近日，F(xiàn)DA發(fā)布了Amneal Pharmaceuticals 的警告信，其中提及內(nèi)毒素檢查相關(guān)的缺陷，該公司存在內(nèi)毒素檢查過程中：
移液槍使用不規(guī)范
未按要求停頓以檢查凝膠硬度
第一個內(nèi)毒素檢測人員判讀速度過快，無法充分觀察或確認(rèn)整個過程，第二個檢測人員仍在確認(rèn)記錄上簽字確認(rèn)
未實時記錄陰性結(jié)果
在實際觀察并確認(rèn)結(jié)果前，已將陽性對照結(jié)果判定為合格
FDA在警告信中表示：該公司必須徹底、系統(tǒng)審查其實驗室流程、檢驗方法、設(shè)備能力及文件記錄操作，以確保符合CGMP要求，并防止未來再次發(fā)生類似問題，并要求提供詳細(xì)的整改計劃。
缺陷翻譯如下：
During our inspection, we observed the preparation and reading of bacterial endotoxin tests and identified numerous deficiencies:
在檢查過程中，我們觀察了細(xì)菌內(nèi)毒素試驗的準(zhǔn)備與結(jié)果判讀過程，并發(fā)現(xiàn)多項缺陷：
Failure to completely discharge the micropipette solution during preparation of water for injection samples, which may compromise the accuracy and reproducibility of the test results.
制備注射用水樣品時，未將移液槍中的溶液完全排出，這可能影響測試結(jié)果的準(zhǔn)確性和可重復(fù)性。
Transfer of gel-clot sample tubes from the incubator to the waste container in a single rapid motion during microbiological analysis, without the crucial pause required to inspect the firmness of the gel for endotoxin detection.
微生物測試過程中，將凝膠法（gel-clot）樣品管從培養(yǎng)箱轉(zhuǎn)移至廢棄物容器過程中，未按要求停頓以檢查凝膠硬度，而該步驟對細(xì)菌內(nèi)毒素檢測至關(guān)重要。
The analyst responsible for the (b)(4) verification of the gel-clot assessment was unable to adequately observe or verify the process due to the primary microbiologist’s rapid assessment. Despite this basic deficiency, the secondary analyst signed off on the verification.
負(fù)責(zé)凝膠法（b）（4）結(jié)果確認(rèn)的檢測人員，因第一個微生物檢測人員判讀速度過快，無法充分觀察或確認(rèn)整個過程。盡管存在這一基礎(chǔ)性缺陷，第二個檢測人員仍在確認(rèn)記錄上簽字確認(rèn)。
Inadequate documentation practices when recording sample results of bacterial endotoxin tests for water for injection, including non-contemporaneous documenting of negative sample results and assigning a passing result to a positive control sample prior to the actual observation and confirmation of the result.
記錄注射用水內(nèi)毒素試驗樣品結(jié)果時，記錄操作存在不足，包括：未實時記錄陰性結(jié)果；在實際觀察并確認(rèn)結(jié)果前，已將陽性對照結(jié)果判定為合格。
In your response, you state that you revised various procedures, provided associated training, retested reserve samples of potentially impacted drug products, and purchased new equipment to increase laboratory automation.
貴公司在回復(fù)中表示，已修訂多項程序、開展相關(guān)培訓(xùn)、對可能受影響藥品的留樣進行重新檢驗，并采購新設(shè)備以提高實驗室自動化水平。
Your response is inadequate due to its limited scope, which primarily addressed the specific deficiencies identified during the FDA inspection. You did not conduct a comprehensive evaluation to determine if similar deficiencies exist in other laboratory operations or address additional opportunities for laboratory equipment automation.
貴公司的回復(fù)范圍有限，僅針對 FDA 檢查中發(fā)現(xiàn)的特定缺陷進行了回應(yīng)，因此回復(fù)是不充分的。貴公司未開展全面評估，以確認(rèn)其他實驗室操作中是否存在類似缺陷，也未探討實驗室設(shè)備自動化可進一步提升的空間。
It is imperative that your organization conducts a more thorough and systemic review of all laboratory processes, testing methodologies, equipment capabilities, and documentation practices to ensure compliance with CGMP and prevent recurrence of similar issues in the future.
貴公司必須對所有實驗室流程、檢驗方法、設(shè)備能力及文件記錄操作進行更徹底、系統(tǒng)性的審查，以確保符合CGMP要求，并防止未來再次發(fā)生類似問題。
In response to this letter, provide:
回復(fù)此函，請?zhí)峁┮韵拢?/span>
A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
對貴公司的實驗室操作、程序、方法、設(shè)備、文檔記錄及分析人員能力進行全面評估?；谠撛u估，提供詳細(xì)的整改計劃，并說明將如何評估實驗室體系整改后的有效性。
A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
對貴公司生產(chǎn)和實驗室操作全流程所使用的文件記錄體系進行全面評估，明確文件記錄操作存在不足的環(huán)節(jié)。同時提供詳細(xì)的CAPA計劃，全面整改貴公司文件記錄操作，確保在整個操作過程中，所有記錄均具備可追溯性、清晰性、完整性、原始性、準(zhǔn)確性和實時性。
此前，FDA對百特制藥印度工廠的檢查中還提及內(nèi)毒素檢查OOS處理不當(dāng)?shù)娜毕荩?/span>
You failed to conduct adequate investigations into endotoxin testing and your 100% automated visual inspection system. You conducted investigations that were not thorough, expanded to an appropriate scope, or based on scientifically supported root cause(s). You did not identify and implement appropriate corrective actions and preventive actions (CAPA). Specifically,
你們未能對內(nèi)毒素檢測和100%自動燈檢系統(tǒng)進行充分調(diào)查。你們進行了不徹底、未能擴展到適當(dāng)范圍或基于科學(xué)支持的根本原因的調(diào)查。你們沒有確定并實施適當(dāng)?shù)募m正措施和預(yù)防措施（CAPA）。具體說來：
Your firm invalidated multiple endotoxin tests for finished products upon discovery of particulate matter in one or more wells used to perform the kinetic-turbidimetric assay (KTA) method. You failed to characterize the particulate matter and attributed the particulates to environmental and laboratory conditions, such as air ducts and activities being performed by personnel in the immediate vicinity of the analysis. You did not definitively identify the source or sources of the particulate matter, define the scope of potentially impacted operations (including potential manufacturing causes), and implement scientifically justified CAPA in a timely manner.
貴公司在用于執(zhí)行動力學(xué)比濁測定（KTA）方法的一個或多個孔中發(fā)現(xiàn)顆粒物后，判定多個成品的內(nèi)毒素測試無效。你們未能確認(rèn)這些顆粒物，并將顆粒歸因于環(huán)境和實驗室條件，例如空氣管道和檢測（區(qū)域）附近人員正在進行的活動。你們沒有明確確定顆粒物的來源，定義可能受影響的范圍（包括潛在的生產(chǎn)原因），并及時實施科學(xué)合理的 CAPA。
In a previous inspection (May 2022), FDA cited your firm for inadequate investigations into these and other similar out-of-specification (OOS) endotoxin testing that you invalidated due to uncharacterized particulate contamination in one or more wells during KTA analyses. Prior to and during an October 5, 2022 regulatory meeting with your firm, we requested you perform a retrospective assessment of investigations associated with OOS endotoxin results or endotoxin testing deviations. During the current inspection, your personnel explained that these investigations were not reopened or otherwise reassessed. Although you retained a third-party consultant to perform a retrospective assessment of endotoxin investigations associated with OOS endotoxin result investigations, you did not provide the third-party consultant with an investigation cited during the May 2022 inspection. You also did not ensure the assessment included approximately 20 invalidated laboratory tests generated in 2021 and 2022 (including multiple investigations since the May 2022 inspection).
在之前的檢查（2022 年 5 月）中，F(xiàn)DA 引用了貴公司對這些和其他類似的不合格 （OOS） 內(nèi)毒素測試的調(diào)查不充分，這些測試在 KTA 分析期間一個或多個孔中存在未表征的顆粒污染被判定無效。在 2022 年 10 月 5 日與貴公司舉行監(jiān)管會議之前和期間，我們要求你們對與 OOS 內(nèi)毒素結(jié)果或內(nèi)毒素檢測偏差相關(guān)的調(diào)查進行回顧性評估。在本次檢查期間，你們的人員解釋說，這些調(diào)查沒有重新開始或以其他方式重新評估。盡管你們聘請了第三方顧問對與 OOS 內(nèi)毒素結(jié)果調(diào)查相關(guān)的內(nèi)毒素調(diào)查進行回顧性評估，但你們沒有向第三方顧問提供 2022 年 5 月檢查期間引用的調(diào)查。你們也沒有確保評估包括 2021 年和 2022 年產(chǎn)生的大約 20 項無效實驗室測試（包括自 2022 年 5 月檢查以來的多項調(diào)查）。
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