利巴韦林工艺验证
利巴韦林泡腾颗粒剂的制备工艺改进
取利 巴韦林泡 腾颗粒剂研细 ，精 密称取 的样品细粉置 １ ０ ０ ｍｌ 容量瓶
中， 加 流 动相 ６ ０ ｍｌ ， 超声十分钟， 取 续滤 液 作 为 供 试品 溶 液 。 ３ ． ４阴性 干 扰 试 验
参 考 文 献 ［ １ 】 李英， 刘文娟， 多力坤． 利 巴 韦 林 吸 入 治 疗 毛 细 支 气 管 炎 的 临 床 观 察 『 Ｊ １ ． 巾 国药 师 ， ￣ ０ ０ ７ （ １ Ｏ ） ．
速 １ ． ０ ｍ Ｌ・ ａ ｒ ｉ ｎ ～ ； 柱温 ： ３ Ｏ ℃。
吸道合 胞病毒肺 炎、 水痘、 带状疱疹等 ｌ 。 本实验对利 巴韦林泡腾颗粒剂的
制 备 工 艺 进行 研 究 。
１仪器与试药 高精度实验室酸 度计 （ ｔ － 海禾工科学仪器有限公司） ： Ｈ ＤＩ ２ ０ 一 Ｒ Ｔ进口 低温循环水 浴 （ 上海 凌初环保仪 器有限公 司） ； ８ ０ Ｋ Ｈ Ｚ高频超 声波清洗机 （ 北京博宇宝威实验设备有限公司） ； Ｒ Ｅ一 ５ ２ ９ ８旋转蒸发器 （ 上海亚 荣生化
２ ． １粘 合 剂 的 考 察
在处方中去利 巴韦林，按方中比例和 制备 工艺方法制成 阴性制剂， 用 以上选定的测定 条件进行吸收曲线绘制 ， 在选 定条件 测得的阴性液吸收 曲线 在 与 利 巴 韦林 相 同保 留时 间 处 不存 在 吸 收 峰 ， 因 此 说 明 选定 的 条件 测 定利巴韦林无干扰 ， 具有较强的专属性 。 ３ ． ５标准 曲线的制备 将浓度为 ８ ０ ￣ ｇ ／ ｍ ｌ ， ６ ０ ｔ ￣ ｇ ／ ｍｌ ， ４ ０ ￣ ｇ ／ ｍ ｌ ， ２ ０ ￣ ｇ ／ ｍｌ ， １ ０ ０ ， ｇ ／ ｍｌ ， ５ ｌ ｘ ｇ ／ ｍ ｌ 的对照 品溶液分别吸取 ２ ０ １ ￣ Ｌ注入 Ｈ Ｐ Ｌ Ｃ， 以进 样量（ ｇ ） 为横坐标 ， 峰面积积分值 Ａ为纵坐标 ， 绘制标准 曲线． 试验 表明， 利 巴韦林对照品在 ８ Ｏ ～ ５ ｔ Ｌ ｇ ／ ｍ ｌ 范 围 内 线 性关 系 良好 。 ４讨 论 本 实验对利 巴韦林泡腾颗粒剂 的制备工艺进行研究。 木实验 分别对粘 合剂、 混合时间、 粉碎 目数行了考察 ， 得到 最佳的工艺为 ５ ％羟丙 甲纤维 素 为粘合剂 ， 制 软材的混合时间为 ５分 钟， ８ ０目为原辅 料粉碎 目数。本实验 分 别在 ２ ０个不同部位取样 ， 采用高效液相法测定利巴韦林含量 。 实验结果 衷 明利 巴韦 林 泡 腾 颗 粒 剂均 一 度 较 好 。 ■
利巴韦林滴鼻液中间产品检验操作规程
目的：为检验利巴韦林滴鼻液中间产品规定一个标准的程序，,以便获得准确的实验数据。
范围：适用于利巴韦林滴鼻液中间产品的检验。
职责：检验员，检验室主任对本规程实施负责。
规程：1性状：本品为无色澄明液体。
2鉴别2.1 试剂与仪器2.1.1 氢氧化钠试液 2.1.2 红色石蕊试纸2.1.3 0.03mol/L硫酸铵溶液2.2 项目与步骤2.2.1 取本品约0.1g，加水10ml使溶解，加氢氧化钠试液5ml，加热至沸，即发生氨臭，能使湿润的石蕊试纸变蓝色为符合规定。
2.2.2 在含量测定项下记录的色谱图中，供试品溶液的主峰保留时间与利巴韦林对照品峰的保留时间一致为符合规定。
3 检查3.1 试剂与仪器3.1.1 PHS-3C精密PH计 3.1.2 量筒，注射器3.2 项目与步骤3.2.1 PH值：取本品约50ml，置100ml烧杯中，按PH值测定法(SOP-QC-312-00)检查，PH值为5.0-7.0为符合规定。
3.2.2 装量：照最低装量检查法 (SOP-QC-332-00) 检查，应符合规定。
4 含量测定4.1 试剂与仪器4.1.1 C 18硅胶色谱柱 4.1.2 利巴韦林对照品4.1.3 容量瓶(50ml ，100ml)，移液管 (2ml) 4.1.4 注射器(10ml)，过滤器，滤膜 4.1.5 电子天平 (万分之一克) 4.1.6 高效液相色谱仪4.2 检验步骤按高效液相色谱法 (SOP-QC-306-00) 检测。
4.2.1 色谱条件与系统适用性试验用C 18硅胶色谱柱，流动相为水，流速每分钟为0.9ml ，检测波长为207nm ，量取利巴韦林对照品溶液[*]10μl ，注入液相色谱仪，理论板数按利巴韦林峰计算，应不低于2500。
4.2.2 利巴韦林对照溶液与样品溶液的制备以及测定 利巴韦林对照溶液的制备：[*]精密称取利巴韦林对照品约100mg ，置100ml 量瓶中，加水适量超声振荡溶解后，加水稀释至刻度，摇匀，精密量取该溶液5 ml ，置100ml 量瓶中，加水稀释至刻度，摇匀，作为对照溶液。
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。
利巴韦林软胶囊的制备工艺及质量探究
利巴韦林软胶囊的制备工艺及质量探究利巴韦林软胶囊的制备工艺及质量探究摘要：针对利巴韦林软胶囊的制备和生产工艺以及质量控制过程中可以应用的措施进行简要的分析和研究。
方法：使用正交设计实验方法筛选出合理的处方，同时还要确认制备的具体方法，之后还要采取高效液相色谱仪对胶囊中的溶出度和具体的含量进行检测。
结果：利巴韦林软胶囊在溶出度测定和含量测定等方面都符合相关的标准和要求。
结论：利巴韦林软胶囊制备工艺的选择具有非常强的科学性和合理性，同时其制备的工艺也相对比较简单可行，具有良好的稳定性和安全性，检测出的效果也非常的好，准确性很高，因此这种方法可以当做是质量控制的一种有效的方式。
关键词：利巴韦林软胶囊;制备工艺;处方;含量测定利巴韦林通常又被人们叫做三氮唑核苷和病毒唑，这也是一种疗效非常好的广谱抗病毒药物，同时它也是一种应用相对比较广泛的技术，主要是应用在治疗由于病毒引起的疾病，或者是肿瘤等等，它对多种细菌都有着非常好的抑制作用，，软胶囊是胶囊中比较常见的一种形式，它是针剂以后发展出来的又一种非常好的药体形式，它可以将粉末状或者是油状的药物充分的碾压，之后将其放入胶囊膜当中的方法，这种剂型和其他的剂型相比有着非常大的优势，它有效成分的利用率更高，同时密封的`质量也更好，在外观方面也比较符合人们的审美要求。
1、仪器与试剂1.1仪器。
LC-10AT型高效液相色谱仪旧本岛津);MA110型电子分析天平(上海天平仪器厂);ZRS-4型智能溶出仪(天津大学无线电厂)，LTV-2201型紫外扫描仪旧本岛津)。
1.2试齐。
利巴韦林原料药(山东济宁第一制药厂);利巴韦林对照品(中国药品生物制品检定所提供)硫酸按(分析纯);盐酸(分析纯);明胶(分析纯);甘油(分析纯);聚乙二醇400(PEG400，分析纯)。
2、处方与制备工艺2.1 正交设计实验相关的研究人员考虑到利巴韦林在PEG400当中溶解度无法达到相关的要求，这样就会使得整个胶囊呈现出非常明显的混悬液状态，因此为了改善胶囊内部物质的溶解度以及稳定性，在主品的含量已经固定的情况下选择了两个非常重要的因素(A和B)，然后进行了正交实验，在获得了实验数据和结果之后对其进行了严格的分析，最后选择了处方。
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```````````````````````````````````````````````````````````````````````````````````````````````````````````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。
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。
利巴韦林软胶囊的制备工艺及质量研究
利 巴韦林 ， 又名三氮唑核苷 、 病毒 唑 ， 是一种疗效显 著地广谱抗 表 １ 正 交试 验 表 病毒药物 ， 临床应用广泛 ， 主要用 于治疗 病毒性疾病和肿瘤等病症 。 其对 呼吸道合胞病 毒 、 流感病毒 、 甲型肝炎病 毒等多种 病毒 的生 长 具有抑制作用 。 软胶囊是胶囊剂 的一种 ， 是继 片剂 、 针剂后发展起 来的一种新剂 型， 其特性是能将 油状 药物 、 药 物溶液或药物混 悬液 、 糊状物甚 至药 物粉末定量压注并包封 于胶 膜 内，从而形成 了大小 、 形状不 同的密封胶囊 。 其与其他剂型相 比较 ， 具有生物利用度高 、 密 封性好 、 外形美观等特点 。 本实验采用利 巴韦林作为模 型药来制备 软胶囊 ， 并建立 了其体外分 析方 法。同时通过正交设计实验来筛选 出合适的处方， 并对其溶 出度及含量进行 了测定 。 １仪器与试剂 １ ． １ 仪器 。Ｌ Ｃ 一 １ ０ Ａ Ｔ型高效液相色谱仪（ 日本 岛津） ； ＭＡ １ １ ０型 电 ３ ． １ ． ３ 线性关 系考察 。精 密称 取适 量利巴韦林对照 品， 并加入适 子分析天平（ 上海天平仪器厂） ； Ｚ Ｒ Ｓ 一 ４型智能溶 出仪 （ 天津大学无线 电厂 ） ， ｕ Ｖ 一 ２ ２ ０ １ 型紫外扫描仪ｆ 日本岛津） 。 量 的人工 胃液使之溶解并稀释成 约 １ ｍｇ ／ ｍＬ的溶液， 然后精密量取 １ ． ２试剂 。 利 巴韦林原料药（ 山东济 宁第一制药厂）； 利 巴韦林对 上述溶液 ０ ． １ ， ０ ． ２ ， ０ ． ４ ，０ ． ６ ，０ ． ８ ｍＬ ，分别 将其 置于 １ ０ ｍＬ的容量瓶 照品（ 中国药 品生 物制 品检 定所提供 ） 。硫 酸铵（ 分析纯） ； 盐酸（ 分析 中， 同样 加入适量 的人 工 胃液稀释至刻度， 摇匀， 分别进样 ２ ０ ｕ ｌ ， 测定 峰面积 。进样 量。 （ ） 与峰面积㈣ 的线性关 系如下：Ｙ ＝ ４ １ ３ ０ ２＋ １ ５ ９ １ ． 纯） ； 明胶（ 分析纯） ； 甘油（ 分析纯） ； 聚乙二醇４ ０ ０（ Ｐ Ｅ Ｃ ， ４ ０ ０ ， 分析纯） 。 ２ 处 方 与 制 备 工 艺 ８ Ｘ ，ｒ ＝ ０ ． ９ ９ ９ ８ 。 结果表 明利 巴韦林 在 ０ ． ２ — １ ． ６ ｕ ｇ的范围内具有 良好的 ２ ． １ 正交 设计 试验 。研究 者考 虑到处 方 中的主 药利 巴韦林 在 线性关 系。 ３ ． １ ． ４精密度实验 。精密称取适量利 巴韦林 对照品， 并用 人工 胃 Ｐ Ｅ Ｇ ４ ０ ０中的溶解度 不好， 使软 胶囊 内容物 呈混 悬液状态 ， 所 以为使 ０ ｕ ｇ ／ ｍ Ｌ的对照 品溶液 ， 按照上述确定 的色谱 软胶囊 的内容物混悬液物理稳定性 良好 ， 在 主药含量 固定不 变的前 液将 其配制成浓度为 ５ 提下， 研究 者选 用两 个重 要 因素 （ Ａ与 Ｂ ） 进行 正交 实验 ， 选用 Ｌ ４ 条件来进行 测定， 计算精密度， Ｒ Ｓ Ｄ ＝ Ｉ ． ２ ３ ％。结果表 明该 实验的精 密 度 良好 。 （ ２ ３ ） 表考察后确定处 方。 ３ ． １ ． ５稳定性 实验 。精密 吸取 ５ ０ ｕ ｇ ／ ｍ Ｌ的利 巴韦林 盐酸水溶 液 因素 Ａ为助 悬 剂 的种 类 ： Ａ１ 选择 Ｐ Ｖ Ｐ（ Ｋ ｇ ０ ） ； Ａ ２选 择 Ｈ Ｐ ＭＣ ０ ｕ ｌ ， 然后 分别 于 ０ ，１ ， ２ ， ４ ，６ ， ８ ｈ后将样 品注入高效液相色谱 仪 （ Ｋ ４ Ｍ） ； Ａ ３ 选择西黄耆胶 。因素 Ｂ为助悬剂 的用量 ： Ｂ１ 为５ ｍ ｇ ； Ｂ ２ ２ 并记 录峰面积， 结果 Ｒ Ｓ Ｄ ＝ ０ ． ０ ９ ％。结果表明样品溶液在 为０ ｍｇ 。根据 ２ ０ １ ０年版药典二部附录 Ｉ Ｏ中对混悬剂的要求来 配 中进行测定， ｈ内的稳定性 良好 。 制样品， 配制后将样 品静置 ３ ｈ ， 样 品的沉 降体 积 比（ ） 【 ｉ ） 应大于 ０ ． ９ ， 且 ８ ３ ． ２溶出度的测定 。 取利 巴韦林软胶囊， 按照 ２ ０ １ ０年版药典二部 沉降体积 比越接近 １ ． ０处方越优。 再分散性 ） 是指为使静置的混悬 附录中溶 出度 的测定方法来进行测定， 取０ ． １ ｍ ｏ ｌ ／ Ｌ的盐酸溶液 ９ ０ ０ 剂再次分散均匀 的振摇次数 。 ０ ０ ｒ ／ ｍ ｉ ｎ ， ４ ５ ａｉ ｒ ｎ后 ，取适量 的溶 出 由表 １ 可 以看 出， 处方 ３ ，４的沉 降体 积 比不符合药 典要 求， 故 ｍＬ来作 为溶 出介 质，转速 为 １ ． ４ ５ ｕ ｍ的微孔滤膜进行过滤， 取续滤液， 即为供试品溶液。然 弃去 。而处方 １ ， ２的沉降体积 比均符 合要求， 但处方 １ 再分散性 差 液，用 ０ 后照含量测定项下的方法， 进样 ２ ０ ｕ ｌ ， 记 录色谱 图。同时另取适量利 且应用辅料较多， 故选择处方 ２ 。即助悬剂为 Ｐ Ｖ Ｐ（ Ｋ ９ ０ ）５ ｍ ｇ 。 巴韦林对照品将其配制成浓度为 ５ ０ ｕ ｇ ／ ｍ Ｌ的溶 液， 同法测定， 按外标 ２ ． ２处 方 与制 备 工 艺
利巴韦林滴眼液中间产品检验操作规程
目的：为检验利巴韦林滴眼液中间产品规定一个标准的程序，,以便获得准确的实验数据。
范围：适用于利巴韦林滴眼液中间产品的检验。
职责：检验员，检验室主任对本规程实施负责。
规程：1性状：本品为无色澄明液体。
2鉴别2.1 试剂与仪器2.1.1 氢氧化钠试液 2.1.2 红色石蕊试纸2.1.3 0.03mol/L硫酸铵溶液2.2 项目与步骤2.2.1 取本品约0.1g，加水10ml使溶解，加氢氧化钠试液5ml，加热至沸，即发生氨臭，能使湿润的石蕊试纸变蓝色为符合规定。
2.2.2 在含量测定项下记录的色谱图中，供试品溶液的主峰保留时间与利巴韦林对照品峰的保留时间一致为符合规定。
3 检查3.1 试剂与仪器3.1.1 PHS-3C精密PH计 3.1.2 量筒，注射器3.1.3 澄明度检测仪3.2 项目与步骤3.2.1 PH值：取本品约50ml，置100ml烧杯中，按PH值测定法(SOP-QC-312-00)检查，PH值为5.0-7.0为符合规定。
3.2.2 装量：照最低装量检查法 (SOP-QC-332-00) 检查，应符合规定。
3.2.3 澄明度：取本品，照澄明度检查细则和判断标准(SOP-QC-342-00)检查，应符合规定。
4 含量测定4.1 试剂与仪器4.1.1 利巴韦林对照品 4.1.2 3,5-二羟基甲苯试液4.1.3 容量瓶(25ml ，100ml)，移液管 (2ml,5ml)4.1.4 紫外分光光度计4.1.5 电子天平 (万分之一克)4.1.6 小型三用水箱4.2 检验步骤按紫外分光光度法 (SOP-QC-301-00) 检测。
4.2.1 对照品溶液的制备：精密称取利巴韦林对照品约100mg ，置100ml 容量瓶中，加水稀释至刻度，摇匀；精密量取5ml 置100ml 容量瓶中，加水5ml 稀释至刻度，摇匀，精密量取2ml 置25ml 容量瓶中，加3.5-二羟甲基苯试液5ml 。
4.2.2 供试品溶液的制备：精密量取样品溶液5ml 置100ml 容量瓶中，加水稀释至刻度，摇匀；精密量取2ml 置25ml 容量瓶中，加3.5-二羟甲基苯试液5ml 。
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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。
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：国家药品监督治理局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，产品质量差不多稳固，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先万级洁净区变更为现在的A级洁净区，生产操作人员在原先知识的基础上按照新版GMP进行再次培训，不管从操作技术依旧生产理念都有专门大的提升。
验证目的按照2010版GMP要求，通过对利巴韦林注射液(1ml：100mg)产品工艺的验证，判定生产系统各要素和生产过程中可能阻碍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、稳固的利巴韦林注射液。
同时确定岗位SOP修订的合理性，分析阻碍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。
验证的范畴此次验证是在该产品正常生产所需的厂房设施、生产设备、仪器外表、检验设施设备及检验方法均通过了验证和校验、参与验证的有关人员都通过培训的前提下，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。
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负责验证的和谐工作，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、外表、量器等的校正。
4.2.3负责设备的爱护保养。
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，若因专门缘故确需变更时，应填写验证方案变更申请书，报验证组批准。
5.验证预备5.1设备生产利巴韦林注射液(1ml：100mg)所用设备见附表1，所列设备均已通过验证和再验证见附表2。
5.2.人员参加验证人员必须通过培训，培训结果及有关文件见附表3。
.6.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。