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近日，F(xiàn)DA在Empower Clinic Services, LLC dba Empower Pharma的警告信中提及多項(xiàng)環(huán)境監(jiān)測(cè)偏差處理相關(guān)的缺陷：

該公司在 ISO 5 生產(chǎn)區(qū)域內(nèi)的環(huán)境監(jiān)測(cè)（EM）檢測(cè)到陽性微生物生長(zhǎng)，但還是放行了該批無菌藥品。

該公司此后答復(fù)：已修改了EM響應(yīng)計(jì)劃程序，要求：在最終無菌過濾和灌裝期間，在 ISO 5區(qū)域內(nèi)檢測(cè)到微生物將導(dǎo)致相關(guān)批次的拒簽。但是FDA認(rèn)為該回復(fù)不充分并表示：該修訂僅限于無菌灌裝和過濾的兩個(gè)生產(chǎn)步驟。

FDA發(fā)現(xiàn)該公司ISO 5 層流罩內(nèi)部有縫隙和小孔。該公司的氣流流型研究未包括縫隙和小孔對(duì)氣流的影響。

該公司ISO 5層流罩的非活性粒子超出行動(dòng)限。該公司的調(diào)查表明，可能導(dǎo)致偏差的因素是機(jī)器或操作人員，并得出結(jié)論：沒有已知的產(chǎn)品影響，并放行了整批產(chǎn)品，但它沒有提供放行整個(gè)批次的充分理由。FDA在警告信中表示：任何超過既定行動(dòng)限的偏差都可能影響產(chǎn)品質(zhì)量。

該公司在操作人員的手指采樣中檢查到一種真菌，即 漿果紅酵母菌（Rhodotorula bacarum）。該公司的調(diào)查表明最可能的原因是操作人員更衣或無菌技術(shù)不良。因此，操作人員被取消了無菌生產(chǎn)資格，并且該批次被拒絕。然而，調(diào)查并不充分，因?yàn)樗狈?duì)操作人員在 EM 結(jié)果出來之前生產(chǎn)的所有批次的評(píng)估。

此外，該公司在 2023 年 8 月16 日至 9 月 14 日期間啟動(dòng)了大約14 個(gè)不符合項(xiàng) （NC） 來調(diào)查EM偏移。在短短20天內(nèi)，大約報(bào)告了 32 次 EM 偏移。大量 EM 偏差“引起了對(duì)無菌生產(chǎn)設(shè)施內(nèi)整體受控狀態(tài)的擔(dān)憂。

在更衣間的日常環(huán)境監(jiān)測(cè)樣本中發(fā)現(xiàn)了木犀草假單胞菌，同一天XX批產(chǎn)品被無菌灌裝。產(chǎn)品被放行。

缺陷翻譯如下：

1. Your firm released a batch of a drug product intended to be sterile even though positive microbial growth was detected during environmental monitoring (EM) within the ISO 5 production area. You did not provide an adequate product impact assessment for Pyridoxine HCL lot 609763 compounded on April 18, 2024, when our investigators identified the observation during the inspection. As noted above, we acknowledge your recall of this lot on September 5, 2024. Your response stated you have revised your EM response program procedure to include the requirement that any recovery of a microorganism within an ISO 5 area during final aseptic filtration and filling shall result in the rejection of the associated batch. However, your revision was limited to only two processing steps for aseptic filling and filtration, although any operation in the ISO 5 area has the potential to be affected. Your responses did not provide an investigation update for the microbial failure in which 1 CFU of Bacillus altitudinis/pumilus/safensis was recovered on a surface contact plate inside the ISO 5 laminar airflow hood (LAFH) during aseptic filling. You identified the likely root cause as man (human) and a contributing factor as method due to sampling error, but your investigation did not include any documented preventive actions regarding proper aseptic technique and proper sampling.

貴公司在 ISO 5 生產(chǎn)區(qū)域內(nèi)的環(huán)境監(jiān)測(cè)（EM）檢測(cè)到陽性微生物生長(zhǎng)，但還是放行了該批無菌藥品。你們未對(duì)609763批次的鹽酸吡哆醇進(jìn)行適當(dāng)?shù)漠a(chǎn)品影響評(píng)估，直到2024 年 4 月 18 日我們的檢查人員在檢查期間發(fā)現(xiàn)該結(jié)果。我們知道你們于2024 年 9 月 5 日召回此批產(chǎn)品。你們回復(fù)表示，已修改了EM 響應(yīng)計(jì)劃程序，以包括以下要求：在最終無菌過濾和灌裝期間，在 ISO 5區(qū)域內(nèi)檢測(cè)到微生物將導(dǎo)致相關(guān)批次的拒簽。盡管在ISO 5 區(qū)域的任何操作都有可能被（EM陽性）影響，但是，你們的修訂僅限于無菌灌裝和過濾的兩個(gè)生產(chǎn)步驟。你們的回復(fù)沒有提供微生物偏差的調(diào)查更新，其中在無菌灌裝期間，在ISO 5 層流罩 （LAFH） 內(nèi)的表面接觸皿上檢測(cè)到 1 CFU 的高地芽孢桿菌/短小芽孢桿菌/沙福芽孢桿菌。你們確定了可能的根本原因是人為因素（采樣錯(cuò)誤），但你們的調(diào)查不包括任何關(guān)于適當(dāng)無菌技術(shù)和正確采樣的書面預(yù)防措施。

2. Our investigators observed 6-inch horizontal gaps below the back wall of the ISO 5 LAFH and the bar holes on the side wall of the ISO 5 E2150 LAFH. Your smoke study from June 26, 2023, was not conducted under dynamic conditions to demonstrate unidirectional airflow to include the impact of the gaps and bar holes on your aseptic process in your ISO 5 LAFHs, and to show that airflow could exit through the gaps in the back wall, which could prevent airflow from the ISO 7 cleanroom from entering the ISO 5 LAFH. We acknowledge that you executed an addendum to the original protocol and provided a summary table within document number B-REP-QAL-0168. However, your response did not include an executed protocol per B-PROT-QAL-0069 with documentation completed nor a video with your visual airflow study for review. Your response also lacked an assessment on product impact on lots within expiry made since the smoke study was performed to mitigate any potential concerns until your addendum was completed.

我們的檢查人員觀察到 ISO 5 層流罩內(nèi)的后下方有 6 英寸的縫隙，以及側(cè)壁上有小孔。你們于 2023 年 6 月 26 日煙霧研究不是在動(dòng)態(tài)條件下進(jìn)行的，包括那些縫隙和小孔對(duì) ISO 5層流罩無菌工藝的影響，以證明氣流是單向的，并證明氣流會(huì)通過這些縫隙和小孔對(duì)外排出，以防止ISO 7 潔凈室的氣流進(jìn)入 ISO 5 層流罩。我們確認(rèn)你們執(zhí)行了原始方案的附錄，并在文件編號(hào)B-REP-QAL-0168 中提供了匯總表。但是，你們的回復(fù)不包括根據(jù) B-PROT-QAL-0069執(zhí)行的方案的已完成文件，也沒有包含你們的氣流可視化研究以供審查的視頻。你們的回復(fù)也缺乏對(duì)產(chǎn)品對(duì)有效期內(nèi)批次影響的評(píng)估。

3. Your firm exceeded your action level of non-viable particles in the ISO 5 hood during the production of Ascorbic Acid Preserved 500 mg/mL Injection 30 mL lot(b)(4) filled on June 17, 2024. The (b)(4) system (b)(4) counter recorded a total plate count (TPC) that exceeded the action level for particles greater than or equal to (b)(4) microns, according to your internal specification. Your investigation stated the likely contributing factor to the failure was the machine or operator. Your investigation concluded no known product impact, and you released the full batch of Ascorbic Acid Preserved 500 mg/mL Injection 30 mL lot (b)(4). Your investigation stated the operator was properly gowned and maintained proper aseptic practices, but it did not provide an adequate rationale for releasing the whole batch. Your investigation also did not adequately assess the impact of the failure to the ISO 5 environment, for example investigating other operations that had occurred in the ISO 5 area. Any excursion that exceeds an established action level could potentially affect product quality. This is a repeat violation that was discussed during the May 4, 2023, regulatory meeting regarding your failure to establish and follow appropriate written procedures to prevent microbiological contamination.

貴公司在 2024 年 6 月17 日灌裝的30 mL抗壞血酸保鮮注射液500 mg/mL批次 （b）（4） 的生產(chǎn)過程中， ISO 5 層流罩的非活性粒子超出行動(dòng)限。根據(jù)你們的內(nèi)部標(biāo)準(zhǔn)，（b）（4） 系統(tǒng) （b）（4） 計(jì)數(shù)器記錄的TPC結(jié)果超出行動(dòng)限。你們的調(diào)查表明，可能導(dǎo)致偏差的因素是機(jī)器或操作人員。你們的調(diào)查得出結(jié)論，沒有已知的產(chǎn)品影響，并且你們放行了整批30 mL抗壞血酸保鮮液注射液 500 mg/mL批次 （b）（4）。你們的調(diào)查表明，操作人員穿著適當(dāng)?shù)臐崈舴⒈３至诉m當(dāng)?shù)臒o菌操作，但它沒有提供放行整個(gè)批次的充分理由。你們的調(diào)查也沒有充分評(píng)估偏差對(duì) ISO 5 環(huán)境的影響，例如，調(diào)查在 ISO 5 區(qū)域中發(fā)生的其他操作。任何超過既定行動(dòng)限的偏差都可能影響產(chǎn)品質(zhì)量。

4. Your firm’s investigation of EM out of specification (OOS) results during aseptic batch processing was inadequate. The investigators noted that a fungus,Rhodotorula bacarum, was identified on fingertip samples from an operator during the filling operations on May 4, 2023, of Lipo-B/Methionine/Choline Chloride/Cyanocobalamin 25/50/1 mg/mL, lot (b)(4). Your firm investigated this issue under non-conformance (NC)-000518, but did not determine a definitive root cause. The most probable cause was identified as inadequate gowning or aseptic technique by the operator. Consequently, the operator was disqualified from aseptic production and the batch was rejected. However, the investigation was inadequate as it lacked an assessment on any batches the operator produced before the EM results were available. Also, your investigation stated this employee was working as your (b)(4) equipment lead operator, “which increases the risk of a potential impact to the final product.” Your investigation did not include an assessment of potential other batches involving this operator that utilized the (b)(4) equipment before the EM results were available.

貴公司對(duì)無菌批處理過程中 EM 不合格 （OOS） 結(jié)果的調(diào)查不充分。檢查人員指出，在 2023 年 5 月 4 日的灌裝操作期間，在操作人員的手指采樣中檢查到一種真菌，即 漿果紅酵母菌（Rhodotorula bacarum）。貴公司根據(jù)不合格項(xiàng) （NC） -000518 調(diào)查了此偏差，但未確定明確的根本原因。最可能的原因是操作人員更衣或無菌技術(shù)不良。因此，操作人員被取消了無菌生產(chǎn)資格，并且該批次被拒絕。然而，調(diào)查并不充分，因?yàn)樗狈?duì)操作人員在 EM 結(jié)果出來之前生產(chǎn)的所有批次的評(píng)估。此外，你們的調(diào)查表明，該操作人員是 （b）（4） 設(shè)備的主操員，“這增加了對(duì)最終產(chǎn)品產(chǎn)生潛在影響的風(fēng)險(xiǎn)”。你們的調(diào)查不包括對(duì)涉及該操作人員的其他潛在批次的評(píng)估，該操作人員在 EM 結(jié)果出來之前使用了（b）（4） 設(shè)備。

In addition, your firm opened approximately fourteen non-conformances (NCs) to investigate EM excursions between August 16 through September 14, 2023. According to your investigation report NC-000673, there were approximately thirty-two NCs for EM excursions reported between August 24 through September 14, 2023. Your investigation report stated the presence of a significant number of EM excursions spanning this period “raises concerns regarding the overall state of control within the 503B aseptic processing suites.”

此外，貴公司在 2023 年 8 月16 日至 9 月 14 日期間啟動(dòng)了大約14 個(gè)不符合項(xiàng) （NC） 來調(diào)查EM偏移。根據(jù)你們的調(diào)查報(bào) NC-000673，在 2023 年 8 月 24 日至9 月 14 日期間，大約報(bào)告了 32 次 EM 偏移。你們的調(diào)查報(bào)告指出，在此期間存在大量 EM 偏差“引起了對(duì) 503B 無菌生產(chǎn)設(shè)施內(nèi)整體受控狀態(tài)的擔(dān)憂”。

During a view of the combined NC investigation for these EM excursions, your firm failed to extend the investigation to other batches produced. For example, your firm did not include injectable drug product Glutathione 200mg/mL, lot(b)(4); however this lot was manufactured on August 16, 2023. In addition, Pseudomonas luteola was identified in a routine EM sample collected from the gowning room on August 16, 2023, the same day this lot was aseptically filled. Your response did not include an investigation regarding lot (b)(4). You stated you have revised your Environmental Monitoring Excursion Response Program procedure to extend investigations to other products and lots that may be impacted by the EM excursion. However, it does not appear that your firm is taking a holistic approach to this topic by only making updates to the EM response program procedure. We acknowledge your investigation into these EM excursions stated that most of the referenced batches will be rejected, however we remain concerned with your investigations not always extending to other batches and processes that may be affected. This has been a reoccurring concern from the last inspection and this violation was discussed with you during the May 4, 2023, regulatory meeting.

在審查針對(duì)這些 EM 偏移的調(diào)查期間，貴公司未能將調(diào)查擴(kuò)展到所生產(chǎn)的其他批次。例如，貴公司未包括注射產(chǎn)品谷胱甘肽200 毫克/毫升，批次 （b）（4）;然而，這個(gè)批次是在 2023 年8 月 16 日制造的。此外，在 2023 年 8 月 16 日從更衣間的日常環(huán)境監(jiān)測(cè)樣本中發(fā)現(xiàn)了木犀草假單胞菌，同一天該批次被無菌灌裝。你們的回復(fù)不包括對(duì)批次 （b）（4） 的調(diào)查。你們表示，已修訂了環(huán)境監(jiān)測(cè)偏移響應(yīng)程序，以將調(diào)查范圍擴(kuò)大到可能受EM 偏移影響的其他產(chǎn)品和批次。貴公司似乎并沒有通過更新EM響應(yīng)程序來采取整體方法來解決這個(gè)問題。我們知道你們對(duì)這些EM 偏差的調(diào)查表明，大多數(shù)相關(guān)的批次都將被拒絕，但我們?nèi)匀粨?dān)心你們的調(diào)查并不總是擴(kuò)展到可能受影響的其他批次和工藝。