Inspectional Guidance-Manufacturing Facility Review
1. Aseptically filled pharmaceuticals药品无菌灌装
Check environmental monitoring (EM) data taken from production areas and the testing environment (i.e., S-T-A, settling plates, RODAC, etc) for microbial contamination that matches the microbe isolated from the finished product sterility test
检查生产区域和测试环境中与成品无菌检查分离出的微生物相似的微生物污染的环境监控数据（如S-T-A，沉降菌、表面微生物等）
If no microorganisms are detected, check the adequacy of the EM method used during manufacturing for proper sensitivity and applicability, for example
如果没有微生物检出，请检查生产过程中使用的环境监测方法的灵敏度和适用性，如：
a. Are they using proper medium (i.e. non-selective medium)?
是否使用正确培养基（非选择性培养基）
b. Have they performed growth promotion?
是否进行培养基促生长试验
c. Did they use appropriate incubation time and temperatures?
是否使用适当的培养时间和培养温度
d. Are they sampling in the appropriate room locations, during dynamic conditions, longest time between cleanings/sanitation and at frequency to assure reliability of the results?
动态条件下，是否在适当的房间位置、频率、清洁与消毒的最长时间来取样，以确保结果的可靠性？
e. If they recovered an anaerobic bacterium from the sterility test (Thioglycollate broth) do they perform EM for anaerobic bacteria?
如果无菌测试（硫乙醇酸盐培养基）检出厌氧菌，是否在针对厌氧菌进行环境监测？
Have they performed a filter integrity test on the membrane use for the product sterilization? Review the products pre-filtration bioburden levels to assure that the concentration of bacteria in the bulk has not exceeded the membrane filtration capacity that was determined in their validation studies. Have they changed the source or model for the membrane filter cartridge used in the process?
是否对产品灭菌所用的膜过滤进行了过滤器完整性测试？审查产品过滤前的生物负载水平，确保细菌浓度未超过其验证研究确定的膜过滤能力？在使用过程中是否改变过滤器滤芯的来源或型号？
Has the firm manipulated or excluded some of the data used in the final QC report? Perhaps raw data was averaged to bring the bioburden count below the alert or action levels. It can be helpful to request electronic Excel sheet version of data, to allow sorting (by frequency of organism, location, etc.) and trend analysis; hard copies can be requested later, if necessary.
最终报告中的某些数据是否修改或删除？或许原始数据的平均是为了使生物负荷量低于警戒或行动水平？使用电子Excel表格来对数据进行分类(按微生物检出的频率、位置等)和趋势分析是非常有用的；必要时，进行备份。
Review the media simulation studies. Did the microbial species recovered in past simulation studies match the microbe(s) recovered from the current product test failure?
审查培养基灌装试验。比较以往的灌装试验分离出的微生物种类是否与当前产品测试失败分离出的微生物种类相匹配？
Has there been a change or breach in the personnel barrier system to protect the product? Were there any interventions by maintenance or other staff personal during the manufacturing of the contaminated lots? Review glove/uniform monitoring results.
保护产品不被污染的人员防护系统是否有改变或破坏？受污染的批次在生产过程中是否有维修人员或其他人员进入生产区域？审查手套、洁净服的监测结果。
Review the Antimicrobial Effectiveness challenge studies for the product. Where there any changes to the container/closure component source or requirements?
审核该产品的抗菌效力挑战试验研究。容器或包装组件来源或需求是否有变化？
Were there any changes to the disinfection procedure, reagents use, new personnel, application, equipment (mops, aerosols, etc.) etc.?
消毒程序、试剂的使用、新员工、应用程序、设备(拖把、气溶胶等)等是否有改变？
2. Terminally sterilized drug product终端灭菌药品
Check autoclave validation studies for sterilization process- cold spot, heat penetration (challenged inside dry tubing, connectors/caps/stoppers, largest liquid volume, etc.), changes in chamber load configuration, etc.)
检查灭菌工艺的灭菌器验证——冷点，热穿透（在干燥管，连接器/瓶盖/塞子，最大装载量内等进行挑战试验），改变装载方式等。
Check maintenance records for house steam, records for autoclave repair, new plumbing
检查内部蒸汽维护记录、灭菌器维修记录，新水管装置
Check Biological Indicator (BI) information- improper storage of BIs; changes in the culture (inoculum level and/or BI organism species) and incubation parameters
检查生物指示剂信息——生物指示剂的不正确储存；培养物（接种水平、菌株种类）和培养条件参数的改变
Evaluate the heat resistance characteristics of the microbial isolate found in the product during Sterility testing and determine if it can survive during the process condition , review product container/closure integrity data and possible recent supply source changes to vials or rubber stoppers; Check possible post sterilization package integrity problem- mostly medical device issue.
评估产品无菌测试中检出的微生物的耐热特性，确定其是否在工艺条件下存活，检查产品容器/密封件的完整性数据，以及近期可能对小瓶或橡胶塞的供应商变更；检查灭菌后包装完整性问题-主要是医疗设备问题。
本文来自Pharmaceutical Microbiology Manual2014
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原文始发于微信公众号（药品微生物检测）：Inspectional Guidance 7-生产设备审查
