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1. You do not have a scientific rationale for the environmental monitoring sampling locations in aseptic filling Suites (b)(4). You did not include factors such as smoke study findings, number and location of operators, and historical microbial data in your assessment of hazardous points.
你们缺乏对无菌灌装区环境监控取样位置的科学的评估。你们对危害的评估未包括影响因素如烟雾测试发现的问题，以及历史的微生物监控数据。
For example, we found that settling plates are not appropriately placed in critical areas. Your smoke study showed that during set-up and filling, air flows toward the front (when the (b)(4) is open) or back of the RABS. However, two relevant sampling points were recently eliminated. As a result, these points of increased risk are not monitored.
例如，我们发现在关键区域沉降碟的放置不合理。你们的烟雾测试表明在灌装的准备和灌装阶段，气流流向RABS的前方（当xxx打开的时候）或后方。然而，两个相关的取样点最近被取消了。因此，这些位置风险较高却未被监控。
2. No representative non-viable particle (NVP) monitoring data supports your current ISO-5 classification for the product path from the (b)(4) to the (b)(4), which transfers product to the (b)(4) during aseptic processing of finished drug products.
在终产品的无菌生产过程中，将产品从xxx转移到xxx的ISO-5级区，悬浮粒子取样点（NVP）不具有代表性。
During our inspection, we documented that your NVP probes are placed (b)(4) surface instead of near the working area. Placing the probe (b)(4) instead of near the working area means you are unable to detect NVPs where sterile drugs are exposed during aseptic processing.
在审计过程中，我们记录了你们的NVP探头放置于xxx表面，而非工作区。将NVP探头放置于xxx区而非临近工作的区域，意味着你们在无菌药品的无菌生产中无法探测到NVP。
Additionally, transferring (b)(4) vials from the filling suite to the (b)(4) can take up to (b)(4). This extended exposure time may increase contamination hazards. However, your firm lacks adequate environmental monitoring of this part of the operation. It is essential that your sampling plan include areas where (b)(4) and product are exposed to the environment, and at greater risk of contamination.
此外，将xxx药品瓶从灌装区转移到xxx需要xxx时间。这一暴露时间将会增加污染的风险。然而，你们在此操作区缺乏合适的环境监控。你们的取样计划应包括产品暴露、且污染风险较高的区域，这一点是非常重要的。
3. You did not have settling plates located where the risk of product contamination was greatest. For example, your EM program did not include placement of settling plates near the filling zone, the stopper (b)(4), or the incoming track for (b)(4). The (b)(4) filling line settling plate was positioned where filled (b)(4) had already been stoppered.
你们未在产品的高污染风险区使用沉降碟。例如，你们的环境监控程序未在灌装区附近、胶塞xxx，或其他的物料进入通道放置沉降碟。灌装线xxx的沉降碟仅放置于产品已经被加塞的区域。
分析：取样点的识别过程，其实是对微生物污染风险和污染途径进行充分评估的过程，这需要评估人员对于生产过程、系统设置、污染的来源、污染的途径等具有充分的识别能力。
2关注点二：环境监测之取样操作
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4. Poor Personnel Monitoring Technique人员监控技术不当
Our investigators observed personnel in aseptic manufacturing areas using (b)(4) to sanitize their hands immediately before they touched personnel contact plates. Sanitizing hands immediately before conducting personnel monitoring significantly reduces the likelihood of detecting microbiological contamination in the aseptic manufacturing environment. Indeed, your own training procedures note that employees should not use (b)(4) immediately before performing personnel monitoring.
我们的检查员观察到在无菌生产区，人员在做手指碟监测前用消毒剂消毒双手。人员监控前消毒双手会显着降低无菌生产区微生物污染的发现。事实上，你们的培训程序要求在人员监控前不得消毒双手。
5.Personnel Monitoring人员监控
Deficiencies in your operators’ practices indicate that your manufacturing personnel monitoring program is deficient. For example, in your video of (b)(4) batch (b)(4) manufacturing, we observed an operator entering the RABS and in contact with (b)(4) gloves without sanitizing his gloved hands. These (b)(4) gloves were later worn for aseptic connections, purging filling needles, and interventions on the filling machine. Furthermore, you do not monitor these operators when they exit the area, so you have no way to determine whether the operators who enter RABS without sanitizing compromise the aseptic environment.
人员监控的行为表明人员监控程序是不充分的。例如，在你们某产品生产的视频里，我们观察到一个操作员进入RABS并与xxx手套接触，然而其在接触前未消毒双手。这些手套其后被佩戴用于无菌连接、清洗灌装针、以及灌装机的干涉活动。并且，这些操作人员在离开洁净区时未进行人员监控，因此你们无法确认未消毒就进入RABS的操作人员是否影响了无菌环境。
Additionally, on video and in person, we observed employees with (b)(4) on their hands before EM checks. Sanitizing gloved hands just before sampling is unacceptable because it can prevent recovery of microorganisms. This undermines the reliability of personnel monitoring data.
此外，在视频以及在人员身上，我们观察到在执行EM检查时人员手上有xxx。取样前消毒双手是不能被接受的，因为这会阻碍微生物的检出。这会影响人员监控数据的可靠性。
6. You failed to follow your SOP MIA/007/R11 “Monitoring of Water for Microbiological Quality” for collecting water samples. During our inspection, we documented that the scheduled water drop points for (b)(4) and (b)(4) water were not sampled.
你们未能按照SOP MIA/007/R11 “水系统的微生物监控”进行水系统取样。在审计期间，我们记录了按照计划应取样的取样点xxx和xxx未进行取样。
However, according to the analytical raw data work sheet, microbiological testing was performed for water sampling points (b)(4). We confirmed during the inspection that these samples were not, in fact, collected by your microbiologist.
然而，根据分析原始记录，这些水点进行了微生物测试。事实上在审计期间，我们是通过你们的微生物分析人员确定这些水样是没有采样的。
7. On August 6, 2014, when collecting finger dab samples of the (b)(4) gloves, your microbiologist failed to ensure that each finger touched the surface of the (b)(4) sampling plate.
2015年8月6日，当进行人员手指碟采样时，你们的微生物师未确保被采样人员的每一个手指均与培养基表面接触。
8. Your active air sampling is deficient. The microbiologist sprays the “(b)(4)” of the air sampler where (b)(4) with (b)(4), followed by wiping with a cloth. The media plate is loaded onto the air sampler (b)(4) later. There is no assurance that residual (b)(4) does not impact the detection of contaminants.
你们的浮游菌监测是不充分的。微生物师对浮游菌采样器先进行消毒剂喷洒，再用洁净布进行擦拭。培养基平板然后被放置于浮游菌采样器上。这不能确保残留的消毒剂会影响污染物的检出。
9. During our inspection, we noted that you have no justification for two different action levels for finger dab results. While you have an ISO 5 action level of (b)(4) CFU for set-up personnel, you use an ISO 6 action level of (b)(4) CFU for operators who do not routinely participate in aseptic processing operations using the RABS.
在检查期间，我们注意到你们手指碟的结果有两个不同的行动限却没有理由。在RABS，ISO5级的准备的人员，你们的行动现是xxx CFU，而对无菌灌装的日常操作人员却使用ISO6的xxx CFU。
However, the inspection found that these “ISO 6 operators” made ISO 5 interventions, including within the (b)(4) laminar airflow hood (LAF) and the RABS. Notably, when >(b)(4) CFU was recovered from an “ISO 6 operator” who had accessed the RABS during an intervention, your firm did not consider the result to be outside the action limit.
然而，检查中我们发现这些“ISO6操作人员”进行了ISO5级的干涉活动，包括在xxx层流罩（LAF）和RABS内。显然，当大于xxx CFU的微生物从“ISO6级操作人员”（进入RABS进行干涉活动的人员）采样产生时，你们未考虑这个结果是超出行动限的（ISO5级的行动限）。
分析：环境监测的取样操作是一个容易被忽视，或者是被选择性无视的过程。然而，合适的取样操作是环境监测结果可靠的前提，也是证明环境是否受控的最重要、最直接的证据。因此，有经验的审计官会重点关注取样的操作。
3关注点三：环境监测之培养基质量控制
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10. We note that your firm prepares the media plates used for EM sampling at your site. Prior to using these plates, your firm incubates them for (b)(4) and we are concerned that this practice may compromise the media’s growth promotion potential. Provide evidence to demonstrate that pre-incubation of the media plates does not adversely impact the ability to promote microbial growth. Absent evidence to support this practice, you lack critical information demonstrating the suitability of the Class 100 production environment to assure product sterility.
我们注意到你们公司自制培养基用于环境监控。在使用这些平板前，你们在xxx进行预培养。这样会影响培养基的促生长性能。请提供证据表明培养基的预培养对微生物的促生长性能无影响。如无证据支持，你们缺乏关键的信息以体现100级环境能够保证产品的无菌性。
11. Your environmental monitoring data is not reliable because of the materials you use to conduct EM tests.
因环境监控所用的原材料的问题，你们的环境监控的数据是不可靠的。
On February 6, 2015, our investigator observed (b)(4) environmental monitoring plates previously incubated at (b)(4) C being used for surface and personnel monitoring. Three of (b)(4) plates showed signs of desiccation. Media was shrinking away from the edge of microbial plates.
在2015年2月6日，我们的检查员观察到表面监控和人员监控的平板在采样前于xxx度进行预培养。xxx个平板中的3个平板表现出脱水。培养基从边缘开始收缩。
On February 13, 2015, our investigator observed signs of drying on three of (b)(4) plates used for water samples and four of (b)(4) plates used for bio-burden.
在2015年2月13日，我们的检查员观察到水样测试的xxx个平板中有3个干燥，微生物负载测试的xxx个平板中有4个干燥。
12.The agar level on surface contact plates (used for surface environmental and personnel monitoring sample testing) was below the rim of the plates creating the possibility that the agar would not have contact with the surface intended to be sampled.
接触平板（用于环境表面和人员监控）的琼脂高度低于平板的边缘，这使得琼脂在采样时可能没有接触到被取样位置的表面。
分析：培养基的质量问题已经成为了一个反复出现的发现项，主要体现在培养基的干裂。需要注意的是，干裂的因素很多，可能与培养基制备过程有关、可能与取样方式或取样时间有关、也可能与培养条件有关。因此，需要找到干裂的根本原因，对症下药。
4关注点四：环境监测之风险评估
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13. For example, there was no scientific justification for the sampling plans utilized for environmental monitoring in areas that your firm uses to manufacture terminally sterilized injectables. This included the frequency and locations of viable airborne particulate sampling activities, the locations of non-viable airborne particulate sampling activities, the frequency and locations of non-product contact surface monitoring, and the evaluation of microorganisms found through environmental monitoring activities. Your environmental monitoring program was insufficient to detect contamination of concern, including mold observed on the clean side of the air filters supplying air to the sterile filling areas. In addition, your environmental monitoring records do not identify the locations from which environmental monitoring samples were taken in each manufacturing area and room including, but not limited to: viable airborne particulate monitoring, non-viable airborne particulate monitoring, and large non-product contact surface area monitoring. Your incomplete records make evaluating the air quality of the filling area during the time prior to this inspection more difficult. In your response, you state that you use a formal risk assessment to justify the type, extent, frequency, and location of sampling and test procedures. Xxx also will create a procedure for periodic reassessment of that risk assessment to incorporate any relevant new or emerging information, and you will continue to conduct bioburden testing.
例如，在终端灭菌注射剂生产区的环境监控的取样计划无科学的评估。这包括浮游菌的取样频率和取样点、悬浮粒子取样点、非产品接触表面菌的取样频率和取样点，以及环境监控中发现的微生物的评估。你们的环境监控程序无法有效的监测到担心的微生物污染，包括无菌灌装区空气过滤器洁净送风侧观察到的霉菌。此外，你们的环境监控记录未标注每个生产区和房间的取样位置，包括（但不限于）浮游菌监测、悬浮粒子监测，和非产品接触的表面监控。你们不完整的记录使得这次审计前的灌装区的空气质量的评估更加困难。在你们的回复中，你们声明你们使用了正式的风险评估来评估取样类型、范围、频率和测试程序。xxx也会创建新的程序定期评估相关的新的风险或者出现的状况，并且持续进行微生物负载的测试。
Although we acknowledge your use of formal risk assessments in implementing these revised environmental monitoring procedures and bioburden testing, your response is still deficient. In your response, you downplay the product quality and safety impacts posed by the mold observed on the clean side of HEPA filters supplying air to your sterile filling areas on the grounds that products made in these areas are terminally sterilized. Please note that sterile products should be protected from microbiological contamination during processing, even when terminally sterilized, in order to minimize sterilization challenge and byproducts of excessive bioburden.
尽管我们知道你们在执行更新的环境监控程序和微生物负载测试时使用了正式的风险评估，你们的回复仍然是不充分的。在你们的回复中，你们未足够重视在HEPA过滤器（送风至终端灭菌产品的无菌灌装区）洁净侧观察到的霉菌对产品质量和安全性的影响。请注意，无菌产品应在生产过程中避免被微生物污染，哪怕是终端灭菌产品，以降低灭菌的难度以及过量的微生物带来的副产物。
分析：科学的环境监测风险评估永远是建立对产品的影响基础之上的。
5关注点五：环境监测之异常处理
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14. Your firm failed to conduct thorough investigations of your environmental monitoring (EM) excursions (i.e., exceeds action levels) found in your Class 100 areas. During the inspection, the review of the available data for the period of January 2012 to December 2013 revealed that your firm identified 23 EM samples that exceeded action levels in the Class 100 aseptic area on Line (b)(4) in your building identified as Hikma (b)(4). Our review of the investigations collected during the inspection noted that all investigation reports identified “possible root causes” of the EM excursions as mishandling and/or poor aseptic technique during sampling. In all of these investigations you were unable to determine an actual root cause; yet, you disregarded the EM excursions without justification. In addition, your firm failed to evaluate the potential impact of these EM excursions on the quality of the product manufactured.
贵公司未对100级区环境监控超标进行彻底的调查。在审计中，2012年1月至2013 年的已有监控数据检查表明，在楼宇Hikma xxx中的灌装线xxx的100级区有23个环境监控样品超出行动限。审计时审核的调查报告表明所有的调查报告均显示，环境超标的“可能原因”为环境监控时操作错误和/或无菌操作不当。所有的调查均未调查出根本原因，然而，你们却舍弃掉了超标的结果，未有科学的评估。此外，你们未评估环境超标对产品质量的影响。
15.There is a lack of assurance that you maintain your manufacturing environment in a state of control suitable for aseptic processing.
不能确保无菌生产环境处于受控状态以用于无菌生产
Environmental Monitoring 环境监控
For example, you did not utilize environmental monitoring data to identify environmental control issues and identify appropriate follow-up actions. There were repeated out-of-action-level (OAL) results from microbial testing, but you did not examine the data for trends or take appropriate follow-up action. Your SOP “No. MIP/047/R7 Microbiological evaluation of Clean Rooms and Other Controlled Environments of Suite (b)(4) Area” describes OALs as (b)(4) CFU for setting plates inside the RABS (ISO 5) and (b)(4) CFUs for your ISO 6 area.
例如，你们未使用环境监控数据识别环境控制的问题并制定合适的行动计划。你们有重复的微生物检测OAL（超行动限），然而你们未进行趋势分析或者采取合适的行动。你们的SOP“编号MIP/047/R7 洁净区和其他受控环境的微生物评价”将OAL定义为RABS (iso5)的沉降菌为xxx CFU，ISO6级区为xxx CFU。
In 2014, you reported 375 OAL results (b)(4) or more CFUs in your ISO 6 area. Then, on January 31, 2015, you obtained OAL results of (b)(4) or more CFUs during the manufacture of (b)(4) Injection ((b)(4)) in Suite (b)(4). You also obtained OAL levels from the settle plates inside the RABS ((b)(4) CFU near the (b)(4)), and (b)(4) CFUs were recovered from the air sampling point near the (b)(4). From February 6-7, 2015, you obtained OAL results of (b)(4) or more colony-forming unit (CFU) in three critical ISO 5 areas of Suite (b)(4) during the manufacture of (b)(4) Injection ((b)(4)):
2014年，你们在ISO6级区报告了375个OAL结果（大于等于xxx CFU）。然后，在2015年1月31日，你们在生产xxx注射剂的手套箱内得到了大于等于xxx CFU的OAL结果。你们也在xxx附近的RABS内的沉降碟得到了大于等于xxx CFU的OAL结果，从xxx附近的浮游菌得到了大于等于xxx CFU的OAL结果。从2015年2月6日到7日，在生产xxx注射剂时，你们手套箱xxx的ISO5级区得到了大于等于xxx CFU的OAL结果。
?(b)(4)—(b)(4) CFUs;
?(b)(4)—(b)(4) CFUs (fungi真菌);
?(b)(4)—(b)(4) CFUs
16. b. In your ISO-5 and ISO-7 environments, the building management system (BMS) monitoring differential pressure and the non-viable particle monitoring system (NVPMS) for non-viable particles appear to be out of control. For example:
在你们的ISO-5和ISO-7级环境中，用于压差监控的楼宇监控系统（BMS）和用于悬浮粒子监控的系统（NVPMS）似乎是失控的，例如：
?We found 456,201 alarmed events registered in the computer system monitoring differential air pressures between your ISO-5, ISO-7, and ISO-8 manufacturing environments from February 14, 2013, through September 26, 2014.
从2013年2月14日至2014年9月26日，在ISO-5级、ISO-7级和ISO-8级之间的压差监控系统中，我们发现456,201个报警事件。
?We also found 16,415 alarmed events registered in NVPMS for Suite (b)(4) ISO-5 areas, and 17,809 for Suite (b)(4), from October 2012 to September 2014.
同样，从2012年10月至2014年9月，在悬浮粒子监控系统（NVPMS）中，在ISO-5级区我们发现了16,415个报警事件，在生产区域xxx内发现了17,809个报警事件。
You did not conduct a comprehensive evaluation and risk assessment to determine how these frequent events affecting the aseptic processing areas may have compromised product quality.
你们未进行详尽的评估和风险分析以确定这样的高频事件对无菌生产区域的影响，以及可能对产品质量的影响。
c. Your firm failed to identify the source of gram-negative contamination in your ISO 7 area and to implement appropriate corrective actions and preventive actions.
c. 贵公司未调查出ISO-7级区的革兰氏阴性菌的污染源，从而采取合适的纠正和预防措施。
In your ISO-7 Suite (b)(4), you identified Pseudomonas, sp. during passive air sampling collected from your passage way, in (b)(4) rooms (b)(4) and (b)(4). You did not evaluate the potential routes of contamination.
在你们的ISO-7级的生产区xxx内，在xxx房间和xxx房间的走道内进行浮游菌采样时，你们鉴定出了假单胞菌。你们未评估潜在的污染途径。
Your evaluation of environmental microbial data should not be narrowly limited to specific lots or events. Trend analysis, identifying sources of contamination, and risk assessment are essential to maintain adequate microbiological control.
你们评估环境的微生物监控数据时，不应仅限于特定的批次或事件。趋势分析、污染源的调查和风险评估对微生物控制是十分关键的。
This violation is recurrent. On September 9, 2013, we cited your firm in Warning Letter 320-13-26 for failure to establish an adequate environmental monitoring system. To assure drug sterility, it is vital for you to vigilantly maintain environmental control throughout aseptic operations.
这样的偏离是重复发生的。在2013年9月9日，我们引用了你们公司的警告信320-13-26，未建立合适的环境监控系统。为确保药品的无菌性，维持无菌生产的环境控制是至关重要的。
分析：异常事件的调查和处理是审计的必查项目，深入的调查和有效的CAPA是迎接审计最有效的手段。
6关注点六：培养基模拟灌装
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17. In addition, your firm failed to establish maximum holding times for vials used in media fills, prior to incubation. Your media fill protocol for batch (b)(4) does not establish a set timeframe between completion of filling vials and placing filled vials in the incubators. Our investigator found that, during a media fill operation you filled the vials on July 24 and July 25, 2012, and did not incubate them until July 30, July 31, and August 1, 2012. Your manager attributed the delay to lack of space to perform the visual inspection and to personnel resource constraints. Upon completion of filling the media fill vials, the vials should be incubated under conditions (time and temperature) adequate to allow detection of microorganisms that might otherwise be difficult to culture. Data should be maintained to show monitoring of, and conformance to, those conditions.
此外，你们未建立培养基模拟灌装的瓶子在灌装结束后至放入培养箱培养的放置时间。你们的培养基模拟灌装方案xxx未设定灌装结束后至放入培养箱的时间。我们的检查员发现，在2012年7月24日和2012年7月25日的培养基模拟灌装，你们直到2012年7月30日、31日和8月1日才开始培养。你们的管理人员将此归结于没有空间进行目视检查和人力资源的限制。在培养基模拟灌装结束后，灌装瓶应在规定的时间和温度下进行培养，以便于微生物的检测，否则（微生物）可能会难以培养。应有数据监测和支持放置条件是符合要求的。
Your response indicates that you initiated a change control to have a maximum hold time of (b)(4) from end of filling to start of incubation of the media fill vials. In your response, provide your justification for the (b)(4) maximum hold time. In addition, specify the required storage conditions for the media vials during this hold period and their justification. In you response please also provide a summary of your assessment regarding whether the vial hold conditions between filling and incubation for batch (b)(4) affected the conclusions of your media fill studies, including whether you plan to repeat the studies and the rationale supporting this decision.
你们的回复表明你们启动了一个变更来控制灌装结束至放入培养箱的最大放置时间。在你们的回复中，请提供最大放置时间的理由。此外，请提供放置的条件和理由。在你们的回复中，请提供关于灌装结束至放入培养箱的放置条件是否影响你们培养基模拟灌装研究的结论的评估和总结，包括你们的是否会重新进行培养基模拟灌装的决定以及理由。
分析：关于培养基模拟灌装的发现项很多，笔者在这里列了一个非典型的案例，也是很多公司忽视的问题。培养基模拟灌装是无菌保证的重要一环，所有的环节均需要严格控制。
