of a (b)(4). A similar liquid was dripping from a ceiling pipe junction in the (b)(4) area below this room. The liquid was dripping onto processing equipment labeled as clean and ready for use.

你們未能將你們的設(shè)施保持在可接受的維護(hù)狀態(tài)。例如，檢查人員觀察到一個(gè)房間，在 （b）（4） 的出口管道周?chē)牡匕逵幸粋€(gè)洞，里面中裝有（b）（4）液體。類(lèi)似的液體從這個(gè)房間（b）（4）區(qū)域的天花板管道連接處滴落。液體滴落在標(biāo)已清潔和待使用的生產(chǎn)設(shè)備上。

It is essential your facility is in a good state of repair, and sanitary conditions are maintained to ensure ongoing suitability for drug manufacturing.

你們的設(shè)施必須處于良好的維護(hù)狀態(tài)，并保持衛(wèi)生條件，以確保持續(xù)適合藥品生產(chǎn)。

In your response, you state no production activities were taking place in the (b)(4) area, as it was partially shut down to make various upgrades, and you state the damaged flooring has since been repaired. You also state personnel did not display proper signage in the area, as required by your procedure, and a change control had been initiated. Additionally, your deviation report submitted with your response states personnel were not aware of ongoing maintenance activities in Plant (b)(4).

在你們的回復(fù)中，你們表示 （b）（4） 區(qū)域沒(méi)有進(jìn)行生產(chǎn)活動(dòng)，因?yàn)樗巡糠株P(guān)閉以進(jìn)行各種升級(jí)，并且你們表示損壞的地板已經(jīng)修復(fù)。你們還指出，操作人員沒(méi)有按照你們的程序要求在該區(qū)域展示適當(dāng)?shù)臉?biāo)識(shí)，并且已經(jīng)啟動(dòng)了變更控制。此外，你們與回復(fù)一起提交的偏差報(bào)告指出，操作人員不知道工廠（b）（4）正在進(jìn)行的維護(hù)活動(dòng)。

3. Failure to establish an impurity profile for identified and unidentified impurities.

未能確定已鑒定和未鑒定雜質(zhì)的雜質(zhì)概況

You failed to conduct a comprehensive evaluation of your manufacturing processes to identify all potential impurities. For example, the impurity profile you provided for (b)(4) USP, only listed those impurities described in the United States Pharmacopeia (USP), without considering your unique processes and materials to describe additional impurities in a typical lot. Furthermore, you failed to sufficiently classify each identified impurity. Our inspection also noted impurities are not monitored during stability studies.

你們未能對(duì)制造過(guò)程進(jìn)行全面評(píng)估以識(shí)別所有潛在雜質(zhì)。例如，你們?yōu)?（b）（4） USP產(chǎn)品提供的雜質(zhì)概況僅列出了USP中描述的那些雜質(zhì)，而沒(méi)有考慮特定于你們工藝和物料來(lái)描述典型批次中的其他雜質(zhì)。此外，你們未能對(duì)每個(gè)已識(shí)別的雜質(zhì)進(jìn)行充分分類(lèi)。我們的檢查還注意到，在穩(wěn)定性研究期間沒(méi)有監(jiān)測(cè)雜質(zhì)。

In your response, you include impurity profiles and data from forced degradation studies, which you state was provided to investigators on the final day of the inspection. We acknowledge you also include updated impurity profiles with further details completed since the inspection. You also state drug product manufacturers who you supply perform testing of the drug products for impurities, and you have not received any returned APIs due to quality issues.

在你們的回復(fù)中，你們提供了雜質(zhì)概況和來(lái)自強(qiáng)制降解研究的數(shù)據(jù)，你們聲稱(chēng)這些數(shù)據(jù)是在檢查的最后一天提供給檢查人員的。我們確認(rèn)你們還提供了更新的雜質(zhì)概況，以及自檢查以來(lái)完成的更多詳細(xì)信息。你們還應(yīng)聲明，你們供應(yīng)的藥品制造商對(duì)藥品進(jìn)行雜質(zhì)檢測(cè)，你們還沒(méi)有收到任何因質(zhì)量問(wèn)題退回的API。

Your response is inadequate. Our inspection found you have received at least two lots of returned product due to quality issues in the last two years. You also received a complaint for one lot of (b)(4) USP that failed the customer’s identity testing. Furthermore, you do not provide a retroactive risk assessment of distributing APIs with incomplete impurity profiles, and you lack evidence that you communicated your updated impurity profiles to your customers who you state test the drug products for impurities. Additionally, your APIs are distributed to (b)(4) who typically do not test components for compliance with quality specifications, including impurity testing.

你們的回復(fù)是不充分的。我們的檢查發(fā)現(xiàn)，在過(guò)去兩年中，你們至少收到了兩批因質(zhì)量問(wèn)題而退回的產(chǎn)品。你們還收到了關(guān)于一批 （b）（4） USP產(chǎn)品經(jīng)客戶(hù)鑒定檢查不合格的投訴。此外，你們沒(méi)有提供分銷(xiāo)雜質(zhì)分析不完整的API 的追溯風(fēng)險(xiǎn)評(píng)估，并且你們?nèi)狈ψC據(jù)表明你們將更新的雜質(zhì)分析傳達(dá)給你們聲明對(duì)藥品進(jìn)行雜質(zhì)測(cè)試的客戶(hù)。此外，你們的API 將分發(fā)給 （b）（4），他們通常不測(cè)試組件是否符合質(zhì)量標(biāo)準(zhǔn)，包括雜質(zhì)測(cè)試。