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嘉峪檢測網 2025-02-07 16:29
未對每批培養基進行促生長實驗
lYou did not perform growth promotion testing on each batch of microbiological growth media you prepare for settle plate, bioburden, and sterility testing. In addition, you do not have a written procedure to ensure that prepared media consistently meets appropriate standards of quality and purity.
你沒有對你準備的每批微生物培養基進行促生長試驗，這些培養基用于沉降菌、微生物負載和無菌測試。此外，你沒有書面規程來確保你制備的培養基始終符合適當的質量和純度標準。
培養基存儲不當，缺少促生長試驗，缺少陽性對照
lYour (b)(4) system was not appropriately designed. The system, which you indicated was “sterilized” (b)(4), contained (b)(4) piping with dead legs. This inappropriate system design fosters the development of biofilms. Moreover, due to the deficiencies noted in laboratory controls during the inspection，such as inappropriate storage of media，lack of growth promotion testing，and lack of positive controls, it is not certain you would be able to reliably detect bioburden or microbial limits failures.
你們的(b)(4)系統設計不當。你們標明“已滅菌”的(b)(4) 系統，其(b)(4)管路有死角。系統設計不當易促進生物膜形成。此外，由于在檢查中發現的實驗室控制方面的缺陷，例如培養基存儲不當，缺少促生長試驗，缺少陽性對照，無法確定你們有能力檢測微生物負荷或微生物限度超標情況。
陽性碟子上無菌生長
lNo growth on the positive control plate for media used to test microbiological (b)(4) samples. When a positive control fails to yield growth, test results cannot be considered valid due to the potential for false negatives. (FDA, 2017at)
用來檢測某微生物樣品的陽性培養碟上無菌生長。當陽性試驗無菌生長時，測試結果不能認為是合格的，因為會潛在導致假陰性。
使用有缺陷（脫水）的培養基進行環境監測
lDesiccation of a contact media plate used during environmental monitoring of the sterility testing area. Desiccated, cracked, or otherwise damaged (b)(4) compromises microbial growth promotion and accurate enumeration, and can lead to artificially low microbiological counts and false negatives. Using deficient media compromises the validity of your microbiological test results.
無菌檢測區的環境檢測期間使用的接觸碟脫水了。干燥、破裂或損壞的XX 會影響微生物的生長和精確計數，并可能導致人為的低微生物計數和假陰性。使用有缺陷的培養基會影響你們微生物檢測結果的正確性。
未對無菌區環境中出現的微生物進行鑒別
lAlso, you did not appear to routinely identify (i.e., to species level) bacterial and fungal isolates recovered during environmental monitoring of your aseptic processing room.
另外你們沒有對在你們無菌工藝室的環境監測期間分離出來的細菌和真菌進行常規鑒別（比如鑒別到種屬）。
微生物檢測方法未充分確認 / 驗證
l(b)(4) of your nonsterile API are intended for use in the manufacture of sterile finished dosage forms for U.S. distribution. You did not appropriately verify your test methods for total aerobic microbial count and total combined yeasts and molds. Specifically, you did not show that these methods are capable of recovering microorganisms in the presence of the API.
你們的非無菌原料藥(b)(4)計劃用于生產供美國銷售的無菌成品劑型。你們沒有適當地驗證檢測方法，總需氧微生物計數和酵母菌和霉菌結合總數。具體來說，你們沒有證明在原料藥中微生物回收率的能力。
lsamples that do not have validated (b)(4) method testing to verify whether or not samples meet the microbial enumeration acceptance criteria.” Your firm continues to lack a validated (b)(4) method. While your response indicates that you revised your SOP Microbial Recovery Validation, which references your attempted (b)(4) validation method, the SOP modifications did not address the method inadequacies or demonstrate equivalence or superiority to USP <61> Microbial Examination of Nonsterile Products: Microbial Enumeration Tests and USP <62> Microbial Examination of Nonsterile Products: Tests for Specified Organisms at detecting objectionable organisms such as B. cepacia and enumerating total microbial count levels.
根據貴公司的文件《微生物計數 QTP-079》，“對于沒有驗證(b)(4)方法的樣品，應使用經典方法檢測，以驗證樣品是否滿足微生物計數驗收標準。”你的公司仍然缺乏驗證過的(b)(4)方法。當你的反饋表明你修訂 SOP 微生物回收驗證, 參考你將使用的(b)(4)驗證方法,SOP 的修改沒有解決方法不足或證明等價或優于性 USP < 61 > 無菌藥品微生物檢測:微生物計數測試和 USP < 62 >無菌產品微生物檢查:對特定微生物進行的檢測，以發現有害微生物，如 B. cepacia 菌和微生物總數。
未進行微生物檢測，偽造微生物檢測記錄及結果
lDuring the inspection, investigators visually examined the (b)(4) quality and media growth promotion samples (plates) currently in incubation and compared them with the QC documentation for those samples purported to be in progress (incubation). Your (b)(4) sampling records showed that 45 (b)(4) quality samples had been prepared and incubated on July 9, 2014 ((b)(4), total viable aerobic count) and were in process. During the inspection, three of these plates were not in the incubator, although your (b)(4) sampling logbook recorded the presence of these three plates. QC worksheets for these three plates showed that documentation for the sample preparation and incubation had been created, even though the plates were not actually tested.
在檢查過程中，檢查員目視檢查了正在培養的（b）（4）的質量和培養基促生長樣品（培養皿），并將其與聲稱正在進行（培養）的樣品的質量控制文件進行了比較。你們的（b）（4）取樣記錄顯示，2014 年 7 月 9 日，準 備了 45 份（b）（4）質量樣品并進行培養（（b）（4），總活菌數）并且正在進行中。在檢查過程中，其中三個培養皿不在培養箱中，盡管你們的（b）（4）取樣日志中記錄有這三個培養皿。這三個培養皿的 QC 工作表表明，已經創建了樣品制備和培養的文件，盡管實際上沒有對這些培養皿進行測試。
Your management informed the investigators that one microbial plate had been found. However, upon inspection of this plate, the investigator noted that the handwriting was different from all the other microbial plates. After questioning, your microbiologist admitted that the microbial plate was re- created (falsified) to appear as if the sample was complete.
你們的管理層告訴檢查員找到了一個微生物培養皿。然而，對這個培養皿進行檢查后，檢查員發現，上面的字跡與其他所有的微生物培養皿都不一樣。經過詢問，你們的微生物檢驗人員承認，微生物培養皿是重新制備（偽造）的，使得樣品看起來是完整的。
In the 20–25°C and 30–35°C incubation chambers, our investigator reviewed documentation for 117 growth promotion samples. Only 74 samples were in the chambers; 43 were missing. According to your firm’s response, the plates were missing because, during the inspection, you were moving the microbiology laboratory from the (b)(4) floor to the (b)(4) floor. No one mentioned the laboratory move during the inspection. (FDA, 2016ar)
在 20-25°C 和 30-35°C 的培養箱中，我們的檢查員審查了 117 個促生長樣品的文件。但培養箱里只有 74 個 樣品，其他 43 個缺失。根據貴公司的答復，培養皿不見了是因為在檢查過程中，你們把微生物實驗室從（b） （4）層移到（b）（4）層。但在檢查期間沒有人提到實驗室的變動。
培養箱連接了計算機化系統，但未進行計算機化系統驗證
lOur investigator found that you have not validated 12 computerized systems in your quality control laboratory. These systems are used for your stability chambers, ultraviolet (UV) and infrared (IR) spectrophotometers, and for thin layer chromatography (TLC). (FDA, 2016a)
我們的檢查員發現你們 QC 實驗室中的 12 個計算機化系統沒有驗證。這些系統用于控制你們的穩定性培養箱，紫外（UV）和紅外（IR）分光光度計以及薄層色譜儀（TLC）。
微生物檢測結果未經復核人讀數確認
lOn February 3, 2023, in the QC microbiology laboratory (Room (b)(4)) we observed a QC analyst performing Colony Counting of environmental monitoring (EM) plates with no contemporaneous verification. We were informed that the contemporaneous verification check of the bioburden test is not necessary. It was determined to be low risk after post-mitigation based on the risk assessment report SEA-RIA-000117, “Microbial Colony Counting Contemporaneous Verification Risk Assessment” (version 1). However, the assessment underestimated the risk after post-mitigation and did not consider the criticality of direct product impact processes (lPC, release, PSM). A second analyst verification of the critical manufacturing steps for EM and bioburden plate reading should be implemented from a microbial control perspective to detect any microbial contamination of (b)(4).
2023年2月3日，在QC微生物實驗室(XX房間)，我們觀察到QC分析員在沒有同步確認結果的情況下對環境監測培養皿進行了菌落計數。我們被告知，微生物負荷試驗在進行菌落計數時，實時確認計數結果是不必要的。根據風險評估報告SEA-RIA-000117，“微生物菌落計數同步確認風險評估”(版本1)，在采取緩解措施后，（不同步確認計數結果）被確定為低風險。然而，評估低估了采取緩解措施后的風險，并且沒有考慮產品直接影響過程(中間控制、放行、PSM)的關鍵性。應該從微生物控制的角度對關鍵生產步驟的環境檢測和微生物負荷培養皿計數結果進行第二人的讀數確認，以檢測XXX的任何微生物污染。
來源：Internet
