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、n更多企业学院： 中小企业管理全能版183套讲座+89700份资料总经理、高层管理49套讲座+16388份资料中层管理学院46套讲座+6020份资料国学智慧、易经46套讲座人力资源学院56套讲座+27123份资料各阶段员工培训学院77套讲座+ 324份资料员工管理企业学院67套讲座+ 8720份资料工厂生产管理学院52套讲座+ 13920份资料财务管理学院53套讲座+ 17945份资料销售经理学院56套讲座+ 14350份资料销售人员培训学院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

2、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,利用休哈特控制图、饼图、柱状图等统计工具对生产中的环境、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。采用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,找出生产过程中污染微生物的高风险因素。通过采取措施和措施的有效性论证进行风险控制

3、,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。研究内容主要包括洁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.洁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

4、特控制图按级别分别作图分析,计算出：各洁净级别不同功能间静态沉降菌和悬浮粒子的平均值X、标准偏差和控制线X3；10000级无菌区、100级区不同功能间动态沉降菌的平均值X、标准偏差和控制线X3。从休哈特控制图分析各检测结果均在控制线内。通过对各洁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洁净级别成对应关系；不同洁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

5、批次的检测数据汇总,利用统计工具休哈特控制图进行作图分析。计算平均值X：10000级无菌区分别为1.50、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/碟,从休哈特控制图和计算数据看100级检测结果明显好于10000级无菌区,口罩好于其他部位,各检测结果均在控制线内。3.物料的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

6、菌量,利用统计工具休哈特控制图进行作图分析,计算平均值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。从监控数据和计算结果分析,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控制线范围内波动。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、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控制图进行作图分析。计算各点的平均值X分别

7、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。从计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控制图进行作图分析。微生物和悬浮粒子的平均值X均为OCFU(个)/m3,最大值为0

8、 CFU(个)/m3,最小值为0 CFU(个)/m3。标准偏差均为0 CFU(个)/m3,X3均为0 CFU(个)/m3,从计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定。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响药品微生物质量的洁净区环境、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

9、险分析对收集的数据采用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：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。应采取的措施：是制定人员“无菌室”行为规则,进行无菌操作技能和意识培训；是采用无菌隔离系统；是采用培养基模拟灌装,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；1

10、0000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。采用无菌隔离系统对降低人员的微生物污染能起到较好的效果；采用风险管理的程序、工具和方法能有效地控制无菌工艺注射剂生产过程中的微生物风险,使药品的生产由过程控制转为主动预防,很好的弥补GMP条款在质量控制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 terminall

11、y sterilised processes and aseptic preparerations 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 microbiological contamination factors during the production of t

12、he aseptic preparerations, therefore, 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 en

13、vironments, personnel, materials, water 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

14、 measures,The validity of the measures is sufficent to further decrease the risk of the quality of the aseptic preparerations and ensure the secure pharmacy of patients.This article was composed of the following eight parts:The results analysis of the microbiological and airborne particulate monitor

15、ing 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 airborne particulate monitor

16、ing 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 monitoring in clean zoneBy th

17、e 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 grade 100 zone.The r

18、esults 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 X38 of the static microbes and airborne particles at rest in different rooms in different clean zones, respectively, and those of microbe

19、s 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 through Histograms of the microbes and airborne particles at rest in the criti

20、cal rooms in each clean grades and find thatthe 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 zones have large differences:the best result is in a grade 100 zone, followed by t

21、he 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 face mask by successive 20 batchs of production in a aseptic grade 10000 zone and a

22、 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、0.60、0.50、0.45 CFU/plate for a grade 100 zone, while the standard deviation 8 are calcula

23、ted 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 CFU/plate for a grade 100 zone. We find that 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 test

24、ing result in within the control line.3. The results analysis of microbiological monitoring in materialsBy microbiological monitoring in A, B and C 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

25、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. 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 withi

26、n the control line except several points in A and C injections.4. The results analysis of microbiological monitoring in water for injectionWe 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

27、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 deviation, and X+3are calculated to be 0.10、0.12、0.12、0.14、0.18 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, respective

28、ly. The testing result obtained (from the outlet in the best while that 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

29、 the microbes and airborne particles in the using points of washing bottle 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

30、by Shewhart Control Chart. We find that the values of the average X, standard deviationand X+3are 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 micr

31、obes in each factorThe monitoring data of microbes introduced by the environment 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 conclu

32、de that the proportions of the microbes 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

33、. The risk analysis 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,

34、nitrogen, materials, 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.

35、 Much depends 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

36、 simulation test using a nutrient medium to verify the measures for reducing the contamination introduced by personnel.ConclutionAmong various microbiological risk factors in the production of aseptic preparations of injection, materials, compressed air and nitrogen belong to low risk factors, air i

37、n 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 contamination introduced by personnel.It is effective i

38、n 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 控制【英文关键词】Aseptic prepareration Injection Microbe Risk Contro

39、l【目录】注射剂生产过程中微生物的质量风险控制 中文摘要 8-11 Abstract 11-14 前言 16-20 第一部分 洁净区的沉降菌和悬浮粒子监控数据汇总分析 20-34 1.1 数据来源 20 1.2 收集数据的方法 20-21 1.3 收集的数据 21-30 1.4 数据的分析与讨论 30-32 1.5 小结 32-34 第二部分 人员的微生物污染监控数据汇总分析 34-38 2.1 数据来源 34 2.2 收集数据的方法 34-35 2.3 收集的数据 35-36 2.4 数据的分析与讨论 36-37 2.5 小结 37-38 第三部分 物料的微生物监测数据汇总分析 38-41

40、3.1 数据来源 38 3.2 收集数据的方法 38 3.3 收集的数据 38-40 3.4 数据的分析与讨论 40 3.5 小结 40-41 第四部分 注射用水的微生物监控数据汇总分析 41-44 4.1 数据来源 41 4.2 收集数据的方法 41 4.3 收集的数据 41-43 4.4 数据的分析与讨论 43 4.5 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 44-48 5.1 数据来源 44 5.2 收集数据的方法 44 5.3 收集的数据 44-47 5.4 数据的分析与讨论 47 5.5 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 48-49 6.1 数据来源 48 6.2 计算的结果 48 6.3 结果的分析与讨论 48 6.4 小结 48-49 第七部分 各因素的微生物风险分析 49-51 7.1 分析方法 49 7.2 失败模式和影响因素分析(FMEA)表格 49 7.3 风险排序和分析 49-50 7.4 小结 50-51 第八部分 建议及措施 51-54 8.1 建议 51 8.2 措施论证 51-53 8.3 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 66-67 学位论文评阅及答辩情况表 67