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模板.doc

无菌生产工艺论文：注射剂生产过程中微生物质量风险控制

【汉字摘要】注射剂(injection)是直接注入人体内部一个剂型,常见剂量较大,按其生产工艺不一样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,无菌生产工艺无菌确保水平(SAL)仅是灭菌工艺1/103-/109。无菌生产工艺产品在生产过程中微生物污染原因较多,所以,在临床使用过程中含有较高质量风险。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步骤进行监控和风险确定。采取失败模式及影响原因分析(FMEA)、风险排序和过滤等风险工具对各原因进行风险分析和评定,找出生产过程中污染微生物高风险原因。经过采取方法和方法有效性论证进行风险控制,深入降低无菌生产工艺注射剂微生物风险,确保患者用药安全。研究内容关键包含洁净区微生物和悬浮粒子监控数据汇总分析、人员微生物监控数据汇总分析、物料微生物监测数据汇总分析、注射用水微生物监控数据汇总分析、压缩空气和氮气微生物和悬浮粒子监测数据汇总分析、各原因微生物监控数据平均结果汇总分析、各原因微生物风险评定、提议及方法。1.洁净区微生物和悬浮粒子监控数据汇总分析经过对100000级区、10000级区、10000级无菌区、100级区不一样功效间进行了静态沉降菌和悬浮粒子数据监控和汇总,对10000级无菌区、100级区不一样功效间进行了动态沉降菌监控和汇总。利用统计工具休哈特控制图按等级分别作图分析,计算出：各洁净等级不一样功效间静态沉降菌和悬浮粒子平均值X、标准偏差δ和控制线X±3δ；10000级无菌区、100级区不一样功效间动态沉降菌平均值X、标准偏差δ和控制线X±3δ。从休哈特控制图分析各检测结果均在控制线内。经过对各洁净等级关键功效间静态沉降菌和悬浮粒子分别做柱状图进行比较分析得出：①静态悬浮粒子和沉降菌检测结果和洁净等级成对应关系；②不一样洁净等级检测结果有较大差异,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.人员微生物监控数据汇总分析经过对10000级无菌区、100级区人员手套、袖口、肘部、额头、口罩表面微生物进行20批次检测数据汇总,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δ：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级检测结果显著好于10000级无菌区,口罩好于其它部位,各检测结果均在控制线内。3.物料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δ分别为1.01、0.81、1.03个/100ml；X+3δ分别为4.59、3.73、5.47个/100ml。从监控数据和计算结果分析,三个产品配好药液带菌量有差异,B产品监测数据最好,C产品结果最差,除A、C注射液有部分点超出界限外,其它各批次检测结果均在控制线范围内波动。4.注射用水微生物监控数据汇总分析对注射用水系统罐出口、使用点1、使用点2、使用点3、罐回口取样进行每七天一次微生物监控,然后对连续十二个月数据汇总,利用统计工具休哈特控制图进行作图分析。计算各点平均值X分别为0.10、0.12、0.12、0.14、0.18个/100ml；标准偏差δ分别为0.31、0.33、0.33、0.35、0.39个/100ml；X+3δ分别为1.02、1.12、1.12、1.20、1.36个/100ml。从计算结果和数据改变趋势分析罐出口检测结果最好,罐回口检测结果最差。5.压缩空气和氮气微生物和悬浮粒子监测数据汇总分析经过对压缩空气使用点洗瓶1、洗瓶2、灌装1、灌装2、过滤和对氮气使用点灌装1、灌装2分别采样进行微生物和悬浮粒子检测,每个月一次。,经过对连续十二个月数据汇总,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δ均为0 CFU(个)/m3,X±3δ均为0 CFU(个)/m3,从计算结果和监测数据趋势分析各使用点微生物和悬浮粒子数值稳定。6.各原因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洁净区环境、人员污染、物料、注射用水、压缩空气、氮气所监控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百分比最大是46%(包含10000级无菌区和100级区),其次是药液中所含微生物百分比占42%,环境中微生物所占百分比是9%,注射用水中微生物占3%,压缩空气和氮气微生物所占百分比为零。7.各原因微生物风险分析对搜集数据采取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原因由小到大依次为：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。风险次序数RPN依次为：2、3、8、9、19、32、252。8.提议及方法降低无菌生产工艺注射剂微生物污染风险,在很大程度上取决于人员技能,所接收培训及人员工作态度。应采取方法：①是制订人员“无菌室”行为规则,进行无菌操作技能和意识培训；②是采取无菌隔离系统；③是采取培养基模拟灌装,验证降低人员污染方法有效性。结论在无菌生产工艺注射剂可能影响微生物多种风险原因中：物料、压缩空气、氮气为低风险原因；10000级无菌区空气、100级空气和注射用水为中等风险原因：人员污染为高风险原因。采取无菌隔离系统对降低人员微生物污染能起到很好效果；采取风险管理程序、工具和方法能有效地控制无菌工艺注射剂生产过程中微生物风险,使药品生产由过程控制转为主动预防,很好填补GMP条款在质量控制方法和工具等方面不足。
【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 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 the 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 environments, 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 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 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 airborne 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 monitoring 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 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, and those of 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 through Histograms of the microbes and airborne particles at rest in the critical rooms in each clean grades and find that①the testing results of the static the microbes and airborne particles have correspondence with the grades of the clean zones;②the testing results in different grades of clean zones 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 face 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、0.60、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 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 testing 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+3δfor 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 within 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 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 deviationδ, and X+3δare 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, respectively. 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 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 by Shewhart Control Chart. We find that the values of the average X, standard deviationδand X+3δare 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 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 conclude 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. 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, 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. Much depends on the skills, training and attitudes of personnel involved. The measures should be adopted as follows:①Setting personnel rules in aseptic room and training the aseptic operating skill and consciousness;②Adopting aseptic isolator technology;③Validation of aseptic processing need a process 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 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 contamination 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 控制
【英文关键词】Aseptic prepareration Injection Microbe Risk Control
【目录】注射剂生产过程中微生物质量风险控制

汉字摘要

8-11

Abstract

11-14

序言

16-20

第一部分 洁净区沉降菌和悬浮粒子监控数据汇总分析

20-34

1.1 数据起源

20

1.2 搜集数据方法

20-21

1.3 搜集数据

21-30

1.4 数据分析和讨论

30-32

1.5 小结

32-34

第二部分 人员微生物污染监控数据汇总分析

34-38

2.1 数据起源

34

2.2 搜集数据方法

34-35

2.3 搜集数据

35-36

2.4 数据分析和讨论

36-37

2.5 小结

37-38

第三部分 物料微生物监测数据汇总分析

38-41

3.1 数据起源

38

3.2 搜集数据方法

38

3.3 搜集数据

38-40

3.4 数据分析和讨论

40

3.5 小结

40-41

第四部分 注射用水微生物监控数据汇总分析

41-44

4.1 数据起源

41

4.2 搜集数据方法

41

4.3 搜集数据

41-43

4.4 数据分析和讨论

43

4.5 小结

43-44

第五部分 压缩空气和氮气微生物和悬浮粒子监测数据汇总分析

44-48

5.1 数据起源

44

5.2 搜集数据方法

44

5.3 搜集数据

44-47

5.4 数据分析和讨论

47

5.5 小结

47-48

第六部分 各原因微生物监控数据平均结果汇总分析

48-49

6.1 数据起源

48

6.2 计算结果

48

6.3 结果分析和讨论

48

6.4 小结

48-49

第七部分 各原因微生物风险分析

49-51

7.1 分析方法

49

7.2 失败模式和影响原因分析(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 提议及方法

51-54

8.1 提议

51

8.2 方法论证

51-53

8.3 小结

53-54

第九部分 全文总结

54-55

附图

55-64

参考文件

64-65

致谢

65-66

攻读学位期间发表学术论文目录

66-67

学位论文评阅及答辩情况表

67