利巴韦林注射液生产工艺验证方案
利巴韦林注射液及其制备方法[发明专利]
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(10)申请公布号 (43)申请公布日 2014.08.27C N 104000778A (21)申请号 201410277520.7(22)申请日 2014.06.20201410273720.5 2014.06.18 CNA61K 9/08(2006.01)A61K 31/7056(2006.01)A61P 31/12(2006.01)(71)申请人海南通用康力制药有限公司地址570311 海南省海口市南海大道269号(72)发明人王志涛 林小雪 张丽华(74)专利代理机构广州三环专利代理有限公司44202代理人郝传鑫(54)发明名称利巴韦林注射液及其制备方法(57)摘要本发明公开一种利巴韦林注射液的制备方法，包括以下步骤：a 、将利巴韦林和甘露醇加入部分注射用水中搅拌溶解，然后将注射用水加至总配制量；b 、加入总配制量0.1％的活性炭在室温下搅拌30分钟，过滤至澄明，经微孔为0.22μm的滤膜过滤成滤液；c 、将步骤b 中的所述滤液经过PH 值检测，取PH 值符合注射液要求的所述滤液1.25ml 装入7ml 的管制瓶中，然后半压塞；d 、将步骤c 中的管制瓶放入冷冻干燥机中冷冻干燥17-19小时，然后进行全压塞、扎盖及包装。
本发明同时公开了使用上述方法制得的利巴韦林注射液，所述巴韦林注射液具有纯度高、产品稳定性好及药用效果好等优点。
(66)本国优先权数据(51)Int.Cl.权利要求书1页 说明书3页(19)中华人民共和国国家知识产权局(12)发明专利申请权利要求书1页 说明书3页(10)申请公布号CN 104000778 A1/1页1.一种利巴韦林注射液的制备方法，其特征在于，包括以下步骤：a 、将利巴韦林和甘露醇加入部分注射用水中搅拌溶解，然后将注射用水加至总配制量；b 、加入总配制量0.1％的活性炭在室温下搅拌30分钟，过滤至澄明，经微孔为0.22μm 的滤膜过滤成滤液；c 、将步骤b 中的所述滤液经过PH 值检测，取PH 值符合注射液要求的所述滤液1.25ml 装入7ml 的管制瓶中，然后半压塞；d 、将步骤c 中的管制瓶放入冷冻干燥机中冷冻干燥处理17-19小时，然后进行全压塞、扎盖及包装。
年产2亿支2ml水针剂生产车间工艺设计
制药工程课程设计设计题目：年产2亿支2ml水针剂生产车间工艺设计专业班级：姓名：学号：小组成员：指导老师：设计时间：摘要本文是对年产2亿支2ml，200mg利巴韦林水针剂生产车间工艺设计的详细说明。
一方面，根据任务要求，对工艺流程进行了说明，并绘制了工艺管道流程图，完成了物料衡算和设备选型。
另一方面，按照GMP的要求，设计工艺平面布置，并绘制了平面压差分布图和洗瓶工序的管道布置图。
本设计严格遵守GMP规定，符合安全、环保、技术经济等方面的要求。
关键词：水针剂平面布置联动机组洁净区GMP目录一、工艺概述水针剂的生产步骤主要包括原辅料的准备、配制、灌封、灭菌、质检、包装等环节。
本设计的原料是药用利巴韦林（2ml，200mg），辅料是注射用水。
选择中性玻璃安瓿作为注射液的容器。
水针剂的洁净区划分：注射用水的制备、理瓶、检漏灭菌、灯检、印字包装在一般生产区；原料的配制、粗滤、安瓿的粗洗、精洗在C级洁净区；原料液的精滤、安瓿干燥灭菌、冷却、灌装、封口位于B级洁净区。
（一）工艺流程框图1.1 工艺流程框图（二）工艺用水制备水针剂生产需要大量的纯化水及注射用水。
本工艺中以自来水为原水，首先进行预处理，包括机械过滤、活性碳过滤、保安过滤，然后经过二级渗透处理得到纯化水，纯化水再经紫外线杀菌、微孔过滤后至用水点。
纯化水经过多效蒸馏操作得到蒸馏水，蒸馏水保温循环贮存，蒸馏水经过0.45μm微孔膜过滤即可送至注射用水的用水点。
1、纯化水制备目前在制药企业生产中，纯化水的制备一般有以下四种工艺流程：1)原水→ 预处理→ 阳离子交换→ 阴离子交换→ 混床→ 纯化水2)原水→ 预处理→ 电渗析→ 阳离子交换→ 阴离子交换→ 混床→ 纯化水3)原水→ 预处理→ 一级高压泵→ 一级反渗透→ 二级高压泵→二级反渗透→ 纯化水4)原水→ 预处理→高压泵→反渗透→ 一级混床→ 二级混床→纯化水其中全离子交换用于符合饮用水标准的原水，常用于原水含盐量<500 mg/L；电渗析+离子交换常用于原水含盐量>500 mg/L，使用电渗析，可减少树脂频繁再生，减少离子交换负担，使树脂制水周期延长，减少再生时酸、碱用量和排污量；反渗透+离子交换以反渗透直接作为二级混床的前处理，此时为了减轻混床再生时碱液用量，需在混床前设置脱气塔以脱去CO2。
利巴韦林合成工艺
利巴韦林合成工艺嘿，小伙伴们！今天咱们来一起看看利巴韦林的合成工艺。
这可有点小复杂，但别担心，跟着我的步骤走，保准你能有个大概的了解。
首先呢，原料的准备是关键的第一步。
你得把那些需要用到的原料都找齐喽。
这听起来好像是废话，但我可跟你说，这一步要是没做好，后面就像盖房子没打好地基一样，麻烦着呢！我有时候就粗心大意，以为少个原料后面也能补上，结果差点搞砸整个合成。
所以，这一步可千万别小瞧了啊！原料准备好之后呢，就是反应的起始阶段啦。
这个时候要控制好反应的条件，像温度啊，压力啊之类的。
具体的数值呢，你可以根据自己的经验或者实验室的实际情况来调整，不用太死板。
不过，温度和压力这俩因素真的超级重要哦！我通常会在这个环节多花些时间，反复检查数值设置对不对。
你是不是也觉得这些小细节很容易被忽略呢？然后啊，在反应进行的过程中，要时不时地去观察一下反应的状态。
这个观察可不是随便看看就行的，你得仔细点。
有时候反应可能会出现一些小状况，比如颜色变化啦，产生气泡的速度变化啦之类的。
要是发现有啥不对劲的地方，要赶紧想想办法调整一下。
这就好比你做饭的时候看着锅里的菜，发现快糊了就得赶紧翻一翻是一个道理。
我就有过一次，差点没注意到反应有点异常，还好及时发现了，要不然后果不堪设想呀！在这之后呢，就是对产品进行最后的精制啦。
这一步要把产品弄得更纯更好。
这个过程可能需要多次重复一些操作，直到你得到满意的产品为止。
这一步真的很重要，我通常会再检查一次，真的，确认无误是关键！要是产品不纯，前面的功夫可就白费了，多可惜呀！最后呢，就是对合成出来的利巴韦林进行检测和质量评估啦。
这就像是给你的成果打分一样，看看是不是达到了预期的标准。
要是检测出来有问题，那可能就得回过头去看看是哪个环节出了差错。
这整个合成工艺就像是一场马拉松，每个环节都很重要，可不能在最后掉链子哦！。
利巴韦林注射液生产工艺验证方案
长治市三宝生化药业有限公司编号SBB2.8.5.6利巴韦林注射液生产工艺验证方案长治市三宝生化药业有限公司方案制订签名日期方案会签签名日期生产技术部签名日期验证小组签名日期方案批准质量保证部日期目录1.概述`````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````4` 1.1.产品简述``````````````````````````````````````````````````````````````````````````````````````````````````````````````4 1.2.处方及依据``````````````````````````````````````````````````````````````````````````````````````````````````````````41.3.生产工艺流``````````````````````````````````````````````````````````````````````````````````````````````````````````5`2.验证目的````````````````````````````````````````````````````````````````````````````````````````````````````````````````````53.验证的范围```````````````````````````````````````````````````````````````````````````````````````````````````````````````64.验证各部门职责及组织结构```````````````````````````````````````````````````````````````````````````````65.验证准备````````````````````````````````````````````````````````````````````````````````````````````````````````````````````76.验证内容及实施``````````````````````````````````````````````````````````````````````````````````````````````````````8` 6.1.洗瓶工序````````````````````````````````````````````````````````````````````````````````````````````````````````````8 6.2.配制工序```````````````````````````````````````````````````````````````````````````````````````````````````````````12 6.3.灌封工序```````````````````````````````````````````````````````````````````````````````````````````````````````````15 6.4.灭菌工序```````````````````````````````````````````````````````````````````````````````````````````````````````````20 6.5.灯检工序```````````````````````````````````````````````````````````````````````````````````````````````````````````24 6.6.包装工序```````````````````````````````````````````````````````````````````````````````````````````````````````````266.7.成品检验结果``````````````````````````````````````````````````````````````````````````````````````````````````287.偏差分析``````````````````````````````````````````````````````````````````````````````````````````````````````````````````298.验证结论``````````````````````````````````````````````````````````````````````````````````````````````````````````````````299.附表````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````29 9.1. 设备一览表及生产能力```````````````````````````````````````````````````````````````````````````````30 9.2.设备性能验证确认及检查情况表```````````````````````````````````````````````````````````````31 9.3参加验证人员培训情况检查表````````````````````````````````````````````````````````````````````32 9.4.厂房与公用设施验证的确认和检查情况表`````````````````````````````````````````````34 9.5.空气净化系统、工艺用水系统验证的确认和检查情况表`````````````````35 9.6.计量器具检查情况表```````````````````````````````````````````````````````````````````````````````````````36 9.7.三批（按四批准备）验证使用的原料、辅料和安瓿供应商确认及检查情况表`````````````````````````````````````````````````````````````````````````````37 9.8.质量检验系统验证和准备情况表```````````````````````````````````````````````````````````````38 9.9.检验仪器检查情况表``````````````````````````````````````````````````````````````````````````````````````39 9.10检验试剂检查情况表````````````````````````````````````````````````````````````````````````````````````40 9.11质量监控点、监控内容、监控方法、监控频次表`````````````````````````````411.概述1.1.利巴韦林注射液（1ml：100mg）常温状态下是无色的澄明液体，属抗病毒药，用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎。
利巴韦林工艺验证
利巴韦林工艺验证利巴韦林注射液生产工艺验证方案长治市三宝生化药业有限公司方案制订签名日期方案会签签名日期生产技术部签名日期验证小组签名日期方案批准质量保证部日期目录1.概述``````````````````````````````````````````````````````````````````````````````````` ``````````````````````````````````````````4``````````````````````````````````````41.2.处方及依据``````````````````````````````````````````````````````````````````````` ```````````````````````````````````41.3.生产工艺流``````````````````````````````````````````````````````````````````````` ```````````````````````````````````5`2.验证目的````````````````````````````````````````````````````````````````````````````` ```````````````````````````````````````53.验证的范畴`````````````````````````````````````````````````````````````````````````` `````````````````````````````````````64.验证各部门职责及组织结构```````````````````````````````````````````````````` ```````````````````````````65.验证预备````````````````````````````````````````````````````````````````````````````` ```````````````````````````````````````76.验证内容及实施``````````````````````````````````````````````````````````````````` ```````````````````````````````````8`6.1.洗瓶工序````````````````````````````````````````````````````````````````````````` ```````````````````````````````````86.2.配制工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````126.3.灌封工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````156.4.灭菌工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````206.5.灯检工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````246.6.包装工序````````````````````````````````````````````````````````````````````````` ``````````````````````````````````26```````````````````````````````287.偏差分析````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````298.验证结论````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````299.附表``````````````````````````````````````````````````````````````````````````````````` `````````````````````````````````````````299.1. 设备一览表及生产能力````````````````````````````````````````````````````` ``````````````````````````309.2.设备性能验证确认及检查情形表``````````````````````````````````````````` ````````````````````319.3参加验证人员培训情形检查表`````````````````````````````````````````````` ``````````````````````329.4.厂房与公用设施验证的确认和检查情形表``````````````````````````````` ``````````````349.5.空气净化系统、工艺用水系统验证的确认和检查情形表````````````` ````359.6.计量器具检查情形表`````````````````````````````````````````````````````````` `````````````````````````````369.7.三批（按四批预备）验证使用的原料、辅料和安瓿供应商确认及检查情形表```````````````````````````````````````````````````` `````````````````````````379.8.质量检验系统验证和预备情形表``````````````````````````````````````````` ````````````````````389.9.检验仪器检查情形表`````````````````````````````````````````````````````````` ````````````````````````````399.10检验试剂检查情形表````````````````````````````````````````````````````````` ```````````````````````````409.11质量监控点、监控内容、监控方法、监控频次表````````````````````` ````````411.概述1.1.利巴韦林注射液（1ml：100mg）常温状态下是无色的澄明液体，属抗病毒药，用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎。
产品工艺验证
产品工艺验证Credit is the best character, there is no one, so people should look at their character first.产品工艺验证方案产品名称：利巴韦林注射液产品规格： 1ml:100mg方案的确认、批准方案起草人：起草日期：方案审核人：审核日期：方案批准人：签名和日期：验证方案一、品种概述：利巴韦林注射液1ml：100mg属抗病毒药,用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎.该产品于年月经卫生厅批准,已经有近年的生产历史.2008年,该产品生产了批,总产量万支,2009年1-7月份生产了批, 总产量万支.该产品的产量和批次连续两年在公司的小容量注射剂中均属前三位.利巴韦林注射液1ml：00m1g由利巴韦林、氯化钠、注射用水组成,组方相对简单.生产工艺如下：处方：物料名称万ml用量利巴韦林 1000g氯化钠 g药用炭 g注射用水加至 10000万ml生产流程：该产品从年批准生产以来,处方和生产工艺没有发生变更,产品质量基本稳定,没有质量事故发生.年公司搬迁和GMP改造,厂房设施发生了变更,精洗、配制、灌封等工序的生产环境由原来的一般控制区变更为现在的万级洁净区,灌封机由4针机变更为现在的6针机, 年首次通过了药品GMP认证,年通过了GMP复认证.二、验证目的：通过对利巴韦林注射液1ml：100mg产品工艺的验证,判断在的药品GMP管理工作中,岗位SOP修订的合理性,分析影响产品质量的关键因素,纠正偏差,建立生产全过程的运行标准和监控标准,确保产品质量安全有效、稳定均一.同时通过验证,减少误差,降低成本,提高企业运营效率.三、验证的基本原则本次验证是在该产品正常生产所需的厂房设施、生产设备、仪器仪表、检验设施设备及检验方法均经过了验证和校验、参与验证的相关人员都经过培训的前提下,按照批准的生产工艺规程和岗位SOP进行严格监控下的正常生产；所有记录真实、准确；所有抽样检验严格按照批准的规程进行.四、验证准备一、成立验证组织：1、成立验证领导组,确定组长、成员,明确职责.2、成立若干验证工作小组,确定组长、成员,明确职责.二、组织验证人员培训；三、检查和认定厂房与公用设施是否在验证周期内；四、检查和认定空气净化系统是否在验证周期内；五、检查和认定工艺用水系统是否在验证周期内；六、检查并确定生产设备水针车间第生产线是否在验证周期内；七、检查并确定计量器具是否在检定周期内；八、检查参加验证的物料；九、检查质量检验系统验证和准备情况；十、检查并确定检验仪器；十一、检查并确定检验试剂；十二、根据验证要求,在正常监控的基础上,对验证过程中增加监控内容：1、洗瓶工序：安瓿的洁净度、微生物限度、细菌内毒素检查；2、灌封工序：空气洁净度动态检测、灭菌前产品的细菌内毒素、微生物限度检查；3、灭菌工序：在灭菌柜相对冷点、热点处的产品理化指标的检测,在灭菌柜相对冷点处的产品无菌指标的检测；十三、文件准备技术文件、管理文件；十四、拟验证时间：月月日～月日.五、验证实施按照确定的原辅料、包装材料、生产设备、检验仪器和试剂,由各验证小组按照验证方案,连续投料三批,每批万支,进行生产工艺验证.一、洗瓶工序1、因素分析本工序主要控制参数有：a.洗瓶用水水温；b.注水机注满水率；c.甩水机甩净水率；d.终端精洗用水的可见异物；e. 远红外隧道烘箱的灭菌温度和灭菌时间.以上因素中,甩水机甩水效果、注水机注满水率、终端精洗用水的可见异物检查等控制标准生产一直沿用,未做过修订；洗瓶用水水温、远红外隧道烘箱的灭菌温度与灭菌时间等参数因没有明确数据范围,表述不科学.在GMP管理工作中,进行了如下修订.2、验证记录：洗瓶工序监控项目及监控结果1：洗瓶工序监控项目及监控结果2：洗瓶工序洗瓶效果评价结果3、结果评价：根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.二、配制工序1、因素分析本工序主要控制参数有：a. 首次加水量；b. 配制时注射用水温度；c. 投料顺序d. pH值调节范围e.炭吸附时间f. 药液搅拌时间g．使用前后终端过滤器完整性检查以上因素中,首次加水量、配制时注射用水温度、投料顺序、pH值调节范围、炭吸附时间、使用前后终端过滤器完整性检查等控制标准生产一直沿用,未做过修订；药液搅拌时间参数因没有明确数据范围,表述不科学,在实施以品种为单元的GMP管理工作中进行了修订.另在制定本次利巴韦林注射液工艺验证方案时,我们对09年1～7月份批利巴韦林注射液半成品及成品检验结果数据的回顾性分析,半成品含量平均为%、RSD值为%；成品含量平均为%、RSD 值为%；半成品、成品含量相对稳定；pH值范围在～的占%,且pH值灭菌后平均下降；呈下降趋势.现利巴韦林注射液半成品pH值参数范围为～,拟将pH值参数范围调整为.修订的参数及标准如下.2、验证记录配制工序监控项目及监控结果配制工序半成品质量评价结果3、结果评价根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.三、灌封工序1、因素分析本工序主要控制参数有：a. 灌封前可见异物；b. 灌封期间可见异物；c. 灌装量；d.灌封收率以上参数中,灌封前可见异物、灌装量和灌封收率等控制标准生产一直沿用,未做过修订；灌封期间可见异物检查标准曾发生过两次变更,一次是05年因国家标准改变,将灌封期间可见异物检查的不合格率控制标准由%变更为%；另一次是07年企业为有效控制可见异物质量问题,结合的GMP管理工作,将灌封期间可见异物检查的不合格率控制标准由%变更为%.另因为利巴韦林注射液灭菌条件为100℃、30分钟,F0值远小于8,为确保灭菌后产品无菌合格,拟增加生产过程中的环境洁净度、灌封半成品的细菌内毒素、微生物限度等为特殊监控指标.2、验证记录灌封工序监控项目及监控结果附图1： 尘埃粒子、沉降菌采样点采样点南→附表1： 灌封期间可见异物结果 附表2： 细菌内毒素、微生物限度检查结果灌封室尘埃粒子检测结果批灌封室沉降菌检测结果批附表4: 装量检查结果产品批号：根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.四、灭菌工序1、因素分析本工序主要控制参数有：a. 设定灭菌温度、b. 设定灭菌时间、c. 预热时间、d. 最大载量、e. 装载方式以上参数,灭菌温度、灭菌时间为批准的工艺参数；预热时间、最大载量、装载方式为经验总结,生产一直沿用,未做过修订.在实施以品种为单元的GMP管理工作中,通过自查发现,因灭菌过程中灭菌柜存在相对的冷点和热点,冷点影响产品灭菌效果,热点影响产品理化性质,而现检验用样品的取样方法多为随机取样,可能存在质量隐患.本次验证一方面欲通过对灭菌工序主要控制参数的监控,判断参数标准的可控性,另一方面增加冷点处产品的无菌检查,增加产品冷点和热点处理化性质的对比检查,以分析灭菌过程对产品质量的影响,判断是否需修订检验用样品的取样规程.2、验证记录灭菌工序监控项目及监控结果1灭菌工序监控项目及监控结果2灭菌工序半成品质量评价结果3、结果评价根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.五、灯检工序1、因素分析本工序主要监控参数有灯检合格品的漏检率；灯检合格品的漏检率检查标准曾发生过两次变更；一次是05年因国家标准改变,灯检合格品的漏检率控制标准由%变更为%；另一次是07年企业为有效控制可见异物质量问题,结合以品种为单元的GMP管理工作,将灯检合格品的漏检率控制标准由%变更为%.2、验证记录灯检工序监控项目及监控结果3、结果评价根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.六、包装工序1、因素分析本工序安瓿印字内容于执行国家局24号令时,由产品名称、产品批号变更为产品名称、产品批号、有效期；包装操作,于07年由手工装盒变更为机器装盒,手工线扎变更为机器膜扎,其他操作未有改变.2、验证记录包装工序监控项目及监控结果3、结果评价根据监控结果和检测结果判断参数标准的可控性与稳定性,分析是否存在偏差.七、成品检验结果3、结果评价：六、偏差分析根据三批利巴韦林注射液1ml:100mg的验证结果,对比评价标准,寻找偏差,分析偏差产生的原因,提出纠偏措施.七、验证结论通过验证,确定需修订和完善的参数,提出合理化建议.附表1：验证领导组组织及职责附表2：各验证小组组织及职责附表3：参加验证人员培训情况检查表附表4：厂房与公用设施验证的确认和检查情况表附表5：空气净化系统、工艺用水系统验证的确认和检查情况表附表6：水针1线设备性能验证确认及检查情况表。
利巴韦林葡萄糖注射液(100ml)生产工艺规程
技术标准本品为利巴韦林与葡萄糖制成的灭菌水溶液。
1 品名: 利巴韦林葡萄糖注射液2 剂型: 大容量注射剂3 规格: 100ml：利巴韦林0.2g与葡萄糖5g4 代码：Y3155 处方：5·1基准处方利巴韦林 2.0 g葡萄糖50.0 g注射用水至1000ml5·2 标准生产量：1200000 ml/批所用的原辅料及数量名称代码数量利巴韦林Y122 2.4 Kg葡萄糖Y101 60 Kg针用活性炭F101 480g注射用水F108 至1200000 ml6 生产工艺及操作要求：6·1 配制（C级、温度18~26℃、湿度45~65%）：本工序包括称量、浓配、稀配等。
6·1·1 称量：在备料间根据指令核对原辅料品名、规格、批号、生产厂家、数量，本厂检验报告单或合格证(绿色合格证)、递交单。
称量前校准天平、电子称并检查是否在效期内。
按处方要求进行原辅料的称量，填写物料标示卡附于容器内外各一张，注明品名、规格、批号、重量、日期和操作者。
经复核后填写称量记录。
剩余原辅料扎紧袋口，标明原辅料名称、批号、剩余量、使用人，放置于暂存架。
换品种清场时，将剩余料密封，贴上卡片，标明名称、规格、批号、数量、日期，退回脱包间，返至仓库。
6·1·2 浓配：取规定量葡萄糖在浓配间投入到放有适量注射用水(70~85℃)的SH-Ⅰ浓配罐（编号：SB5004-1）中，搅拌溶解，使成50％~60％的浓溶液，加入0.03％（g/ml,以稀配体积计）的针用活性炭，搅拌混匀，煮沸(100℃)30分钟，稍冷，用钛棒过滤器加压过滤，内循环10分钟，泵入稀配罐。
6·1·3 稀配：在稀配间向SH-Ⅰ稀配罐（编号：SB5004-2）中加注射用水至全量的约80%，加规定量利巴韦林，加0.01％（g/ml,以稀配体积计）的针用活性炭，补加注射用水至全量，搅拌、回流15分钟，测pH值（规定：5.5~6.0，若不符合规定用稀盐酸或1M氢氧化钠调整）、含量(利巴韦林为98.0%~101.0%、葡萄糖为99.5%~102.5%)符合规定后，降温至50~60℃，用钛棒过滤器和0.45μm的膜滤芯加压过滤，终端用0.45μm的膜滤芯过滤至灌装。
利巴韦林氯化钠注射液的制备及临床应用
应中和 施劲松 (浙江省永康市第一人民医院 永康 321300)
摘要 目的 :建立利巴韦林氯化钠注射液的制备和质量控制方法 ,观察本制剂的临床疗效 。方法 :采用氯化钠作等渗调节剂 制备输液 ,以 HPLC 法测定制剂中利巴韦林含量 ,将 160 例病毒感染者分组 ,治疗组 50 例 ,对照组 50 例 ,开放组 60 例 ,观察指 标 。结果 :制剂稳定 ,平均回收率99. 92 % ,精密度试验 RSD = 0. 28 % ,临床应用表明治疗组与对照组疗效差异无显著性 ( P > 0. 05) ,总有效率87. 3 %。结论 :本制备工艺可行 ,质量控制方法可靠 ,临床疗效确切 。 关键词 利巴韦林氯化钠注射液 ,制备 ,HPLC 法 ,质量控制
d 为一疗程 ,其他为 7～14 d 。
5. 4 结果 以症状 、体征 、实验室检查等三项均恢 复正常为痊愈 ;病情明显好转 ,但上述三项有一项未
完全恢复正常为显效 ;否则为无效 。以痊愈和显效
计算有效率 ,结果病毒性呼吸道感染治疗组 41 例
(82 %) 、对照组 40 例 (80 %) 有效 ,两者有效率差异
C = 0. 064 0 + 8. 568 ×10 - 5 A , r = 0. 999 9
由此可知利巴韦林在10. 08～90. 72 μg·ml - 1范
围内线性良好 。
3. 4. 4 精密度试验 精密吸取3. 4. 2项下每 1 ml 含 40μg 的对照品溶液 20μl 重复进样 6 次 ,记录峰 面积 ,计算相对标准偏差 RS D ,结果见表 2 。表 2 表 明 6 次重复进样的 RS D 为0. 28 % ,外标法测定利 巴韦林具有良好的重现性 。
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长治市三宝生化药业有限公司编号SBB2.8.5.6利巴韦林注射液生产工艺验证方案长治市三宝生化药业有限公司方案制订签名日期方案会签签名日期生产技术部签名日期验证小组签名日期方案批准质量保证部日期目录1.概述`````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````4` 1.1.产品简述``````````````````````````````````````````````````````````````````````````````````````````````````````````````4 1.2.处方及依据``````````````````````````````````````````````````````````````````````````````````````````````````````````41.3.生产工艺流``````````````````````````````````````````````````````````````````````````````````````````````````````````5`2.验证目的````````````````````````````````````````````````````````````````````````````````````````````````````````````````````53.验证的范围```````````````````````````````````````````````````````````````````````````````````````````````````````````````64.验证各部门职责及组织结构```````````````````````````````````````````````````````````````````````````````65.验证准备````````````````````````````````````````````````````````````````````````````````````````````````````````````````````76.验证内容及实施``````````````````````````````````````````````````````````````````````````````````````````````````````8` 6.1.洗瓶工序````````````````````````````````````````````````````````````````````````````````````````````````````````````8 6.2.配制工序```````````````````````````````````````````````````````````````````````````````````````````````````````````12 6.3.灌封工序```````````````````````````````````````````````````````````````````````````````````````````````````````````15 6.4.灭菌工序```````````````````````````````````````````````````````````````````````````````````````````````````````````206.5.灯检工序```````````````````````````````````````````````````````````````````````````````````````````````````````````246.6.包装工序```````````````````````````````````````````````````````````````````````````````````````````````````````````266.7.成品检验结果``````````````````````````````````````````````````````````````````````````````````````````````````287.偏差分析``````````````````````````````````````````````````````````````````````````````````````````````````````````````````298.验证结论``````````````````````````````````````````````````````````````````````````````````````````````````````````````````299.附表````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````299.1. 设备一览表及生产能力```````````````````````````````````````````````````````````````````````````````309.2.设备性能验证确认及检查情况表```````````````````````````````````````````````````````````````319.3参加验证人员培训情况检查表````````````````````````````````````````````````````````````````````329.4.厂房与公用设施验证的确认和检查情况表`````````````````````````````````````````````349.5.空气净化系统、工艺用水系统验证的确认和检查情况表`````````````````359.6.计量器具检查情况表```````````````````````````````````````````````````````````````````````````````````````369.7.三批（按四批准备）验证使用的原料、辅料和安瓿供应商确认及检查情况表`````````````````````````````````````````````````````````````````````````````379.8.质量检验系统验证和准备情况表```````````````````````````````````````````````````````````````389.9.检验仪器检查情况表``````````````````````````````````````````````````````````````````````````````````````399.10检验试剂检查情况表````````````````````````````````````````````````````````````````````````````````````409.11质量监控点、监控内容、监控方法、监控频次表`````````````````````````````411.概述1.1.利巴韦林注射液（1ml：100mg）常温状态下是无色的澄明液体，属抗病毒药，用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎。
1.2.利巴韦林注射液组方较为简单，具体工艺处方如下：处方：物料名称1ml：100 mg利巴韦林1000g氯化钠87g药用炭20g共制成10000支处方依据：中国药典2010年版二部批准文号：国药准字H19999232批准机构：国家药品监督管理局1.3.生产工艺流程：该产品从2010年批准生产以来，处方和生产工艺没有发生变更，产品质量基本稳定，没有质量事故发生。
2012年公司搬迁和GMP改造，厂房设施发生了变更，精滤、稀配制、灌封等工序的生产环境由原来万级洁净区变更为现在的A级洁净区，生产操作人员在原来知识的基础上按照新版GMP进行再次培训，无论从操作技术还是生产理念都有很大的提高。
2.验证目的根据2010版GMP要求，通过对利巴韦林注射液(1ml：100mg)产品工艺的验证，判断生产系统各要素和生产过程中可能影响产品质量的各种工艺变化因素，对其整个生产过程进行验证，以保证在正常的生产条件下，生产出合格、均一、稳定的利巴韦林注射液。
同时确定岗位SOP修订的合理性，分析影响产品质量的关键因素，纠正偏差，建立生产全过程的运行标准和监控标准，确保产品质量安全有效。
3.验证的范围本次验证是在该产品正常生产所需的厂房设施、生产设备、仪器仪表、检验设施设备及检验方法均经过了验证和校验、参与验证的相关人员都经过培训的前提下，按照批准的生产工艺规程和岗位SOP进行严格监控下的正常生产；所有记录真实、准确；所有抽样检验严格按照批准的规程进行。
当上述条件之一改变时，应重新验证。
4.验证各部门职责及组织机构4.1验证组4.1.1负责验证方案的审批。
4.1.2负责验证的协调工作，以保证本验证方案规定项目顺利实施。
4.1.3负责验证数据及结果的审核。
4.1.4负责验证报告的审批。
4.1.5负责发放验证报告证书。
4.1.6负责再验证周期的确认。
4.2设备动力部4.2.1负责组织试验所需仪器、设备的验证。
4.2.2负责仪器、仪表、量器等的校正。
4.2.3负责设备的维护保养。
4.3质保部4.3.1负责制定质量标准和检验操作规程。
4.3.2负责制定取样方案并取样对样品进行检验。
4.3.3负责起草验证方案。
4.3.4负责收集各项验证、试验记录，并对试验结果进行分析后，起草验证告，报验证委员会。
4.4生产组织部4.4.1负责拟定验证方案。
4.4.2负责验证方案的实施。
4.4.3负责设备操作。
4.5验证过程应严格按照本方案规定的内容进行，若因特殊原因确需变更时，应填写验证方案变更申请书，报验证组批准。