2022年注射剂生产过程中微生物的质量风险控制论文.docx

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1、精选学习资料 - - - - - - - - - 更多企业学院：中小企业治理全能版总经理、高层治理183 套讲座 +89700份资料 49 套讲座 +16388份资料中层治理学院46 套讲座 +6020份资料国学聪明、易经46 套讲座人力资源学院56 套讲座 +27123份资料名师归纳总结 - - - - - - -第 1 页,共 13 页精选学习资料 - - - - - - - - - 各阶段员工培训学院员工治理企业学院工厂生产治理学院财务治理学院销售经理学院销售人员培训学院77 套讲座 + 324 份资料 67 套讲座 + 8720 份资料 52 套讲座 + 13920 份资料 53 套讲

2、座 + 17945 份资料 56 套讲座 + 14350 份资料 72 套讲座 + 4879 份资料无菌生产工艺论文： 注射剂生产过程中微生物的质量风险控 制【中文摘要】注射剂 injection是直接注入人体内部的一种剂型, 常用剂量较大 , 按其生产工艺的不同可分为最终灭菌工艺和非最终灭菌工艺也即无菌生产工艺两种, 无菌生产工艺的无菌保证水平SAL仅是灭菌工艺的 1/103-/109 ；无菌生产工艺产品在生产过程中 微生物污染的因素较多 , 因此, 在临床使用过程中具有较高的质量风 险；本课题以 5ml 无菌生产工艺注射剂为例 , 利用休哈特掌握图、饼 图、柱状图等统计工具对生产中的环境、

3、人员、物料、注射用水、压 缩空气、氮气等可能引入或污染微生物的环节进行监控和风险确认；采纳失败模式及影响因素分析FMEA、风险排序和过滤等风险工具对各因素进行风险分析和评估 , 找诞生产过程中污染微生物的高风险因素；通过实行措施和措施的有效性论证进行风险掌握 , 进一步降低无菌生产工艺注射剂的微生物风险, 保证患者用药安全；争论内容主要名师归纳总结 包括干净区的微生物和悬浮粒子监控数据汇总分析、人员的微生物监第 2 页,共 13 页- - - - - - -精选学习资料 - - - - - - - - - 控数据汇总分析、 物料的微生物监测数据汇总分析、注射用水的微生 物监控数据汇总分析、 压

4、缩空气和氮气的微生物和悬浮粒子监测数据 汇总分析、 各因素的微生物监控数据平均结果汇总分析、各因素的微 生物风险评估、 建议及措施； 1. 干净区的微生物和悬浮粒子监控数据 汇总分析通过对 100000级区、 10000级区、 10000 级无菌区、 100 级 区不同的功能间进行了静态沉降菌和悬浮粒子的数据监控和汇总 , 对 10000级无菌区、 100 级区不同的功能间进行了动态沉降菌的监控和 汇总；利用统计工具休哈特掌握图按级别分别作图分析 , 运算出：各 干净级别不同功能间静态沉降菌和悬浮粒子的平均值 X、标准偏差 和掌握线 X 3 ；10000 级无菌区、 100 级区不同功能间动态

5、沉降菌 的平均值 X、标准偏差 和掌握线 X 3 ；从休哈特掌握图分析各检 测结果均在掌握线内； 通过对各干净级别关键功能间的静态沉降菌和悬浮粒子分别做柱状图进行比较分析得出：静态悬浮粒子和沉降菌的检测结果和干净级别成对应关系；不同干净级别的检测结果有较大差别 ,100 级区检测结果最好 ,10000 级无菌区次之 ,100000 级区检测结果最差；2. 人员的微生物监控数据汇总分析通过对 10000 级无菌区、100 级区人员的手套、袖口、肘部、额头、口罩表面的微生物进行 20 批次的检测数据汇总 , 利用统计工具休哈特掌握图进行作图分析；运算平均值 X：10000 级无菌区分别为1.50

6、、1.25 、1.55 、1.15 、1.15CFU/碟,100 级区分别为 0.70 、0.55 、0.60 、0.50 、0.45 CFU/碟；标准偏差 ：10000级无菌区分别为0.51 、0.44 、0.51 、0.59 、0.37 CFU/ 碟,100 级区分别为 0.47 、0.51 、0.50 、0.51 、0.51 CFU/名师归纳总结 - - - - - - -第 3 页,共 13 页精选学习资料 - - - - - - - - - 碟, 从休哈特掌握图和运算数据看100 级检测结果明显好于10000 级无菌区 , 口罩好于其他部位 , 各检测结果均在掌握线内； 3. 物料的

7、微生物监测数据汇总分析连续取样30 批监测 A、B、C三个注射液配好药液带菌量 , 利用统计工具休哈特掌握图进行作图分析 , 运算平均值 X分别为 1.57 、1.31 、2.37 个/100ml ；标准偏差 分别为 1.01 、0.81 、1.03 个/100ml ；X+3 分别为 4.59 、3.73 、5.47 个/100ml ；从监控数据和运算结果分析 , 三个产品配好药液的带菌量有差别 ,B 产品监测数据最好 ,C 产品结果最差 , 除 A、C注射液有个别点超出界限外 , 其余各批次检测结果均在掌握线范畴内波动；4. 注射用水的微生物监控数据汇总分析对注射用水系统的罐出口、使用点 1

8、、使用点 2、使用点3、罐回口取样进行每周一次的微生物监控, 然后对连续一年的数据汇总, 利用统计工具休哈特掌握图进行作图分析；运算各点的平均值 X分别为 0.10 、0.12 、0.12 、0.14 、0.18 个/100ml ；标准偏差 分别为 0.31 、0.33 、0.33 、0.35 、0.39 个/100ml ；X+3 分别为 1.02 、1.12 、1.12 、1.20 、1.36 个/100ml ；从运算结果和数据变化趋势分析罐出口检测结果最好 , 罐回口检测结果最差； 5. 压缩空气和氮气的微生物和悬浮粒子监测数据汇总分析通过对压缩空气的使用点洗瓶1、洗瓶 2、灌装 1、灌装

9、 2、过滤和对氮气的使用点灌装 1、灌装 2分别采样进行微生物和悬浮粒子检测, 每月一次；, 通过对连续一年的数据汇总 , 利用统计工具休哈特掌握图进行作图分析；微生物和悬浮 粒子的平均值 X均为 OCFU个/m3, 最大值为 0 CFU个/m3, 最小值为 0 CFU个/m3 ；标准偏差 均为 0 CFU个/m3,X 3 均为 0 名师归纳总结 - - - - - - -第 4 页,共 13 页精选学习资料 - - - - - - - - - CFU个/m3, 从运算结果和监测数据趋势分析各使用点的微生物和悬 浮粒子数值稳固； 6. 各因素的微生物监控数据平均结果汇总分析对无 菌生产工艺中影

10、响药品微生物质量的干净区环境、人员污染、物料、注射用水、压缩空气、氮气所监控的微生物数据进行平均汇总 , 然后 做出饼图进行分析后得出：人员动态微生物污染所占比例最大是 46%包括 10000级无菌区和 100级区, 其次是药液中所含微生物的比例占 42%,环境中的微生物所占比例是9%,注射用水中微生物占3%,压缩空气和氮气微生物所占比例为零；7. 各因素的微生物风险分析对收集的数据采纳 FMEA表格进行风险排序和过滤 , 得出影响无菌生产工艺注射液微生物风险因素由小到大依次为：压缩空气、氮气、物料、注射用水、 100 级区空气、 10000 级无菌区空气、人员污染；风险顺序数 RPN依次为：

11、 2、3、8、9、19、32、252；8. 建议及措施降低无菌生产工艺注射剂的微生物污染风险, 在很大程度上取决于人员的技能, 所接受的培训及人员的工作态度；应实行的措施：是制定人员“ 无菌室” 行为规章 , 进行无菌操作技能和意识培训；是采纳无菌隔离系统；是采纳培育基模拟灌装, 验证降低人员污染措施有效性；结论在无菌生产工艺注射剂可能影响微生物的各种风险因素中：物料、压缩空气、氮气为低风险因素；10000级无菌区空气、 100级空气和注射用水为中等风险因素：人员污染为高风险因素； 采纳无菌隔离系统对降低人员的微生物污染能起到较好的成效；采纳风险治理的程序、工具和方法能有效地掌握无菌工艺注射剂

12、生产过程中的微生物风险, 使药品的生产由过程掌握转为主动预防, 很好的补偿 GMP条款名师归纳总结 - - - - - - -第 5 页,共 13 页精选学习资料 - - - - - - - - - 在质量掌握方法和工具等方面的不足；【英文摘要】 Injection is a dosage form of injecting directly into human, which is usually with larger dosage. Injection can be classified into terminally sterilised processes and aseptic p

13、reparerations according to the productive technology. The sterile guarantee level of the aseptic preparerations is only 1/103-/109 of that of the terminally sterilised processes. Since there are many contamination factors during the production of microbiological the aseptic preparerations, therefore

14、, high quality risks exist in the clinical practice.The current study takes the 5ml injection produced by aseptic preparerations as an example, and uses Shewhart Control Chart, Pie Chart and Histograms to monitor the microbiological contaminations introduced by environments, personnel, materials, wa

15、ter for injection, compressed air, nitrogen during production. We hope to find a high microbiological risk factor by performing risk assessment on each factor through Failure Mode Effects Analysis, Risk ranking and filtering. We then perform risk control by taking measures,The validity of the measur

16、es is sufficent to further decrease the risk of the quality of the aseptic preparerations and ensure the secure pharmacy of patients.This article was 名师归纳总结 - - - - - - -第 6 页,共 13 页精选学习资料 - - - - - - - - - composed of the following eight parts:The results analysis of the microbiological and airborn

17、e particulate monitoring in clean zone; The results analysis of the personal microbiological monitoring; The results analysis of microbiological monitoring in materials; The results analysis of microbiological monitoring in water for injection; The results analysis of the microbiological and airborn

18、e particulate monitoring in the compressed and nitrogen; The Meta-analysis of the average results of monitoring data of the microbes in each factor; The risk analysis of microbes in each factor; Suggestions and measures.1. The results analysis of the microbiological and airborne particulate monitori

19、ng in clean zoneBy the microbiological and airborne particulate monitoring at rest in different room include a grade 100000 zone, a grade 10000 zone, a aseptic grade 10000 zone, a grade 100 zone, and by the microbiological monitoring in operation in different room in a aseptic grade 10000 zone and a

20、 grade 100 zone.The results are then analyzed according their grades through Shewhart Control Chart to calculated the average value of X, the standard deviation 8 and the control line X 38 of the static microbes and airborne particles at rest in different rooms in different clean zones, respectively

21、, and those of 名师归纳总结 - - - - - - -第 7 页,共 13 页精选学习资料 - - - - - - - - - microbes in operation in different rooms in a aseptic grade 10000 zone and a grade 100 zone. We find that each testing result is fall within the control line from the Shewhart Control Chart.We then perform a comparative analysis

22、 through Histograms of the microbes and airborne particles at rest in the critical rooms in each clean grades and find that the testing results of the static the microbes and airborne particles have correspondence with the grades of the clean zones; the testing results in different grades of clean z

23、ones have large differences:the best result is in a grade 100 zone, followed by the aseptic grade 10000 zone and grade 100000 zone.2. The results analysis of the personal microbiological monitoringBy microbiological monitoring on the surface of the personal gloves, sleeves, elbows, forehead and a fa

24、ce mask by successive 20 batchs of production in a aseptic grade 10000 zone and a grade 100 zone. The results are then summarized and analyzed by Shewhart Control Charts. The average values of x are calculated to be 1.50 、1.25 、1.55 、1.15 、1.15 CFU/plate for a aseptic grade 10000 zone,0.70 、0.55 、0.

25、60 、0.50 、0.45 CFU/plate for a grade 100 zone, while the standard deviation 8 are calculated to be 0.51 、0.44 、0.51 、0.59 、0.37 CFU/plate for a aseptic grade 10000 zone and 0.47、0.51 、0.50 、0.51 、0.51 名师归纳总结 - - - - - - -第 8 页,共 13 页精选学习资料 - - - - - - - - - CFU/plate for a grade 100 zone. We find th

26、at the testing result in a grade 100 zone is obviously better than that in a aseptic grade 10000 zone, and the face mask is better than others. Each testing result in within the control line.3. The results analysis of microbiological monitoring in materialsBy microbiological monitoring in A, B and C

27、 injections in successive 30 batchs, The results are analysis by using Shewhart Control chart. The average values of X, the standard deviation 8, and x+3 for A, B and C injections are calculated to be 1.57 、1.31 、2.37 CFU/100ml,1.01 、0.81 、1.03 CFU/100ml and 4.59 、3.73 、5.47 CFU/100ml, respectively.

28、 We find difference of the quantity of microbes between the A, B and C injections:the testing data of A is best while C is worst. All testing results fall within the control line except several points in A and C injections.4. The results analysis of microbiological monitoring in water for injectionW

29、e firstly monitor the microbes in the outlet, point of use 1,2,3 and inlet of the system of the water for injection weekly and then summarized and analysis the data obtained in a whole year by Shewhart Control Chart. For the outlet, point of use 1,2 3 and inlet, the average values of X, the standard

30、 deviation , and X+3 are calculated to be 0.10、0.12 、0.12 、0.14 、0.18 名师归纳总结 - - - - - - -第 9 页,共 13 页精选学习资料 - - - - - - - - - CFU/100ml,0.31 、0.33 、0.33 、0.35 、0.39 CFU/100ml and 1.02、1.12 、1.12 、1.20 、1.36 CFU/100ml, respectively. The testing result obtained from the outlet in the best while that

31、obtained from the inlet is the worst from the calculated results and the variation trend of data.5. The results analysis of the microbiological and airborne particulate monitoring in the compressed and nitrogenWe firstly monitor the microbes and airborne particles in the using points of washing bott

32、le 1,2, filling 1,2, filtration of the compressed air and monitor the microbes and airborne particles in the using points of filling 1,2 of the nitrogen monthly, and then summarize and analysis the data obtained in a whole year by Shewhart Control Chart. We find that the values of the average X, sta

33、ndard deviation and X+3 are all calculated to be 0 CFU/m3, indicating that the values of the microbes and airborne particles in each using point are stable.6. The Meta-analysis of the average results of monitoring data of the microbes in each factorThe monitoring data of microbes introduced by the e

34、nvironment of the clean zones, personnel contamination, materials, water for injection, compressed air and nitrogen during the aseptic prepareration firstly averaged and summarized. We then analyze the data by pie chart and conclude that the proportions of the microbes 名师归纳总结 - - - - - - -第 10 页,共 1

35、3 页精选学习资料 - - - - - - - - - introduced by personnel contamination in operation in containing a aseptic grade 10000 zone and a grade 100 zone, materials, the environments and water for injection are 46%,42%,9% and 3%, respectively, while that of the compressed air and nitrogen is zero.7. The risk ana

36、lysis of microbes in each factorThe Risk ranking and filtering are performed on the collected data by Failure Mode Effects Analysis and conclude that the influence of each risk factor on the microbes in injections produced by aseptic preparations from small to large is compressed air, nitrogen, mate

37、rials, water for injection, air in a aseptic grade 10000 zone, air in a grade 100 zone, personnel contamination with according Risk Priority Number of 2,3,8,9,19,32 and 252.8. Suggestions and measuresIn order to minimize risks of microbiological contamination of aseptic preparerations. Much depends

38、on the skills, training and attitudes of personnel involved. The measures should be adopted as follows: Setting personnel rules in aseptic room and training the aseptic operating skill and consciousness; Adopting aseptic isolator technology;Validation of aseptic processing need a process simulation

39、test using a nutrient medium to verify the measures for reducing the contamination introduced by personnel.ConclutionAmong various 名师归纳总结 - - - - - - -第 11 页,共 13 页精选学习资料 - - - - - - - - - microbiological risk factors in the production of aseptic preparations of injection, materials, compressed air

40、and nitrogen belong to low risk factors, air in a aseptic grade 10000 zone, air in a grade 100 zone and water for injection belong to medium risk factor, while personnel contamination belong to high risk factor.Adopting aseptic isolator technology can effectively reduce the microbiological contamina

41、tion introduced by personnel.It is effective in controling microbiological risk by making use of risk management process and tools and ways in the production of aseptic preparations of injection and can cover the Shortage of GMP in quality control tools and ways. 【关键词】无菌生产工艺注射剂 微生物 风险 掌握【英文关键词】 Asep

42、tic prepareration Injection Microbe Risk Control 【目录】注射剂生产过程中微生物的质量风险掌握中文摘要8-11Abstract11-14前言 16-20 第一部分干净区的沉降菌和悬浮粒子监控数据汇总分析20-341.1 数据来源 201.2 收集数据的方法20-211.3 收集的数据 21-301.4 数据的分析与争论 30-321.5 小结 32-34 其次部分 人员的微生物污染监控数据汇总分析 34-382.1 数 据来源 342.2 收集数据的方法 34-352.3 收集的数据 35-362.4 数据的分析与争论 36-372.5 小结 3

43、7-38 第三部分物料的微生物监测数名师归纳总结 - - - - - - -第 12 页,共 13 页精选学习资料 - - - - - - - - - 据汇总分析 38-413.1 数据来源 383.2 收集数据的方法 383.3 收集的数据 38-403.4 数据的分析与争论403.5 小结 40-41 第四部分注射用水的微生物监控数据汇总分析41-444.1 数据来源 414.2 收集数据的方法 414.3 收集的数据 41-434.4 数据的分析与争论 434.5 小结 43-44 第五部分压缩空气和氮气的微生物和悬浮粒子监测数据汇总分析 44-485.1 数据来源 445.2 收集数据

44、的方法 445.3 收集的数据 44-475.4 数据的分析与争论475.5 小结 47-48 第六部分各因素的微生物监控数据平均结果汇总分析48-496.1 数据来源 486.2 运算的结果 486.3 结果的分析与争论 486.4 小结 48-49 第七部分 各因素的微生物风险分析49-517.1 分析方法 497.2 失败模式和影响因素分析 FMEA表格 497.3 风险排序和分析 49-507.4 小结 50-51 第 八部分 建议及措施 51-548.1 建议 518.2 措施论证 51-538.3 小结 53-54 第九部分 全文总结 54-55 附图 55-64 参考文献 64-65 致谢65-66 攻读学位期间发表的学术论文目录 情形表 67 66-67 学位论文评阅及答辩名师归纳总结 - - - - - - -第 13 页,共 13 页