未对每批培养基进行促生长实验

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.

你没有对你准备的每批微生物培养基进行促生长试验，这些培养基用于沉降菌、微生物负载和无菌测试。此外，你没有书面规程来确保你制备的培养基始终符合适当的质量和纯度标准。

培养基存储不当，缺少促生长试验，缺少阳性对照

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.

你们的(b)(4)系统设计不当。你们标明“已灭菌”的(b)(4) 系统，其(b)(4)管路有死角。系统设计不当易促进生物膜形成。此外，由于在检查中发现的实验室控制方面的缺陷，例如培养基存储不当，缺少促生长试验，缺少阳性对照，无法确定你们有能力检测微生物负荷或微生物限度超标情况。

阳性碟子上无菌生长

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)

用来检测某微生物样品的阳性培养碟上无菌生长。当阳性试验无菌生长时，测试结果不能认为是合格的，因为会潜在导致假阴性。

使用有缺陷（脱水）的培养基进行环境监测

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.

无菌检测区的环境检测期间使用的接触碟脱水了。干燥、破裂或损坏的XX 会影响微生物的生长和精确计数，并可能导致人为的低微生物计数和假阴性。使用有缺陷的培养基会影响你们微生物检测结果的正确性。

未对无菌区环境中出现的微生物进行鉴别

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.

另外你们没有对在你们无菌工艺室的环境监测期间分离出来的细菌和真菌进行常规鉴别（比如鉴别到种属）。

微生物检测方法未充分确认 / 验证

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.  

你们的非无菌原料药(b)(4)计划用于生产供美国销售的无菌成品剂型。你们没有适当地验证检测方法，总需氧微生物计数和酵母菌和霉菌结合总数。具体来说，你们没有证明在原料药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.

根据贵公司的文件《微生物计数 QTP-079》，“对于没有验证(b)(4)方法的样品，应使用经典方法检测，以验证样品是否满足微生物计数验收标准。”你的公司仍然缺乏验证过的(b)(4)方法。当你的反馈表明你修订 SOP 微生物回收验证, 参考你将使用的(b)(4)验证方法,SOP 的修改没有解决方法不足或证明等价或优于性 USP < 61 > 无菌药品微生物检测:微生物计数测试和 USP < 62 >无菌产品微生物检查:对特定微生物进行的检测，以发现有害微生物，如 B. cepacia 菌和微生物总数。

未进行微生物检测，伪造微生物检测记录及结果

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.

在检查过程中，检查员目视检查了正在培养的（b）（4）的质量和培养基促生长样品（培养皿），并将其与声称正在进行（培养）的样品的质量控制文件进行了比较。你们的（b）（4）取样记录显示，2014 年 7 月 9 日，准 备了 45 份（b）（4）质量样品并进行培养（（b）（4），总活菌数）并且正在进行中。在检查过程中，其中三个培养皿不在培养箱中，尽管你们的（b）（4）取样日志中记录有这三个培养皿。这三个培养皿的 QC 工作表表明，已经创建了样品制备和培养的文件，尽管实际上没有对这些培养皿进行测试。

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.

你们的管理层告诉检查员找到了一个微生物培养皿。然而，对这个培养皿进行检查后，检查员发现，上面的字迹与其他所有的微生物培养皿都不一样。经过询问，你们的微生物检验人员承认，微生物培养皿是重新制备（伪造）的，使得样品看起来是完整的。

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 的培养箱中，我们的检查员审查了 117 个促生长样品的文件。但培养箱里只有 74 个 样品，其他 43 个缺失。根据贵公司的答复，培养皿不见了是因为在检查过程中，你们把微生物实验室从（b） （4）层移到（b）（4）层。但在检查期间没有人提到实验室的变动。

培养箱连接了计算机化系统，但未进行计算机化系统验证

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)

我们的检查员发现你们 QC 实验室中的 12 个计算机化系统没有验证。这些系统用于控制你们的稳定性培养箱，紫外（UV）和红外（IR）分光光度计以及薄层色谱仪（TLC）。

微生物检测结果未经复核人读数确认

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微生物实验室(XX房间)，我们观察到QC分析员在没有同步确认结果的情况下对环境监测培养皿进行了菌落计数。我们被告知，微生物负荷试验在进行菌落计数时，实时确认计数结果是不必要的。根据风险评估报告SEA-RIA-000117，“微生物菌落计数同步确认风险评估”(版本1)，在采取缓解措施后，（不同步确认计数结果）被确定为低风险。然而，评估低估了采取缓解措施后的风险，并且没有考虑产品直接影响过程(中间控制、放行、PSM)的关键性。应该从微生物控制的角度对关键生产步骤的环境检测和微生物负荷培养皿计数结果进行第二人的读数确认，以检测XXX的任何微生物污染。