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未對(duì)每批培養(yǎng)基進(jìn)行促生長(zhǎng)實(shí)驗(yàn)

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(méi)有對(duì)你準(zhǔn)備的每批微生物培養(yǎng)基進(jìn)行促生長(zhǎng)試驗(yàn)，這些培養(yǎng)基用于沉降菌、微生物負(fù)載和無(wú)菌測(cè)試。此外，你沒(méi)有書(shū)面規(guī)程來(lái)確保你制備的培養(yǎng)基始終符合適當(dāng)?shù)馁|(zhì)量和純度標(biāo)準(zhǔn)。

培養(yǎng)基存儲(chǔ)不當(dāng)，缺少促生長(zhǎng)試驗(yàn)，缺少陽(yáng)性對(duì)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(tǒng)設(shè)計(jì)不當(dāng)。你們標(biāo)明“已滅菌”的(b)(4) 系統(tǒng)，其(b)(4)管路有死角。系統(tǒng)設(shè)計(jì)不當(dāng)易促進(jìn)生物膜形成。此外，由于在檢查中發(fā)現(xiàn)的實(shí)驗(yàn)室控制方面的缺陷，例如培養(yǎng)基存儲(chǔ)不當(dāng)，缺少促生長(zhǎng)試驗(yàn)，缺少陽(yáng)性對(duì)照，無(wú)法確定你們有能力檢測(cè)微生物負(fù)荷或微生物限度超標(biāo)情況。

陽(yáng)性碟子上無(wú)菌生長(zhǎng)

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(lái)檢測(cè)某微生物樣品的陽(yáng)性培養(yǎng)碟上無(wú)菌生長(zhǎng)。當(dāng)陽(yáng)性試驗(yàn)無(wú)菌生長(zhǎng)時(shí)，測(cè)試結(jié)果不能認(rèn)為是合格的，因?yàn)闀?huì)潛在導(dǎo)致假陰性。

使用有缺陷（脫水）的培養(yǎng)基進(jìn)行環(huán)境監(jiān)測(cè)

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(wú)菌檢測(cè)區(qū)的環(huán)境檢測(cè)期間使用的接觸碟脫水了。干燥、破裂或損壞的XX 會(huì)影響微生物的生長(zhǎng)和精確計(jì)數(shù)，并可能導(dǎo)致人為的低微生物計(jì)數(shù)和假陰性。使用有缺陷的培養(yǎng)基會(huì)影響你們微生物檢測(cè)結(jié)果的正確性。

未對(duì)無(wú)菌區(qū)環(huán)境中出現(xiàn)的微生物進(jìn)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(méi)有對(duì)在你們無(wú)菌工藝室的環(huán)境監(jiān)測(cè)期間分離出來(lái)的細(xì)菌和真菌進(jìn)行常規(guī)鑒別（比如鑒別到種屬）。

微生物檢測(cè)方法未充分確認(rèn) / 驗(yàn)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(wú)菌原料藥(b)(4)計(jì)劃用于生產(chǎn)供美國(guó)銷售的無(wú)菌成品劑型。你們沒(méi)有適當(dāng)?shù)仳?yàn)證檢測(cè)方法，總需氧微生物計(jì)數(shù)和酵母菌和霉菌結(jié)合總數(shù)。具體來(lái)說(shuō)，你們沒(méi)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(jù)貴公司的文件《微生物計(jì)數(shù) QTP-079》，“對(duì)于沒(méi)有驗(yàn)證(b)(4)方法的樣品，應(yīng)使用經(jīng)典方法檢測(cè)，以驗(yàn)證樣品是否滿足微生物計(jì)數(shù)驗(yàn)收標(biāo)準(zhǔn)。”你的公司仍然缺乏驗(yàn)證過(guò)的(b)(4)方法。當(dāng)你的反饋表明你修訂 SOP 微生物回收驗(yàn)證, 參考你將使用的(b)(4)驗(yàn)證方法,SOP 的修改沒(méi)有解決方法不足或證明等價(jià)或優(yōu)于性 USP < 61 > 無(wú)菌藥品微生物檢測(cè):微生物計(jì)數(shù)測(cè)試和 USP < 62 >無(wú)菌產(chǎn)品微生物檢查:對(duì)特定微生物進(jìn)行的檢測(cè)，以發(fā)現(xiàn)有害微生物，如 B. cepacia 菌和微生物總數(shù)。

未進(jìn)行微生物檢測(cè)，偽造微生物檢測(cè)記錄及結(jié)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(guò)程中，檢查員目視檢查了正在培養(yǎng)的（b）（4）的質(zhì)量和培養(yǎng)基促生長(zhǎng)樣品（培養(yǎng)皿），并將其與聲稱正在進(jìn)行（培養(yǎng)）的樣品的質(zhì)量控制文件進(jìn)行了比較。你們的（b）（4）取樣記錄顯示，2014 年 7 月 9 日，準(zhǔn) 備了 45 份（b）（4）質(zhì)量樣品并進(jìn)行培養(yǎng)（（b）（4），總活菌數(shù)）并且正在進(jìn)行中。在檢查過(guò)程中，其中三個(gè)培養(yǎng)皿不在培養(yǎng)箱中，盡管你們的（b）（4）取樣日志中記錄有這三個(gè)培養(yǎng)皿。這三個(gè)培養(yǎng)皿的 QC 工作表表明，已經(jīng)創(chuàng)建了樣品制備和培養(yǎng)的文件，盡管實(shí)際上沒(méi)有對(duì)這些培養(yǎng)皿進(jìn)行測(cè)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(gè)微生物培養(yǎng)皿。然而，對(duì)這個(gè)培養(yǎng)皿進(jìn)行檢查后，檢查員發(fā)現(xiàn)，上面的字跡與其他所有的微生物培養(yǎng)皿都不一樣。經(jīng)過(guò)詢問(wèn)，你們的微生物檢驗(yàn)人員承認(rèn)，微生物培養(yǎng)皿是重新制備（偽造）的，使得樣品看起來(lái)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(yǎng)箱中，我們的檢查員審查了 117 個(gè)促生長(zhǎng)樣品的文件。但培養(yǎng)箱里只有 74 個(gè) 樣品，其他 43 個(gè)缺失。根據(jù)貴公司的答復(fù)，培養(yǎng)皿不見(jiàn)了是因?yàn)樵跈z查過(guò)程中，你們把微生物實(shí)驗(yàn)室從（b） （4）層移到（b）（4）層。但在檢查期間沒(méi)有人提到實(shí)驗(yàn)室的變動(dòng)。

培養(yǎng)箱連接了計(jì)算機(jī)化系統(tǒng)，但未進(jìn)行計(jì)算機(jī)化系統(tǒng)驗(yàn)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(fā)現(xiàn)你們 QC 實(shí)驗(yàn)室中的 12 個(gè)計(jì)算機(jī)化系統(tǒng)沒(méi)有驗(yàn)證。這些系統(tǒng)用于控制你們的穩(wěn)定性培養(yǎng)箱，紫外（UV）和紅外（IR）分光光度計(jì)以及薄層色譜儀（TLC）。

微生物檢測(cè)結(jié)果未經(jīng)復(fù)核人讀數(shù)確認(rèn)

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(shí)驗(yàn)室(XX房間)，我們觀察到QC分析員在沒(méi)有同步確認(rèn)結(jié)果的情況下對(duì)環(huán)境監(jiān)測(cè)培養(yǎng)皿進(jìn)行了菌落計(jì)數(shù)。我們被告知，微生物負(fù)荷試驗(yàn)在進(jìn)行菌落計(jì)數(shù)時(shí)，實(shí)時(shí)確認(rèn)計(jì)數(shù)結(jié)果是不必要的。根據(jù)風(fēng)險(xiǎn)評(píng)估報(bào)告SEA-RIA-000117，“微生物菌落計(jì)數(shù)同步確認(rèn)風(fēng)險(xiǎn)評(píng)估”(版本1)，在采取緩解措施后，（不同步確認(rèn)計(jì)數(shù)結(jié)果）被確定為低風(fēng)險(xiǎn)。然而，評(píng)估低估了采取緩解措施后的風(fēng)險(xiǎn)，并且沒(méi)有考慮產(chǎn)品直接影響過(guò)程(中間控制、放行、PSM)的關(guān)鍵性。應(yīng)該從微生物控制的角度對(duì)關(guān)鍵生產(chǎn)步驟的環(huán)境檢測(cè)和微生物負(fù)荷培養(yǎng)皿計(jì)數(shù)結(jié)果進(jìn)行第二人的讀數(shù)確認(rèn)，以檢測(cè)XXX的任何微生物污染。