注射剂生产过程中微生物的质量风险控制论文ixqo.docx

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2、879份资料无菌生产工工艺论文：注射剂生生产过程中中微生物的的质量风险险控制【中文摘要要】注射剂剂(injjectiion)是是直接注入入人体内部部的一种剂剂型,常用用剂量较大大,按其生生产工艺的的不同可分分为最终灭灭菌工艺和和非最终灭灭菌工艺也也即无菌生生产工艺两两种,无菌菌生产工艺艺的无菌保保证水平(SAL)仅是灭菌菌工艺的11/1033-/1009。无菌菌生产工艺艺产品在生生产过程中中微生物污污染的因素素较多,因因此,在临临床使用过过程中具有有较高的质质量风险。本课题以以5ml无无菌生产工工艺注射剂剂为例,利利用休哈特特控制图、饼图、柱柱状图等统统计工具对对生产中的的环境、人人员、物料料

3、、注射用用水、压缩缩空气、氮氮气等可能能引入或污污染微生物物的环节进进行监控和和风险确认认。采用失失败模式及及影响因素素分析(FFMEA)、风险排排序和过滤滤等风险工工具对各因因素进行风风险分析和和评估,找找出生产过过程中污染染微生物的的高风险因因素。通过过采取措施施和措施的的有效性论论证进行风风险控制,进一步降降低无菌生生产工艺注注射剂的微微生物风险险,保证患患者用药安安全。研究究内容主要要包括洁净净区的微生生物和悬浮浮粒子监控控数据汇总总分析、人人员的微生生物监控数数据汇总分分析、物料料的微生物物监测数据据汇总分析析、注射用用水的微生生物监控数数据汇总分分析、压缩缩空气和氮氮气的微生生物和

4、悬浮浮粒子监测测数据汇总总分析、各各因素的微微生物监控控数据平均均结果汇总总分析、各各因素的微微生物风险险评估、建建议及措施施。1.洁洁净区的微微生物和悬悬浮粒子监监控数据汇汇总分析通通过对10000000级区、1100000级区、1100000级无菌区区、1000级区不同同的功能间间进行了静静态沉降菌菌和悬浮粒粒子的数据据监控和汇汇总,对1100000级无菌区区、1000级区不同同的功能间间进行了动动态沉降菌菌的监控和和汇总。利利用统计工工具休哈特特控制图按按级别分别别作图分析析,计算出出：各洁净净级别不同同功能间静静态沉降菌菌和悬浮粒粒子的平均均值X、标标准偏差和控制线线X3；100000

5、级无无菌区、1100级区区不同功能能间动态沉沉降菌的平平均值X、标准偏差差和控制线线X3。从休哈哈特控制图图分析各检检测结果均均在控制线线内。通过过对各洁净净级别关键键功能间的的静态沉降降菌和悬浮浮粒子分别别做柱状图图进行比较较分析得出出：静态悬浮浮粒子和沉沉降菌的检检测结果和和洁净级别别成对应关关系；不同洁净净级别的检检测结果有有较大差别别,1000级区检测测结果最好好,100000级无无菌区次之之,1000000级级区检测结结果最差。2.人员员的微生物物监控数据据汇总分析析通过对1100000级无菌区区、1000级区人员员的手套、袖口、肘肘部、额头头、口罩表表面的微生生物进行220批次的的

6、检测数据据汇总,利利用统计工工具休哈特特控制图进进行作图分分析。计算算平均值XX：100000级无无菌区分别别为1.550、1.25、11.55、1.155、1.115CFUU/碟,1100级区区分别为00.70、0.555、0.660、0.50、00.45 CFU/碟；标准准偏差：100000级无无菌区分别别为0.551、0.44、00.51、0.599、0.337 CFFU/碟,100级级区分别为为0.477、0.551、0.50、00.51、0.511 CFUU/碟,从从休哈特控控制图和计计算数据看看100级级检测结果果明显好于于100000级无菌菌区,口罩罩好于其他他部位,各各检测结果

7、果均在控制制线内。33.物料的的微生物监监测数据汇汇总分析连连续取样330批监测测A、B、C三个注注射液配好好药液带菌菌量,利用用统计工具具休哈特控控制图进行行作图分析析,计算平平均值X分分别为1.57、11.31、2.377个/1000ml；标准偏差差分别为11.01、0.811、1.003个/1100mll；X+33分别为44.59、3.733、5.447个/1100mll。从监控控数据和计计算结果分分析,三个个产品配好好药液的带带菌量有差差别,B产产品监测数数据最好,C产品结结果最差,除A、CC注射液有有个别点超超出界限外外,其余各各批次检测测结果均在在控制线范范围内波动动。4.注注射用

8、水的的微生物监监控数据汇汇总分析对对注射用水水系统的罐罐出口、使使用点1、使用点22、使用点点3、罐回回口取样进进行每周一一次的微生生物监控,然后对连连续一年的的数据汇总总,利用统统计工具休休哈特控制制图进行作作图分析。计算各点点的平均值值X分别为为0.100、0.112、0.12、00.14、0.188个/1000ml；标准偏差差分别为00.31、0.333、0.333、0.35、00.39个个/1000ml；XX+3分别为11.02、1.122、1.112、1.20、11.36个个/1000ml。从从计算结果果和数据变变化趋势分分析罐出口口检测结果果最好,罐罐回口检测测结果最差差。5.压压

9、缩空气和和氮气的微微生物和悬悬浮粒子监监测数据汇汇总分析通通过对压缩缩空气的使使用点洗瓶瓶1、洗瓶瓶2、灌装装1、灌装装2、过滤滤和对氮气气的使用点点灌装1、灌装2分分别采样进进行微生物物和悬浮粒粒子检测,每月一次次。,通过过对连续一一年的数据据汇总,利利用统计工工具休哈特特控制图进进行作图分分析。微生生物和悬浮浮粒子的平平均值X均均为OCFFU(个)/m3,最大值为为0 CFFU(个)/m3,最小值为为0 CFFU(个)/m3。标准偏差差均为0 CFU(个)/mm3,X3均为0 CFU(个)/mm3,从计计算结果和和监测数据据趋势分析析各使用点点的微生物物和悬浮粒粒子数值稳稳定。6.各因素的

10、的微生物监监控数据平平均结果汇汇总分析对对无菌生产产工艺中影影响药品微微生物质量量的洁净区区环境、人人员污染、物料、注注射用水、压缩空气气、氮气所所监控的微微生物数据据进行平均均汇总,然然后做出饼饼图进行分分析后得出出：人员动动态微生物物污染所占占比例最大大是46%(包括1100000级无菌区区和1000级区),其次是药药液中所含含微生物的的比例占442%,环环境中的微微生物所占占比例是99%,注射射用水中微微生物占33%,压缩缩空气和氮氮气微生物物所占比例例为零。77.各因素素的微生物物风险分析析对收集的的数据采用用FMEAA表格进行行风险排序序和过滤,得出影响响无菌生产产工艺注射射液微生物

11、物风险因素素由小到大大依次为：压缩空气气、氮气、物料、注注射用水、100级级区空气、100000级无菌菌区空气、人员污染染。风险顺顺序数RPPN依次为为：2、33、8、99、19、32、2252。88.建议及及措施降低低无菌生产产工艺注射射剂的微生生物污染风风险,在很很大程度上上取决于人人员的技能能,所接受受的培训及及人员的工工作态度。应采取的的措施：是制定人人员“无菌室”行为规则则,进行无无菌操作技技能和意识识培训；是采用无无菌隔离系系统；是采用培培养基模拟拟灌装,验验证降低人人员污染措措施有效性性。结论在在无菌生产产工艺注射射剂可能影影响微生物物的各种风风险因素中中：物料、压缩空气气、氮气

12、为为低风险因因素；100000级级无菌区空空气、1000级空气气和注射用用水为中等等风险因素素：人员污污染为高风风险因素。采用无菌菌隔离系统统对降低人人员的微生生物污染能能起到较好好的效果；采用风险险管理的程程序、工具具和方法能能有效地控控制无菌工工艺注射剂剂生产过程程中的微生生物风险,使药品的的生产由过过程控制转转为主动预预防,很好好的弥补GGMP条款款在质量控控制方法和和工具等方方面的不足足。【英文摘要要】Injjectiion iis a dosaage fform of iinjecctingg dirrectlly innto hhumann, whhich is uusuallly

13、 wwith largger ddosagge. IInjecctionn cann be classsifiied iinto termminallly ssteriiliseed prrocessses and asepptic prepparerratioons aaccorrdingg to the prodductiive ttechnnologgy. TThe ssteriile gguaraanteee levvel oof thhe asseptiic prreparrerattionss is onlyy 1/1103-/109 of tthat of tthe ttermi

14、inallly stterillisedd proocessses. Sincce thhere are manyy miccrobiiologgicall conntamiinatiion ffactoors ddurinng thhe prroducctionn of the asepptic prepparerratioons, therreforre, hhigh quallity riskks exxist in tthe ccliniical praccticee.Thee currrentt stuudy ttakess thee 5mll injjectiion pproduu

15、ced by aasepttic pprepaareraationns ass an exammple, andd usees Shhewhaart CContrrol CChartt, Piie Chhart and Histtograams tto moonitoor thhe miicrobbioloogicaal coontamminattionss inttroduuced by eenvirronmeents, perrsonnnel, mateerialls, wwaterr forr injjectiion, comppresssed aair, nitrrogenn durr

16、ing prodductiion. We hhope to ffind a hiigh mmicroobiollogiccal rrisk facttor bby peerforrmingg rissk asssesssmentt on eachh facctor throough Faillure Modee Efffectss Anaalysiis, RRisk rankking and filtterinng. WWe thhen pperfoorm rrisk conttrol by ttakinng meeasurres,TThe vvaliddity of tthe mmeasuu

17、res is ssuffiicentt to furtther decrreasee thee rissk off thee quaalityy of the asepptic prepparerratioons aand eensurre thhe seecuree phaarmaccy off pattientts.Thhis aarticcle wwas ccompoosed of tthe ffolloowingg eigght ppartss:Thee ressultss anaalysiis off thee miccrobiiologgicall andd airrbornne

18、paarticculatte moonitooringg in cleaan zoone; The resuults anallysiss of the perssonall miccrobiiologgicall monnitorring; Thee ressultss anaalysiis off miccrobiiologgicall monnitorring in mmaterrialss; Thhe reesultts annalyssis oof miicrobbioloogicaal moonitooringg in wateer foor innjecttion; Thee r

19、essultss anaalysiis off thee miccrobiiologgicall andd airrbornne paarticculatte moonitooringg in the comppresssed aand nnitroogen; Thee Metta-annalyssis oof thhe avveragge reesultts off monnitorring dataa of the micrrobess in eachh facctor; Thee rissk annalyssis oof miicrobbes iin eaach ffactoor; SS

20、uggeestioons aand mmeasuures.1. TThe rresullts aanalyysis of tthe mmicroobiollogiccal aand aairboorne partticullate moniitoriing iin cllean zoneeBy tthe mmicroobiollogiccal aand aairboorne partticullate moniitoriing aat reest iin diifferrent roomm inccludee a ggradee 1000000 zonee, a gradde 100000 z

21、onee, a asepptic gradde 100000 zonee, a gradde 1000 zoone, and by tthe mmicroobiollogiccal mmonittorinng inn opeeratiion iin diifferrent roomm in a asseptiic grrade 100000 zoone aand aa graade 1100 zzone.The resuults are thenn anaalyzeed acccordding theiir grradess thrroughh Sheewharrt Coontrool Chh

22、art to ccalcuulateed thhe avveragge vaalue of XX, thhe sttandaard ddeviaationn 8 aand tthe ccontrrol lline X38 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 100

23、00 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 thatthe testing

24、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 the aseptic grade 10000 zone and grade 100000 zone.2. The

25、 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 ana

26、lyzed 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 asept

27、ic 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 ana

28、lysis 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+3for A, B and C injections are calculated to be 1.57、1.31

29、、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 inje

30、ctions.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.

31、 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, respectively. The testing result obtained (from the outlet in the

32、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

33、 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 th

34、e 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 microbes in each factorThe monitoring data of microbes intro

35、duced 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 pe

36、rsonnel 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 r

37、anking 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 asept

38、ic 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 p

39、ersonnel 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 test using a nutrient medium to verify the m

40、easures 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 an

41、d 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

42、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的质量风险控制 中文摘要 8-11 Abstract 11-14 前言 16-2

43、0 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 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

44、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